Assessment and quantification of patient set-up errors in nasopharyngeal cancer patients and their biological and dosimetric impact in terms of generalized equivalent uniform dose (gEUD), tumour control probability (TCP) and normal tissue complication probability (NTCP).

PubMed

Boughalia, A; Marcie, S; Fellah, M; Chami, S; Mekki, F

2015-06-01

The aim of this study is to assess and quantify patients' set-up errors using an electronic portal imaging device and to evaluate their dosimetric and biological impact in terms of generalized equivalent uniform dose (gEUD) on predictive models, such as the tumour control probability (TCP) and the normal tissue complication probability (NTCP). 20 patients treated for nasopharyngeal cancer were enrolled in the radiotherapy-oncology department of HCA. Systematic and random errors were quantified. The dosimetric and biological impact of these set-up errors on the target volume and the organ at risk (OARs) coverage were assessed using calculation of dose-volume histogram, gEUD, TCP and NTCP. For this purpose, an in-house software was developed and used. The standard deviations (1SDs) of the systematic set-up and random set-up errors were calculated for the lateral and subclavicular fields and gave the following results: ∑ = 0.63 ± (0.42) mm and σ = 3.75 ± (0.79) mm, respectively. Thus a planning organ at risk volume (PRV) margin of 3 mm was defined around the OARs, and a 5-mm margin used around the clinical target volume. The gEUD, TCP and NTCP calculations obtained with and without set-up errors have shown increased values for tumour, where ΔgEUD (tumour) = 1.94% Gy (p = 0.00721) and ΔTCP = 2.03%. The toxicity of OARs was quantified using gEUD and NTCP. The values of ΔgEUD (OARs) vary from 0.78% to 5.95% in the case of the brainstem and the optic chiasm, respectively. The corresponding ΔNTCP varies from 0.15% to 0.53%, respectively. The quantification of set-up errors has a dosimetric and biological impact on the tumour and on the OARs. The developed in-house software using the concept of gEUD, TCP and NTCP biological models has been successfully used in this study. It can be used also to optimize the treatment plan established for our patients. The gEUD, TCP and NTCP may be more suitable tools to assess the treatment plans before treating the patients.

Methods for Reducing Normal Tissue Complication Probabilities in Oropharyngeal Cancer: Dose Reduction or Planning Target Volume Elimination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samuels, Stuart E.; Eisbruch, Avraham; Vineberg, Karen

Purpose: Strategies to reduce the toxicities of head and neck radiation (ie, dysphagia [difficulty swallowing] and xerostomia [dry mouth]) are currently underway. However, the predicted benefit of dose and planning target volume (PTV) reduction strategies is unknown. The purpose of the present study was to compare the normal tissue complication probabilities (NTCP) for swallowing and salivary structures in standard plans (70 Gy [P70]), dose-reduced plans (60 Gy [P60]), and plans eliminating the PTV margin. Methods and Materials: A total of 38 oropharyngeal cancer (OPC) plans were analyzed. Standard organ-sparing volumetric modulated arc therapy plans (P70) were created and then modified by eliminatingmore » the PTVs and treating the clinical tumor volumes (CTVs) only (C70) or maintaining the PTV but reducing the dose to 60 Gy (P60). NTCP dose models for the pharyngeal constrictors, glottis/supraglottic larynx, parotid glands (PGs), and submandibular glands (SMGs) were analyzed. The minimal clinically important benefit was defined as a mean change in NTCP of >5%. The P70 NTCP thresholds and overlap percentages of the organs at risk with the PTVs (56-59 Gy, vPTV{sub 56}) were evaluated to identify the predictors for NTCP improvement. Results: With the P60 plans, only the ipsilateral PG (iPG) benefited (23.9% vs 16.2%; P<.01). With the C70 plans, only the iPG (23.9% vs 17.5%; P<.01) and contralateral SMG (cSMG) (NTCP 32.1% vs 22.9%; P<.01) benefited. An iPG NTCP threshold of 20% and 30% predicted NTCP benefits for the P60 and C70 plans, respectively (P<.001). A cSMG NTCP threshold of 30% predicted for an NTCP benefit with the C70 plans (P<.001). Furthermore, for the iPG, a vPTV{sub 56} >13% predicted benefit with P60 (P<.001) and C70 (P=.002). For the cSMG, a vPTV{sub 56} >22% predicted benefit with C70 (P<.01). Conclusions: PTV elimination and dose-reduction lowered the NTCP of the iPG, and PTV elimination lowered the NTCP of the cSMG. NTCP thresholds and the percentage of overlap of the PTV with organs at risk can predict which patients will benefit and inform future clinical trial design.« less

Influence of different dose calculation algorithms on the estimate of NTCP for lung complications

PubMed Central

Bäck, Anna

2013-01-01

Due to limitations and uncertainties in dose calculation algorithms, different algorithms can predict different dose distributions and dose‐volume histograms for the same treatment. This can be a problem when estimating the normal tissue complication probability (NTCP) for patient‐specific dose distributions. Published NTCP model parameters are often derived for a different dose calculation algorithm than the one used to calculate the actual dose distribution. The use of algorithm‐specific NTCP model parameters can prevent errors caused by differences in dose calculation algorithms. The objective of this work was to determine how to change the NTCP model parameters for lung complications derived for a simple correction‐based pencil beam dose calculation algorithm, in order to make them valid for three other common dose calculation algorithms. NTCP was calculated with the relative seriality (RS) and Lyman‐Kutcher‐Burman (LKB) models. The four dose calculation algorithms used were the pencil beam (PB) and collapsed cone (CC) algorithms employed by Oncentra, and the pencil beam convolution (PBC) and anisotropic analytical algorithm (AAA) employed by Eclipse. Original model parameters for lung complications were taken from four published studies on different grades of pneumonitis, and new algorithm‐specific NTCP model parameters were determined. The difference between original and new model parameters was presented in relation to the reported model parameter uncertainties. Three different types of treatments were considered in the study: tangential and locoregional breast cancer treatment and lung cancer treatment. Changing the algorithm without the derivation of new model parameters caused changes in the NTCP value of up to 10 percentage points for the cases studied. Furthermore, the error introduced could be of the same magnitude as the confidence intervals of the calculated NTCP values. The new NTCP model parameters were tabulated as the algorithm was varied from PB to PBC, AAA, or CC. Moving from the PB to the PBC algorithm did not require new model parameters; however, moving from PB to AAA or CC did require a change in the NTCP model parameters, with CC requiring the largest change. It was shown that the new model parameters for a given algorithm are different for the different treatment types. PACS numbers: 87.53.‐j, 87.53.Kn, 87.55.‐x, 87.55.dh, 87.55.kd PMID:24036865

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC-recommended NTCP model.

PubMed

Liu, Mitchell; Moiseenko, Vitali; Agranovich, Alexander; Karvat, Anand; Kwan, Winkle; Saleh, Ziad H; Apte, Aditya A; Deasy, Joseph O

2010-10-01

Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman-Kutcher-Burman NTCP model. Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearman's rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the χ(2) test (p = 0.44). Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort.

Sensitivity of NTCP parameter values against a change of dose calculation algorithm.

PubMed

Brink, Carsten; Berg, Martin; Nielsen, Morten

2007-09-01

Optimization of radiation treatment planning requires estimations of the normal tissue complication probability (NTCP). A number of models exist that estimate NTCP from a calculated dose distribution. Since different dose calculation algorithms use different approximations the dose distributions predicted for a given treatment will in general depend on the algorithm. The purpose of this work is to test whether the optimal NTCP parameter values change significantly when the dose calculation algorithm is changed. The treatment plans for 17 breast cancer patients have retrospectively been recalculated with a collapsed cone algorithm (CC) to compare the NTCP estimates for radiation pneumonitis with those obtained from the clinically used pencil beam algorithm (PB). For the PB calculations the NTCP parameters were taken from previously published values for three different models. For the CC calculations the parameters were fitted to give the same NTCP as for the PB calculations. This paper demonstrates that significant shifts of the NTCP parameter values are observed for three models, comparable in magnitude to the uncertainties of the published parameter values. Thus, it is important to quote the applied dose calculation algorithm when reporting estimates of NTCP parameters in order to ensure correct use of the models.

Sensitivity of NTCP parameter values against a change of dose calculation algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brink, Carsten; Berg, Martin; Nielsen, Morten

2007-09-15

Optimization of radiation treatment planning requires estimations of the normal tissue complication probability (NTCP). A number of models exist that estimate NTCP from a calculated dose distribution. Since different dose calculation algorithms use different approximations the dose distributions predicted for a given treatment will in general depend on the algorithm. The purpose of this work is to test whether the optimal NTCP parameter values change significantly when the dose calculation algorithm is changed. The treatment plans for 17 breast cancer patients have retrospectively been recalculated with a collapsed cone algorithm (CC) to compare the NTCP estimates for radiation pneumonitis withmore » those obtained from the clinically used pencil beam algorithm (PB). For the PB calculations the NTCP parameters were taken from previously published values for three different models. For the CC calculations the parameters were fitted to give the same NTCP as for the PB calculations. This paper demonstrates that significant shifts of the NTCP parameter values are observed for three models, comparable in magnitude to the uncertainties of the published parameter values. Thus, it is important to quote the applied dose calculation algorithm when reporting estimates of NTCP parameters in order to ensure correct use of the models.« less

Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome?

PubMed

Nesvacil, Nicole; Tanderup, Kari; Lindegaard, Jacob C; Pötter, Richard; Kirisits, Christian

2016-09-01

The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves. A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed. Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2. TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai An; Erickson, Beth; Li, X. Allen

2009-05-01

Purpose: The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. Method and Materials: The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10more » cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. Results: There are five parameters in the model: TD{sub 50}, m, n, {alpha}/{beta} and f. With two parameters n and {alpha}/{beta} fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD{sub 50}(1) = 40.3 {+-} 8.4Gy, m =0.36 {+-} 0.09, f = 0.156 {+-} 0.074 Gy and TD{sub 50}(1) = 23.9 {+-} 5.3Gy, m = 0.41 {+-} 0.15, f = 0.0 {+-} 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. Conclusion: The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.« less

Multivariate Normal Tissue Complication Probability Modeling of Heart Valve Dysfunction in Hodgkin Lymphoma Survivors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cella, Laura, E-mail: laura.cella@cnr.it; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples; Liuzzi, Raffaele

Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Methods and Materials: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under themore » receiver operating characteristic curve (AUC). Results: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. Conclusions: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.« less

Assessment and quantification of patient set-up errors in nasopharyngeal cancer patients and their biological and dosimetric impact in terms of generalized equivalent uniform dose (gEUD), tumour control probability (TCP) and normal tissue complication probability (NTCP)

PubMed Central

Marcie, S; Fellah, M; Chami, S; Mekki, F

2015-01-01

Objective: The aim of this study is to assess and quantify patients' set-up errors using an electronic portal imaging device and to evaluate their dosimetric and biological impact in terms of generalized equivalent uniform dose (gEUD) on predictive models, such as the tumour control probability (TCP) and the normal tissue complication probability (NTCP). Methods: 20 patients treated for nasopharyngeal cancer were enrolled in the radiotherapy–oncology department of HCA. Systematic and random errors were quantified. The dosimetric and biological impact of these set-up errors on the target volume and the organ at risk (OARs) coverage were assessed using calculation of dose–volume histogram, gEUD, TCP and NTCP. For this purpose, an in-house software was developed and used. Results: The standard deviations (1SDs) of the systematic set-up and random set-up errors were calculated for the lateral and subclavicular fields and gave the following results: ∑ = 0.63 ± (0.42) mm and σ = 3.75 ± (0.79) mm, respectively. Thus a planning organ at risk volume (PRV) margin of 3 mm was defined around the OARs, and a 5-mm margin used around the clinical target volume. The gEUD, TCP and NTCP calculations obtained with and without set-up errors have shown increased values for tumour, where ΔgEUD (tumour) = 1.94% Gy (p = 0.00721) and ΔTCP = 2.03%. The toxicity of OARs was quantified using gEUD and NTCP. The values of ΔgEUD (OARs) vary from 0.78% to 5.95% in the case of the brainstem and the optic chiasm, respectively. The corresponding ΔNTCP varies from 0.15% to 0.53%, respectively. Conclusion: The quantification of set-up errors has a dosimetric and biological impact on the tumour and on the OARs. The developed in-house software using the concept of gEUD, TCP and NTCP biological models has been successfully used in this study. It can be used also to optimize the treatment plan established for our patients. Advances in knowledge: The gEUD, TCP and NTCP may be more suitable tools to assess the treatment plans before treating the patients. PMID:25882689

A prospective cohort study on radiation-induced hypothyroidism: development of an NTCP model.

PubMed

Boomsma, Marjolein J; Bijl, Hendrik P; Christianen, Miranda E M C; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J H M; van der Laan, Bernard F A M; Wolffenbuttel, Bruce H R; Oosting, Sjoukje F; Schilstra, Cornelis; Langendijk, Johannes A

2012-11-01

To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm(3)). Model performance was good with an area under the curve (AUC) of 0.85. This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume. Copyright © 2012 Elsevier Inc. All rights reserved.

Variation of normal tissue complication probability (NTCP) estimates of radiation-induced hypothyroidism in relation to changes in delineation of the thyroid gland.

PubMed

Rønjom, Marianne F; Brink, Carsten; Lorenzen, Ebbe L; Hegedüs, Laszlo; Johansen, Jørgen

2015-01-01

To examine the variations of risk-estimates of radiation-induced hypothyroidism (HT) from our previously developed normal tissue complication probability (NTCP) model in patients with head and neck squamous cell carcinoma (HNSCC) in relation to variability of delineation of the thyroid gland. In a previous study for development of an NTCP model for HT, the thyroid gland was delineated in 246 treatment plans of patients with HNSCC. Fifty of these plans were randomly chosen for re-delineation for a study of the intra- and inter-observer variability of thyroid volume, Dmean and estimated risk of HT. Bland-Altman plots were used for assessment of the systematic (mean) and random [standard deviation (SD)] variability of the three parameters, and a method for displaying the spatial variation in delineation differences was developed. Intra-observer variability resulted in a mean difference in thyroid volume and Dmean of 0.4 cm(3) (SD ± 1.6) and -0.5 Gy (SD ± 1.0), respectively, and 0.3 cm(3) (SD ± 1.8) and 0.0 Gy (SD ± 1.3) for inter-observer variability. The corresponding mean differences of NTCP values for radiation-induced HT due to intra- and inter-observer variations were insignificantly small, -0.4% (SD ± 6.0) and -0.7% (SD ± 4.8), respectively, but as the SDs show, for some patients the difference in estimated NTCP was large. For the entire study population, the variation in predicted risk of radiation-induced HT in head and neck cancer was small and our NTCP model was robust against observer variations in delineation of the thyroid gland. However, for the individual patient, there may be large differences in estimated risk which calls for precise delineation of the thyroid gland to obtain correct dose and NTCP estimates for optimized treatment planning in the individual patient.

Normal tissue complication probability model parameter estimation for xerostomia in head and neck cancer patients based on scintigraphy and quality of life assessments

PubMed Central

2012-01-01

Background With advances in modern radiotherapy (RT), many patients with head and neck (HN) cancer can be effectively cured. However, xerostomia is a common complication in patients after RT for HN cancer. The purpose of this study was to use the Lyman–Kutcher–Burman (LKB) model to derive parameters for the normal tissue complication probability (NTCP) for xerostomia based on scintigraphy assessments and quality of life (QoL) questionnaires. We performed validation tests of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines against prospectively collected QoL and salivary scintigraphic data. Methods Thirty-one patients with HN cancer were enrolled. Salivary excretion factors (SEFs) measured by scintigraphy and QoL data from self-reported questionnaires were used for NTCP modeling to describe the incidence of grade 3+ xerostomia. The NTCP parameters estimated from the QoL and SEF datasets were compared. Model performance was assessed using Pearson’s chi-squared test, Nagelkerke’s R2, the area under the receiver operating characteristic curve, and the Hosmer–Lemeshow test. The negative predictive value (NPV) was checked for the rate of correctly predicting the lack of incidence. Pearson’s chi-squared test was used to test the goodness of fit and association. Results Using the LKB NTCP model and assuming n=1, the dose for uniform irradiation of the whole or partial volume of the parotid gland that results in 50% probability of a complication (TD50) and the slope of the dose–response curve (m) were determined from the QoL and SEF datasets, respectively. The NTCP-fitted parameters for local disease were TD50=43.6 Gy and m=0.18 with the SEF data, and TD50=44.1 Gy and m=0.11 with the QoL data. The rate of grade 3+ xerostomia for treatment plans meeting the QUANTEC guidelines was specifically predicted, with a NPV of 100%, using either the QoL or SEF dataset. Conclusions Our study shows the agreement between the NTCP parameter modeling based on SEF and QoL data, which gave a NPV of 100% with each dataset, and the QUANTEC guidelines, thus validating the cut-off values of 20 and 25 Gy. Based on these results, we believe that the QUANTEC 25/20-Gy spared-gland mean-dose guidelines are clinically useful for avoiding xerostomia in the HN cohort. PMID:23206972

Normal tissue complication probability model parameter estimation for xerostomia in head and neck cancer patients based on scintigraphy and quality of life assessments.

PubMed

Lee, Tsair-Fwu; Chao, Pei-Ju; Wang, Hung-Yu; Hsu, Hsuan-Chih; Chang, PaoShu; Chen, Wen-Cheng

2012-12-04

With advances in modern radiotherapy (RT), many patients with head and neck (HN) cancer can be effectively cured. However, xerostomia is a common complication in patients after RT for HN cancer. The purpose of this study was to use the Lyman-Kutcher-Burman (LKB) model to derive parameters for the normal tissue complication probability (NTCP) for xerostomia based on scintigraphy assessments and quality of life (QoL) questionnaires. We performed validation tests of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines against prospectively collected QoL and salivary scintigraphic data. Thirty-one patients with HN cancer were enrolled. Salivary excretion factors (SEFs) measured by scintigraphy and QoL data from self-reported questionnaires were used for NTCP modeling to describe the incidence of grade 3+ xerostomia. The NTCP parameters estimated from the QoL and SEF datasets were compared. Model performance was assessed using Pearson's chi-squared test, Nagelkerke's R2, the area under the receiver operating characteristic curve, and the Hosmer-Lemeshow test. The negative predictive value (NPV) was checked for the rate of correctly predicting the lack of incidence. Pearson's chi-squared test was used to test the goodness of fit and association. Using the LKB NTCP model and assuming n=1, the dose for uniform irradiation of the whole or partial volume of the parotid gland that results in 50% probability of a complication (TD50) and the slope of the dose-response curve (m) were determined from the QoL and SEF datasets, respectively. The NTCP-fitted parameters for local disease were TD50=43.6 Gy and m=0.18 with the SEF data, and TD50=44.1 Gy and m=0.11 with the QoL data. The rate of grade 3+ xerostomia for treatment plans meeting the QUANTEC guidelines was specifically predicted, with a NPV of 100%, using either the QoL or SEF dataset. Our study shows the agreement between the NTCP parameter modeling based on SEF and QoL data, which gave a NPV of 100% with each dataset, and the QUANTEC guidelines, thus validating the cut-off values of 20 and 25 Gy. Based on these results, we believe that the QUANTEC 25/20-Gy spared-gland mean-dose guidelines are clinically useful for avoiding xerostomia in the HN cohort.

Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jakobi, Annika, E-mail: Annika.Jakobi@OncoRay.de; Bandurska-Luque, Anna; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden

Purpose: The purpose of this study was to determine, by treatment plan comparison along with normal tissue complication probability (NTCP) modeling, whether a subpopulation of patients with head and neck squamous cell carcinoma (HNSCC) could be identified that would gain substantial benefit from proton therapy in terms of NTCP. Methods and Materials: For 45 HNSCC patients, intensity modulated radiation therapy (IMRT) was compared to intensity modulated proton therapy (IMPT). Physical dose distributions were evaluated as well as the resulting NTCP values, using modern models for acute mucositis, xerostomia, aspiration, dysphagia, laryngeal edema, and trismus. Patient subgroups were defined based onmore » primary tumor location. Results: Generally, IMPT reduced the NTCP values while keeping similar target coverage for all patients. Subgroup analyses revealed a higher individual reduction of swallowing-related side effects by IMPT for patients with tumors in the upper head and neck area, whereas the risk reduction of acute mucositis was more pronounced in patients with tumors in the larynx region. More patients with tumors in the upper head and neck area had a reduction in NTCP of more than 10%. Conclusions: Subgrouping can help to identify patients who may benefit more than others from the use of IMPT and, thus, can be a useful tool for a preselection of patients in the clinic where there are limited PT resources. Because the individual benefit differs within a subgroup, the relative merits should additionally be evaluated by individual treatment plan comparisons.« less

The Impact of Monte Carlo Dose Calculations on Intensity-Modulated Radiation Therapy

NASA Astrophysics Data System (ADS)

Siebers, J. V.; Keall, P. J.; Mohan, R.

The effect of dose calculation accuracy for IMRT was studied by comparing different dose calculation algorithms. A head and neck IMRT plan was optimized using a superposition dose calculation algorithm. Dose was re-computed for the optimized plan using both Monte Carlo and pencil beam dose calculation algorithms to generate patient and phantom dose distributions. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) were computed to estimate the plan outcome. For the treatment plan studied, Monte Carlo best reproduces phantom dose measurements, the TCP was slightly lower than the superposition and pencil beam results, and the NTCP values differed little.

SU-E-T-571: Prostate IMRT QA: Prediction of the Range of Rectal NTCP Using a 2D Field Approach Based on Variations of the Rectal Wall Motion and Thickness.

PubMed

Grigorov, G; Chow, J; Foster, K

2012-06-01

The aims of this study is to (1) introduce a 2D field of possible rectal normal tissue complication probability (NTCP) in prostate intensity modulated radiotherapy (IMRT) plan, so that based on a given prescribed dose the rectal NTCP is merely a function of the rectal wall thickness and rectal motion; and (2) separate the 2D field of rectal NTCP into area of low risk and area of high risk for rectal toxicity < Grade II, based on the threshold rectal NTCP. The 2D field of NTCP model was developed using ten randomly selected prostate IMRT plans. The clinical rectal geometry was initially represented by the cylindrical contour in the treatment planning system. Different combinations of rectal motions, rectal wall thicknesses, planning target volume margins and prescribed doses were used to determine the NTCP in prostate IMRT plans. It was found that the functions bordering the 2D field for the given AP, LR and SI direction can be described as exponential, quadratic and linear equations, respectively. A ratio of the area of 2D field containing data of the low risk NTCP to the entire area of the field was introduced and calculated. Although our method is based on the Kutcher's dose response model and published tissue parameters, other mathematical models can be used in our approach. The 2D field of rectal NTCP is useful to estimate the rectal NTCP range in the prostate pre-treatment and treatment QA. Our method can determine the patient's threshold immobilization for a given rectal wall thickness so that prescribed dose can be delivered to the prostate to avoid rectal complication. Our method is also applicable to multi-phase prostate IMRT, and can be adapted to any treatment planning systems. © 2012 American Association of Physicists in Medicine.

A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E.M.C.

Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroidmore » gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm{sup 3}). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L.; Liu, H. Helen; Wang, Shulian

Purpose: The aim of this study was to investigate the effect of radiation dose distribution in the lung on the risk of postoperative pulmonary complications among esophageal cancer patients. Methods and Materials: We analyzed data from 110 patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery at our institution from 1998 to 2003. The endpoint for analysis was postsurgical pneumonia or acute respiratory distress syndrome. Dose-volume histograms (DVHs) and dose-mass histograms (DMHs) for the whole lung were used to fit normal-tissue complication probability (NTCP) models, and the quality of fits were compared using bootstrap analysis. Results: Normal-tissue complicationmore » probability modeling identified that the risk of postoperative pulmonary complications was most significantly associated with small absolute volumes of lung spared from doses {>=}5 Gy (VS5), that is, exposed to doses <5 Gy. However, bootstrap analysis found no significant difference between the quality of this model and fits based on other dosimetric parameters, including mean lung dose, effective dose, and relative volume of lung receiving {>=}5 Gy, probably because of correlations among these factors. The choice of DVH vs. DMH or the use of fractionation correction did not significantly affect the results of the NTCP modeling. The parameter values estimated for the Lyman NTCP model were as follows (with 95% confidence intervals in parentheses): n = 1.85 (0.04, {infinity}), m = 0.55 (0.22, 1.02), and D {sub 5} = 17.5 Gy (9.4 Gy, 102 Gy). Conclusions: In this cohort of esophageal cancer patients, several dosimetric parameters including mean lung dose, effective dose, and absolute volume of lung receiving <5 Gy provided similar descriptions of the risk of postoperative pulmonary complications as a function of Radiation dose distribution in the lung.« less

On the use of biomathematical models in patient-specific IMRT dose QA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhen Heming; Nelms, Benjamin E.; Tome, Wolfgang A.

2013-07-15

Purpose: To investigate the use of biomathematical models such as tumor control probability (TCP) and normal tissue complication probability (NTCP) as new quality assurance (QA) metrics.Methods: Five different types of error (MLC transmission, MLC penumbra, MLC tongue and groove, machine output, and MLC position) were intentionally induced to 40 clinical intensity modulated radiation therapy (IMRT) patient plans (20 H and N cases and 20 prostate cases) to simulate both treatment planning system errors and machine delivery errors in the IMRT QA process. The changes in TCP and NTCP for eight different anatomic structures (H and N: CTV, GTV, both parotids,more » spinal cord, larynx; prostate: CTV, rectal wall) were calculated as the new QA metrics to quantify the clinical impact on patients. The correlation between the change in TCP/NTCP and the change in selected DVH values was also evaluated. The relation between TCP/NTCP change and the characteristics of the TCP/NTCP curves is discussed.Results:{Delta}TCP and {Delta}NTCP were summarized for each type of induced error and each structure. The changes/degradations in TCP and NTCP caused by the errors vary widely depending on dose patterns unique to each plan, and are good indicators of each plan's 'robustness' to that type of error.Conclusions: In this in silico QA study the authors have demonstrated the possibility of using biomathematical models not only as patient-specific QA metrics but also as objective indicators that quantify, pretreatment, a plan's robustness with respect to possible error types.« less

Influence of dose calculation algorithms on the predicted dose distribution and NTCP values for NSCLC patients.

PubMed

Nielsen, Tine B; Wieslander, Elinore; Fogliata, Antonella; Nielsen, Morten; Hansen, Olfred; Brink, Carsten

2011-05-01

To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms. Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections. There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%. Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest.

On the use of published radiobiological parameters and the evaluation of NTCP models regarding lung pneumonitis in clinical breast radiotherapy.

PubMed

Svolos, Patricia; Tsougos, Ioannis; Kyrgias, Georgios; Kappas, Constantine; Theodorou, Kiki

2011-04-01

In this study we sought to evaluate and accent the importance of radiobiological parameter selection and implementation to the normal tissue complication probability (NTCP) models. The relative seriality (RS) and the Lyman-Kutcher-Burman (LKB) models were studied. For each model, a minimum and maximum set of radiobiological parameter sets was selected from the overall published sets applied in literature and a theoretical mean parameter set was computed. In order to investigate the potential model weaknesses in NTCP estimation and to point out the correct use of model parameters, these sets were used as input to the RS and the LKB model, estimating radiation induced complications for a group of 36 breast cancer patients treated with radiotherapy. The clinical endpoint examined was Radiation Pneumonitis. Each model was represented by a certain dose-response range when the selected parameter sets were applied. Comparing the models with their ranges, a large area of coincidence was revealed. If the parameter uncertainties (standard deviation) are included in the models, their area of coincidence might be enlarged, constraining even greater their predictive ability. The selection of the proper radiobiological parameter set for a given clinical endpoint is crucial. Published parameter values are not definite but should be accompanied by uncertainties, and one should be very careful when applying them to the NTCP models. Correct selection and proper implementation of published parameters provides a quite accurate fit of the NTCP models to the considered endpoint.

Differences in delineation guidelines for head and neck cancer result in inconsistent reported dose and corresponding NTCP.

PubMed

Brouwer, Charlotte L; Steenbakkers, Roel J H M; Gort, Elske; Kamphuis, Marije E; van der Laan, Hans Paul; Van't Veld, Aart A; Sijtsema, Nanna M; Langendijk, Johannes A

2014-04-01

To test the hypothesis that delineation of swallowing organs at risk (SWOARs) based on different guidelines results in differences in dose-volume parameters and subsequent normal tissue complication probability (NTCP) values for dysphagia-related endpoints. Nine different SWOARs were delineated according to five different delineation guidelines in 29 patients. Reference delineation was performed according to the guidelines and NTCP-models of Christianen et al. Concordance Index (CI), dosimetric consequences, as well as differences in the subsequent NTCPs were calculated. The median CI of the different delineation guidelines with the reference guidelines was 0.54 for the pharyngeal constrictor muscles, 0.56 for the laryngeal structures and 0.07 for the cricopharyngeal muscle and esophageal inlet muscle. The average difference in mean dose to the SWOARs between the guidelines with the largest difference (maxΔD) was 3.5±3.2Gy. A mean ΔNTCP of 2.3±2.7% was found. For two patients, ΔNTCP exceeded 10%. The majority of the patients showed little differences in NTCPs between the different delineation guidelines. However, large NTCP differences >10% were found in 7% of the patients. For correct use of NTCP models in individual patients, uniform delineation guidelines are of great importance. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The significance of the choice of radiobiological (NTCP) models in treatment plan objective functions.

PubMed

Miller, J; Fuller, M; Vinod, S; Suchowerska, N; Holloway, L

2009-06-01

A Clinician's discrimination between radiation therapy treatment plans is traditionally a subjective process, based on experience and existing protocols. A more objective and quantitative approach to distinguish between treatment plans is to use radiobiological or dosimetric objective functions, based on radiobiological or dosimetric models. The efficacy of models is not well understood, nor is the correlation of the rank of plans resulting from the use of models compared to the traditional subjective approach. One such radiobiological model is the Normal Tissue Complication Probability (NTCP). Dosimetric models or indicators are more accepted in clinical practice. In this study, three radiobiological models, Lyman NTCP, critical volume NTCP and relative seriality NTCP, and three dosimetric models, Mean Lung Dose (MLD) and the Lung volumes irradiated at 10Gy (V10) and 20Gy (V20), were used to rank a series of treatment plans using, harm to normal (Lung) tissue as the objective criterion. None of the models considered in this study showed consistent correlation with the Radiation Oncologists plan ranking. If radiobiological or dosimetric models are to be used in objective functions for lung treatments, based on this study it is recommended that the Lyman NTCP model be used because it will provide most consistency with traditional clinician ranking.

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takam, Rungdham; Bezak, Eva; Yeoh, Eric E.

2010-09-15

Purpose: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences inmore » radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muller, L; Soldner, A; Kirk, M

Purpose: The beam range uncertainty presents a special challenge for proton therapy. Novel technologies currently under development offer strategies to reduce the range uncertainty [1,2]. This work quantifies the potential advantages that could be realized by such a reduction for dosimetrically challenging chordomas at the base of skull. Therapeutic improvement was assessed by evaluating tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP). Methods: Treatment plans were made for a modulated-scanned proton delivery technique using the Eclipse treatment planning system. The prescription dose was 7920 cGy to the CTV. Three different range uncertainty scenarios were considered: 5 mm (3.5%more » of the beam range + 1 mm, representing current clinical practice, “Curr”), 2 mm (1.3%), and 1 mm (0.7%). For each of 4 patients, 3 different PTVs were defined via uniform expansion of the CTV by the value of the range uncertainty. Tumor control probability (TCP) and normal tissue complication probabilities (NTCPs) for organs-at-risk (OARs) were calculated using the Lyman-Kutcher-Burman[3] formalism and published model parameters [ref Terahara[4], quantec S10, Burman Red Journal v21 pp 123]. Our plan optimization strategy was to achieve PTV close to prescription while maintaining OAR NTCP values at or better than the Curr plan. Results: The average TCP values for the 5, 2, and 1 mm range uncertainty scenarios are 51%, 55% and 65%. The improvement in TCP for patients was between 4 and 30%, depending primarily on the proximity of the GTV to OAR. The average NTCPs for the brainstem and cord were about 4% and 1%, respectively, for all target margins. Conclusion: For base of skull chordomas, reduced target margins can substantially increase the TCP without increasing the NTCP. This work demonstrates the potential significance of a reduction in the range uncertainty for proton beams.« less

Potential for intensity-modulated radiation therapy to permit dose escalation for canine nasal cancer.

PubMed

Vaudaux, Catherine; Schneider, Uwe; Kaser-Hotz, Barbara

2007-01-01

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary

Prediction of radiation-induced normal tissue complications in radiotherapy using functional image data

NASA Astrophysics Data System (ADS)

Nioutsikou, Elena; Partridge, Mike; Bedford, James L.; Webb, Steve

2005-03-01

The aim of this study has been to explicitly include the functional heterogeneity of an organ as a factor that contributes to the probability of complication of normal tissues following radiotherapy. Situations for which the inclusion of this information can be advantageous to the design of treatment plans are then investigated. A Java program has been implemented for this purpose. This makes use of a voxelated model of a patient, which is based on registered anatomical and functional data in order to enable functional voxel weighting. Using this model, the functional dose-volume histogram (fDVH) and the functional normal tissue complication probability (fNTCP) are then introduced as extensions to the conventional dose-volume histogram (DVH) and normal tissue complication probability (NTCP). In the presence of functional heterogeneity, these tools are physically more meaningful for plan evaluation than the traditional indices, as they incorporate additional information and are anticipated to show a better correlation with outcome. New parameters mf, nf and TD50f are required to replace the m, n and TD50 parameters. A range of plausible values was investigated, awaiting fitting of these new parameters to patient outcomes where functional data have been measured. As an example, the model is applied to two lung datasets utilizing accurately registered computed tomography (CT) and single photon emission computed tomography (SPECT) perfusion scans. Assuming a linear perfusion-function relationship, the biological index mean perfusion weighted lung dose (MPWLD) has been extracted from integration over outlined regions of interest. In agreement with the MPWLD ranking, the fNTCP predictions reveal that incorporation of functional imaging in radiotherapy treatment planning is most beneficial for organs with a large volume effect and large focal areas of dysfunction. There is, however, no additional advantage in cases presenting with homogeneous function. Although presented for lung radiotherapy, this model is general. It can also be applied to positron emission tomography (PET)-CT or functional magnetic resonance imaging (fMRI)-CT registered data and extended to the functional description of tumour control probability.

Biological mechanisms of normal tissue damage: importance for the design of NTCP models.

PubMed

Trott, Klaus-Rüdiger; Doerr, Wolfgang; Facoetti, Angelica; Hopewell, John; Langendijk, Johannes; van Luijk, Peter; Ottolenghi, Andrea; Smyth, Vere

2012-10-01

The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited. This paper examines the radiobiological mechanisms underlying the most important complications induced by radiotherapy, with the aim of identifying the essential parameters and functional relationships needed for effective predictive NTCP models. The clinical features of the complications are identified and reduced as much as possible into component parts. In a second step, experimental and clinical data are considered in order to identify the gross anatomical structures involved, and which dose distributions lead to these complications. Finally, the pathogenic pathways and cellular and more specific anatomical parameters that have to be considered in this pathway are determined. This analysis is carried out for some of the most critical organs and sites in radiotherapy, i.e. spinal cord, lung, rectum, oropharynx and heart. Signs and symptoms of severe late normal tissue complications present a very variable picture in the different organs at risk. Only in rare instances is the entire organ the critical target which elicits the particular complication. Moreover, the biological mechanisms that are involved in the pathogenesis differ between the different complications, even in the same organ. Different mechanisms are likely to be related to different shapes of dose effect relationships and different relationships between dose per fraction, dose rate, and overall treatment time and effects. There is good reason to conclude that each type of late complication after radiotherapy depends on its own specific mechanism which is triggered by the radiation exposure of particular structures or sub-volumes of (or related to) the respective organ at risk. Hence each complication will need the development of an NTCP model designed to accommodate this structure. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Impact of the NTCP modeling on medical decision to select eligible patient for proton therapy: the usefulness of EUD as an indicator to rank modern photon vs proton treatment plans.

PubMed

Chaikh, Abdulhamid; Calugaru, Valentin; Bondiau, Pierre-Yves; Thariat, Juliette; Balosso, Jacques

2018-06-07

The aim of this study is to evaluate the impact of normal tissue complication probability (NTCP)-based radiobiological models on the estimated risk for late radiation lung damages. The second goal is to propose a medical decision-making approach to select the eligible patient for particle therapy. 14 pediatric patients undergoing cranio-spinal irradiation were evaluated. For each patient, two treatment plans were generated using photon and proton therapy with the same dose prescriptions. Late radiation damage to lung was estimated using three NTCP concepts: the Lyman-Kutcher-Burman, the equivalent uniform dose (EUD) and the mean lung dose according to the quantitative analysis of normal tissue effects in the clinic QUANTEC review. Wilcoxon paired test was used to calculate p-value. Proton therapy achieved lower lung EUD (Gy). The average NTCP values were significantly lower with proton plans, p < 0.05, using the three NTCP concepts. However, applying the same TD 50/5 using radiobiological models to compare NTCP from proton and photon therapy, the ΔNTCP was not a convincing method to measure the potential benefit of proton therapy. Late radiation pneumonitis estimated from the mean lung dose model correlated with QUANTEC data better. treatment effectiveness assessed on NTCP reduction depends on radiobiological predictions and parameters used as inputs for in silico evaluation. Since estimates of absolute NTCP values from LKB and GN models are imprecise due to EUD ≪ TD 50/5 , a reduction of the EUD value with proton plans would better predict a reduction of dose/toxicity. The EUD concept appears as a robust radiobiological surrogate of the dose distribution to select the optimal patient's plan.

Multivariable normal-tissue complication modeling of acute esophageal toxicity in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy.

PubMed

Wijsman, Robin; Dankers, Frank; Troost, Esther G C; Hoffmann, Aswin L; van der Heijden, Erik H F M; de Geus-Oei, Lioe-Fee; Bussink, Johan

2015-10-01

The majority of normal-tissue complication probability (NTCP) models for acute esophageal toxicity (AET) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with (chemo-)radiotherapy are based on three-dimensional conformal radiotherapy (3D-CRT). Due to distinct dosimetric characteristics of intensity-modulated radiation therapy (IMRT), 3D-CRT based models need revision. We established a multivariable NTCP model for AET in 149 AS-NSCLC patients undergoing IMRT. An established model selection procedure was used to develop an NTCP model for Grade ⩾2 AET (53 patients) including clinical and esophageal dose-volume histogram parameters. The NTCP model predicted an increased risk of Grade ⩾2 AET in case of: concurrent chemoradiotherapy (CCR) [adjusted odds ratio (OR) 14.08, 95% confidence interval (CI) 4.70-42.19; p<0.001], increasing mean esophageal dose [Dmean; OR 1.12 per Gy increase, 95% CI 1.06-1.19; p<0.001], female patients (OR 3.33, 95% CI 1.36-8.17; p=0.008), and ⩾cT3 (OR 2.7, 95% CI 1.12-6.50; p=0.026). The AUC was 0.82 and the model showed good calibration. A multivariable NTCP model including CCR, Dmean, clinical tumor stage and gender predicts Grade ⩾2 AET after IMRT for AS-NSCLC. Prior to clinical introduction, the model needs validation in an independent patient cohort. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

SU-F-T-378: Evaluation of Dose-Volume Variability and Parameters Between Prostate IMRT and VMAT Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, J; Jiang, R; Kiciak, A

2016-06-15

Purpose: This study compared the rectal dose-volume consistency, equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) in prostate intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Methods: For forty prostate IMRT and fifty VMAT patients treated using the same dose prescription (78 Gy/39 fraction) and dose-volume criteria in inverse planning optimization, the rectal EUD and NTCP were calculated for each patient. The rectal dose-volume consistency, showing the variability of dose-volume histogram (DVH) among patients, was defined and calculated based on the deviation between the mean and corresponding rectal DVH. Results: From both the prostate IMRT andmore » VMAT plans, the rectal EUD and NTCP were found decreasing with the rectal volume. The decrease rates for the IMRT plans (EUD = 0.47 × 10{sup −3} Gy cm{sup −3} and NTCP = 3.94 × 10{sup −2} % cm{sup −3}) were higher than those for the VMAT (EUD = 0.28 × 10{sup −3} Gy cm{sup −3} and NTCP = 2.61 × 10{sup −2} % cm{sup −3}). In addition, the dependences of the rectal EUD and NTCP on the dose-volume consistency were found very similar between the prostate IMRT and VMAT plans. This shows that both delivery techniques have similar variations of the rectal EUD and NTCP on the dose-volume consistency. Conclusion: Dependences of the dose-volume consistency on the rectal EUD and NTCP were compared between the prostate IMRT and VMAT plans. It is concluded that both rectal EUD and NTCP decreased with an increase of the rectal volume. The variation rates of the rectal EUD and NTCP on the rectal volume were higher for the IMRT plans than VMAT. However, variations of the rectal dose-volume consistency on the rectal EUD and NTCP were found not significant for both delivery techniques.« less

Irradiation of the inguinal lymph nodes in patients of differing body habitus: a comparison of techniques and resulting normal tissue complication probabilities.

PubMed

Brown, Paul D; Kline, Robert W; Petersen, Ivy A; Haddock, Michael G

2004-01-01

The treatment of the inguinal lymph nodes with radiotherapy is strongly influenced by the body habitus of the patient. The effect of 7 radiotherapy techniques on femoral head doses was studied. Three female patients of differing body habitus (ectomorph, mesomorph, endomorph) were selected. Radiation fields included the pelvis and contiguous inguinal regions and were representative of fields used in the treatment of cancers of the lower pelvis. Seven treatment techniques were compared. In the ectomorph and mesomorph, normal tissue complication probability (NTCP) for the femoral heads was lowest with use of anteroposterior (AP) and modified posteroanterior (PA) field with inguinal electron field supplements (technique 1). In the endomorph, NTCP was lowest with use of AP and modified PA field without electron field supplements (technique 2) or a 4-field approach (technique 6). Technique 1 for ectomorphs and mesomorphs and techniques 2 and 6 for endomorphs were optimal techniques for providing relatively homogeneous dose distributions within the target area while minimizing the dose to the femoral heads.

Evaluation of normal lung tissue complication probability in gated and conventional radiotherapy using the 4D XCAT digital phantom.

PubMed

Shahzadeh, Sara; Gholami, Somayeh; Aghamiri, Seyed Mahmood Reza; Mahani, Hojjat; Nabavi, Mansoure; Kalantari, Faraz

2018-06-01

The present study was conducted to investigate normal lung tissue complication probability in gated and conventional radiotherapy (RT) as a function of diaphragm motion, lesion size, and its location using 4D-XCAT digital phantom in a simulation study. Different time series of 3D-CT images were generated using the 4D-XCAT digital phantom. The binary data obtained from this phantom were then converted to the digital imaging and communication in medicine (DICOM) format using an in-house MATLAB-based program to be compatible with our treatment planning system (TPS). The 3D-TPS with superposition computational algorithm was used to generate conventional and gated plans. Treatment plans were generated for 36 different XCAT phantom configurations. These included four diaphragm motions of 20, 25, 30 and 35 mm, three lesion sizes of 3, 4, and 5 cm in diameter and each tumor was placed in four different lung locations (right lower lobe, right upper lobe, left lower lobe and left upper lobe). The complication of normal lung tissue was assessed in terms of mean lung dose (MLD), the lung volume receiving ≥20 Gy (V20), and normal tissue complication probability (NTCP). The results showed that the gated RT yields superior outcomes in terms of normal tissue complication compared to the conventional RT. For all cases, the gated radiation therapy technique reduced the mean dose, V20, and NTCP of lung tissue by up to 5.53 Gy, 13.38%, and 23.89%, respectively. The results of this study showed that the gated RT provides significant advantages in terms of the normal lung tissue complication, compared to the conventional RT, especially for the lesions near the diaphragm. Copyright © 2018 Elsevier Ltd. All rights reserved.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

PubMed

Dean, J A; Welsh, L C; Wong, K H; Aleksic, A; Dunne, E; Islam, M R; Patel, A; Patel, P; Petkar, I; Phillips, I; Sham, J; Schick, U; Newbold, K L; Bhide, S A; Harrington, K J; Nutting, C M; Gulliford, S L

2017-04-01

A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Towards a model-based patient selection strategy for proton therapy: External validation of photon-derived Normal Tissue Complication Probability models in a head and neck proton therapy cohort

PubMed Central

Blanchard, P; Wong, AJ; Gunn, GB; Garden, AS; Mohamed, ASR; Rosenthal, DI; Crutison, J; Wu, R; Zhang, X; Zhu, XR; Mohan, R; Amin, MV; Fuller, CD; Frank, SJ

2017-01-01

Objective To externally validate head and neck cancer (HNC) photon-derived normal tissue complication probability (NTCP) models in patients treated with proton beam therapy (PBT). Methods This prospective cohort consisted of HNC patients treated with PBT at a single institution. NTCP models were selected based on the availability of data for validation and evaluated using the leave-one-out cross-validated area under the curve (AUC) for the receiver operating characteristics curve. Results 192 patients were included. The most prevalent tumor site was oropharynx (n=86, 45%), followed by sinonasal (n=28), nasopharyngeal (n=27) or parotid (n=27) tumors. Apart from the prediction of acute mucositis (reduction of AUC of 0.17), the models overall performed well. The validation (PBT) AUC and the published AUC were respectively 0.90 versus 0.88 for feeding tube 6 months post-PBT; 0.70 versus 0.80 for physician rated dysphagia 6 months post-PBT; 0.70 versus 0.80 for dry mouth 6 months post-PBT; and 0.73 versus 0.85 for hypothyroidism 12 months post-PBT. Conclusion While the drop in NTCP model performance was expected in PBT patients, the models showed robustness and remained valid. Further work is warranted, but these results support the validity of the model-based approach for treatment selection for HNC patients. PMID:27641784

Validation of automatic segmentation of ribs for NTCP modeling.

PubMed

Stam, Barbara; Peulen, Heike; Rossi, Maddalena M G; Belderbos, José S A; Sonke, Jan-Jakob

2016-03-01

Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP). Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared. Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar. Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

IMRT: Improvement in treatment planning efficiency using NTCP calculation independent of the dose-volume-histogram

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grigorov, Grigor N.; Chow, James C.L.; Grigorov, Lenko

2006-05-15

The normal tissue complication probability (NTCP) is a predictor of radiobiological effect for organs at risk (OAR). The calculation of the NTCP is based on the dose-volume-histogram (DVH) which is generated by the treatment planning system after calculation of the 3D dose distribution. Including the NTCP in the objective function for intensity modulated radiation therapy (IMRT) plan optimization would make the planning more effective in reducing the postradiation effects. However, doing so would lengthen the total planning time. The purpose of this work is to establish a method for NTCP determination, independent of a DVH calculation, as a quality assurancemore » check and also as a mean of improving the treatment planning efficiency. In the study, the CTs of ten randomly selected prostate patients were used. IMRT optimization was performed with a PINNACLE3 V 6.2b planning system, using planning target volume (PTV) with margins in the range of 2 to 10 mm. The DVH control points of the PTV and OAR were adapted from the prescriptions of Radiation Therapy Oncology Group protocol P-0126 for an escalated prescribed dose of 82 Gy. This paper presents a new model for the determination of the rectal NTCP ({sub R}NTCP). The method uses a special function, named GVN (from Gy, Volume, NTCP), which describes the {sub R}NTCP if 1 cm{sup 3} of the volume of intersection of the PTV and rectum (R{sub int}) is irradiated uniformly by a dose of 1 Gy. The function was 'geometrically' normalized using a prostate-prostate ratio (PPR) of the patients' prostates. A correction of the {sub R}NTCP for different prescribed doses, ranging from 70 to 82 Gy, was employed in our model. The argument of the normalized function is the R{sub int}, and parameters are the prescribed dose, prostate volume, PTV margin, and PPR. The {sub R}NTCPs of another group of patients were calculated by the new method and the resulting difference was <{+-}5% in comparison to the NTCP calculated by the PINNACLE3 software where Kutcher's dose-response model for NTCP calculation is adopted.« less

Random Forests to Predict Rectal Toxicity Following Prostate Cancer Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ospina, Juan D.; INSERM, U1099, Rennes; Escuela de Estadística, Universidad Nacional de Colombia Sede Medellín, Medellín

2014-08-01

Purpose: To propose a random forest normal tissue complication probability (RF-NTCP) model to predict late rectal toxicity following prostate cancer radiation therapy, and to compare its performance to that of classic NTCP models. Methods and Materials: Clinical data and dose-volume histograms (DVH) were collected from 261 patients who received 3-dimensional conformal radiation therapy for prostate cancer with at least 5 years of follow-up. The series was split 1000 times into training and validation cohorts. A RF was trained to predict the risk of 5-year overall rectal toxicity and bleeding. Parameters of the Lyman-Kutcher-Burman (LKB) model were identified and a logistic regression modelmore » was fit. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve (AUC). Results: The 5-year grade ≥2 overall rectal toxicity and grade ≥1 and grade ≥2 rectal bleeding rates were 16%, 25%, and 10%, respectively. Predictive capabilities were obtained using the RF-NTCP model for all 3 toxicity endpoints, including both the training and validation cohorts. The age and use of anticoagulants were found to be predictors of rectal bleeding. The AUC for RF-NTCP ranged from 0.66 to 0.76, depending on the toxicity endpoint. The AUC values for the LKB-NTCP were statistically significantly inferior, ranging from 0.62 to 0.69. Conclusions: The RF-NTCP model may be a useful new tool in predicting late rectal toxicity, including variables other than DVH, and thus appears as a strong competitor to classic NTCP models.« less

Estimation of parameters of dose volume models and their confidence limits

NASA Astrophysics Data System (ADS)

van Luijk, P.; Delvigne, T. C.; Schilstra, C.; Schippers, J. M.

2003-07-01

Predictions of the normal-tissue complication probability (NTCP) for the ranking of treatment plans are based on fits of dose-volume models to clinical and/or experimental data. In the literature several different fit methods are used. In this work frequently used methods and techniques to fit NTCP models to dose response data for establishing dose-volume effects, are discussed. The techniques are tested for their usability with dose-volume data and NTCP models. Different methods to estimate the confidence intervals of the model parameters are part of this study. From a critical-volume (CV) model with biologically realistic parameters a primary dataset was generated, serving as the reference for this study and describable by the NTCP model. The CV model was fitted to this dataset. From the resulting parameters and the CV model, 1000 secondary datasets were generated by Monte Carlo simulation. All secondary datasets were fitted to obtain 1000 parameter sets of the CV model. Thus the 'real' spread in fit results due to statistical spreading in the data is obtained and has been compared with estimates of the confidence intervals obtained by different methods applied to the primary dataset. The confidence limits of the parameters of one dataset were estimated using the methods, employing the covariance matrix, the jackknife method and directly from the likelihood landscape. These results were compared with the spread of the parameters, obtained from the secondary parameter sets. For the estimation of confidence intervals on NTCP predictions, three methods were tested. Firstly, propagation of errors using the covariance matrix was used. Secondly, the meaning of the width of a bundle of curves that resulted from parameters that were within the one standard deviation region in the likelihood space was investigated. Thirdly, many parameter sets and their likelihood were used to create a likelihood-weighted probability distribution of the NTCP. It is concluded that for the type of dose response data used here, only a full likelihood analysis will produce reliable results. The often-used approximations, such as the usage of the covariance matrix, produce inconsistent confidence limits on both the parameter sets and the resulting NTCP values.

Normal tissue complication probability modelling of tissue fibrosis following breast radiotherapy

NASA Astrophysics Data System (ADS)

Alexander, M. A. R.; Brooks, W. A.; Blake, S. W.

2007-04-01

Cosmetic late effects of radiotherapy such as tissue fibrosis are increasingly regarded as being of importance. It is generally considered that the complication probability of a radiotherapy plan is dependent on the dose uniformity, and can be reduced by using better compensation to remove dose hotspots. This work aimed to model the effects of improved dose homogeneity on complication probability. The Lyman and relative seriality NTCP models were fitted to clinical fibrosis data for the breast collated from the literature. Breast outlines were obtained from a commercially available Rando phantom using the Osiris system. Multislice breast treatment plans were produced using a variety of compensation methods. Dose-volume histograms (DVHs) obtained for each treatment plan were reduced to simple numerical parameters using the equivalent uniform dose and effective volume DVH reduction methods. These parameters were input into the models to obtain complication probability predictions. The fitted model parameters were consistent with a parallel tissue architecture. Conventional clinical plans generally showed reducing complication probabilities with increasing compensation sophistication. Extremely homogenous plans representing idealized IMRT treatments showed increased complication probabilities compared to conventional planning methods, as a result of increased dose to areas receiving sub-prescription doses using conventional techniques.

Integration of radiobiological modeling and indices in comparative plan evaluation: A study comparing VMAT and 3D-CRT in patients with NSCLC.

PubMed

Roy, Soumyajit; Badragan, Iulian; Ahmed, Sheikh Nisar; Sia, Michael; Singh, Jorawur; Bahl, Gaurav

2018-03-01

The purpose of this article was to generate an algorithm to calculate radiobiological endpoints and composite indices and use them to compare volumetric modulated arc therapy (VMAT) and 3-dimensional conformal radiation therapy (3D-CRT) techniques in patients with locally advanced non-small cell lung cancer. The study included 25 patients with locally advanced non-small cell lung cancer treated with 3D-CRT at our center between January 1, 2010, and December 31, 2014. The planner generated VMAT plans using clones of the original computed tomography scans and regions of interest volumes, which did not include the original 3D plans. Both 3D-CRT and VMAT plans were generated using the same dose-volume constraint worksheet. The dose-volume histogram parameters for planning target volume and relevant organs at risk (OAR) were reviewed. The calculation engine was written in the R programming language; the user interface was developed with the "shiny" R Web library. Dose-volume histogram data were imported into the calculation engine and tumor control probability (TCP), normal tissue complication probability (NTCP), composite cardiopulmonary toxicity index (CPTI), morbidity index: MI = ∑ j = 1 #ofrelevantOARs (w j  ∗ NTCP j ), uncomplicated TCP (UTCP=TCP∗∏k=1#ofOARs1-NTCP K 100, and therapeutic gain (TG): ie, TG = TCP ∗ (100 - MI) were calculated. TCP was better with 3D-CRT (12.62% vs 11.71%, P < .001), whereas VMAT demonstrated superior NTCP esophagus (4.45% vs 7.39%, P = .02). NTCP spinal cord (0.001% vs 0.009%, P = .001), and NTCP heart/perfusion defect (44.57% vs 56.42%, P = .016). There was no difference in NTCP lung (6.27% vs 7.62%, P = .221) and NTCP heart/pericarditis (0.001% vs 0.15%, P = .129) between 2 techniques. VMAT showed substantial improvement in morbidity index (11.06% vs. 14.31%, P = 0.01), CPTI (47.59% vs 59.41%, P = .03), TG (P = .035), and trend toward superiority in UTCP (5.89 vs 4.75, P=.057). The study highlights the utility of the radiobiological algorithm and summary indices in comparative plan evaluation and demonstrates benefits of VMAT over 3D-CRT. Copyright © 2018 Elsevier Inc. All rights reserved.

Automatically-generated rectal dose constraints in intensity-modulated radiation therapy for prostate cancer

NASA Astrophysics Data System (ADS)

Hwang, Taejin; Kim, Yong Nam; Kim, Soo Kon; Kang, Sei-Kwon; Cheong, Kwang-Ho; Park, Soah; Yoon, Jai-Woong; Han, Taejin; Kim, Haeyoung; Lee, Meyeon; Kim, Kyoung-Joo; Bae, Hoonsik; Suh, Tae-Suk

2015-06-01

The dose constraint during prostate intensity-modulated radiation therapy (IMRT) optimization should be patient-specific for better rectum sparing. The aims of this study are to suggest a novel method for automatically generating a patient-specific dose constraint by using an experience-based dose volume histogram (DVH) of the rectum and to evaluate the potential of such a dose constraint qualitatively. The normal tissue complication probabilities (NTCPs) of the rectum with respect to V %ratio in our study were divided into three groups, where V %ratio was defined as the percent ratio of the rectal volume overlapping the planning target volume (PTV) to the rectal volume: (1) the rectal NTCPs in the previous study (clinical data), (2) those statistically generated by using the standard normal distribution (calculated data), and (3) those generated by combining the calculated data and the clinical data (mixed data). In the calculated data, a random number whose mean value was on the fitted curve described in the clinical data and whose standard deviation was 1% was generated by using the `randn' function in the MATLAB program and was used. For each group, we validated whether the probability density function (PDF) of the rectal NTCP could be automatically generated with the density estimation method by using a Gaussian kernel. The results revealed that the rectal NTCP probability increased in proportion to V %ratio , that the predictive rectal NTCP was patient-specific, and that the starting point of IMRT optimization for the given patient might be different. The PDF of the rectal NTCP was obtained automatically for each group except that the smoothness of the probability distribution increased with increasing number of data and with increasing window width. We showed that during the prostate IMRT optimization, the patient-specific dose constraints could be automatically generated and that our method could reduce the IMRT optimization time as well as maintain the IMRT plan quality.

Comparison and Limitations of DVH-Based NTCP Models Derived From 3D-CRT and IMRT Data for Prediction of Gastrointestinal Toxicities in Prostate Cancer Patients by Using Propensity Score Matched Pair Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Troeller, Almut; Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität, Munich; Yan, Di, E-mail: dyan@beaumont.edu

2015-02-01

Purpose: This study compared normal tissue complication probability (NTCP) modeling of chronic gastrointestinal toxicities following prostate cancer treatment for 2 treatment modalities. Possible factors causing discrepancies in optimal NTCP model parameters between 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated RT (IMRT) were analyzed and discussed, including the impact of patient characteristics, image guidance, toxicity scoring bias, and NTCP model limitations. Methods and Materials: Rectal wall dose-volume histograms of 1115 patients treated for prostate cancer under an adaptive radiation therapy protocol were used to model gastrointestinal toxicity grade ≥2 (according to Common Terminology Criteria for Adverse Events). A total ofmore » 457 patients were treated with 3D-CRT and 658 with IMRT. 3D-CRT patients were matched to IMRT patients based on various patient characteristics, using a propensity score–based algorithm. Parameters of the Lyman equivalent uniform dose and cut-off dose logistic regression NTCP models were estimated for the 2 matched treatment modalities and the combined group. Results: After they were matched, the 3D-CRT and IMRT groups contained 275 and 550 patients with a large discrepancy of 28.7% versus 7.8% toxicities, respectively (P<.001). For both NTCP models, optimal parameters found for the 3D-CRT groups did not fit the IMRT patients well and vice versa. Models developed for the combined data overestimated NTCP for the IMRT patients and underestimated NTCP for the 3D-CRT group. Conclusions: Our analysis did not reveal a single definitive cause for discrepancies of model parameters between 3D-CRT and IMRT. Patient characteristics and bias in toxicity scoring, as well as image guidance alone, are unlikely causes of the large discrepancy of toxicities. Whether the cause was inherent to the specific NTCP models used in this study needs to be verified by future investigations. Because IMRT is increasingly used clinically, it is important that appropriate NTCP model parameters are determined for this treatment modality.« less

Comparison and limitations of DVH-based NTCP models derived from 3D-CRT and IMRT data for prediction of gastrointestinal toxicities in prostate cancer patients by using propensity score matched pair analysis.

PubMed

Troeller, Almut; Yan, Di; Marina, Ovidiu; Schulze, Derek; Alber, Markus; Parodi, Katia; Belka, Claus; Söhn, Matthias

2015-02-01

This study compared normal tissue complication probability (NTCP) modeling of chronic gastrointestinal toxicities following prostate cancer treatment for 2 treatment modalities. Possible factors causing discrepancies in optimal NTCP model parameters between 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated RT (IMRT) were analyzed and discussed, including the impact of patient characteristics, image guidance, toxicity scoring bias, and NTCP model limitations. Rectal wall dose-volume histograms of 1115 patients treated for prostate cancer under an adaptive radiation therapy protocol were used to model gastrointestinal toxicity grade ≥2 (according to Common Terminology Criteria for Adverse Events). A total of 457 patients were treated with 3D-CRT and 658 with IMRT. 3D-CRT patients were matched to IMRT patients based on various patient characteristics, using a propensity score-based algorithm. Parameters of the Lyman equivalent uniform dose and cut-off dose logistic regression NTCP models were estimated for the 2 matched treatment modalities and the combined group. After they were matched, the 3D-CRT and IMRT groups contained 275 and 550 patients with a large discrepancy of 28.7% versus 7.8% toxicities, respectively (P<.001). For both NTCP models, optimal parameters found for the 3D-CRT groups did not fit the IMRT patients well and vice versa. Models developed for the combined data overestimated NTCP for the IMRT patients and underestimated NTCP for the 3D-CRT group. Our analysis did not reveal a single definitive cause for discrepancies of model parameters between 3D-CRT and IMRT. Patient characteristics and bias in toxicity scoring, as well as image guidance alone, are unlikely causes of the large discrepancy of toxicities. Whether the cause was inherent to the specific NTCP models used in this study needs to be verified by future investigations. Because IMRT is increasingly used clinically, it is important that appropriate NTCP model parameters are determined for this treatment modality. Copyright © 2015 Elsevier Inc. All rights reserved.

SU-E-J-116: Uncertainties Associated with Dose Summation of High-Dose Rate Brachytherapy and Intensity Modulated Radiotherapy for Gynecological Cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kauweloa, K; Bergamo, A; Gutierrez, A

Purpose: Determining the cumulative dose distribution (CDD) for gynecological patients treated with both high-dose rate (HDR) brachytherapy and intensity-modulated radiotherapy (IMRT) is challenging. The purpose of this work is to study the uncertainty of performing this with a structure-guided deformable (SGD) approach in Velocity. Methods: For SGD, the Hounsfield units inside specified contours are overridden to set uniform values. Deformable image registration (DIR) is the run on these process images, which forces the DIR to focus on these contour boundaries. 18 gynecological cancer patients were used in this study. The original bladder and rectum planning contours for these patients weremore » used to drive the SGD. A second set of contours were made of the bladder by the same person with the intent of carefully making them completely consistent with each other. This second set was utilized to evaluate the spatial accuracy of the SGD. The determined spatial accuracy was then multiplied by the local dose gradient to determine a dose uncertainty associated with the SGD dose warping. The normal tissue complication probability (NTCP) was then calculated for each dose volume histogram (DVH) that included four different probabilistic uncertainties associated with the spatial errors (e.g., 68.3% and 95.4%). Results: The NTCPs for each DVH (e.g., NTCP-−95.4%, NTCP-−68.3%, NTCP-68.3%, NTCP-95.4%) differed amongst patients. All patients had an NTCP-−95.4% close to 0%, while NTCP-95.4% ranged from 0.67% to 100%. Nine patients had an NTCP-−95.4% less than 50% while the remaining nine patients had NTCP-95.4% greater than 50%. Conclusion: The uncertainty associated with this CDD technique renders a large NTCP uncertainty. Thus, it is currently not practical for clinical use. The two ways to improve this would be to use more precise contours to drive the SGD and to use a more accurate DIR algorithm.« less

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

Development of multivariate NTCP models for radiation-induced hypothyroidism: a comparative analysis.

PubMed

Cella, Laura; Liuzzi, Raffaele; Conson, Manuel; D'Avino, Vittoria; Salvatore, Marco; Pacelli, Roberto

2012-12-27

Hypothyroidism is a frequent late side effect of radiation therapy of the cervical region. Purpose of this work is to develop multivariate normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RHT) and to compare them with already existing NTCP models for RHT. Fifty-three patients treated with sequential chemo-radiotherapy for Hodgkin's lymphoma (HL) were retrospectively reviewed for RHT events. Clinical information along with thyroid gland dose distribution parameters were collected and their correlation to RHT was analyzed by Spearman's rank correlation coefficient (Rs). Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for NTCP modeling. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC). Models were tested against external published data on RHT and compared with other published NTCP models. If we express the thyroid volume exceeding X Gy as a percentage (Vx(%)), a two-variable NTCP model including V30(%) and gender resulted to be the optimal predictive model for RHT (Rs = 0.615, p < 0.001. AUC = 0.87). Conversely, if absolute thyroid volume exceeding X Gy (Vx(cc)) was analyzed, an NTCP model based on 3 variables including V30(cc), thyroid gland volume and gender was selected as the most predictive model (Rs = 0.630, p < 0.001. AUC = 0.85). The three-variable model performs better when tested on an external cohort characterized by large inter-individuals variation in thyroid volumes (AUC = 0.914, 95% CI 0.760-0.984). A comparable performance was found between our model and that proposed in the literature based on thyroid gland mean dose and volume (p = 0.264). The absolute volume of thyroid gland exceeding 30 Gy in combination with thyroid gland volume and gender provide an NTCP model for RHT with improved prediction capability not only within our patient population but also in an external cohort.

Modeling late rectal toxicities based on a parameterized representation of the 3D dose distribution

NASA Astrophysics Data System (ADS)

Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Partridge, Mike

2011-04-01

Many models exist for predicting toxicities based on dose-volume histograms (DVHs) or dose-surface histograms (DSHs). This approach has several drawbacks as firstly the reduction of the dose distribution to a histogram results in the loss of spatial information and secondly the bins of the histograms are highly correlated with each other. Furthermore, some of the complex nonlinear models proposed in the past lack a direct physical interpretation and the ability to predict probabilities rather than binary outcomes. We propose a parameterized representation of the 3D distribution of the dose to the rectal wall which explicitly includes geometrical information in the form of the eccentricity of the dose distribution as well as its lateral and longitudinal extent. We use a nonlinear kernel-based probabilistic model to predict late rectal toxicity based on the parameterized dose distribution and assessed its predictive power using data from the MRC RT01 trial (ISCTRN 47772397). The endpoints under consideration were rectal bleeding, loose stools, and a global toxicity score. We extract simple rules identifying 3D dose patterns related to a specifically low risk of complication. Normal tissue complication probability (NTCP) models based on parameterized representations of geometrical and volumetric measures resulted in areas under the curve (AUCs) of 0.66, 0.63 and 0.67 for predicting rectal bleeding, loose stools and global toxicity, respectively. In comparison, NTCP models based on standard DVHs performed worse and resulted in AUCs of 0.59 for all three endpoints. In conclusion, we have presented low-dimensional, interpretable and nonlinear NTCP models based on the parameterized representation of the dose to the rectal wall. These models had a higher predictive power than models based on standard DVHs and their low dimensionality allowed for the identification of 3D dose patterns related to a low risk of complication.

SU-E-T-454: Impact of Calculation Grid Size On Dosimetry and Radiobiological Parameters for Head and Neck IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, S; Das, I; Indiana University Health Methodist Hospital, Indianapolis, IN

2014-06-01

Purpose: IMRT has become standard of care for complex treatments to optimize dose to target and spare normal tissues. However, the impact of calculation grid size is not widely known especially dose distribution, tumor control probability (TCP) and normal tissue complication probability (NTCP) which is investigated in this study. Methods: Ten head and neck IMRT patients treated with 6 MV photons were chosen for this study. Using Eclipse TPS, treatment plans were generated for different grid sizes in the range 1–5 mm for the same optimization criterion with specific dose-volume constraints. The dose volume histogram (DVH) was calculated for allmore » IMRT plans and dosimetric data were compared. ICRU-83 dose points such as D2%, D50%, D98%, as well as the homogeneity and conformity indices (HI, CI) were calculated. In addition, TCP and NTCP were calculated from DVH data. Results: The PTV mean dose and TCP decreases with increasing grid size with an average decrease in mean dose by 2% and TCP by 3% respectively. Increasing grid size from 1–5 mm grid size, the average mean dose and NTCP for left parotid was increased by 6.0% and 8.0% respectively. Similar patterns were observed for other OARs such as cochlea, parotids and spinal cord. The HI increases up to 60% and CI decreases on average by 3.5% between 1 and 5 mm grid that resulted in decreased TCP and increased NTCP values. The number of points meeting the gamma criteria of ±3% dose difference and ±3mm DTA was higher with a 1 mm on average (97.2%) than with a 5 mm grid (91.3%). Conclusion: A smaller calculation grid provides superior dosimetry with improved TCP and reduced NTCP values. The effect is more pronounced for smaller OARs. Thus, the smallest possible grid size should be used for accurate dose calculation especially in H and N planning.« less

WE-AB-207B-01: Dose Tolerance for SBRT/SABR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimm, J

Purpose: Stereotactic body radiation therapy (SBRT) / stereotactic ablative body radiotherapy (SABR) is gaining popularity, but quantitative dose tolerance has still been lacking. To improve this, the April 2016 issue of Seminars in Radiation Oncology will have normal tissue complication probability (NTCP) models for 10 critical structures: optic pathway, cochlea, oral mucosa, esophagus, chestwall, aorta, bronchi, duodenum, small bowel, and spinal cord. Methods: The project included more than 1500 treatments in 1–5 fractions using CyberKnife, Gamma Knife, or LINAC, with 60 authors from 15 institutions. NTCP models were constructed from the 97 grade 2–3 complications, predominantly scored using the commonmore » terminology criteria for adverse events (CTCAEv4). Dose volume histogram (DVH) data from each institutional dataset was loaded into the DVH Evaluator software (DiversiLabs, LLC, Huntingdon Valley, Pa) for modeling. The current state of the literature for the critical structures was depicted using DVH Risk Maps: comparative graphs of dose tolerance limits that can include estimated risk levels, reported complications, DVH data for study patients, as well as high- and low-risk dose tolerance limits. Results: For relatively acceptable toxicity like grade 1–3 rib fractures and chestwall pain, the high-risk limits have 50% risk and the low-risk limits have 5% risk. Emami et al (IJROBP 1991 May 15;21(1):109–22) used 50% and 5% risk levels for all structures, whereas this effort used clinically acceptable ranges for each: in structures like aorta or spinal cord where complications must be avoided, the high- and low-risk limits have about 3% and 1% risk, respectively, in this issue of Seminars. These statistically based guidelines can help ensure plan quality for each patient. Conclusion: NTCP for SBRT is now becoming available. Hypofractionated dose tolerance can be dramatically different than extrapolations of conventional fractionation so NTCP analysis of the SBRT/SBRT data is important to ensure safe clinical practice. Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and was used to analyze the data.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Z; Li, B; Department of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences

Purpose: The aim of this research was to investigate the feasibility of Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model in analyzing hepatitis B virus (HBV) reactivation in patients receiving conformal radiotherapy for patients with hepatocellular carcinoma (HCC). Methods: Between June 2009 and June 2012, 108 HBV-related HCC patients (90 were specifically selected and 18 patients were excluded) treated with conformal RT at three centers were enrolled in this retrospective study. They were all diagnosed as HCC by pathology or cytology. All 90 patients were followed up to September 2013 with a median follow-up time of 25.2 months. The parametersmore » (TD50 (1), n, and m) of the modified LKB NTCP model were derived using maximum likelihood estimation. Bootstrap and leave-one-out were employed to test the generalizability of the results for use in a general population. Results: The incidences of complications in the study population were as follows: radiation-induced liver diseases (RILD) were 17.6%, HBV reactivation was 24.8%, and HBV reactivation-induced hepatitis was 22.7%, respectively. In multivariate analysis, the NTCP (p<0.001), and V20 were associated with HBV reactivation. TD50 (1), m and n were 42.9Gy (95% CI) (38.2–46.8), 0.14 (0.12–0.15) and 0.30 (0.2–0.33), respectively, for HBV reactivation. Bootstrap and leave-one-out results showed that the HBV parameter fits were extremely robust. Conclusion: A modified LKB NTCP model has been established to predict HBV reactivation for patients with HCC receiving conformal RT. The finding derives parameters set to predict potential endpoints of HBV reactivation.« less

Monte Carlo role in radiobiological modelling of radiotherapy outcomes

NASA Astrophysics Data System (ADS)

El Naqa, Issam; Pater, Piotr; Seuntjens, Jan

2012-06-01

Radiobiological models are essential components of modern radiotherapy. They are increasingly applied to optimize and evaluate the quality of different treatment planning modalities. They are frequently used in designing new radiotherapy clinical trials by estimating the expected therapeutic ratio of new protocols. In radiobiology, the therapeutic ratio is estimated from the expected gain in tumour control probability (TCP) to the risk of normal tissue complication probability (NTCP). However, estimates of TCP/NTCP are currently based on the deterministic and simplistic linear-quadratic formalism with limited prediction power when applied prospectively. Given the complex and stochastic nature of the physical, chemical and biological interactions associated with spatial and temporal radiation induced effects in living tissues, it is conjectured that methods based on Monte Carlo (MC) analysis may provide better estimates of TCP/NTCP for radiotherapy treatment planning and trial design. Indeed, over the past few decades, methods based on MC have demonstrated superior performance for accurate simulation of radiation transport, tumour growth and particle track structures; however, successful application of modelling radiobiological response and outcomes in radiotherapy is still hampered with several challenges. In this review, we provide an overview of some of the main techniques used in radiobiological modelling for radiotherapy, with focus on the MC role as a promising computational vehicle. We highlight the current challenges, issues and future potentials of the MC approach towards a comprehensive systems-based framework in radiobiological modelling for radiotherapy.

The impact of PET/CT scanning on the size of target volumes, radiation exposure of organs at risk, TCP and NTCP, in the radiotherapy planning of non-small cell lung cancer.

PubMed

Vojtíšek, Radovan; Mužík, Jan; Slampa, Pavel; Budíková, Marie; Hejsek, Jaroslav; Smolák, Petr; Ferda, Jiří; Fínek, Jindřich

2014-05-01

To compare radiotherapy plans made according to CT and PET/CT and to investigate the impact of changes in target volumes on tumour control probability (TCP), normal tissue complication probability (NTCP) and the impact of PET/CT on the staging and treatment strategy. Contemporary studies have proven that PET/CT attains higher sensitivity and specificity in the diagnosis of lung cancer and also leads to higher accuracy than CT alone in the process of target volume delineation in NSCLC. Between October 2009 and March 2012, 31 patients with locally advanced NSCLC, who had been referred to radical radiotherapy were involved in our study. They all underwent planning PET/CT examination. Then we carried out two separate delineations of target volumes and two radiotherapy plans and we compared the following parameters of those plans: staging, treatment purpose, the size of GTV and PTV and the exposure of organs at risk (OAR). TCP and NTCP were also compared. PET/CT information led to a significant decrease in the sizes of target volumes, which had the impact on the radiation exposure of OARs. The reduction of target volume sizes was not reflected in the significant increase of the TCP value. We found that there is a very strong direct linear relationship between all evaluated dosimetric parameters and NTCP values of all evaluated OARs. Our study found that the use of planning PET/CT in the radiotherapy planning of NSCLC has a crucial impact on the precise determination of target volumes, more precise staging of the disease and thus also on possible changes of treatment strategy.

Impact of geometric uncertainties on dose calculations for intensity modulated radiation therapy of prostate cancer

NASA Astrophysics Data System (ADS)

Jiang, Runqing

Intensity-modulated radiation therapy (IMRT) uses non-uniform beam intensities within a radiation field to provide patient-specific dose shaping, resulting in a dose distribution that conforms tightly to the planning target volume (PTV). Unavoidable geometric uncertainty arising from patient repositioning and internal organ motion can lead to lower conformality index (CI) during treatment delivery, a decrease in tumor control probability (TCP) and an increase in normal tissue complication probability (NTCP). The CI of the IMRT plan depends heavily on steep dose gradients between the PTV and organ at risk (OAR). Geometric uncertainties reduce the planned dose gradients and result in a less steep or "blurred" dose gradient. The blurred dose gradients can be maximized by constraining the dose objective function in the static IMRT plan or by reducing geometric uncertainty during treatment with corrective verification imaging. Internal organ motion and setup error were evaluated simultaneously for 118 individual patients with implanted fiducials and MV electronic portal imaging (EPI). A Gaussian probability density function (PDF) is reasonable for modeling geometric uncertainties as indicated by the 118 patients group. The Gaussian PDF is patient specific and group standard deviation (SD) should not be used for accurate treatment planning for individual patients. In addition, individual SD should not be determined or predicted from small imaging samples because of random nature of the fluctuations. Frequent verification imaging should be employed in situations where geometric uncertainties are expected. Cumulative PDF data can be used for re-planning to assess accuracy of delivered dose. Group data is useful for determining worst case discrepancy between planned and delivered dose. The margins for the PTV should ideally represent true geometric uncertainties. The measured geometric uncertainties were used in this thesis to assess PTV coverage, dose to OAR, equivalent uniform dose per fraction (EUDf) and NTCP. The dose distribution including geometric uncertainties was determined from integration of the convolution of the static dose gradient with the PDF. Integration of the convolution of the static dose and derivative of the PDF can also be used to determine the dose including geometric uncertainties although this method was not investigated in detail. Local maximum dose gradient (LMDG) was determined via optimization of dose objective function by manually adjusting DVH control points or selecting beam numbers and directions during IMRT treatment planning. Minimum SD (SDmin) is used when geometric uncertainty is corrected with verification imaging. Maximum SD (SDmax) is used when the geometric uncertainty is known to be large and difficult to manage. SDmax was 4.38 mm in anterior-posterior (AP) direction, 2.70 mm in left-right (LR) direction and 4.35 mm in superior-inferior (SI) direction; SDmin was 1.1 mm in all three directions if less than 2 mm threshold was used for uncorrected fractions in every direction. EUDf is a useful QA parameter for interpreting the biological impact of geometric uncertainties on the static dose distribution. The EUD f has been used as the basis for the time-course NTCP evaluation in the thesis. Relative NTCP values are useful for comparative QA checking by normalizing known complications (e.g. reported in the RTOG studies) to specific DVH control points. For prostate cancer patients, rectal complications were evaluated from specific RTOG clinical trials and detailed evaluation of the treatment techniques (e.g. dose prescription, DVH, number of beams, bean angles). Treatment plans that did not meet DVH constraints represented additional complication risk. Geometric uncertainties improved or worsened rectal NTCP depending on individual internal organ motion within patient.

Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: Normal tissue complication probability modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peeters, Stephanie; Hoogeman, Mischa S.; Heemsbergen, Wilma D.

2006-09-01

Purpose: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity. Methods and Materials: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifyingmore » factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used. Results: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence. Conclusions: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.« less

Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams.

PubMed

Mondlane, Gracinda; Ureba, Ana; Gubanski, Michael; Lind, Pehr A; Siegbahn, Albert

2018-05-01

Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side-effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

SU-D-16A-04: Accuracy of Treatment Plan TCP and NTCP Values as Determined Via Treatment Course Delivery Simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Siebers, J; Xu, H; Gordon, J

2014-06-01

Purpose: To to determine if tumor control probability (TCP) and normal tissue control probability (NTCP) values computed on the treatment planning image are representative of TCP/NTCP distributions resulting from probable positioning variations encountered during external-beam radiotherapy. Methods: We compare TCP/NTCP as typically computed on the planning PTV/OARs with distributions of those parameters computed for CTV/OARs via treatment delivery simulations which include the effect of patient organ deformations for a group of 19 prostate IMRT pseudocases. Planning objectives specified 78 Gy to PTV1=prostate CTV+5 mm margin, 66 Gy to PTV2=seminal vesicles+8 mm margin, and multiple bladder/rectum OAR objectives to achieve typicalmore » clinical OAR sparing. TCP were computed using the Poisson Model while NTCPs used the Lyman-Kutcher-Bruman model. For each patient, 1000 30-fraction virtual treatment courses were simulated with each fractional pseudo- time-oftreatment anatomy sampled from a principle component analysis patient deformation model. Dose for each virtual treatment-course was determined via deformable summation of dose from the individual fractions. CTVTCP/ OAR-NTCP values were computed for each treatment course, statistically analyzed, and compared with the planning PTV-TCP/OARNTCP values. Results: Mean TCP from the simulations differed by <1% from planned TCP for 18/19 patients; 1/19 differed by 1.7%. Mean bladder NTCP differed from the planned NTCP by >5% for 12/19 patients and >10% for 4/19 patients. Similarly, mean rectum NTCP differed by >5% for 12/19 patients, >10% for 4/19 patients. Both mean bladder and mean rectum NTCP differed by >5% for 10/19 patients and by >10% for 2/19 patients. For several patients, planned NTCP was less than the minimum or more than the maximum from the treatment course simulations. Conclusion: Treatment course simulations yield TCP values that are similar to planned values, while OAR NTCPs differ significantly, indicating the need for probabilistic methods or PRVs for OAR risk assessment. Presenting author receives support from Philips Medical Systems.« less

The Quest for Evidence for Proton Therapy: Model-Based Approach and Precision Medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Widder, Joachim, E-mail: j.widder@umcg.nl; Schaaf, Arjen van der; Lambin, Philippe

Purpose: Reducing dose to normal tissues is the advantage of protons versus photons. We aimed to describe a method for translating this reduction into a clinically relevant benefit. Methods and Materials: Dutch scientific and health care governance bodies have recently issued landmark reports regarding generation of relevant evidence for new technologies in health care including proton therapy. An approach based on normal tissue complication probability (NTCP) models has been adopted to select patients who are most likely to experience fewer (serious) adverse events achievable by state-of-the-art proton treatment. Results: By analogy with biologically targeted therapies, the technology needs to be testedmore » in enriched cohorts of patients exhibiting the decisive predictive marker: difference in normal tissue dosimetric signatures between proton and photon treatment plans. Expected clinical benefit is then estimated by virtue of multifactorial NTCP models. In this sense, high-tech radiation therapy falls under precision medicine. As a consequence, randomizing nonenriched populations between photons and protons is predictably inefficient and likely to produce confusing results. Conclusions: Validating NTCP models in appropriately composed cohorts treated with protons should be the primary research agenda leading to urgently needed evidence for proton therapy.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, S; Suh, T; Chung, J

Purpose: The purpose of this study is to evaluate the dosimetric and radiobiological impact of Acuros XB (AXB) and Anisotropic Analytic Algorithm (AAA) dose calculation algorithms on prostate stereotactic body radiation therapy plans with both conventional flattened (FF) and flattening-filter free (FFF) modes. Methods: For thirteen patients with prostate cancer, SBRT planning was performed using 10-MV photon beam with FF and FFF modes. The total dose prescribed to the PTV was 42.7 Gy in 7 fractions. All plans were initially calculated using AAA algorithm in Eclipse treatment planning system (11.0.34), and then were re-calculated using AXB with the same MUsmore » and MLC files. The four types of plans for different algorithms and beam energies were compared in terms of homogeneity and conformity. To evaluate the radiobiological impact, the tumor control probability (TCP) and normal tissue complication probability (NTCP) calculations were performed. Results: For PTV, both calculation algorithms and beam modes lead to comparable homogeneity and conformity. However, the averaged TCP values in AXB plans were always lower than in AAA plans with an average difference of 5.3% and 6.1% for 10-MV FFF and FF beam, respectively. In addition, the averaged NTCP values for organs at risk (OARs) were comparable. Conclusion: This study showed that prostate SBRT plan were comparable dosimetric results with different dose calculation algorithms as well as delivery beam modes. For biological results, even though NTCP values for both calculation algorithms and beam modes were similar, AXB plans produced slightly lower TCP compared to the AAA plans.« less

Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy.

PubMed

Dankers, Frank; Wijsman, Robin; Troost, Esther G C; Monshouwer, René; Bussink, Johan; Hoffmann, Aswin L

2017-05-07

In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade  ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC  =  0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

PubMed

McQuaid, D; Dunlop, A; Nill, S; Franzese, C; Nutting, C M; Harrington, K J; Newbold, K L; Bhide, S A

2016-08-01

The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

Analysis of acute radiation-induced esophagitis in non-small-cell lung cancer patients using the Lyman NTCP model.

PubMed

Zhu, Jian; Zhang, Zi-Cheng; Li, Bao-Sheng; Liu, Min; Yin, Yong; Yu, Jin-Ming; Luo, Li-Min; Shu, Hua-Zhong; De Crevoisier, Renaud

2010-12-01

To analyze acute esophagitis (AE) in a Chinese population receiving 3D conformal radiotherapy (3DCRT) for non-small cell lung cancer (NSCLC), combined or not with chemotherapy (CT), using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model. 157 Chinese patients (pts) presented with NSCLC received 3DCRT: alone (34 pts) or combined with sequential CT (59 pts) (group 1) or with concomitant CT (64 pts) (group 2). Parameters (TD(50), n, and m) of the LKB NTCP model predicting for>grade 2 AE (RTOG grading) were identified using maximum likelihood analysis. Univariate and multivariate analyses using a binary regression logistic model were performed to identify patient, tumor and dosimetric predictors of AE. Grade 2 or 3 AE occurred in 24% and 52% of pts in group 1 and 2, respectively (p<0.001). For the 93 group 1 pts, the fitted LKB model parameters were: m=0.15, n=0.29 and TD(50)=46 Gy. For the 64 group 2 pts, the parameters were: m=0.42, n=0.09 and TD(50)=36 Gy. In multivariate analysis, the only significant predictors of AE were: NTCP (p<0.001) and V(50), as continuous variable (RR=1.03, p=0.03) or being more than a threshold value of 11% (RR=3.6, p=0.009). A LKB NTCP model has been established to predict AE in a Chinese population, receiving thoracic RT, alone or combined with CT. The parameters of the models appear slightly different than the previous one described in Western countries, with a lower volume effect for Chinese patients. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery.

PubMed

Tommasino, Francesco; Durante, Marco; D'Avino, Vittoria; Liuzzi, Raffaele; Conson, Manuel; Farace, Paolo; Palma, Giuseppe; Schwarz, Marco; Cella, Laura; Pacelli, Roberto

2017-05-01

Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC. Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures. Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p < 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint. Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

Dosimetric Analysis of Radiation-induced Gastric Bleeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Mary, E-mail: maryfeng@umich.edu; Normolle, Daniel; Pan, Charlie C.

2012-09-01

Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at amore » median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.« less

Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy

NASA Astrophysics Data System (ADS)

Dankers, Frank; Wijsman, Robin; Troost, Esther G. C.; Monshouwer, René; Bussink, Johan; Hoffmann, Aswin L.

2017-05-01

In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade  ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC  =  0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

Method for Automatic Selection of Parameters in Normal Tissue Complication Probability Modeling.

PubMed

Christophides, Damianos; Appelt, Ane L; Gusnanto, Arief; Lilley, John; Sebag-Montefiore, David

2018-07-01

To present a fully automatic method to generate multiparameter normal tissue complication probability (NTCP) models and compare its results with those of a published model, using the same patient cohort. Data were analyzed from 345 rectal cancer patients treated with external radiation therapy to predict the risk of patients developing grade 1 or ≥2 cystitis. In total, 23 clinical factors were included in the analysis as candidate predictors of cystitis. Principal component analysis was used to decompose the bladder dose-volume histogram into 8 principal components, explaining more than 95% of the variance. The data set of clinical factors and principal components was divided into training (70%) and test (30%) data sets, with the training data set used by the algorithm to compute an NTCP model. The first step of the algorithm was to obtain a bootstrap sample, followed by multicollinearity reduction using the variance inflation factor and genetic algorithm optimization to determine an ordinal logistic regression model that minimizes the Bayesian information criterion. The process was repeated 100 times, and the model with the minimum Bayesian information criterion was recorded on each iteration. The most frequent model was selected as the final "automatically generated model" (AGM). The published model and AGM were fitted on the training data sets, and the risk of cystitis was calculated. The 2 models had no significant differences in predictive performance, both for the training and test data sets (P value > .05) and found similar clinical and dosimetric factors as predictors. Both models exhibited good explanatory performance on the training data set (P values > .44), which was reduced on the test data sets (P values < .05). The predictive value of the AGM is equivalent to that of the expert-derived published model. It demonstrates potential in saving time, tackling problems with a large number of parameters, and standardizing variable selection in NTCP modeling. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

An NTCP Analysis of Urethral Complications from Low Doserate Mono- and Bi-Radionuclide Brachytherapy.

PubMed

Nuttens, V E; Nahum, A E; Lucas, S

2011-01-01

Urethral NTCP has been determined for three prostates implanted with seeds based on (125)I (145 Gy), (103)Pd (125 Gy), (131)Cs (115 Gy), (103)Pd-(125)I (145 Gy), or (103)Pd-(131)Cs (115 Gy or 130 Gy). First, DU(20), meaning that 20% of the urhral volume receive a dose of at least DU(20), is converted into an I-125 LDR equivalent DU(20) in order to use the urethral NTCP model. Second, the propagation of uncertainties through the steps in the NTCP calculation was assessed in order to identify the parameters responsible for large data uncertainties. Two sets of radiobiological parameters were studied. The NTCP results all fall in the 19%-23% range and are associated with large uncertainties, making the comparison difficult. Depending on the dataset chosen, the ranking of NTCP values among the six seed implants studied changes. Moreover, the large uncertainties on the fitting parameters of the urethral NTCP model result in large uncertainty on the NTCP value. In conclusion, the use of NTCP model for permanent brachytherapy is feasible but it is essential that the uncertainties on the parameters in the model be reduced.

WE-AB-202-01: Evaluating the Toxicity Reduction with CT-Ventilation Functional Avoidance Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vinogradskiy, Y; Miyasaka, Y; Kadoya, N

Purpose: CT-ventilation is an exciting new imaging modality that uses 4DCTs to calculate lung ventilation. Studies have proposed to use 4DCT-ventilation imaging for functional avoidance radiotherapy which implies designing treatment plans to spare functional portions of the lung. Although retrospective studies have been performed to evaluate the dosimetric gains to functional lung; no work has been done to translate the dosimetric gains to an improvement in pulmonary toxicity. The purpose of our work was to evaluate the potential reduction in toxicity for 4DCT-ventilation based functional avoidance. Methods: 70 lung cancer patients with 4DCT imaging were used for the study. CT-ventilationmore » maps were calculated using the patient’s 4DCT, deformable image registrations, and a density-change-based algorithm. Radiation pneumonitis was graded using imaging and clinical information. Log-likelihood methods were used to fit a normal-tissue-complication-probability (NTCP) model predicting grade 2+ radiation pneumonitis as a function of doses (mean and V20) to functional lung (>15% ventilation). For 20 patients a functional plan was generated that reduced dose to functional lung while meeting RTOG 0617-based constraints. The NTCP model was applied to the functional plan to determine the reduction in toxicity with functional planning Results: The mean dose to functional lung was 16.8 and 17.7 Gy with the functional and clinical plans respectively. The corresponding grade 2+ pneumonitis probability was 26.9% with the clinically-used plan and 24.6% with the functional plan (8.5% reduction). The V20-based grade 2+ pneumonitis probability was 23.7% with the clinically-used plan and reduced to 19.6% with the functional plan (20.9% reduction). Conclusion: Our results revealed a reduction of 9–20% in complication probability with functional planning. To our knowledge this is the first study to apply complication probability to convert dosimetric results to toxicity improvement. The results presented in the current work provide seminal data for prospective clinical trials in functional avoidance. YV discloses funding from State of Colorado. TY discloses National Lung Cancer Partnership; Young Investigator Research grant.« less

Physical and biological pretreatment quality assurance of the head and neck cancer plan with the volumetric modulated arc therapy

NASA Astrophysics Data System (ADS)

Park, So-Hyun; Lee, Dong-Soo; Lee, Yun-Hee; Lee, Seu-Ran; Kim, Min-Ju; Suh, Tae-Suk

2015-09-01

The aim of this work is to demonstrate both the physical and the biological quality assurance (QA) aspects as pretreatment QA of the head and neck (H&N) cancer plan for the volumetric modulated arc therapy (VMAT). Ten H&N plans were studied. The COMPASS® dosimetry analysis system and the tumor control probability (TCP) and the normal tissue complication probability (NTCP) calculation free program were used as the respective measurement and calculation tools. The reliability of these tools was verified by a benchmark study in accordance with the TG-166 report. For the physical component of QA, the gamma passing rates and the false negative cases between the calculated and the measured data were evaluated. The biological component of QA was performed based on the equivalent uniform dose (EUD), TCP and NTCP values. The evaluation was performed for the planning target volumes (PTVs) and the organs at risks (OARs), including the eyes, the lens, the parotid glands, the esophagus, the spinal cord, and the brainstem. All cases had gamma passing rates above 95% at an acceptance tolerance level with the 3%/3 mm criteria. In addition, the false negative instances were presented for the PTVs and OARs. The gamma passing rates exhibited a weak correlation with false negative cases. For the biological QA, the physical dose errors affect the EUD and the TCP for the PTVs, but no linear correlation existed between them. The EUD and NTCP for the OARs were shown the random differences that could not be attributed to the dose errors from the physical QA. The differences in the EUD and NTCP between the calculated and the measured results were mainly demonstrated for the parotid glands. This study describes the importance and the necessity of improved QA to accompany both the physical and the biological aspects for accurate radiation treatment.

Postoperative radiotherapy following mastectomy for patients with left-sided breast cancer: A comparative dosimetric study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jiahao, E-mail: mashenglin@medmail.com.cn; Li, Xiadong; Deng, Qinghua

2015-10-01

The purposes of this article were to compare the biophysical dosimetry for postmastectomy left-sided breast cancer using 4 different radiotherapy (RT) techniques. In total, 30 patients with left-sided breast cancer were randomly selected for this treatment planning study. They were planned using 4 RT techniques, including the following: (1) 3-dimensional conventional tangential fields (TFs), (2) tangential intensity-modulated therapy (T-IMRT), (3) 4 fields IMRT (4F-IMRT), and (4) single arc volumetric-modulated arc therapy (S-VMAT). The planning target volume (PTV) dose was prescribed 50 Gy, the comparison of target dose distribution, conformity index, homogeneity index, dose to organs at risk (OARs), tumor controlmore » probability (TCP), normal tissue complication probability (NTCP), and number of monitor units (MUs) between 4 plans were investigated for their biophysical dosimetric difference. The target conformity and homogeneity of S-VMAT were better than the other 3 kinds of plans, but increased the volume of OARs receiving low dose (V{sub 5}). TCP of PTV and NTCP of the left lung showed no statistically significant difference in 4 plans. 4F-IMRT plan was superior in terms of target coverage and protection of OARs and demonstrated significant advantages in decreasing the NTCP of heart by 0.07, 0.03, and 0.05 compared with TFs, T-IMRT, and S-VMAT plan. Compared with other 3 plans, TFs reduced the average number of MUs. Of the 4 techniques studied, this analysis supports 4F-IMRT as the most appropriate balance of target coverage and normal tissue sparing.« less

Prostate Stereotactic Ablative Radiation Therapy Using Volumetric Modulated Arc Therapy to Dominant Intraprostatic Lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murray, Louise J.; University of Leeds, Leeds; Lilley, John

2014-06-01

Purpose: To investigate boosting dominant intraprostatic lesions (DILs) in the context of stereotactic ablative radiation therapy (SABR) and to examine the impact on tumor control probability (TCP) and normal tissue complication probability (NTCP). Methods and Materials: Ten prostate datasets were selected. DILs were defined using T2-weighted, dynamic contrast-enhanced and diffusion-weighted magnetic resonance imaging. Four plans were produced for each dataset: (1) no boost to DILs; (2) boost to DILs, no seminal vesicles in prescription; (3) boost to DILs, proximal seminal vesicles (proxSV) prescribed intermediate dose; and (4) boost to DILs, proxSV prescribed higher dose. The prostate planning target volume (PTV)more » prescription was 42.7 Gy in 7 fractions. DILs were initially prescribed 115% of the PTV{sub Prostate} prescription, and PTV{sub DIL} prescriptions were increased in 5% increments until organ-at-risk constraints were reached. TCP and NTCP calculations used the LQ-Poisson Marsden, and Lyman-Kutcher-Burman models respectively. Results: When treating the prostate alone, the median PTV{sub DIL} prescription was 125% (range: 110%-140%) of the PTV{sub Prostate} prescription. Median PTV{sub DIL} D50% was 55.1 Gy (range: 49.6-62.6 Gy). The same PTV{sub DIL} prescriptions and similar PTV{sub DIL} median doses were possible when including the proxSV within the prescription. TCP depended on prostate α/β ratio and was highest with an α/β ratio = 1.5 Gy, where the additional TCP benefit of DIL boosting was least. Rectal NTCP increased with DIL boosting and was considered unacceptably high in 5 cases, which, when replanned with an emphasis on reducing maximum dose to 0.5 cm{sup 3} of rectum (Dmax{sub 0.5cc}), as well as meeting existing constraints, resulted in considerable rectal NTCP reductions. Conclusions: Boosting DILs in the context of SABR is technically feasible but should be approached with caution. If this therapy is adopted, strict rectal constraints are required including Dmax{sub 0.5cc}. If the α/β ratio of prostate cancer is 1.5 Gy or less, then high TCP and low NTCP can be achieved by prescribing SABR to the whole prostate, without the need for DIL boosting.« less

Impact of spot size on plan quality of spot scanning proton radiosurgery for peripheral brain lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Dongxu, E-mail: dongxu-wang@uiowa.edu; Dirksen, Blake; Hyer, Daniel E.

Purpose: To determine the plan quality of proton spot scanning (SS) radiosurgery as a function of spot size (in-air sigma) in comparison to x-ray radiosurgery for treating peripheral brain lesions. Methods: Single-field optimized (SFO) proton SS plans with sigma ranging from 1 to 8 mm, cone-based x-ray radiosurgery (Cone), and x-ray volumetric modulated arc therapy (VMAT) plans were generated for 11 patients. Plans were evaluated using secondary cancer risk and brain necrosis normal tissue complication probability (NTCP). Results: For all patients, secondary cancer is a negligible risk compared to brain necrosis NTCP. Secondary cancer risk was lower in proton SSmore » plans than in photon plans regardless of spot size (p = 0.001). Brain necrosis NTCP increased monotonically from an average of 2.34/100 (range 0.42/100–4.49/100) to 6.05/100 (range 1.38/100–11.6/100) as sigma increased from 1 to 8 mm, compared to the average of 6.01/100 (range 0.82/100–11.5/100) for Cone and 5.22/100 (range 1.37/100–8.00/100) for VMAT. An in-air sigma less than 4.3 mm was required for proton SS plans to reduce NTCP over photon techniques for the cohort of patients studied with statistical significance (p = 0.0186). Proton SS plans with in-air sigma larger than 7.1 mm had significantly greater brain necrosis NTCP than photon techniques (p = 0.0322). Conclusions: For treating peripheral brain lesions—where proton therapy would be expected to have the greatest depth-dose advantage over photon therapy—the lateral penumbra strongly impacts the SS plan quality relative to photon techniques: proton beamlet sigma at patient surface must be small (<7.1 mm for three-beam single-field optimized SS plans) in order to achieve comparable or smaller brain necrosis NTCP relative to photon radiosurgery techniques. Achieving such small in-air sigma values at low energy (<70 MeV) is a major technological challenge in commercially available proton therapy systems.« less

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy.

PubMed

Jakobi, Annika; Stützer, Kristin; Bandurska-Luque, Anna; Löck, Steffen; Haase, Robert; Wack, Linda-Jacqueline; Mönnich, David; Thorwarth, Daniel; Perez, Damien; Lühr, Armin; Zips, Daniel; Krause, Mechthild; Baumann, Michael; Perrin, Rosalind; Richter, Christian

2015-01-01

To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only. For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCPIMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCPIMXT-Mix) were calculated. Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCPIMXT-Mix values were a factor 2-10 smaller than ∆NTCPIMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost. The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.

SU-F-T-681: Does the Biophysical Modeling for Immunological Aspects in Radiotherapy Precisely Predict Tumor and Normal Tissue Responses?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oita, M; Nakata, K; Sasaki, M

2016-06-15

Purpose: Recent advances in immunotherapy make possible to combine with radiotherapy. The aim of this study was to assess the TCP/NTCP model with immunological aspects including stochastic distribution as intercellular uncertainties. Methods: In the clinical treatment planning system (Eclipse ver.11.0, Varian medical systems, US), biological parameters such as α/β, D50, γ, n, m, TD50 including repair parameters (bi-exponential repair) can be set as any given values to calculate the TCP/NTCP. Using a prostate cancer patient data with VMAT commissioned as a 6-MV photon beam of Novalis-Tx (BrainLab, US) in clinical use, the fraction schedule were hypothesized as 70–78Gy/35–39fr, 72–81Gy/40–45fr, 52.5–66Gy/16–22fr,more » 35–40Gy/5fr of 5–7 fractions in a week. By use of stochastic biological model applying for Gaussian distribution, the effects of the TCP/NTCP variation of repair parameters of the immune system as well as the intercellular uncertainty of tumor and normal tissues have been evaluated. Results: As respect to the difference of the α/β, the changes of the TCP/NTCP were increased in hypo-fraction regimens. The difference between the values of n and m affect the variation of the NTCP with the fraction schedules, independently. The elongation of repair half-time (long) increased the TCP/NTCP twice or much higher in the case of hypo-fraction scheme. For tumor, the repopulation parameters such as Tpot and Tstart, which is immunologically working to the tumor, improved TCP. Conclusion: Compared to default fixed value, which has affected by the probability of cell death and cure, hypo-fractionation schemes seemed to have advantages for the variations of the values of m. The possibility of an increase of the α/β or TD50 and repair parameters in tumor and normal tissue by immunological aspects were highly expected. For more precise prediction, treatment planning systems should be incorporated the complicated biological optimization in clinical practice combined with basic experiments data.« less

NTCP Modeling of Subacute/Late Laryngeal Edema Scored by Fiberoptic Examination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rancati, Tiziana; Fiorino, Claudio, E-mail: fiorino.claudio@hsr.i; Sanguineti, Giuseppe

2009-11-01

Purpose: Finding best-fit parameters of normal tissue complication probability (NTCP) models for laryngeal edema after radiotherapy for head and neck cancer. Methods and Materials: Forty-eight patients were considered for this study who met the following criteria: (1) grossly uninvolved larynx, (2) no prior major surgery except for neck dissection and tonsillectomy, (3) at least one fiberoptic examination of the larynx within 2 years from radiotherapy, (4) minimum follow-up of 15 months. Larynx dose-volume histograms (DVHs) were corrected into a linear quadratic equivalent one at 2 Gy/fr with alpha/beta = 3 Gy. Subacute/late edema was prospectively scored at each follow-up examinationmore » according to the Radiation Therapy Oncology Group scale. G2-G3 edema within 15 months from RT was considered as our endpoint. Two NTCP models were considered: (1) the Lyman model with DVH reduced to the equivalent uniform dose (EUD; LEUD) and (2) the Logit model with DVH reduced to the EUD (LOGEUD). The parameters for the models were fit to patient data using a maximum likelihood analysis. Results: All patients had a minimum of 15 months follow-up (only 8/48 received concurrent chemotherapy): 25/48 (52.1%) experienced G2-G3 edema. Both NTCP models fit well the clinical data: with LOGEUD the relationship between EUD and NTCP can be described with TD50 = 46.7 +- 2.1 Gy, n = 1.41 +- 0.8 and a steepness parameter k = 7.2 +- 2.5 Gy. Best fit parameters for LEUD are n = 1.17 +- 0.6, m = 0.23 +- 0.07 and TD50 = 47.3 +- 2.1 Gy. Conclusions: A clear volume effect was found for edema, consistent with a parallel architecture of the larynx for this endpoint. On the basis of our findings, an EUD <30-35 Gy should drastically reduce the risk of G2-G3 edema.« less

NTCP modeling analysis of acute hematologic toxicity in whole pelvic radiation therapy for gynecologic malignancies - A dosimetric comparison of IMRT and spot-scanning proton therapy (SSPT).

PubMed

Yoshimura, Takaaki; Kinoshita, Rumiko; Onodera, Shunsuke; Toramatsu, Chie; Suzuki, Ryusuke; Ito, Yoichi M; Takao, Seishin; Matsuura, Taeko; Matsuzaki, Yuka; Umegaki, Kikuo; Shirato, Hiroki; Shimizu, Shinichi

2016-09-01

This treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT). The normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45Gy(RBE) in 1.8Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared. The bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP=0.04±0.01 and 0.19±0.03, p=0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI=0.97±0.01 and 0.96±0.02, p=0.3177, and HI=1.24±0.11 and 1.27±0.05, p=0.8473, respectively). The SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

The effect of 6 and 15 MV on intensity-modulated radiation therapy prostate cancer treatment: plan evaluation, tumour control probability and normal tissue complication probability analysis, and the theoretical risk of secondary induced malignancies

PubMed Central

Hussein, M; Aldridge, S; Guerrero Urbano, T; Nisbet, A

2012-01-01

Objective The aim of this study was to investigate the effect of 6 and 15-MV photon energies on intensity-modulated radiation therapy (IMRT) prostate cancer treatment plan outcome and to compare the theoretical risks of secondary induced malignancies. Methods Separate prostate cancer IMRT plans were prepared for 6 and 15-MV beams. Organ-equivalent doses were obtained through thermoluminescent dosemeter measurements in an anthropomorphic Aldersen radiation therapy human phantom. The neutron dose contribution at 15 MV was measured using polyallyl-diglycol-carbonate neutron track etch detectors. Risk coefficients from the International Commission on Radiological Protection Report 103 were used to compare the risk of fatal secondary induced malignancies in out-of-field organs and tissues for 6 and 15 MV. For the bladder and the rectum, a comparative evaluation of the risk using three separate models was carried out. Dose–volume parameters for the rectum, bladder and prostate planning target volume were evaluated, as well as normal tissue complication probability (NTCP) and tumour control probability calculations. Results There is a small increased theoretical risk of developing a fatal cancer from 6 MV compared with 15 MV, taking into account all the organs. Dose–volume parameters for the rectum and bladder show that 15 MV results in better volume sparing in the regions below 70 Gy, but the volume exposed increases slightly beyond this in comparison with 6 MV, resulting in a higher NTCP for the rectum of 3.6% vs 3.0% (p=0.166). Conclusion The choice to treat using IMRT at 15 MV should not be excluded, but should be based on risk vs benefit while considering the age and life expectancy of the patient together with the relative risk of radiation-induced cancer and NTCPs. PMID:22010028

Treatment plan comparison of linac step and shoot, tomotherapy, rapidarc, and proton therapy for prostate cancer by using the dosimetrical and the biological indices

NASA Astrophysics Data System (ADS)

Lee, Suk; Cao, Yuan Jie; Chang, Kyung Hwan; Shim, Jang Bo; Kim, Kwang Hyeon; Lee, Nam Kwon; Park, Young Je; Kim, Chul Yong; Cho, Sam Ju; Lee, Sang Hoon; Min, Chul Kee; Kim, Woo Chul; Cho, Kwang Hwan; Huh, Hyun Do; Lim, Sangwook; Shin, Dongho

2015-07-01

The purpose of this study was to use various dosimetrical indices to determine the best intensitymodulated radiation therapy (IMRT) modality - for treating patients with prostate cancer. Ten patients with prostate cancer were included in this study. IMRT plans were designed to include different modalities, including the linac step and shoot, tomotherapy, RapidArc, and proton systems. Various dosimetrical indices, like the prescription isodose to target volume (PITV) ratio, conformity index (CI), homogeneity index (HI), target coverage index (TCI), modified dose homogeneity index (MHI), conformation number (CN), critical organ scoring index (COSI), and quality factor (QF), were determined to compare the different treatment plans. Biological indices, such as the generalized equivalent uniform dose (gEUD) based the tumor control probability (TCP), and the normal tissue complication probability (NTCP), were also calculated and used to compare the treatment plans. The RapidArc plan attained better PTV coverage, as evidenced by its superior PITV, CI, TCI, MHI, and CN values. Regarding organ at risks (OARs), proton therapy exhibited superior dose sparing for the rectum and the bowel in low dose volumes, whereas the tomotherapy and RapidArc plans achieved better dose sparing in high dose volumes. The QF scores showed no significant difference among these plans (p = 0.701). The average TCPs for prostate tumors in the RapidArc, linac and proton plans were higher than the average TCP for Tomotherapy (98.79%, 98.76%, and 98.75% vs. 98.70%, respectively). Regarding the rectum NTCP, RapidArc showed the most favorable result (0.09%) whereas linac resulted in the best bladder NTCP (0.08%).

Optimizer convergence and local minima errors and their clinical importance

NASA Astrophysics Data System (ADS)

Jeraj, Robert; Wu, Chuan; Mackie, Thomas R.

2003-09-01

Two of the errors common in the inverse treatment planning optimization have been investigated. The first error is the optimizer convergence error, which appears because of non-perfect convergence to the global or local solution, usually caused by a non-zero stopping criterion. The second error is the local minima error, which occurs when the objective function is not convex and/or the feasible solution space is not convex. The magnitude of the errors, their relative importance in comparison to other errors as well as their clinical significance in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP) were investigated. Two inherently different optimizers, a stochastic simulated annealing and deterministic gradient method were compared on a clinical example. It was found that for typical optimization the optimizer convergence errors are rather small, especially compared to other convergence errors, e.g., convergence errors due to inaccuracy of the current dose calculation algorithms. This indicates that stopping criteria could often be relaxed leading into optimization speed-ups. The local minima errors were also found to be relatively small and typically in the range of the dose calculation convergence errors. Even for the cases where significantly higher objective function scores were obtained the local minima errors were not significantly higher. Clinical evaluation of the optimizer convergence error showed good correlation between the convergence of the clinical TCP or NTCP measures and convergence of the physical dose distribution. On the other hand, the local minima errors resulted in significantly different TCP or NTCP values (up to a factor of 2) indicating clinical importance of the local minima produced by physical optimization.

Optimizer convergence and local minima errors and their clinical importance.

PubMed

Jeraj, Robert; Wu, Chuan; Mackie, Thomas R

2003-09-07

Two of the errors common in the inverse treatment planning optimization have been investigated. The first error is the optimizer convergence error, which appears because of non-perfect convergence to the global or local solution, usually caused by a non-zero stopping criterion. The second error is the local minima error, which occurs when the objective function is not convex and/or the feasible solution space is not convex. The magnitude of the errors, their relative importance in comparison to other errors as well as their clinical significance in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP) were investigated. Two inherently different optimizers, a stochastic simulated annealing and deterministic gradient method were compared on a clinical example. It was found that for typical optimization the optimizer convergence errors are rather small, especially compared to other convergence errors, e.g., convergence errors due to inaccuracy of the current dose calculation algorithms. This indicates that stopping criteria could often be relaxed leading into optimization speed-ups. The local minima errors were also found to be relatively small and typically in the range of the dose calculation convergence errors. Even for the cases where significantly higher objective function scores were obtained the local minima errors were not significantly higher. Clinical evaluation of the optimizer convergence error showed good correlation between the convergence of the clinical TCP or NTCP measures and convergence of the physical dose distribution. On the other hand, the local minima errors resulted in significantly different TCP or NTCP values (up to a factor of 2) indicating clinical importance of the local minima produced by physical optimization.

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer☆

PubMed Central

Warren, Samantha; Partridge, Mike; Carrington, Rhys; Hurt, Chris; Crosby, Thomas; Hawkins, Maria A.

2014-01-01

Purpose This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm3. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001. Conclusions Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials. PMID:25304796

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, M; Choi, E; Chuong, M

Purpose: To evaluate weather the current radiobiological models can predict the normal liver complications of radioactive Yttrium-90 ({sup 90}Y) selective-internal-radiation-treatment (SIRT) for metastatic liver lesions based on the post-infusion {sup 90}Y PET images. Methods: A total of 20 patients with metastatic liver tumors treated with SIRT that received a post-infusion {sup 90}Y-PET/CT scan were analyzed in this work. The 3D activity distribution of the PET images was converted into a 3D dose distribution via a kernel convolution process. The physical dose distribution was converted into the equivalent dose (EQ2) delivered at 2 Gy based on the linear-quadratic (LQ) model consideringmore » the dose rate effect. The biological endpoint of this work was radiation-induce liver disease (RILD). The NTCPs were calculated with four different repair-times (T1/2-Liver-Repair= 0,0.5,1.0,2.0 hr) and three published NTCP models (Lyman-external-RT, Lyman 90Y-HCC-SIRT, parallel model) were compared to the incidence of RILD of the recruited patients to evaluate their ability of outcome prediction. Results: The mean normal liver physical dose (avg. 51.9 Gy, range 31.9–69.8 Gy) is higher than the suggested liver dose constraint for external beam treatment (∼30 Gy). However, none of the patients in our study developed RILD after the SIRT. The estimated probability of ‘no patient developing RILD’ obtained from the two Lyman models are 46.3% to 48.3% (T1/2-Liver-Repair= 0hr) and <1% for all other repair times. For the parallel model, the estimated probability is 97.3% (0hr), 51.7% (0.5hr), 2.0% (1.0hr) and <1% (2.0hr). Conclusion: Molecular-images providing the distribution of {sup 90}Y enable the dose-volume based dose/outcome analysis for SIRT. Current NTCP models fail to predict RILD complications in our patient population, unless a very short repair-time for the liver is assumed. The discrepancy between the Lyman {sup 90}Y-HCC-SIRT model predicted and the clinically observed outcomes further demonstrates the need of an NTCP model specific to the metastatic liver SIRT.« less

Single-cell-based computer simulation of the oxygen-dependent tumour response to irradiation

NASA Astrophysics Data System (ADS)

Harting, Christine; Peschke, Peter; Borkenstein, Klaus; Karger, Christian P.

2007-08-01

Optimization of treatment plans in radiotherapy requires the knowledge of tumour control probability (TCP) and normal tissue complication probability (NTCP). Mathematical models may help to obtain quantitative estimates of TCP and NTCP. A single-cell-based computer simulation model is presented, which simulates tumour growth and radiation response on the basis of the response of the constituting cells. The model contains oxic, hypoxic and necrotic tumour cells as well as capillary cells which are considered as sources of a radial oxygen profile. Survival of tumour cells is calculated by the linear quadratic model including the modified response due to the local oxygen concentration. The model additionally includes cell proliferation, hypoxia-induced angiogenesis, apoptosis and resorption of inactivated tumour cells. By selecting different degrees of angiogenesis, the model allows the simulation of oxic as well as hypoxic tumours having distinctly different oxygen distributions. The simulation model showed that poorly oxygenated tumours exhibit an increased radiation tolerance. Inter-tumoural variation of radiosensitivity flattens the dose response curve. This effect is enhanced by proliferation between fractions. Intra-tumoural radiosensitivity variation does not play a significant role. The model may contribute to the mechanistic understanding of the influence of biological tumour parameters on TCP. It can in principle be validated in radiation experiments with experimental tumours.

Consequences of additional use of PET information for target volume delineation and radiotherapy dose distribution for esophageal cancer.

PubMed

Muijs, Christina T; Schreurs, Liesbeth M; Busz, Dianne M; Beukema, Jannet C; van der Borden, Arnout J; Pruim, Jan; Van der Jagt, Eric J; Plukker, John Th; Langendijk, Johannes A

2009-12-01

To determine the consequences of target volume (TV) modifications, based on the additional use of PET information, on radiation planning, assuming PET/CT-imaging represents the true extent of the tumour. For 21 patients with esophageal cancer, two separate TV's were retrospectively defined based on CT (CT-TV) and co-registered PET/CT images (PET/CT-TV). Two 3D-CRT plans (prescribed dose 50.4 Gy) were constructed to cover the corresponding TV's. Subsequently, these plans were compared for target coverage, normal tissue dose-volume histograms and the corresponding normal tissue complication probability (NTCP) values. The addition of PET led to the modification of CT-TV with at least 10% in 12 of 21 patients (57%) (reduction in 9, enlargement in 3). PET/CT-TV was inadequately covered by the CT-based treatment plan in 8 patients (36%). Treatment plan modifications resulted in significant changes (p<0.05) in dose distributions to heart and lungs. Corresponding changes in NTCP values ranged from -3% to +2% for radiation pneumonitis and from -0.2% to +1.2% for cardiac mortality. This study demonstrated that TV's based on CT might exclude PET-avid disease. Consequences are under dosing and thereby possibly ineffective treatment. Moreover, the addition of PET in radiation planning might result in clinical important changes in NTCP.

Limiting the risk of cardiac toxicity with esophageal-sparing intensity modulated radiotherapy for locally advanced lung cancers.

PubMed

Woodford, Katrina; Panettieri, Vanessa; Ruben, Jeremy D; Senthi, Sashendra

2016-05-01

Intensity modulated radiotherapy (IMRT) is routinely utilized in the treatment of locally advanced non-small cell lung cancer (NSCLC). RTOG 0617 found that overall survival was impacted by increased low (5 Gy) and intermediate (30 Gy) cardiac doses. We evaluated the impact of esophageal-sparing IMRT on cardiac doses with and without the heart considered in the planning process and predicted toxicity compared to 3D-conventional radiotherapy (3DCRT). Ten consecutive patients with N2 Stage III NSCLC treated to 60 Gy in 30 fractions, between February 2012 and September 2014, were evaluated. For each patient, 3DCRT and esophageal-sparing IMRT plans were generated. IMRT plans were then created with and without the heart considered in the optimization process. To compare plans, the dose delivered to 95% and 99% of the target (D95% and D99%), and doses to the esophagus, lung and heart were compared by determining the volume receiving X dose (VXGy) and the normal tissue complication probability (NTCP) calculated. IMRT reduced maximum esophagus dose to below 60 Gy in all patients and produced significant reductions to V50Gy, V40Gy and esophageal NTCP. The cost of this reduction was a non-statistically, non-clinically significant increase in low dose (5 Gy) lung exposure that did not worsen lung NTCP. IMRT plans produced significant cardiac sparing, with the amount of improvement correlating to the amount of heart overlapping with the target. When included in plan optimization, for selected patients further sparing of the heart and improvement in heart NTCP was possible. Esophageal-sparing IMRT can significantly spare the heart even if it is not considered in the optimization process. Further sparing can be achieved if plan optimization constrains low and intermediate heart doses, without compromising lung doses.

SU-E-T-69: A Radiobiological Investigation of Dose Escalation in Lower Oesophageal Tumours with a Focus On Gastric Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carrington, R; Staffurth, J; Spezi, E

2015-06-15

The incidence of lower third oesophageal tumours is increasing in most Western populations. With the role of radiotherapy dose escalation being identified as a research priority in improving outcomes, it is important to quantify the increased toxicity that this may pose to sites such as the lower oesophagus. This study therefore aims to investigate the feasibility of lower oesophageal dose escalation with a focus on stomach tissue toxicity.The original 3D-conformal plans (50Gy3D) from 10 patients in the SCOPE1 trial were reviewed and compared to two RapidArc plans created retrospectively to represent the treatment arms of the forthcoming SCOPE2 trial: 50GyRAmore » and 60GyRA (50Gy to PTV1 with a simultaneously integrated boost of 60Gy to PTV2). The stomach was contoured as stomach wall and dose constraints set according to QUANTEC. Normal tissue complication probability (NTCP) was estimated for the stomach wall for an endpoint of gastric bleeding. There was a mean increase of 5.93% in NTCP from 50Gy3D to 60GyRA and a mean increase of 8.15% in NTCP from the 50GyRA to 60GyRA. With NTCP modelling restricted to volumes outside PTV2, there was a mean decrease of 0.92% in NTCP from the 50Gy3D to 60GyRA, and a mean increase of 2.25% from 50GyRA to 60GyRA. There was a strong correlation between the NTCP and Stomach Wall/PTV1 overlap volume for all plans (R=0.80, 0.77 and 0.77 for 60GyRA, 50GyRA and 50Gy3D respectively). There was also a strong correlation between NTCP and the Stomach Wall/PTV2 overlap volume for 60GyRA (R= 0.82).Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach within the boost volume. It is recommended that stomach toxicity be closely monitored prospectively when treating patients with lower oesophageal tumours in the forthcoming SCOPE 2 trial. Rhys Carrington received a PhD studentship grant from Cancer Research Wales. Grant number: 2445; Dr Warren and Dr Partridge are supported by Cancer Research UK. Grant number: C5255/A15935. Dr Hawkins is supported by MRC grant MC-PC-12001/2.« less

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M., E-mail: jrobertson@beaumont.ed; Soehn, Matthias; Yan Di

Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to developmore » a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.« less

Evaluation of dose response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy

NASA Astrophysics Data System (ADS)

Tsougos, Ioannis; Mavroidis, Panayiotis; Rajala, Juha; Theodorou, Kyriaki; Järvenpää, Ritva; Pitkänen, Maunu A.; Holli, Kaija; Ojala, Antti T.; Lind, Bengt K.; Hyödynmaa, Simo; Kappas, Constantin

2005-08-01

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al (2003 Int. J. Radiat. Oncol. Biol. Phys. 55 724-35) and Gagliardi et al (2000 Int. J. Radiat. Oncol. Biol. Phys. 46 373-81) parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.

Normal tissue complication probability (NTCP) parameters for breast fibrosis: pooled results from two randomised trials.

PubMed

Mukesh, Mukesh B; Harris, Emma; Collette, Sandra; Coles, Charlotte E; Bartelink, Harry; Wilkinson, Jenny; Evans, Philip M; Graham, Peter; Haviland, Jo; Poortmans, Philip; Yarnold, John; Jena, Raj

2013-08-01

The dose-volume effect of radiation therapy on breast tissue is poorly understood. We estimate NTCP parameters for breast fibrosis after external beam radiotherapy. We pooled individual patient data of 5856 patients from 2 trials including whole breast irradiation followed with or without a boost. A two-compartment dose volume histogram model was used with boost volume as the first compartment and the remaining breast volume as second compartment. Results from START-pilot trial (n=1410) were used to test the predicted models. 26.8% patients in the Cambridge trial (5 years) and 20.7% patients in the EORTC trial (10 years) developed moderate-severe breast fibrosis. The best fit NTCP parameters were BEUD3(50)=136.4 Gy, γ50=0.9 and n=0.011 for the Niemierko model and BEUD3(50)=132 Gy, m=0.35 and n=0.012 for the Lyman Kutcher Burman model. The observed rates of fibrosis in the START-pilot trial agreed well with the predicted rates. This large multi-centre pooled study suggests that the effect of volume parameter is small and the maximum RT dose is the most important parameter to influence breast fibrosis. A small value of volume parameter 'n' does not fit with the hypothesis that breast tissue is a parallel organ. However, this may reflect limitations in our current scoring system of fibrosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The effect of dose escalation on gastric toxicity when treating lower oesophageal tumours: a radiobiological investigation.

PubMed

Carrington, Rhys; Staffurth, John; Warren, Samantha; Partridge, Mike; Hurt, Chris; Spezi, Emiliano; Gwynne, Sarah; Hawkins, Maria A; Crosby, Thomas

2015-11-19

Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach. 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm(3). The original 3D conformal plans (50 Gy3D) were compared to newly created RapidArc plans of 50 GyRA and 60 GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared. There was a significant increase in NTCP of the stomach wall when moving from the 50 GyRA to the 60 GyRA plans (11-17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60 GyRA plans. Radiobiological modelling suggests that increasing the prescribed dose to 60 Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60 Gy.

Age and Comorbid Illness Are Associated With Late Rectal Toxicity Following Dose-Escalated Radiation Therapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamstra, Daniel A.; Stenmark, Matt H.; Ritter, Tim

2013-04-01

Purpose: To assess the impacts of patient age and comorbid illness on rectal toxicity following external beam radiation therapy (EBRT) for prostate cancer and to assess the Qualitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) normal tissue complication probability (NTCP) model in this context. Methods and Materials: Rectal toxicity was analyzed in 718 men previously treated for prostate cancer with EBRT (≥75 Gy). Comorbid illness was scored using the Charlson Comorbidity Index (CCMI), and the NTCP was evaluated with the QUANTEC model. The influence of clinical and treatment-related parameters on rectal toxicity was assessed by Kaplan-Meier and Coxmore » proportional hazards models. Results: The cumulative incidence of rectal toxicity grade ≥2 was 9.5% and 11.6% at 3 and 5 years and 3.3% and 3.9% at 3 and 5 years for grade ≥3 toxicity, respectively. Each year of age predicted an increasing relative risk of grade ≥2 (P<.03; hazard ratio [HR], 1.04 [95% confidence interval (CI), 1.01-1.06]) and ≥3 rectal toxicity (P<.0001; HR, 1.14 [95% CI,1.07-1.22]). Increasing CCMI predicted rectal toxicity where a history of either myocardial infarction (MI) (P<.0001; HR, 5.1 [95% CI, 1.9-13.7]) or congestive heart failure (CHF) (P<.0006; HR, 5.4 [95% CI, 0.6-47.5]) predicted grade ≥3 rectal toxicity, with lesser correlation with grade ≥2 toxicity (P<.02 for MI, and P<.09 for CHF). An age comorbidity model to predict rectal toxicity was developed and confirmed in a validation cohort. The use of anticoagulants increased toxicity independent of age and comorbidity. NTCP was prognostic for grade ≥3 (P=.015) but not grade ≥2 (P=.49) toxicity. On multivariate analysis, age, MI, CHF, and an NTCP >20% all correlated with late rectal toxicity. Conclusions: Patient age and a history of MI or CHF significantly impact rectal toxicity following EBRT for the treatment of prostate cancer, even after controlling for NTCP.« less

Radiobiological modeling of two stereotactic body radiotherapy schedules in patients with stage I peripheral non-small cell lung cancer.

PubMed

Huang, Bao-Tian; Lin, Zhu; Lin, Pei-Xian; Lu, Jia-Yang; Chen, Chuang-Zhen

2016-06-28

This study aims to compare the radiobiological response of two stereotactic body radiotherapy (SBRT) schedules for patients with stage I peripheral non-small cell lung cancer (NSCLC) using radiobiological modeling methods. Volumetric modulated arc therapy (VMAT)-based SBRT plans were designed using two dose schedules of 1 × 34 Gy (34 Gy in 1 fraction) and 4 × 12 Gy (48 Gy in 4 fractions) for 19 patients diagnosed with primary stage I NSCLC. Dose to the gross target volume (GTV), planning target volume (PTV), lung and chest wall (CW) were converted to biologically equivalent dose in 2 Gy fraction (EQD2) for comparison. Five different radiobiological models were employed to predict the tumor control probability (TCP) value. Three additional models were utilized to estimate the normal tissue complication probability (NTCP) value for the lung and the modified equivalent uniform dose (mEUD) value to the CW. Our result indicates that the 1 × 34 Gy dose schedule provided a higher EQD2 dose to the tumor, lung and CW. Radiobiological modeling revealed that the TCP value for the tumor, NTCP value for the lung and mEUD value for the CW were 7.4% (in absolute value), 7.2% (in absolute value) and 71.8% (in relative value) higher on average, respectively, using the 1 × 34 Gy dose schedule.

Consequences of anorectal cancer atlas implementation in the cooperative group setting: radiobiologic analysis of a prospective randomized in silico target delineation study.

PubMed

Mavroidis, Panayiotis; Giantsoudis, Drosoula; Awan, Musaddiq J; Nijkamp, Jasper; Rasch, Coen R N; Duppen, Joop C; Thomas, Charles R; Okunieff, Paul; Jones, William E; Kachnic, Lisa A; Papanikolaou, Niko; Fuller, Clifton D

2014-09-01

The aim of this study is to ascertain the subsequent radiobiological impact of using a consensus guideline target volume delineation atlas. Using a representative case and target volume delineation instructions derived from a proposed IMRT rectal cancer clinical trial, gross tumor volume (GTV) and clinical/planning target volumes (CTV/PTV) were contoured by 13 physician observers (Phase 1). The observers were then randomly assigned to follow (atlas) or not-follow (control) a consensus guideline/atlas for anorectal cancers, and instructed to re-contour the same case (Phase 2). The atlas group was found to have increased tumor control probability (TCP) after the atlas intervention for both the CTV (p<0.0001) and PTV1 (p=0.0011) with decreasing normal tissue complication probability (NTCP) for small intestine, while the control group did not. Additionally, the atlas group had reduced variance in TCP for all target volumes and reduced variance in NTCP for the bowel. In Phase 2, the atlas group had increased TCP relative to the control for CTV (p=0.03). Visual atlas and consensus treatment guideline usage in the development of rectal cancer IMRT treatment plans reduced the inter-observer radiobiological variation, with clinically relevant TCP alteration for CTV and PTV volumes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Quantifying Unnecessary Normal Tissue Complication Risks due to Suboptimal Planning: A Secondary Study of RTOG 0126.

PubMed

Moore, Kevin L; Schmidt, Rachel; Moiseenko, Vitali; Olsen, Lindsey A; Tan, Jun; Xiao, Ying; Galvin, James; Pugh, Stephanie; Seider, Michael J; Dicker, Adam P; Bosch, Walter; Michalski, Jeff; Mutic, Sasa

2015-06-01

The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol. A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol. Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study. Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Dosimetric evaluation of planning target volume margin reduction for prostate cancer via image-guided intensity-modulated radiation therapy

NASA Astrophysics Data System (ADS)

Hwang, Taejin; Kang, Sei-Kwon; Cheong, Kwang-Ho; Park, Soah; Yoon, Jai-Woong; Han, Taejin; Kim, Haeyoung; Lee, Meyeon; Kim, Kyoung-Joo; Bae, Hoonsik; Suh, Tae-Suk

2015-07-01

The aim of this study was to quantitatively estimate the dosimetric benefits of the image-guided radiation therapy (IGRT) system for the prostate intensity-modulated radiation therapy (IMRT) delivery. The cases of eleven patients who underwent IMRT for prostate cancer without a prostatectomy at our institution between October 2012 and April 2014 were retrospectively analyzed. For every patient, clinical target volume (CTV) to planning target volume (PTV) margins were uniformly used: 3 mm, 5 mm, 7 mm, 10 mm, 12 mm, and 15 mm. For each margin size, the IMRT plans were independently optimized by one medical physicist using Pinnalce3 (ver. 8.0.d, Philips Medical System, Madison, WI) in order to maintain the plan quality. The maximum geometrical margin (MGM) for every CT image set, defined as the smallest margin encompassing the rectum at least at one slice, was between 13 mm and 26 mm. The percentage rectum overlapping PTV (%V ROV ), the rectal normal tissue complication probability (NTCP) and the mean rectal dose (%RD mean ) increased in proportion to the increase of PTV margin. However the bladder NTCP remained around zero to some extent regardless of the increase of PTV margin while the percentage bladder overlapping PTV (%V BOV ) and the mean bladder dose (%BD mean ) increased in proportion to the increase of PTV margin. Without relatively large rectum or small bladder, the increase observed for rectal NTCP, %RDmean and %BD mean per 1-mm PTV margin size were 1.84%, 2.44% and 2.90%, respectively. Unlike the behavior of the rectum or the bladder, the maximum dose on each femoral head had little effect on PTV margin. This quantitative study of the PTV margin reduction supported that IG-IMRT has enhanced the clinical effects over prostate cancer with the reduction of normal organ complications under the similar level of PTV control.

Helical Tomotherapy vs. Intensity-Modulated Proton Therapy for Whole Pelvis Irradiation in High-Risk Prostate Cancer Patients: Dosimetric, Normal Tissue Complication Probability, and Generalized Equivalent Uniform Dose Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Widesott, Lamberto, E-mail: widesott@yahoo.it; Pierelli, Alessio; Fiorino, Claudio

2011-08-01

Purpose: To compare intensity-modulated proton therapy (IMPT) and helical tomotherapy (HT) treatment plans for high-risk prostate cancer (HRPCa) patients. Methods and Materials: The plans of 8 patients with HRPCa treated with HT were compared with IMPT plans with two quasilateral fields set up (-100{sup o}; 100{sup o}) and optimized with the Hyperion treatment planning system. Both techniques were optimized to simultaneously deliver 74.2 Gy/Gy relative biologic effectiveness (RBE) in 28 fractions on planning target volumes (PTVs)3-4 (P + proximal seminal vesicles), 65.5 Gy/Gy(RBE) on PTV2 (distal seminal vesicles and rectum/prostate overlapping), and 51.8 Gy/Gy(RBE) to PTV1 (pelvic lymph nodes). Normalmore » tissue calculation probability (NTCP) calculations were performed for the rectum, and generalized equivalent uniform dose (gEUD) was estimated for the bowel cavity, penile bulb and bladder. Results: A slightly better PTV coverage and homogeneity of target dose distribution with IMPT was found: the percentage of PTV volume receiving {>=}95% of the prescribed dose (V{sub 95%}) was on average >97% in HT and >99% in IMPT. The conformity indexes were significantly lower for protons than for photons, and there was a statistically significant reduction of the IMPT dosimetric parameters, up to 50 Gy/Gy(RBE) for the rectum and bowel and 60 Gy/Gy(RBE) for the bladder. The NTCP values for the rectum were higher in HT for all the sets of parameters, but the gain was small and in only a few cases statistically significant. Conclusions: Comparable PTV coverage was observed. Based on NTCP calculation, IMPT is expected to allow a small reduction in rectal toxicity, and a significant dosimetric gain with IMPT, both in medium-dose and in low-dose range in all OARs, was observed.« less

Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.

PubMed

Kuang, Yu; Wu, Lili; Hirata, Emily; Miyazaki, Kyle; Sato, Miles; Kwee, Sandi A

2015-04-01

This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by (18)F-choline positron emission tomography/computed tomography (PET/CT). Thirty patients with localized prostate cancer underwent (18)F-choline PET/CT before treatment. Two VMAT plans, plan79 Gy and plan100-105 Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) prescription was 79 Gy in both plans, but plan100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on (18)F-choline PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan100-105 Gy had significantly higher TCP than plan79 Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan100-105 Gy. VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a (18)F-choline PET-defined IDL. Copyright © 2015 Elsevier Inc. All rights reserved.

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk; Partridge, Mike; Carrington, Rhys

2014-10-01

Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5more » Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.« less

Dosimetric comparison of standard three-dimensional conformal radiotherapy followed by intensity-modulated radiotherapy boost schedule (sequential IMRT plan) with simultaneous integrated boost-IMRT (SIB IMRT) treatment plan in patients with localized carcinoma prostate.

PubMed

Bansal, A; Kapoor, R; Singh, S K; Kumar, N; Oinam, A S; Sharma, S C

2012-07-01

DOSIMETERIC AND RADIOBIOLOGICAL COMPARISON OF TWO RADIATION SCHEDULES IN LOCALIZED CARCINOMA PROSTATE: Standard Three-Dimensional Conformal Radiotherapy (3DCRT) followed by Intensity Modulated Radiotherapy (IMRT) boost (sequential-IMRT) with Simultaneous Integrated Boost IMRT (SIB-IMRT). Thirty patients were enrolled. In all, the target consisted of PTV P + SV (Prostate and seminal vesicles) and PTV LN (lymph nodes) where PTV refers to planning target volume and the critical structures included: bladder, rectum and small bowel. All patients were treated with sequential-IMRT plan, but for dosimetric comparison, SIB-IMRT plan was also created. The prescription dose to PTV P + SV was 74 Gy in both strategies but with different dose per fraction, however, the dose to PTV LN was 50 Gy delivered in 25 fractions over 5 weeks for sequential-IMRT and 54 Gy delivered in 27 fractions over 5.5 weeks for SIB-IMRT. The treatment plans were compared in terms of dose-volume histograms. Also, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) obtained with the two plans were compared. The volume of rectum receiving 70 Gy or more (V > 70 Gy) was reduced to 18.23% with SIB-IMRT from 22.81% with sequential-IMRT. SIB-IMRT reduced the mean doses to both bladder and rectum by 13% and 17%, respectively, as compared to sequential-IMRT. NTCP of 0.86 ± 0.75% and 0.01 ± 0.02% for the bladder, 5.87 ± 2.58% and 4.31 ± 2.61% for the rectum and 8.83 ± 7.08% and 8.25 ± 7.98% for the bowel was seen with sequential-IMRT and SIB-IMRT plans respectively. For equal PTV coverage, SIB-IMRT markedly reduced doses to critical structures, therefore should be considered as the strategy for dose escalation. SIB-IMRT achieves lesser NTCP than sequential-IMRT.

68Ga-PSMA-PET/CT imaging of localized primary prostate cancer patients for intensity modulated radiation therapy treatment planning with integrated boost.

PubMed

Thomas, Lena; Kantz, Steffi; Hung, Arthur; Monaco, Debra; Gaertner, Florian C; Essler, Markus; Strunk, Holger; Laub, Wolfram; Bundschuh, Ralph A

2018-07-01

The purpose of our study was to show the feasibility and potential benefits of using 68 Ga-PSMA-PET/CT imaging for radiation therapy treatment planning of patients with primary prostate cancer using either integrated boost on the PET-positive volume or localized treatment of the PET-positive volume. The potential gain of such an approach, the improvement of tumor control, and reduction of the dose to organs-at-risk at the same time was analyzed using the QUANTEC biological model. Twenty-one prostate cancer patients (70 years average) without previous local therapy received 68 Ga-PSMA-PET/CT imaging. Organs-at-risk and standard prostate target volumes were manually defined on the obtained datasets. A PET active volume (PTV_PET) was segmented with a 40% of the maximum activity uptake in the lesion as threshold followed by manual adaption. Five different treatment plan variations were calculated for each patient. Analysis of derived treatment plans was done according to QUANTEC with in-house developed software. Tumor control probability (TCP) and normal tissue complication probability (NTCP) was calculated for all plan variations. Comparing the conventional plans to the plans with integrated boost and plans just treating the PET-positive tumor volume, we found that TCP increased to (95.2 ± 0.5%) for an integrated boost with 75.6 Gy, (98.1 ± 0.3%) for an integrated boost with 80 Gy, (94.7 ± 0.8%) for treatment of PET-positive volume with 75 Gy, and to (99.4 ± 0.1%) for treating PET-positive volume with 95 Gy (all p < 0.0001). For the integrated boost with 80 Gy, a significant increase of the median NTCP of the rectum was found, for all other plans no statistical significant increase in the NTCP neither of the rectum nor the bladder was found. Our study demonstrates that the use of 68 Ga-PSMA-PET/CT image information allows for more individualized prostate treatment planning. TCP values of identified active tumor volumes were increased, while rectum and bladder NTCP values either remained the same or were even lower. However, further studies need to clarify the clinical benefit for the patients applying these techniques.

A NTCP approach for estimating the outcome in radioiodine treatment of hyperthyroidism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strigari, L.; Sciuto, R.; Benassi, M.

2008-09-15

Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have led to accurate dosimetry capable of avoiding the risks of adverse effects and the optimization of the treatment. The aim of this study was to test the capability of a radiobiological model, based on normal tissue complication probability (NTCP), to predict the outcome after oral therapeutic {sup 131}I administration. Following dosimetric study, 79 patients underwent treatment for hyperthyroidism using radioiodine and then 67 had at least a one-year follow up. The delivered dose was calculated using the MIRD formula, takingmore » into account the measured maximum uptake of administered iodine transferred to the thyroid, U0, and the effective clearance rate, T{sub eff} and target mass. The dose was converted to normalized total dose delivered at 2 Gy per fraction (NTD{sub 2}). Furthermore, the method to take into account the reduction of the mass of the gland during radioiodine therapy was also applied. The clinical outcome and dosimetric parameters were analyzed in order to study the dose-response relationship for hypothyroidism. The TD{sub 50} and m parameters of the NTCP model approach were then estimated using the likelihood method. The TD{sub 50}, expressed as NTD{sub 2}, resulted in 60 Gy (95% C.I.: 45-75 Gy) and 96 Gy (95% C.I.: 86-109 Gy) for patients affected by Graves or autonomous/multinodular disease, respectively. This supports the clinical evidence that Graves' disease should be characterized by more radiosensitive cells compared to autonomous nodules. The m parameter for all patients was 0.27 (95% C.I.: 0.22-0.36). These parameters were compared with those reported in the literature for hypothyroidism induced after external beam radiotherapy. The NTCP model correctly predicted the clinical outcome after the therapeutic administration of radioiodine in our series.« less

Sodium-dependent bile salt transporters of the SCL10A Transporter Family: More than solute transporters

PubMed Central

Anwer, M. Sawkat; Stieger, Bruno

2013-01-01

Summary The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na+-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide or NTCP) and SLC10A2 (apical sodium-dependent bile salt transporter or ASBT) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes. PMID:24196564

The use of spatial dose gradients and probability density function to evaluate the effect of internal organ motion for prostate IMRT treatment planning

NASA Astrophysics Data System (ADS)

Jiang, Runqing; Barnett, Rob B.; Chow, James C. L.; Chen, Jeff Z. Y.

2007-03-01

The aim of this study is to investigate the effects of internal organ motion on IMRT treatment planning of prostate patients using a spatial dose gradient and probability density function. Spatial dose distributions were generated from a Pinnacle3 planning system using a co-planar, five-field intensity modulated radiation therapy (IMRT) technique. Five plans were created for each patient using equally spaced beams but shifting the angular displacement of the beam by 15° increments. Dose profiles taken through the isocentre in anterior-posterior (A-P), right-left (R-L) and superior-inferior (S-I) directions for IMRT plans were analysed by exporting RTOG file data from Pinnacle. The convolution of the 'static' dose distribution D0(x, y, z) and probability density function (PDF), denoted as P(x, y, z), was used to analyse the combined effect of repositioning error and internal organ motion. Organ motion leads to an enlarged beam penumbra. The amount of percentage mean dose deviation (PMDD) depends on the dose gradient and organ motion probability density function. Organ motion dose sensitivity was defined by the rate of change in PMDD with standard deviation of motion PDF and was found to increase with the maximum dose gradient in anterior, posterior, left and right directions. Due to common inferior and superior field borders of the field segments, the sharpest dose gradient will occur in the inferior or both superior and inferior penumbrae. Thus, prostate motion in the S-I direction produces the highest dose difference. The PMDD is within 2.5% when standard deviation is less than 5 mm, but the PMDD is over 2.5% in the inferior direction when standard deviation is higher than 5 mm in the inferior direction. Verification of prostate organ motion in the inferior directions is essential. The margin of the planning target volume (PTV) significantly impacts on the confidence of tumour control probability (TCP) and level of normal tissue complication probability (NTCP). Smaller margins help to reduce the dose to normal tissues, but may compromise the dose coverage of the PTV. Lower rectal NTCP can be achieved by either a smaller margin or a steeper dose gradient between PTV and rectum. With the same DVH control points, the rectum has lower complication in the seven-beam technique used in this study because of the steeper dose gradient between the target volume and rectum. The relationship between dose gradient and rectal complication can be used to evaluate IMRT treatment planning. The dose gradient analysis is a powerful tool to improve IMRT treatment plans and can be used for QA checking of treatment plans for prostate patients.

The use of spatial dose gradients and probability density function to evaluate the effect of internal organ motion for prostate IMRT treatment planning.

PubMed

Jiang, Runqing; Barnett, Rob B; Chow, James C L; Chen, Jeff Z Y

2007-03-07

The aim of this study is to investigate the effects of internal organ motion on IMRT treatment planning of prostate patients using a spatial dose gradient and probability density function. Spatial dose distributions were generated from a Pinnacle3 planning system using a co-planar, five-field intensity modulated radiation therapy (IMRT) technique. Five plans were created for each patient using equally spaced beams but shifting the angular displacement of the beam by 15 degree increments. Dose profiles taken through the isocentre in anterior-posterior (A-P), right-left (R-L) and superior-inferior (S-I) directions for IMRT plans were analysed by exporting RTOG file data from Pinnacle. The convolution of the 'static' dose distribution D0(x, y, z) and probability density function (PDF), denoted as P(x, y, z), was used to analyse the combined effect of repositioning error and internal organ motion. Organ motion leads to an enlarged beam penumbra. The amount of percentage mean dose deviation (PMDD) depends on the dose gradient and organ motion probability density function. Organ motion dose sensitivity was defined by the rate of change in PMDD with standard deviation of motion PDF and was found to increase with the maximum dose gradient in anterior, posterior, left and right directions. Due to common inferior and superior field borders of the field segments, the sharpest dose gradient will occur in the inferior or both superior and inferior penumbrae. Thus, prostate motion in the S-I direction produces the highest dose difference. The PMDD is within 2.5% when standard deviation is less than 5 mm, but the PMDD is over 2.5% in the inferior direction when standard deviation is higher than 5 mm in the inferior direction. Verification of prostate organ motion in the inferior directions is essential. The margin of the planning target volume (PTV) significantly impacts on the confidence of tumour control probability (TCP) and level of normal tissue complication probability (NTCP). Smaller margins help to reduce the dose to normal tissues, but may compromise the dose coverage of the PTV. Lower rectal NTCP can be achieved by either a smaller margin or a steeper dose gradient between PTV and rectum. With the same DVH control points, the rectum has lower complication in the seven-beam technique used in this study because of the steeper dose gradient between the target volume and rectum. The relationship between dose gradient and rectal complication can be used to evaluate IMRT treatment planning. The dose gradient analysis is a powerful tool to improve IMRT treatment plans and can be used for QA checking of treatment plans for prostate patients.

Convex reformulation of biologically-based multi-criteria intensity-modulated radiation therapy optimization including fractionation effects

NASA Astrophysics Data System (ADS)

Hoffmann, Aswin L.; den Hertog, Dick; Siem, Alex Y. D.; Kaanders, Johannes H. A. M.; Huizenga, Henk

2008-11-01

Finding fluence maps for intensity-modulated radiation therapy (IMRT) can be formulated as a multi-criteria optimization problem for which Pareto optimal treatment plans exist. To account for the dose-per-fraction effect of fractionated IMRT, it is desirable to exploit radiobiological treatment plan evaluation criteria based on the linear-quadratic (LQ) cell survival model as a means to balance the radiation benefits and risks in terms of biologic response. Unfortunately, the LQ-model-based radiobiological criteria are nonconvex functions, which make the optimization problem hard to solve. We apply the framework proposed by Romeijn et al (2004 Phys. Med. Biol. 49 1991-2013) to find transformations of LQ-model-based radiobiological functions and establish conditions under which transformed functions result in equivalent convex criteria that do not change the set of Pareto optimal treatment plans. The functions analysed are: the LQ-Poisson-based model for tumour control probability (TCP) with and without inter-patient heterogeneity in radiation sensitivity, the LQ-Poisson-based relative seriality s-model for normal tissue complication probability (NTCP), the equivalent uniform dose (EUD) under the LQ-Poisson model and the fractionation-corrected Probit-based model for NTCP according to Lyman, Kutcher and Burman. These functions differ from those analysed before in that they cannot be decomposed into elementary EUD or generalized-EUD functions. In addition, we show that applying increasing and concave transformations to the convexified functions is beneficial for the piecewise approximation of the Pareto efficient frontier.

"SABER": A new software tool for radiotherapy treatment plan evaluation.

PubMed

Zhao, Bo; Joiner, Michael C; Orton, Colin G; Burmeister, Jay

2010-11-01

Both spatial and biological information are necessary in order to perform true optimization of a treatment plan and for predicting clinical outcome. The goal of this work is to develop an enhanced treatment plan evaluation tool which incorporates biological parameters and retains spatial dose information. A software system is developed which provides biological plan evaluation with a novel combination of features. It incorporates hyper-radiosensitivity using the induced-repair model and applies the new concept of dose convolution filter (DCF) to simulate dose wash-out effects due to cell migration, bystander effect, and/or tissue motion during treatment. Further, the concept of spatial DVH (sDVH) is introduced to evaluate and potentially optimize the spatial dose distribution in the target volume. Finally, generalized equivalent uniform dose is derived from both the physical dose distribution (gEUD) and the distribution of equivalent dose in 2 Gy fractions (gEUD2) and the software provides three separate models for calculation of tumor control probability (TCP), normal tissue complication probability (NTCP), and probability of uncomplicated tumor control (P+). TCP, NTCP, and P+ are provided as a function of prescribed dose and multivariable TCP, NTCP, and P+ plots are provided to illustrate the dependence on individual parameters used to calculate these quantities. Ten plans from two clinical treatment sites are selected to test the three calculation models provided by this software. By retaining both spatial and biological information about the dose distribution, the software is able to distinguish features of radiotherapy treatment plans not discernible using commercial systems. Plans that have similar DVHs may have different spatial and biological characteristics and the application of novel tools such as sDVH and DCF within the software may substantially change the apparent plan quality or predicted plan metrics such as TCP and NTCP. For the cases examined, both the calculation method and the application of DCF can change the ranking order of competing plans. The voxel-by-voxel TCP model makes it feasible to incorporate spatial variations of clonogen densities (n), radiosensitivities (SF2), and fractionation sensitivities (alpha/beta) as those data become available. The new software incorporates both spatial and biological information into the treatment planning process. The application of multiple methods for the incorporation of biological and spatial information has demonstrated that the order of application of biological models can change the order of plan ranking. Thus, the results of plan evaluation and optimization are dependent not only on the models used but also on the order in which they are applied. This software can help the planner choose more biologically optimal treatment plans and potentially predict treatment outcome more accurately.

Radiation-induced complications in prostate cancer patients treated with radiotherapy

NASA Astrophysics Data System (ADS)

Azuddin, A. Yusof; Rahman, I. Abdul; Siah, N. J.; Mohamed, F.; Saadc, M.; Ismail, F.

2014-09-01

The purpose of the study is to determine the relationship between radiation-induced complications with dosimetric and radiobiological parameters for prostate cancer patients that underwent the conformal radiotherapy treatment. 17 prostate cancer patients that have been treated with conformal radiotherapy were retrospectively analysed. The dosimetric data was retrieved in the form of dose-volume histogram (DVH) from Radiotherapy Treatment Planning System. The DVH was utilised to derived Normal Tissue Complication Probability (NTCP) in radiobiological data. Follow-up data from medical records were used to grade the occurrence of acute gastrointestinal (GI) and genitourinary (GU) complications using Radiation Therapy Oncology Group (RTOG) scoring system. The chi-square test was used to determine the relationship between radiation-induced complication with dosimetric and radiobiological parameters. 8 (47%) and 7 (41%) patients were having acute GI and GU complications respectively. The acute GI complication can be associated with V60rectum, rectal mean dose and NTCPrectum with p-value of 0.016, 0.038 and 0.049 respectively. There are no significant relationships of acute GU complication with dosimetric and radiobiological variables. Further study can be done by increase the sample size and follow up duration for deeper understanding of the factors that effecting the GU and GI complication in prostate cancer radiotherapy.

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy.

PubMed

Mavroidis, Panayiotis; Pearlstein, Kevin A; Dooley, John; Sun, Jasmine; Saripalli, Srinivas; Das, Shiva K; Wang, Andrew Z; Chen, Ronald C

2018-02-02

To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post-prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms. Ninety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image-guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by ≥2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods. For the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D 50  = 64.2Gy, m = 0.50, n = 1.0; 2) D 50  = 95.0Gy, m = 0.45, n = 0.50; 3) D 50  = 83.1Gy, m = 0.56, n = 1.00; and 4) D 50  = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3. Different dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes.

An assessment of PTV margin based on actual accumulated dose for prostate cancer radiotherapy

NASA Astrophysics Data System (ADS)

Wen, Ning; Kumarasiri, Akila; Nurushev, Teamour; Burmeister, Jay; Xing, Lei; Liu, Dezhi; Glide-Hurst, Carri; Kim, Jinkoo; Zhong, Hualiang; Movsas, Benjamin; Chetty, Indrin J.

2013-11-01

The purpose of this work is to present the results of a margin reduction study involving dosimetric and radiobiologic assessment of cumulative dose distributions, computed using an image guided adaptive radiotherapy based framework. Eight prostate cancer patients, treated with 7-9, 6 MV, intensity modulated radiation therapy (IMRT) fields, were included in this study. The workflow consists of cone beam CT (CBCT) based localization, deformable image registration of the CBCT to simulation CT image datasets (SIM-CT), dose reconstruction and dose accumulation on the SIM-CT, and plan evaluation using radiobiological models. For each patient, three IMRT plans were generated with different margins applied to the CTV. The PTV margin for the original plan was 10 mm and 6 mm at the prostate/anterior rectal wall interface (10/6 mm) and was reduced to: (a) 5/3 mm, and (b) 3 mm uniformly. The average percent reductions in predicted tumor control probability (TCP) in the accumulated (actual) plans in comparison to the original plans over eight patients were 0.4%, 0.7% and 11.0% with 10/6 mm, 5/3 mm and 3 mm uniform margin respectively. The mean increase in predicted normal tissue complication probability (NTCP) for grades 2/3 rectal bleeding for the actual plans in comparison to the static plans with margins of 10/6, 5/3 and 3 mm uniformly was 3.5%, 2.8% and 2.4% respectively. For the actual dose distributions, predicted NTCP for late rectal bleeding was reduced by 3.6% on average when the margin was reduced from 10/6 mm to 5/3 mm, and further reduced by 1.0% on average when the margin was reduced to 3 mm. The average reduction in complication free tumor control probability (P+) in the actual plans in comparison to the original plans with margins of 10/6, 5/3 and 3 mm was 3.7%, 2.4% and 13.6% correspondingly. The significant reduction of TCP and P+ in the actual plan with 3 mm margin came from one outlier, where individualizing patient treatment plans through margin adaptation based on biological models, might yield higher quality treatments.

Quantifying Unnecessary Normal Tissue Complication Risks due to Suboptimal Planning: A Secondary Study of RTOG 0126

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, Kevin L., E-mail: kevinmoore@ucsd.edu; Schmidt, Rachel; Moiseenko, Vitali

Purpose: The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol. Methods and Materials: A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative tomore » observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH{sub 0126,top10%}). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed “high-quality,” “low-quality,” and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol. Results: Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH{sub 0126,top10%} to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study. Conclusions: Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications.« less

Biological Modeling Based Outcome Analysis (BMOA) in 3D Conformal Radiation Therapy (3DCRT) Treatments for Lung and Breast Cancers

NASA Astrophysics Data System (ADS)

Pyakuryal, Anil; Chen, Chiu-Hao; Dhungana, Sudarshan

2010-03-01

3DCRT treatments are the most commonly used techniques in the treatment of lung and breast cancers. The purpose of this study was to perform the BMOA of the 3DCRT plans designed for the treatment of breast and lung cancers utilizing HART program (Med. Phys. 36, p.2547(2009)). The BMOA parameters include normal tissue complication probability (NTCP), tumor control probability (TCP), and the complication-free tumor control probability (P+). The 3DCRT plans were designed for (i) the palliative treatment of 8 left lung cancer patients (CPs) at early stage (m=8), (ii) the curative treatment of 8 left lung CPs at stages II and III (k=8), and (iii) the curative treatment of 8 left breast CPs (n=8). The NTCPs were noticeably small (<2%) for heart, lungs and cord in both types of treatments except for the esophagus in lung CPs (k=8). Assessments of the TCPs and P+s also indicated good improvements in local tumor control in all plans. Homogeneous target coverage and improved dose conformality were the major advantages of such techniques in the treatment of breast cancer. These achievements support the efficacy of the 3DCRT techniques for the efficient treatment of various types of cancer.

Focal dose escalation for prostate cancer using 68Ga-HBED-CC PSMA PET/CT and MRI: a planning study based on histology reference.

PubMed

Zamboglou, Constantinos; Thomann, Benedikt; Koubar, Khodor; Bronsert, Peter; Krauss, Tobias; Rischke, Hans C; Sachpazidis, Ilias; Drendel, Vanessa; Salman, Nasr; Reichel, Kathrin; Jilg, Cordula A; Werner, Martin; Meyer, Philipp T; Bock, Michael; Baltas, Dimos; Grosu, Anca L

2018-05-02

Focal radiation therapy has gained of interest in treatment of patients with primary prostate cancer (PCa). The question of how to define the intraprostatic boost volume is still open. Previous studies showed that multiparametric MRI (mpMRI) or PSMA PET alone could be used for boost volume definition. However, other studies proposed that the combined usage of both has the highest sensitivity in detection of intraprostatic lesions. The aim of this study was to demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of radiation therapy dose painting using 68 Ga-HBED-CC PSMA PET/CT, mpMRI or the combination of both in primary PCa. Ten patients underwent PSMA PET/CT and mpMRI followed by prostatectomy. Three gross tumour volumes (GTVs) were created based on PET (GTV-PET), mpMRI (GTV-MRI) and the union of both (GTV-union). Two plans were generated for each GTV. Plan95 consisted of whole-prostate IMRT to 77 Gy in 35 fractions and a simultaneous boost to 95 Gy (Plan95 PET /Plan95 MRI /Plan95 union ). Plan80 consisted of whole-prostate IMRT to 76 Gy in 38 fractions and a simultaneous boost to 80 Gy (Plan80 PET /Plan80 MRI /Plan80 union ). TCPs were calculated for GTV-histo (TCP-histo), which was delineated based on PCa distribution in co-registered histology slices. NTCPs were assessed for bladder and rectum. Dose constraints of published protocols were reached in every treatment plan. Mean TCP-histo were 99.7% (range: 97%-100%) and 75.5% (range: 33%-95%) for Plan95 union and Plan80 union , respectively. Plan95 union had significantly higher TCP-histo values than Plan95 MRI (p = 0.008) and Plan95 PET (p = 0.008). Plan80 union had significantly higher TCP-histo values than Plan80 MRI (p = 0.012), but not than Plan80 PET (p = 0.472). Plan95 MRI had significantly lower NTCP-rectum than Plan95 union (p = 0.012). No significant differences in NTCP-rectum and NTCP-bladder were observed for all other plans (p > 0.05). IMRT dose escalation on GTVs based on mpMRI, PSMA PET/CT and the combination of both was feasible. Boosting GTV-union resulted in significantly higher TCP-histo with no or minimal increase of NTCPs compared to the other plans.

Comparison of IMRT planning with two-step and one-step optimization: a strategy for improving therapeutic gain and reducing the integral dose

NASA Astrophysics Data System (ADS)

Abate, A.; Pressello, M. C.; Benassi, M.; Strigari, L.

2009-12-01

The aim of this study was to evaluate the effectiveness and efficiency in inverse IMRT planning of one-step optimization with the step-and-shoot (SS) technique as compared to traditional two-step optimization using the sliding windows (SW) technique. The Pinnacle IMRT TPS allows both one-step and two-step approaches. The same beam setup for five head-and-neck tumor patients and dose-volume constraints were applied for all optimization methods. Two-step plans were produced converting the ideal fluence with or without a smoothing filter into the SW sequence. One-step plans, based on direct machine parameter optimization (DMPO), had the maximum number of segments per beam set at 8, 10, 12, producing a directly deliverable sequence. Moreover, the plans were generated whether a split-beam was used or not. Total monitor units (MUs), overall treatment time, cost function and dose-volume histograms (DVHs) were estimated for each plan. PTV conformality and homogeneity indexes and normal tissue complication probability (NTCP) that are the basis for improving therapeutic gain, as well as non-tumor integral dose (NTID), were evaluated. A two-sided t-test was used to compare quantitative variables. All plans showed similar target coverage. Compared to two-step SW optimization, the DMPO-SS plans resulted in lower MUs (20%), NTID (4%) as well as NTCP values. Differences of about 15-20% in the treatment delivery time were registered. DMPO generates less complex plans with identical PTV coverage, providing lower NTCP and NTID, which is expected to reduce the risk of secondary cancer. It is an effective and efficient method and, if available, it should be favored over the two-step IMRT planning.

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy

PubMed Central

Brodin, N P; Björk-Eriksson, T; Birk Christensen, C; Kiil-Berthelsen, A; Aznar, M C; Hollensen, C; Markova, E; Munck af Rosenschöld, P

2015-01-01

Objective: To investigate the impact of including fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). Methods: Target volumes were first delineated without and subsequently re-delineated with access to 18F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). Results: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. Conclusion: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. Advances in knowledge: 18F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT. PMID:25494657

Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sumida, Iori, E-mail: sumida@radonc.med.osaka-u.ac.jp; Yamaguchi, Hajime; Kizaki, Hisao

2015-07-15

Purpose: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). Methods and Materials: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV,more » spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. Results: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03–.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. Conclusions: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution.« less

A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Houweling, Antonetta C., E-mail: A.Houweling@umcutrecht.n; Philippens, Marielle E.P.; Dijkema, Tim

2010-03-15

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulatedmore » salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.« less

TU-A-BRD-01: Outcomes of Hypofractionated Treatments - Initial Results of the WGSBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, X; Lee, P; Ohri, N

2014-06-15

Stereotactic Body Radiation Therapy (SBRT) has emerged in recent decades as a treatment paradigm that is becoming increasingly important in clinical practice. Clinical outcomes data are rapidly accumulating. Although published relations between outcomes and dose distributions are still sparse, the field has progressed to the point where evidence-based normal tissue dose-volume constraints, prescription strategies, and Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) models can be developed. The Working Group on SBRT (WGSBRT), under the Biological Effects Subcommittee of AAPM, is a group of physicists and physicians working in the area of SBRT. It is currently performing criticalmore » literature reviews to extract and synthesize usable data and to develop guidelines and models to aid with safe and effective treatment. The group is investigating clinically relevant findings from SBRT in six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session of AAPM 2014, interim results are presented on TCP for lung and liver, NTCP for thoracic organs, and radiobiological foundations:• Lung TCP: Detailed modeling of TCP data from 118 published studies on early stage lung SBRT investigates dose response and hypothesized mechanisms to explain the improved outcomes of SBRT. This is presented from the perspective of a physicist, a physician, and a radiobiologist.• Liver TCP: For primary and metastatic liver tumors, individual patient data were extracted from published reports to examine the effects of biologically effective dose on local control.• Thoracic NTCP: Clinically significant SBRT toxicity of lung, rib / chest wall and other structures are evaluated and compared among published clinical data, in terms of risk, risk factors, and safe practice.• Improving the clinical utility of published toxicity reports from SBRT and Hypofractionated treatments. What do we want, and how do we get it? Methods and problems of synthesizing data from published reports. Learning Objectives: Common SBRT fractionation schemes and current evidence for efficacy. Evidence for normal tissue tolerances in hypofractionated treatments. Clinically relevant radiobiological effects at large fraction sizes.« less

Animation and radiobiological analysis of 3D motion in conformal radiotherapy.

PubMed

MacKay, R I; Graham, P A; Moore, C J; Logue, J P; Sharrock, P J

1999-07-01

To allow treatment plans to be evaluated against the range of expected organ motion and set up error anticipated during treatment. Planning tools have been developed to allow concurrent animation and radiobiological analysis of three dimensional (3D) target and organ motion in conformal radiotherapy. Surfaces fitted to structures outlined on CT studies are projected onto pre-treatment images or onto megavoltage images collected during the patient treatment. Visual simulation of tumour and normal tissue movement is then performed by the application of three dimensional affine transformations, to the selected surface. Concurrent registration of the surface motion with the 3D dose distribution allows calculation of the change in dose to the volume. Realistic patterns of motion can be applied to the structure to simulate inter-fraction motion and set-up error. The biologically effective dose for the structure is calculated for each fraction as the surface moves over the course of the treatment and is used to calculate the normal tissue complication probability (NTCP) or tumour control probability (TCP) for the moving structure. The tool has been used to evaluate conformal therapy plans against set up measurements recorded during patient treatments. NTCP and TCP were calculated for a patient whose set up had been corrected after systematic deviations from plan geometry were measured during treatment, the effect of not making the correction were also assessed. TCP for the moving tumour was reduced if inadequate margins were set for the treatment. Modelling suggests that smaller margins could have been set for the set up corrected during the course of the treatment. The NTCP for the rectum was also higher for the uncorrected set up due to a more rectal tissue falling in the high dose region. This approach provides a simple way for clinical users to utilise information incrementally collected throughout the whole of a patient's treatment. In particular it is possible to test the robustness of a patient plan against a range of possible motion patterns. The methods described represent a move from the inspection of static pre-treatment plans to a review of the dynamic treatment.

Dosimetric comparison of standard three-dimensional conformal radiotherapy followed by intensity-modulated radiotherapy boost schedule (sequential IMRT plan) with simultaneous integrated boost–IMRT (SIB IMRT) treatment plan in patients with localized carcinoma prostate

PubMed Central

Bansal, A.; Kapoor, R.; Singh, S. K.; Kumar, N.; Oinam, A. S.; Sharma, S. C.

2012-01-01

Aims: Dosimeteric and radiobiological comparison of two radiation schedules in localized carcinoma prostate: Standard Three-Dimensional Conformal Radiotherapy (3DCRT) followed by Intensity Modulated Radiotherapy (IMRT) boost (sequential-IMRT) with Simultaneous Integrated Boost IMRT (SIB-IMRT). Material and Methods: Thirty patients were enrolled. In all, the target consisted of PTV P + SV (Prostate and seminal vesicles) and PTV LN (lymph nodes) where PTV refers to planning target volume and the critical structures included: bladder, rectum and small bowel. All patients were treated with sequential-IMRT plan, but for dosimetric comparison, SIB-IMRT plan was also created. The prescription dose to PTV P + SV was 74 Gy in both strategies but with different dose per fraction, however, the dose to PTV LN was 50 Gy delivered in 25 fractions over 5 weeks for sequential-IMRT and 54 Gy delivered in 27 fractions over 5.5 weeks for SIB-IMRT. The treatment plans were compared in terms of dose–volume histograms. Also, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) obtained with the two plans were compared. Results: The volume of rectum receiving 70 Gy or more (V > 70 Gy) was reduced to 18.23% with SIB-IMRT from 22.81% with sequential-IMRT. SIB-IMRT reduced the mean doses to both bladder and rectum by 13% and 17%, respectively, as compared to sequential-IMRT. NTCP of 0.86 ± 0.75% and 0.01 ± 0.02% for the bladder, 5.87 ± 2.58% and 4.31 ± 2.61% for the rectum and 8.83 ± 7.08% and 8.25 ± 7.98% for the bowel was seen with sequential-IMRT and SIB-IMRT plans respectively. Conclusions: For equal PTV coverage, SIB-IMRT markedly reduced doses to critical structures, therefore should be considered as the strategy for dose escalation. SIB-IMRT achieves lesser NTCP than sequential-IMRT. PMID:23204659

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuang, Yu; Wu, Lili; Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong

Purpose: This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by {sup 18}F-choline positron emission tomography/computed tomography (PET/CT). Methods and Materials: Thirty patients with localized prostate cancer underwent {sup 18}F-choline PET/CT before treatment. Two VMAT plans, plan{sub 79} {sub Gy} and plan{sub 100-105} {sub Gy}, were compared for each patient. The whole-prostate planning target volume (PTV{sub prostate}) prescription was 79 Gy in both plans, but plan{sub 100-105} {sub Gy} added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, definedmore » by 60% and 70% of maximum prostatic uptake on {sup 18}F-choline PET (IDL{sub suv60%} and IDL{sub suv70%}, respectively, with IDL{sub suv70%} nested inside IDL{sub suv60%} to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). Results: Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDL{sub suv60%} adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan{sub 100-105} {sub Gy} had significantly higher TCP than plan{sub 79} {sub Gy} across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan{sub 100-105} {sub Gy}. Conclusions: VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a {sup 18}F-choline PET-defined IDL.« less

LASSO NTCP predictors for the incidence of xerostomia in patients with head and neck squamous cell carcinoma and nasopharyngeal carcinoma

PubMed Central

Lee, Tsair-Fwu; Liou, Ming-Hsiang; Huang, Yu-Jie; Chao, Pei-Ju; Ting, Hui-Min; Lee, Hsiao-Yi

2014-01-01

To predict the incidence of moderate-to-severe patient-reported xerostomia among head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Multivariable normal tissue complication probability (NTCP) models were developed by using quality of life questionnaire datasets from 152 patients with HNSCC and 84 patients with NPC. The primary endpoint was defined as moderate-to-severe xerostomia after IMRT. The numbers of predictive factors for a multivariable logistic regression model were determined using the least absolute shrinkage and selection operator (LASSO) with bootstrapping technique. Four predictive models were achieved by LASSO with the smallest number of factors while preserving predictive value with higher AUC performance. For all models, the dosimetric factors for the mean dose given to the contralateral and ipsilateral parotid gland were selected as the most significant predictors. Followed by the different clinical and socio-economic factors being selected, namely age, financial status, T stage, and education for different models were chosen. The predicted incidence of xerostomia for HNSCC and NPC patients can be improved by using multivariable logistic regression models with LASSO technique. The predictive model developed in HNSCC cannot be generalized to NPC cohort treated with IMRT without validation and vice versa. PMID:25163814

Dosimetric comparison of volumetric modulated Arc therapy, step-and-shoot, and sliding window IMRT for prostate cancer

NASA Astrophysics Data System (ADS)

Schnell, Erich; Herman, Tania De La Fuente; Young, Julie; Hildebrand, Kim; Algan, Ozer; Syzek, Elizabeth; Herman, Terence; Ahmad, Salahuddin

2012-10-01

This study aims to evaluate treatment plans generated by Step-and-Shoot (SS), Sliding Window (SW) and Volumetric Modulated Arc Therapy (VMAT) in order to assess the differences in dose volume histograms of planning target volume (PTV) and organs at risk (OAR), conformity indices, radiobiological evaluations, and plan quality for prostate cancer cases. Six prostate cancer patients treated in our center were selected for this retrospective study. Treatment plans were generated with Eclipse version 8.9 using 10 MV photon beams. For VMAT, Varian Rapid Arc with 1 or 2 arcs, and for SS and SW IMRT, 7-9 fields were used. Each plan had three PTVs with prescription doses of 81, 59.4, and 45 Gy to prostate, to prostate and lymph nodes, and to pelvis, respectively. Doses to PTV and OAR and the conformal indices (COIN) were compared among three techniques. The equivalent uniform dose (EUD), tumor control probability (TCP) and normal tissue complication probability (NTCP) were calculated and compared. The mean doses to the PTV prostate on average were 83 Gy and the percent differences of mean dose among all techniques were below 0.28. For bladder and rectum, the percent differences of mean dose among all techniques were below 2.2. The COIN did not favour any particular delivery method over the other. The TCP was higher with SS and SW for four patients and higher with VMAT for two patients. The NTCP for the rectum was the lowest with VMAT in five out of the six patients. The results show similar target coverage in general.

Radiobiological and treatment planning study of a simultaneously integrated boost for canine nasal tumors using helical tomotherapy.

PubMed

Gutíerrez, Alonso N; Deveau, Michael; Forrest, Lisa J; Tomé, Wolfgang A; Mackie, Thomas R

2007-01-01

Feasibility of delivering a simultaneously integrated boost to canine nasal tumors using helical tomotherapy to improve tumor control probability (TCP) via an increase in total biological equivalent uniform dose (EUD) was evaluated. Eight dogs with varying size nasal tumors (5.8-110.9 cc) were replanned to 42 Gy to the nasal cavity and integrated dose boosts to gross disease of 45.2, 48.3, and 51.3 Gy in 10 fractions. EUD values were calculated for tumors and mean normalized total doses (NTD(mean)) for organs at risk (OAR). Normal Tissue Complication Probability (NTCP) values were obtained for OARs, and estimated TCP values were computed using a logistic dose-response model and based on deliverable EUD boost doses. Significant increases in estimated TCP to 54%, 74%, and 86% can be achieved with 10%, 23%, and 37% mean relative EUD boosts to the gross disease, respectively. NTCP values for blindness of either eye and for brain necrosis were < 0.01% for all boosts. Values for cataract development were 31%, 42%, and 46% for studied boost schemas, respectively. Average NTD(mean) to eyes and brain for mean EUD boosts were 10.2, 11.3, and 12.1 Gy3, and 7.5, 7.2, and 7.9 Gy2, respectively. Using helical tomotherapy, simultaneously integrated dose boosts can be delivered to increase the estimated TCP at 1-year without significantly increasing the NTD(mean) to eyes and brain. Delivery of these treatments in a prospective trial may allow quantification of a dose-response relationship in canine nasal tumors.

SU-E-T-572: Normal Lung Tissue Sparing in Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, C; Ju, S; Ahn, Y

2015-06-15

Purpose: To compare normal lung-sparing capabilities of three advanced radiation therapy techniques for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Four-dimensional computed tomography (4DCT) was performed in 10 patients with stage IIIb LA-NSCLC. The internal target volume (ITV); planning target volume (PTV); and organs at risks (OARs) such as spinal cord, total normal lung, heart, and esophagus were delineated for each CT data set. Intensity-modulated radiation therapy (IMRT), Tomohelical-IMRT (TH-IMRT), and TomoDirect-IMRT (TD-IMRT) plans were generated (total prescribed dose, 66 Gy in 33 fractions to the PTV) for each patient. To reduce the normal lung dose, complete and directionalmore » block function was applied outside the normal lung far from the target for both TH-IMRT and TD-IMRT, while pseudo- OAR was set in the same region for IMRT. Dosimetric characteristics of the three plans were compared in terms of target coverage, the sparing capability for the OAR, and the normal tissue complication probability (NTCP). Beam delivery efficiency was also compared. Results: TH-IMRT and TD-IMRT provided better target coverage than IMRT plans. Lung volume receiving ≥–30 Gy, mean dose, and NTCP were significant with TH-IMRT than with IMRT (p=0.006), and volume receiving ≥20–30 Gy was lower in TD-IMRT than in IMRT (p<0.05). Compared with IMRT, TH-IMRT had better sparing effect on the spinal cord (Dmax, NTCP) and heart (V45) (p<0.05). NTCP for the spinal cord, V45 and V60 for the heart, and Dmax for the esophagus were significantly lower in TD-IMRT than in IMRT. The monitor units per fraction were clearly smaller for IMRT than for TH-IMRT and TD-IMRT (p=0.006). Conclusion: In LA-NSCLC, TH-IMRT gave superior PTV coverage and OAR sparing compared to IMRT. TH-IMRT provided better control of the lung volume receiving ≥5–30 Gy. The delivery time and monitor units were lower in TD-IMRT than in TH-IMRT.« less

Derivation of the expressions for γ50 and D50 for different individual TCP and NTCP models

NASA Astrophysics Data System (ADS)

Stavreva, N.; Stavrev, P.; Warkentin, B.; Fallone, B. G.

2002-10-01

This paper presents a complete set of formulae for the position (D50) and the normalized slope (γ50) of the dose-response relationship based on the most commonly used radiobiological models for tumours as well as for normal tissues. The functional subunit response models (critical element and critical volume) are used in the derivation of the formulae for the normal tissue. Binomial statistics are used to describe the tumour control probability, the functional subunit response as well as the normal tissue complication probability. The formulae are derived for the single hit and linear quadratic models of cell kill in terms of the number of fractions and dose per fraction. It is shown that the functional subunit models predict very steep, almost step-like, normal tissue individual dose-response relationships. Furthermore, the formulae for the normalized gradient depend on the cellular parameters α and β when written in terms of number of fractions, but not when written in terms of dose per fraction.

Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer.

PubMed

Rosenzweig, K E; Mychalczak, B; Fuks, Z; Hanley, J; Burman, C; Ling, C C; Armstrong, J; Ginsberg, R; Kris, M G; Raben, A; Leibel, S

2000-01-01

Three-dimensional conformal radiotherapy (3D-CRT) is a mode of high-precision radiotherapy designed to increase the tumor dose and decrease the dose to normal tissues. This study reports the final results of the first two dose levels (70.2 Gy and 75.6 Gy) of a phase I dose-escalation study using 3D-CRT for the treatment of non-small cell lung cancer. Fifty-two patients were treated with 3D-CRT without chemotherapy. The median age was 67 years (range, 39-82 years). The majority of patients had locally advanced cancer. Tumor was staged as I/II in 10%, IIIA in 40%, and IIIB in 50%. Radiation was delivered in daily fractions of 1.8 Gy, 5 days a week. A radiation dose level was considered complete when 10 patients received the intended dose without unacceptable acute morbidity. Toxicity was scored according to the Radiation Therapy Oncology Group grading scheme. Twenty patients were initially assigned to the 70.2-Gy level; 14 of them received the intended dose. Three patients experienced severe acute toxicity, two with grade 3 (requiring steroids or oxygen) and a third with grade 5 (fatal) acute radiation pneumonitis. Because of the grade 5 pulmonary toxicity, the protocol was modified, and only patients with a calculated risk of normal tissue complication of less than 25% were eligible for dose escalation. Patients who had a normal tissue complication probability (NTCP) of greater than 25% received a lower dose of radiation. An additional 18 patients were entered on the modified study; 11 of them received 70.2 Gy. One patient experienced grade 3 acute pneumonitis. Despite dose reduction in four patients because of an unacceptably high NTCP, two additional patients developed grade 3 pulmonary toxicity. Fourteen patients were accrued to the 75.6-Gy dose level, and 10 received the intended dose. One of the 10 patients experienced grade 3 pulmonary toxicity and one developed grade 3 esophageal toxicity. Three patients were treated to lower doses as a result of their calculated NTCP without toxicity, and one patient refused treatment. The 2-year local control, disease-free survival, and overall survival rates were 37%, 12%, and 24%, respectively. The median survival time was 11 months. Treatment to 70.2 Gy and 75.6 Gy using 3D-CRT was delivered with acceptable morbidity when NTCP constraints were observed. Local control was encouraging in these patients with locally advanced disease. Patients are currently being accrued to the 81-Gy level of the study.

Dosimetric and radiobiological consequences of computed tomography-guided adaptive strategies for intensity modulated radiation therapy of the prostate.

PubMed

Battista, Jerry J; Johnson, Carol; Turnbull, David; Kempe, Jeff; Bzdusek, Karl; Van Dyk, Jacob; Bauman, Glenn

2013-12-01

To examine a range of scenarios for image-guided adaptive radiation therapy of prostate cancer, including different schedules for megavoltage CT imaging, patient repositioning, and dose replanning. We simulated multifraction dose distributions with deformable registration using 35 sets of megavoltage CT scans of 13 patients. We computed cumulative dose-volume histograms, from which tumor control probabilities and normal tissue complication probabilities (NTCPs) for rectum were calculated. Five-field intensity modulated radiation therapy (IMRT) with 18-MV x-rays was planned to achieve an isocentric dose of 76 Gy to the clinical target volume (CTV). The differences between D95, tumor control probability, V70Gy, and NTCP for rectum, for accumulated versus planned dose distributions, were compared for different target volume sizes, margins, and adaptive strategies. The CTV D95 for IMRT treatment plans, averaged over 13 patients, was 75.2 Gy. Using the largest CTV margins (10/7 mm), the D95 values accumulated over 35 fractions were within 2% of the planned value, regardless of the adaptive strategy used. For tighter margins (5 mm), the average D95 values dropped to approximately 73.0 Gy even with frequent repositioning, and daily replanning was necessary to correct this deficit. When personalized margins were applied to an adaptive CTV derived from the first 6 treatment fractions using the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm, target coverage could be maintained using a single replan 1 week into therapy. For all approaches, normal tissue parameters (rectum V(70Gy) and NTCP) remained within acceptable limits. The frequency of adaptive interventions depends on the size of the CTV combined with target margins used during IMRT optimization. The application of adaptive target margins (<5 mm) to an adaptive CTV determined 1 week into therapy minimizes the need for subsequent dose replanning. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of the radiobiological gamma index with motion interplay in tangential IMRT breast treatment

PubMed Central

Sumida, Iori; Yamaguchi, Hajime; Das, Indra J.; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Tamari, Kiesuke; Suzuki, Osamu; Seo, Yuji; Isohashi, Fumiaki; Yoshioka, Yasuo; Ogawa, Kazuhiko

2016-01-01

The purpose of this study was to evaluate the impact of the motion interplay effect in early-stage left-sided breast cancer intensity-modulated radiation therapy (IMRT), incorporating the radiobiological gamma index (RGI). The IMRT dosimetry for various breathing amplitudes and cycles was investigated in 10 patients. The predicted dose was calculated using the convolution of segmented measured doses. The physical gamma index (PGI) of the planning target volume (PTV) and the organs at risk (OAR) was calculated by comparing the original with the predicted dose distributions. The RGI was calculated from the PGI using the tumor control probability (TCP) and the normal tissue complication probability (NTCP). The predicted mean dose and the generalized equivalent uniform dose (gEUD) to the target with various breathing amplitudes were lower than the original dose (P < 0.01). The predicted mean dose and gEUD to the OARs with motion were higher than for the original dose to the OARs (P < 0.01). However, the predicted data did not differ significantly between the various breathing cycles for either the PTV or the OARs. The mean RGI gamma passing rate for the PTV was higher than that for the PGI (P < 0.01), and for OARs, the RGI values were higher than those for the PGI (P < 0.01). The gamma passing rates of the RGI for the target and the OARs other than the contralateral lung differed significantly from those of the PGI under organ motion. Provided an NTCP value <0.05 is considered acceptable, it may be possible, by taking breathing motion into consideration, to escalate the dose to achieve the PTV coverage without compromising the TCP. PMID:27534793

A Monte Carlo study of the impact of the choice of rectum volume definition on estimates of equivalent uniform doses and the volume parameter

NASA Astrophysics Data System (ADS)

Kvinnsland, Yngve; Muren, Ludvig Paul; Dahl, Olav

2004-08-01

Calculations of normal tissue complication probability (NTCP) values for the rectum are difficult because it is a hollow, non-rigid, organ. Finding the true cumulative dose distribution for a number of treatment fractions requires a CT scan before each treatment fraction. This is labour intensive, and several surrogate distributions have therefore been suggested, such as dose wall histograms, dose surface histograms and histograms for the solid rectum, with and without margins. In this study, a Monte Carlo method is used to investigate the relationships between the cumulative dose distributions based on all treatment fractions and the above-mentioned histograms that are based on one CT scan only, in terms of equivalent uniform dose. Furthermore, the effect of a specific choice of histogram on estimates of the volume parameter of the probit NTCP model was investigated. It was found that the solid rectum and the rectum wall histograms (without margins) gave equivalent uniform doses with an expected value close to the values calculated from the cumulative dose distributions in the rectum wall. With the number of patients available in this study the standard deviations of the estimates of the volume parameter were large, and it was not possible to decide which volume gave the best estimates of the volume parameter, but there were distinct differences in the mean values of the values obtained.

Role of the parameters involved in the plan optimization based on the generalized equivalent uniform dose and radiobiological implications

NASA Astrophysics Data System (ADS)

Widesott, L.; Strigari, L.; Pressello, M. C.; Benassi, M.; Landoni, V.

2008-03-01

We investigated the role and the weight of the parameters involved in the intensity modulated radiation therapy (IMRT) optimization based on the generalized equivalent uniform dose (gEUD) method, for prostate and head-and-neck plans. We systematically varied the parameters (gEUDmax and weight) involved in the gEUD-based optimization of rectal wall and parotid glands. We found that the proper value of weight factor, still guaranteeing planning treatment volumes coverage, produced similar organs at risks dose-volume (DV) histograms for different gEUDmax with fixed a = 1. Most of all, we formulated a simple relation that links the reference gEUDmax and the associated weight factor. As secondary objective, we evaluated plans obtained with the gEUD-based optimization and ones based on DV criteria, using the normal tissue complication probability (NTCP) models. gEUD criteria seemed to improve sparing of rectum and parotid glands with respect to DV-based optimization: the mean dose, the V40 and V50 values to the rectal wall were decreased of about 10%, the mean dose to parotids decreased of about 20-30%. But more than the OARs sparing, we underlined the halving of the OARs optimization time with the implementation of the gEUD-based cost function. Using NTCP models we enhanced differences between the two optimization criteria for parotid glands, but no for rectum wall.

Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus.

PubMed

Lambrecht, Maarten; Eekers, Daniëlle B P; Alapetite, Claire; Burnet, Neil G; Calugaru, Valentin; Coremans, Ida E M; Fossati, Piero; Høyer, Morten; Langendijk, Johannes A; Romero, Alejandra Méndez; Paulsen, Frank; Perpar, Ana; Renard, Laurette; de Ruysscher, Dirk; Timmermann, Beate; Vitek, Pavel; Weber, Damien C; van der Weide, Hiske L; Whitfield, Gillian A; Wiggenraad, Ruud; Roelofs, Erik; Nyström, Petra Witt; Troost, Esther G C

2018-05-17

For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study. We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology. For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given. The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities. Copyright © 2018 Elsevier B.V. All rights reserved.

WE-F-304-05: Cranial TCP/NTCP Modeling Insights and Caveats

DOE Office of Scientific and Technical Information (OSTI.GOV)

El Naqa, I.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

SU-E-T-628: Predicted Risk of Post-Irradiation Cerebral Necrosis in Pediatric Brain Cancer Patients: A Treatment Planning Comparison of Proton Vs. Photon Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freund, D; Zhang, R; Sanders, M

Purpose: Post-irradiation cerebral necrosis (PICN) is a severe late effect that can Result from brain cancers treatment using radiation therapy. The purpose of this study was to compare the treatment plans and predicted risk of PICN after volumetric modulated arc therapy (VMAT) to the risk after passively scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT) in a cohort of pediatric patients. Methods: Thirteen pediatric patients with varying age and sex were selected for this study. A clinical treatment volume (CTV) was constructed for 8 glioma patients and 5 ependymoma patients. Prescribed dose was 54 Gy over 30 fractionsmore » to the planning volume. Dosimetric endpoints were compared between VMAT and proton plans. The normal tissue complication probability (NTCP) following VMAT and proton therapy planning was also calculated using PICN as the biological endpoint. Sensitivity tests were performed to determine if predicted risk of PICN was sensitive to positional errors, proton range errors and selection of risk models. Results: Both PSPT and IMPT plans resulted in a significant increase in the maximum dose and reduction in the total brain volume irradiated to low doses compared with the VMAT plans. The average ratios of NTCP between PSPT and VMAT were 0.56 and 0.38 for glioma and ependymoma patients respectively and the average ratios of NTCP between IMPT and VMAT were 0.67 and 0.68 for glioma and ependymoma plans respectively. Sensitivity test revealed that predicted ratios of risk were insensitive to range and positional errors but varied with risk model selection. Conclusion: Both PSPT and IMPT plans resulted in a decrease in the predictive risk of necrosis for the pediatric plans studied in this work. Sensitivity analysis upheld the qualitative findings of the risk models used in this study, however more accurate models that take into account dose and volume are needed.« less

Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy.

PubMed

Koontz, Bridget F; Das, Shiva; Temple, Kathy; Bynum, Sigrun; Catalano, Suzanne; Koontz, Jason I; Montana, Gustavo S; Oleson, James R

2009-01-01

Adjuvant radiotherapy for locally advanced prostate cancer improves biochemical and clinical disease-free survival. While comparisons in intact prostate cancer show a benefit for intensity modulated radiation therapy (IMRT) over 3D conformal planning, this has not been studied for post-prostatectomy radiotherapy (RT). This study compares normal tissue and target dosimetry and radiobiological modeling of IMRT vs. 3D conformal planning in the postoperative setting. 3D conformal plans were designed for 15 patients who had been treated with IMRT planning for salvage post-prostatectomy RT. The same computed tomography (CT) and target/normal structure contours, as well as prescription dose, was used for both IMRT and 3D plans. Normal tissue complication probabilities (NTCPs) were calculated based on the dose given to the bladder and rectum by both plans. Dose-volume histogram and NTCP data were compared by paired t-test. Bladder and rectal sparing were improved with IMRT planning compared to 3D conformal planning. The volume of the bladder receiving at least 75% (V75) and 50% (V50) of the dose was significantly reduced by 28% and 17%, respectively (p = 0.002 and 0.037). Rectal dose was similarly reduced, V75 by 33% and V50 by 17% (p = 0.001 and 0.004). While there was no difference in the volume of rectum receiving at least 65 Gy (V65), IMRT planning significant reduced the volume receiving 40 Gy or more (V40, p = 0.009). Bladder V40 and V65 were not significantly different between planning modalities. Despite these dosimetric differences, there was no significant difference in the NTCP for either bladder or rectal injury. IMRT planning reduces the volume of bladder and rectum receiving high doses during post-prostatectomy RT. Because of relatively low doses given to the bladder and rectum, there was no statistically significant improvement in NTCP between the 3D conformal and IMRT plans.

TU-CD-BRB-01: Normal Lung CT Texture Features Improve Predictive Models for Radiation Pneumonitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krafft, S; The University of Texas Graduate School of Biomedical Sciences, Houston, TX; Briere, T

2015-06-15

Purpose: Existing normal tissue complication probability (NTCP) models for radiation pneumonitis (RP) traditionally rely on dosimetric and clinical data but are limited in terms of performance and generalizability. Extraction of pre-treatment image features provides a potential new category of data that can improve NTCP models for RP. We consider quantitative measures of total lung CT intensity and texture in a framework for prediction of RP. Methods: Available clinical and dosimetric data was collected for 198 NSCLC patients treated with definitive radiotherapy. Intensity- and texture-based image features were extracted from the T50 phase of the 4D-CT acquired for treatment planning. Amore » total of 3888 features (15 clinical, 175 dosimetric, and 3698 image features) were gathered and considered candidate predictors for modeling of RP grade≥3. A baseline logistic regression model with mean lung dose (MLD) was first considered. Additionally, a least absolute shrinkage and selection operator (LASSO) logistic regression was applied to the set of clinical and dosimetric features, and subsequently to the full set of clinical, dosimetric, and image features. Model performance was assessed by comparing area under the curve (AUC). Results: A simple logistic fit of MLD was an inadequate model of the data (AUC∼0.5). Including clinical and dosimetric parameters within the framework of the LASSO resulted in improved performance (AUC=0.648). Analysis of the full cohort of clinical, dosimetric, and image features provided further and significant improvement in model performance (AUC=0.727). Conclusions: To achieve significant gains in predictive modeling of RP, new categories of data should be considered in addition to clinical and dosimetric features. We have successfully incorporated CT image features into a framework for modeling RP and have demonstrated improved predictive performance. Validation and further investigation of CT image features in the context of RP NTCP modeling is warranted. This work was supported by the Rosalie B. Hite Fellowship in Cancer research awarded to SPK.« less

Using a Reduced Spot Size for Intensity-Modulated Proton Therapy Potentially Improves Salivary Gland-Sparing in Oropharyngeal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Water, Tara A. van de, E-mail: t.a.van.de.water@rt.umcg.nl; Lomax, Antony J.; Bijl, Hendrik P.

2012-02-01

Purpose: To investigate whether intensity-modulated proton therapy with a reduced spot size (rsIMPT) could further reduce the parotid and submandibular gland dose compared with previously calculated IMPT plans with a larger spot size. In addition, it was investigated whether the obtained dose reductions would theoretically translate into a reduction of normal tissue complication probabilities (NTCPs). Methods: Ten patients with N0 oropharyngeal cancer were included in a comparative treatment planning study. Both IMPT plans delivered simultaneously 70 Gy to the boost planning target volume (PTV) and 54 Gy to the elective nodal PTV. IMPT and rsIMPT used identical three-field beam arrangements.more » In the IMPT plans, the parotid and submandibular salivary glands were spared as much as possible. rsIMPT plans used identical dose-volume objectives for the parotid glands as those used by the IMPT plans, whereas the objectives for the submandibular glands were tightened further. NTCPs were calculated for salivary dysfunction and xerostomia. Results: Target coverage was similar for both IMPT techniques, whereas rsIMPT clearly improved target conformity. The mean doses in the parotid glands and submandibular glands were significantly lower for three-field rsIMPT (14.7 Gy and 46.9 Gy, respectively) than for three-field IMPT (16.8 Gy and 54.6 Gy, respectively). Hence, rsIMPT significantly reduced the NTCP of patient-rated xerostomia and parotid and contralateral submandibular salivary flow dysfunction (27%, 17%, and 43% respectively) compared with IMPT (39%, 20%, and 79%, respectively). In addition, mean dose values in the sublingual glands, the soft palate and oral cavity were also decreased. Obtained dose and NTCP reductions varied per patient. Conclusions: rsIMPT improved sparing of the salivary glands and reduced NTCP for xerostomia and parotid and submandibular salivary dysfunction, while maintaining similar target coverage results. It is expected that rsIMPT improves quality of life during and after radiotherapy treatment.« less

SU-G-BRC-04: Collimator Angle Optimization in Volumetric Modulated Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andersen, A; Johnson, C; Bartlett, G

2016-06-15

Purpose: Volumetric modulated arc therapy (VMAT) has revolutionized radiation treatment by decreasing treatment time and monitor units, thus reducing scattered and whole body radiation dose. As the collimator angle changes the apparent leaf gap becomes larger which can impact plan quality, organ at risk (OAR) sparing as well as IMRT QA passing rate which is investigated. Methods: Two sites (prostate and head and neck) that have maximum utilization of VMAT were investigated. Two previously treated VMAT patients were chosen. For each patient 10 plans were created by maintaining constant optimization constraints while varying collimator angles from 0-90 deg at anmore » interval of 10 degrees for the first arc and the appropriate complimentary angle for the second arc. Plans were created with AAA algorithm using 6 MV beam on a Varian IX machine with Millennium 120 MLC. The dose-volume histogram (DVH) for each plan was exported and dosimetric parameters (D98, D95, D50, D2) as well homogeneity index (HI) and conformity index (CI) were computed. Each plan was validated for QA using ArcCheck with gamma index passing criteria of 2%/2 mm and 3%/3 mm. Additionally, normal tissue complication probability (NTCP) for each OAR was computed using Uzan-Nahum software. Results: The CI values for both sites had no impact as target volume coverage in every collimator angle were the same since it was optimized for adequate coverage. The HI which is representative of DVH gradient or dose uniformity in PTV showed a clear trend in both sites. The NTCP for OAR (brain and cochlea) in H&N plan and (bladder and rectum) in prostate plan showed a distinct superiority for collimator angles between 15-30 deg. The gamma passing rates were not correlated with angle. Conclusion: Based on CI, HI, NTCP and gamma passing index, it can be concluded that collimator angles should be maintained within 15–30 deg.« less

Comparison between the four-field box and field-in-field techniques for conformal radiotherapy of the esophagus using dose-volume histograms and normal tissue complication probabilities.

PubMed

Allaveisi, Farzaneh; Moghadam, Amir Nami

2017-06-01

We evaluated and compared the performance of the field-in-field (FIF) to that of the four-field box (4FB) technique regarding dosimetric and radiobiological parameters for radiotherapy of esophageal carcinoma. Twenty patients with esophageal cancer were selected. For each patient, two treatment plans were created: 4FB and FIF. The parameters compared included the conformity index (CI), homogeneity index (HI), D mean , D max , tumor control probability (TCP), V 20Gy and V 30Gy of the heart and lungs, normal tissue complication probability (NTCP), and monitor units per fraction (MU/fr). A paired t-test analysis did not show any significant differences (p > 0.05) between the two techniques in terms of the CI and TCP. However, the HI significantly improved when the FIF was applied. D max of the PTV, lung, and spinal cord were also significantly better with the FIF. Moreover, the lung V 20Gy as well as the NTCPs of the lung and spinal cord significantly reduced when the FIF was used, and the MU/fr was significantly decreased. The FIF showed evident advantages over 4FB: a more homogeneous dose distribution, lower D max values, and fewer required MUs, while it also retained PTV dose conformality. FIF should be considered as a simple technique to use clinically in cases with esophageal malignancies, especially in clinics with no IMRT.

N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection.

PubMed

Appelman, Monique D; Chakraborty, Anindita; Protzer, Ulrike; McKeating, Jane A; van de Graaf, Stan F J

2017-01-01

The sodium/bile acid cotransporter NTCP was recently identified as a receptor for hepatitis B virus (HBV). NTCP is glycosylated and the role of glycans in protein trafficking or viral receptor activity is not known. NTCP contains two N-linked glycosylation sites and asparagine amino acid residues N5 and N11 were mutated to a glutamine to generate NTCP with a single glycan (NTCP-N5Q or NTCP- N11Q) or no glycans (NTCP- N5,11Q). HepG2 cells expressing NTCP with a single glycan supported HBV infection at a comparable level to NTCP-WT. The physiological function of NTCP, the uptake of bile acids, was also not affected in cells expressing these single glycosylation variants, consistent with their trafficking to the plasma membrane. However, glycosylation-deficient NTCP (NTCP-N5,11Q) failed to support HBV infection, showed minimal cellular expression and was degraded in the lysosome. This affected the physiological bile acid transporter function of NTCP-N5,11Q in a similar fashion. In conclusion, N-glycosylation is required for efficient NTCP localization at the plasma membrane and subsequent HBV infection and these characteristics are preserved in NTCP carrying a single carbohydrate moiety.

N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection

PubMed Central

Appelman, Monique D.; Chakraborty, Anindita; Protzer, Ulrike; McKeating, Jane A.

2017-01-01

The sodium/bile acid cotransporter NTCP was recently identified as a receptor for hepatitis B virus (HBV). NTCP is glycosylated and the role of glycans in protein trafficking or viral receptor activity is not known. NTCP contains two N-linked glycosylation sites and asparagine amino acid residues N5 and N11 were mutated to a glutamine to generate NTCP with a single glycan (NTCP-N5Q or NTCP- N11Q) or no glycans (NTCP- N5,11Q). HepG2 cells expressing NTCP with a single glycan supported HBV infection at a comparable level to NTCP-WT. The physiological function of NTCP, the uptake of bile acids, was also not affected in cells expressing these single glycosylation variants, consistent with their trafficking to the plasma membrane. However, glycosylation-deficient NTCP (NTCP-N5,11Q) failed to support HBV infection, showed minimal cellular expression and was degraded in the lysosome. This affected the physiological bile acid transporter function of NTCP-N5,11Q in a similar fashion. In conclusion, N-glycosylation is required for efficient NTCP localization at the plasma membrane and subsequent HBV infection and these characteristics are preserved in NTCP carrying a single carbohydrate moiety. PMID:28125599

Radiobiological concepts for treatment planning of schemes that combines external beam radiotherapy and systemic targeted radiotherapy

NASA Astrophysics Data System (ADS)

Fabián Calderón Marín, Carlos; González González, Joaquín Jorge; Laguardia, Rodolfo Alfonso

2017-09-01

The combination of radiotherapy modalities with external bundles and systemic radiotherapy (CIERT) could be a reliable alternative for patients with multiple lesions or those where treatment planning maybe difficult because organ(s)-at-risk (OARs) constraints. Radiobiological models should have the capacity for predicting the biological irradiation response considering the differences in the temporal pattern of dose delivering in both modalities. Two CIERT scenarios were studied: sequential combination in which one modality is executed following the other one and concurrent combination when both modalities are running simultaneously. Expressions are provided for calculation of the dose-response magnitudes Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP). General results on radiobiological modeling using the linear-quadratic (LQ) model are also discussed. Inter-subject variation of radiosensitivity and volume irradiation effect in CIERT are studied. OARs should be under control during the planning in concurrent CIERT treatment as the administered activity is increased. The formulation presented here may be used for biological evaluation of prescriptions and biological treatment planning of CIERT schemes in clinical situation.

[Clinical evaluation of heavy-particle radiotherapy using dose volume histogram (DVH)].

PubMed

Terahara, A; Nakano, T; Tsujii, H

1998-01-01

Radiotherapy with heavy particles such as proton and heavy-charged particles is a promising modality for treatment of localized malignant tumors because of the good dose distribution. A dose calculation and radiotherapy planning system which is essential for this kind of treatment has been developed in recent years. It has the capability to compute the dose volume histogram (DVH) which contains dose-volume information for the target volume and other interesting volumes. Recently, DVH is commonly used to evaluate and compare dose distributions in radiotherapy with both photon and heavy particles, and it shows that a superior dose distribution is obtained in heavy particle radiotherapy. DVH is also utilized for the evaluation of dose distribution related to clinical outcomes. Besides models such as normal tissue complication probability (NTCP) and tumor control probability (TCP), which can be calculated from DVH are proposed by several authors, they are applied to evaluate dose distributions themselves and to evaluate them in relation to clinical results. DVH is now a useful and important tool, but further studies are needed to use DVH and these models practically for clinical evaluation of heavy-particle radiotherapy.

Normal tissue complication probability (NTCP) models for late rectal bleeding, stool frequency and fecal incontinence after radiotherapy in prostate cancer patients.

PubMed

Schaake, Wouter; van der Schaaf, Arjen; van Dijk, Lisanne V; Bongaerts, Alfons H H; van den Bergh, Alfons C M; Langendijk, Johannes A

2016-06-01

Curative radiotherapy for prostate cancer may lead to anorectal side effects, including rectal bleeding, fecal incontinence, increased stool frequency and rectal pain. The main objective of this study was to develop multivariable NTCP models for these side effects. The study sample was composed of 262 patients with localized or locally advanced prostate cancer (stage T1-3). Anorectal toxicity was prospectively assessed using a standardized follow-up program. Different anatomical subregions within and around the anorectum were delineated. A LASSO logistic regression analysis was used to analyze dose volume effects on toxicity. In the univariable analysis, rectal bleeding, increase in stool frequency and fecal incontinence were significantly associated with a large number of dosimetric parameters. The collinearity between these predictors was high (VIF>5). In the multivariable model, rectal bleeding was associated with the anorectum (V70) and anticoagulant use, fecal incontinence was associated with the external sphincter (V15) and the iliococcygeal muscle (V55). Finally, increase in stool frequency was associated with the iliococcygeal muscle (V45) and the levator ani (V40). No significant associations were found for rectal pain. Different anorectal side effects are associated with different anatomical substructures within and around the anorectum. The dosimetric variables associated with these side effects can be used to optimize radiotherapy treatment planning aiming at prevention of specific side effects and to estimate the benefit of new radiation technologies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity.

PubMed

Leslie, Elaine M; Watkins, Paul B; Kim, Richard B; Brouwer, Kim L R

2007-06-01

Bile acid accumulation in hepatocytes due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) has been proposed as a mechanism for bosentan-induced hepatotoxicity. The observation that bosentan does not induce hepatotoxicity in rats, although bosentan has been reported to inhibit rat Bsep and cause elevated serum bile acids, challenges this mechanism. The lack of hepatotoxicity could be explained if bosentan inhibited hepatocyte uptake as well as canalicular efflux of bile acids. In the current study, bosentan was found to be a more potent inhibitor of Na(+)-dependent taurocholate uptake in rat (IC(50) 5.4 microM) than human (IC(50) 30 microM) suspended hepatocytes. In addition, bosentan was a more potent inhibitor of taurocholate uptake by rat Na(+)-dependent taurocholate co-transporting polypeptide (Ntcp/Slc10a1) (IC(50) 0.71 microM) than human NTCP (SLC10A1) (IC(50) 24 microM) expressed in HEK293 cells. Thus, bosentan is a more potent inhibitor of Ntcp than NTCP, and this should result in less intrahepatocyte accumulation of bile acids in rats during bosentan treatment. To begin characterization of this species difference, two chimeric molecules were generated and expressed in HEK293 cells; NTCP(1-140)/Ntcp(141-362) and Ntcp(1-140)/NTCP(141-349). The mode of bosentan inhibition was noncompetitive for Ntcp, and competitive for NTCP (K(i) 18 microM) and NTCP(1-140)/Ntcp(141-362) (K(i) 1.7 microM); bosentan affected both the K(m) and V(max) of Ntcp(1-140)/NTCP(141-349) (K(i) 7.0 microM). The carboxyl portions of NTCP and Ntcp were found to confer species differences in basal taurocholate transport V(max). In conclusion, differential inhibition of Ntcp and NTCP may represent a novel mechanism for species differences in bosentan-induced hepatotoxicity.

Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes.

PubMed

König, Alexander; Döring, Barbara; Mohr, Christina; Geipel, Andreas; Geyer, Joachim; Glebe, Dieter

2014-10-01

The human liver bile acid transporter Na(+)/taurocholate cotransporting polypeptide (NTCP) has recently been identified as liver-specific receptor for infection of hepatitis B virus (HBV), which attaches via the myristoylated preS1 (myr-preS1) peptide domain of its large surface protein to NTCP. Since binding of the myr-preS1 peptide to NTCP is an initiating step of HBV infection, we investigated if this process interferes with the physiological bile acid transport function of NTCP. HBV infection, myr-preS1 peptide binding, and bile acid transport assays were performed with primary Tupaia belangeri (PTH) and human (PHH) hepatocytes as well as NTCP-transfected human hepatoma HepG2 cells allowing regulated NTCP expression, in the presence of various bile acids, ezetimibe, and myr-preS1 peptides. The myr-preS1 peptide of HBV inhibited bile acid transport in PTH and PHH as well as in NTCP-expressing HEK293 and HepG2 cells. Inversely, HBV infection of PTH, PHH, and NTCP-transfected HepG2 cells was inhibited in a concentration-dependent manner by taurine and glycine conjugates of cholic acid and ursodeoxycholic acid as well as by ezetimibe. In NTCP-HepG2 cells and PTH, NTCP expression, NTCP transport function, myr-preS1 peptide binding, and HBV infection followed comparable kinetics. Myr-preS1 virus binding to NTCP, necessary for productive HBV infection, interferes with the physiological bile acid transport function of NTCP. Therefore, HBV infection via NTCP may be lockable by NTCP substrates and NTCP-inhibiting drugs. This opens a completely new way for an efficient management of HBV infection by the use of NTCP-directed drugs. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Berberine-induced Inactivation of Signal Transducer and Activator of Transcription 5 Signaling Promotes Male-specific Expression of a Bile Acid Uptake Transporter*

PubMed Central

Bu, Pengli; Le, Yuan; Zhang, Yue; Zhang, Youcai; Cheng, Xingguo

2017-01-01

Sodium-taurocholate co-transporting polypeptide (Ntcp/NTCP) is the major uptake transporter of bile salts in mouse and human livers. In certain diseases, including endotoxemia, cholestasis, diabetes, and hepatocarcinoma, Ntcp/NTCP expression is markedly reduced, which interferes with enterohepatic circulation of bile salts, impairing the absorption of lipophilic compounds. Therefore, normal Ntcp/NTCP expression in the liver is physiologically important. Berberine is an herbal medicine used historically to improve liver function and has recently been shown to repress STAT signaling. However, berberine effects on Ntcp/NTCP expression are unknown, prompting use to investigate this possible connection. Our results showed that berberine dose-dependently increased Ntcp expression in male mouse liver and decreased taurocholic acid levels in serum but increased them in the liver. In mouse and human hepatoma cells, berberine induced Ntcp/NTCP mRNA and protein expression and increased cellular uptake of [3H] taurocholate. Mechanistically, berberine decreased nuclear protein levels of phospho-JAK2 and phospho-STAT5, thus disrupting the JAK2-STAT5 signaling. Moreover, berberine stimulated luciferase reporter expression from the mouse Ntcp promoter when one putative STAT5 response element (RE) (−1137 bp) was deleted and from the human NTCP promoter when three putative STAT5REs (−2898, −2164, and −691 bp) were deleted. Chromatin immunoprecipitation demonstrated that berberine decreased binding of phospho-STAT5 protein to the−2164 and −691 bp STAT5REs in the human NTCP promoter. In summary, berberine-disrupted STAT5 signaling promoted mouse and human Ntcp/NTCP expression, resulting in enhanced bile acid uptake. Therefore, berberine may be a therapeutic candidate compound for maintaining bile acid homeostasis. PMID:28154180

Berberine-induced Inactivation of Signal Transducer and Activator of Transcription 5 Signaling Promotes Male-specific Expression of a Bile Acid Uptake Transporter.

PubMed

Bu, Pengli; Le, Yuan; Zhang, Yue; Zhang, Youcai; Cheng, Xingguo

2017-03-17

Sodium-taurocholate co-transporting polypeptide (Ntcp/NTCP) is the major uptake transporter of bile salts in mouse and human livers. In certain diseases, including endotoxemia, cholestasis, diabetes, and hepatocarcinoma, Ntcp/NTCP expression is markedly reduced, which interferes with enterohepatic circulation of bile salts, impairing the absorption of lipophilic compounds. Therefore, normal Ntcp/NTCP expression in the liver is physiologically important. Berberine is an herbal medicine used historically to improve liver function and has recently been shown to repress STAT signaling. However, berberine effects on Ntcp/NTCP expression are unknown, prompting use to investigate this possible connection. Our results showed that berberine dose-dependently increased Ntcp expression in male mouse liver and decreased taurocholic acid levels in serum but increased them in the liver. In mouse and human hepatoma cells, berberine induced Ntcp/NTCP mRNA and protein expression and increased cellular uptake of [3H] taurocholate. Mechanistically, berberine decreased nuclear protein levels of phospho-JAK2 and phospho-STAT5, thus disrupting the JAK2-STAT5 signaling. Moreover, berberine stimulated luciferase reporter expression from the mouse Ntcp promoter when one putative STAT5 response element (RE) (-1137 bp) was deleted and from the human NTCP promoter when three putative STAT5REs (-2898, -2164, and -691 bp) were deleted. Chromatin immunoprecipitation demonstrated that berberine decreased binding of phospho-STAT5 protein to the-2164 and -691 bp STAT5REs in the human NTCP promoter. In summary, berberine-disrupted STAT5 signaling promoted mouse and human Ntcp/NTCP expression, resulting in enhanced bile acid uptake. Therefore, berberine may be a therapeutic candidate compound for maintaining bile acid homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular Determinants of Hepatitis B and D Virus Entry Restriction in Mouse Sodium Taurocholate Cotransporting Polypeptide

PubMed Central

Yan, Huan; Peng, Bo; He, Wenhui; Zhong, Guocai; Qi, Yonghe; Ren, Bijie; Gao, Zhenchao; Jing, Zhiyi; Song, Mei; Xu, Guangwei; Sui, Jianhua

2013-01-01

Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), primarily infect humans, chimpanzees, or tree shrews (Tupaia belangeri). Viral infections in other species are known to be mainly restricted at the entry level since viral replication can be achieved in the cells by transfection of the viral genome. Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for HBV and HDV, and amino acids 157 to 165 of NTCP are critical for viral entry and likely limit viral infection of macaques. However, the molecular determinants for viral entry restriction in mouse NTCP (mNTCP) remain unclear. In this study, mNTCP was found to be unable to support either HBV or HDV infection, although it can bind to pre-S1 of HBV L protein and is functional in transporting substrate taurocholate; comprehensive swapping and point mutations of human NTCP (hNTCP) and mNTCP revealed molecular determinants restricting mNTCP for viral entry of HBV and HDV. Remarkably, when mNTCP residues 84 to 87 were substituted by human counterparts, mNTCP can effectively support viral infections. In addition, a number of cell lines, regardless of their species or tissue origin, supported HDV infection when transfected with hNTCP or mNTCP with residues 84 to 87 replaced by human counterparts, highlighting the central role of NTCP for viral infections mediated by HBV envelope proteins. These studies advance our understanding of NTCP-mediated viral entry of HBV and HDV and have important implications for developing the mouse model for their infections. PMID:23678176

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning bymore » the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations.« less

WE-B-304-03: Biological Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orton, C.

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning bymore » the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations.« less

WE-B-304-02: Treatment Planning Evaluation and Optimization Should Be Biologically and Not Dose/volume Based

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deasy, J.

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning bymore » the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations.« less

WE-B-304-01: Treatment Planning Evaluation and Optimization Should Be Dose/volume and Not Biologically Based

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayo, C.

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning bymore » the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations.« less

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC: A direct comparison of PET-based treatment planning.

PubMed

Fleckenstein, Jochen; Kremp, Katharina; Kremp, Stephanie; Palm, Jan; Rübe, Christian

2016-02-01

The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D-CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels.

Dosimetric and radiobiological characterizations of prostate intensity-modulated radiotherapy and volumetric-modulated arc therapy: A single-institution review of ninety cases

PubMed Central

Khan, Muhammad Isa; Jiang, Runqing; Kiciak, Alexander; ur Rehman, Jalil; Afzal, Muhammad; Chow, James C. L.

2016-01-01

This study reviewed prostate volumetric-modulated arc therapy (VMAT) plans with intensity-modulated radiotherapy (IMRT) plans after prostate IMRT technique was replaced by VMAT in an institution. Characterizations of dosimetry and radiobiological variation in prostate were determined based on treatment plans of 40 prostate IMRT patients (planning target volume = 77.8–335 cm3) and 50 VMAT patients (planning target volume = 120–351 cm3) treated before and after 2013, respectively. Both IMRT and VMAT plans used the same dose-volume criteria in the inverse planning optimization. Dose-volume histogram, mean doses of target and normal tissues (rectum, bladder and femoral heads), dose-volume points (D99% of planning target volume; D30%, D50%, V30 Gy and V35 Gy of rectum and bladder; D5%, V14 Gy, V22 Gy of femoral heads), conformity index (CI), homogeneity index (HI), gradient index (GI), prostate tumor control probability (TCP), and rectal normal tissue complication probability (NTCP) based on the Lyman-Burman-Kutcher algorithm were calculated for each IMRT and VMAT plan. From our results, VMAT plan was found better due to its higher (1.05%) CI, lower (0.83%) HI and (0.75%) GI than IMRT. Comparing doses in normal tissues between IMRT and VMAT, it was found that IMRT mostly delivered higher doses of about 1.05% to the normal tissues than VMAT. Prostate TCP and rectal NTCP were found increased (1%) for VMAT than IMRT. It is seen that VMAT technique can decrease the dose-volume evaluation criteria for the normal tissues. Based on our dosimetric and radiobiological results in treatment plans, it is concluded that our VMAT implementation could produce comparable or slightly better target coverage and normal tissue sparing with a faster treatment time in prostate radiotherapy. PMID:27651562

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer

NASA Astrophysics Data System (ADS)

Tilly, N.; Johansson, J.; Isacsson, U.; Medin, J.; Blomquist, E.; Grusell, E.; Glimelius, B.

2005-06-01

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the αref/βref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE = 1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study—based on in vitro data since human tissue RBE values are scarce and have large uncertainties—can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance

PubMed Central

Kang, Jingting; Wang, Jie; Cheng, Jin; Cao, Zhiliang; Chen, Ran; Li, Huiyu; Liu, Shuang; Chen, Xiangmei; Sui, Jianhua; Lu, Fengmin

2017-01-01

The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a liver specific functional receptor for the hepatitis B virus (HBV). Previous studies indicated that the expression of NTCP may be associated with the proliferation status of hepatocytes. However, the involvement of NTCP in hepatocellular carcinoma (HCC) cells proliferation remains unclear. In this study, we confirmed that NTCP was down-regulated in HCC tumor tissues compared with that in the adjacent non-tumor tissues (P < 0.0001). Clinically, lower expression of NTCP was correlated with poor post-surgery survival rate (P = 0.0009) and larger tumor tissue mass (P = 0.003) of HCC patients. This was supported by the finding that ectopic expression of NTCP in both HepG2 and Huh-7 cells could significantly suppress hepatocytes growth by arresting cells in G0/G1 phase. We also discovered that cyclin D1 could transcriptionally suppress NTCP expression by inhibiting the activity of NTCP promoter, while arresting HCC cells in G0/G1 phase by serum starvation could upregulate NTCP mRNA levels. This is the first study to report that the transcriptional inhibition of NTCP expression during cell cycle progression was mediated by cyclin D1. The down-regulated NTCP expression was associated with poor prognosis and lower HBV cccDNA level in HCC patients. Therefore, NTCP expression levels might serve as a novel prognostic predictive marker for post-surgery survival rate of HCC patients. PMID:28915572

Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance.

PubMed

Kang, Jingting; Wang, Jie; Cheng, Jin; Cao, Zhiliang; Chen, Ran; Li, Huiyu; Liu, Shuang; Chen, Xiangmei; Sui, Jianhua; Lu, Fengmin

2017-08-22

The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a liver specific functional receptor for the hepatitis B virus (HBV). Previous studies indicated that the expression of NTCP may be associated with the proliferation status of hepatocytes. However, the involvement of NTCP in hepatocellular carcinoma (HCC) cells proliferation remains unclear. In this study, we confirmed that NTCP was down-regulated in HCC tumor tissues compared with that in the adjacent non-tumor tissues ( P < 0.0001). Clinically, lower expression of NTCP was correlated with poor post-surgery survival rate ( P = 0.0009) and larger tumor tissue mass ( P = 0.003) of HCC patients. This was supported by the finding that ectopic expression of NTCP in both HepG2 and Huh-7 cells could significantly suppress hepatocytes growth by arresting cells in G0/G1 phase. We also discovered that cyclin D1 could transcriptionally suppress NTCP expression by inhibiting the activity of NTCP promoter, while arresting HCC cells in G0/G1 phase by serum starvation could upregulate NTCP mRNA levels. This is the first study to report that the transcriptional inhibition of NTCP expression during cell cycle progression was mediated by cyclin D1. The down-regulated NTCP expression was associated with poor prognosis and lower HBV cccDNA level in HCC patients. Therefore, NTCP expression levels might serve as a novel prognostic predictive marker for post-surgery survival rate of HCC patients.

SU-F-T-132: Variable RBE Models Predict Possible Underestimation of Vaginal Dose for Anal Cancer Patients Treated Using Single-Field Proton Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNamara, A; Underwood, T; Wo, J

2016-06-15

Purpose: Anal cancer patients treated using a posterior proton beam may be at risk of vaginal wall injury due to the increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the beam distal edge. We investigate the vaginal dose received. Methods: Five patients treated for anal cancer with proton pencil beam scanning were considered, all treated to a prescription dose of 54 Gy(RBE) over 28–30 fractions. Dose and LET distributions were calculated using the Monte Carlo simulation toolkit TOPAS. In addition to the standard assumption of a fixed RBE of 1.1, variable RBE was considered via the applicationmore » of published models. Dose volume histograms (DVHs) were extracted for the planning treatment volume (PTV) and vagina, the latter being used to calculate the vaginal normal tissue complication probability (NTCP). Results: Compared to the assumption of a fixed RBE of 1.1, the variable RBE model predicts a dose increase of approximately 3.3 ± 1.7 Gy at the end of beam range. NTCP parameters for the vagina are incomplete in the current literature, however, inferring value ranges from the existing data we use D{sub 50} = 50 Gy and LKB model parameters a=1–2 and m=0.2–0.4. We estimate the NTCP for the vagina to be 37–48% and 42–47% for the fixed and variable RBE cases, respectively. Additionally, a difference in the dose distribution was observed between the analytical calculation and Monte Carlo methods. We find that the target dose is overestimated on average by approximately 1–2%. Conclusion: For patients treated with posterior beams, the vaginal wall may coincide with the distal end of the proton beam and may receive a substantial increase in dose if variable RBE models are applied compared to using the current clinical standard of RBE equal to 1.1. This could potentially lead to underestimating toxicities when treating with protons.« less

Comparison of PDR brachytherapy and external beam radiation therapy in the case of breast cancer

NASA Astrophysics Data System (ADS)

Teymournia, L.; Berger, D.; Kauer-Dorner, D.; Poljanc, K.; Seitz, W.; Aiginger, H.; Kirisits, C.

2009-04-01

Pulsed dose rate brachytherapy (PDR) was compared to external beam radiation therapy (EBRT) in the case of breast cancer. The benefits were figured out by evaluation of dosimetric parameters and calculating the normal tissue complication probability (NTCP). PDR plans were set up for five randomly chosen left-sided breast cancer patients delivering a total dose of 50.4 Gy to the target (dose rate 0.8 Gy h-1). For EBRT five left-sided breast cancer patients were planned using 3D-conformal tangential photon beams with a prescribed total dose of 50 Gy (2 Gy/fraction) to the total breast volume. For plan ranking and NTCP calculation the physical dose was first converted into the biologically effective dose (BED) and then into the normalized total dose (NTD) using the linear quadratic model with an α/β ratio of 3 Gy. In PDR the relative effectiveness (RE) was calculated for each dose bin of the differential dose volume histogram to get the BED. NTCPs were calculated for the ipsilateral lung and the heart as contoured on CT slices based on the Lyman model and the Kutcher reduction scheme. Dosimetric parameters as Vth (percentage of the total volume exceeding a threshold dose) and Jackson's fdam (fraction of the organ damaged) were also used to figure out the benefits. The comparison of calculated NTCPs in PDR and EBRT showed no difference between these two modalities. All values were below 0.01%. fdam derived from EBRT was always higher (mean value 8.95% versus 1.21% for the lung). The mean V10 and V20 of the lung related to BED were 6.32% and 1.72% for PDR versus 11.72% and 9.59% for EBRT. When using dosimetric parameters as Vth and fdam, PDR was mostly superior to EBRT in respect of sparing normal tissues. NTCP calculation as a single method of modality ranking showed a lack of information, especially when normal tissue was exposed to low radiation doses.

SU-F-T-388: Comparison of Biophysical Indices in Hippocampal-Avoidance Whole Brain VMAT and IMRT Radiation Therapy Treatment Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendall, E; Ahmad, S; Algan, O

2016-06-15

Purpose: To compare biophysical indices of Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) treatment plans for whole brain radiation therapy following the NRG-CC001 protocol. Methods: In this retrospective study, a total of fifteen patients were planned with Varian Eclipse Treatment Planning System using VMAT (RapidArc) and IMRT techniques. The planning target volume (PTV) was defined as the whole brain volume excluding a uniform three-dimensional 5mm expansion of the hippocampus volume. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 95% of the target volume receiving 100% of themore » prescribed dose. The NRG Oncology protocol guidelines were followed for contouring and dose-volume constraints. A single radiation oncologist evaluated all treatment plans. Calculations of statistical significance were performed using Student’s paired t-test. Results: All VMAT and IMRT plans met the NRG-CC001 protocol dose-volume criteria. The average equivalent uniform dose (EUD) for the PTV for VMAT vs. IMRT was respectively (19.05±0.33 Gy vs. 19.38±0.47 Gy) for α/β of 2 Gy and (19.47±0.30 Gy vs. 19.84±0.42 Gy) for α/β of 10 Gy. For the PTV, the average mean and maximum doses were 2% and 5% lower in VMAT plans than in IMRT plans, respectively. The average EUD and the normal tissue complication probability (NTCP) for the hippocampus in VMAT vs. IMRT plans were (15.28±1.35 Gy vs. 15.65±0.99 Gy, p=0.18) and (0.305±0.012 Gy vs. 0.308±0.008 Gy, p=0.192), respectively. The average EUD and NTCP for the optic chiasm were both 2% higher in VMAT than in IMRT plans. Conclusion: Though statistically insignificant, VMAT plans indicate a lower hippocampus EUD than IMRT plans. Also, a small variation in NTCP was found between plans.« less

Using Multivariate Regression Model with Least Absolute Shrinkage and Selection Operator (LASSO) to Predict the Incidence of Xerostomia after Intensity-Modulated Radiotherapy for Head and Neck Cancer

PubMed Central

Ting, Hui-Min; Chang, Liyun; Huang, Yu-Jie; Wu, Jia-Ming; Wang, Hung-Yu; Horng, Mong-Fong; Chang, Chun-Ming; Lan, Jen-Hong; Huang, Ya-Yu; Fang, Fu-Min; Leung, Stephen Wan

2014-01-01

Purpose The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT. Methods and Materials Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3+ xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER3m) and 12 months (XER12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R2, chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC. Results Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R2 was satisfactory and corresponded well with the expected values. Conclusions Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT. PMID:24586971

Using multivariate regression model with least absolute shrinkage and selection operator (LASSO) to predict the incidence of Xerostomia after intensity-modulated radiotherapy for head and neck cancer.

PubMed

Lee, Tsair-Fwu; Chao, Pei-Ju; Ting, Hui-Min; Chang, Liyun; Huang, Yu-Jie; Wu, Jia-Ming; Wang, Hung-Yu; Horng, Mong-Fong; Chang, Chun-Ming; Lan, Jen-Hong; Huang, Ya-Yu; Fang, Fu-Min; Leung, Stephen Wan

2014-01-01

The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT. Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER3m) and 12 months (XER12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R(2), chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC. Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R(2) was satisfactory and corresponded well with the expected values. Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT.

A dileucine motif is involved in plasma membrane expression and endocytosis of rat sodium taurocholate cotransporting polypeptide (Ntcp).

PubMed

Stross, Claudia; Kluge, Stefanie; Weissenberger, Katrin; Winands, Elisabeth; Häussinger, Dieter; Kubitz, Ralf

2013-11-15

The sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake transporter for bile salts into liver parenchymal cells, and PKC-mediated endocytosis was shown to regulate the number of Ntcp molecules at the plasma membrane. In this study, mechanisms of Ntcp internalization were analyzed by flow cytometry, immunofluorescence, and Western blot analyses in HepG2 cells. PKC activation induced endocytosis of Ntcp from the plasma membrane by ~30%. Endocytosis of Ntcp was clathrin dependent and was followed by lysosomal degradation. A dileucine motif located in the third intracellular loop of Ntcp was essential for endocytosis but also for processing and plasma membrane targeting, suggesting a dual function of this motif for intracellular trafficking of Ntcp. Mutation of two of five potential phosphorylation sites surrounding the dileucine motif (Thr225 and Ser226) inhibited PKC-mediated endocytosis. In conclusion, we could identify a motif, which is critical for Ntcp plasma membrane localization. Endocytic retrieval protects hepatocytes from elevated bile salt concentrations and is of special interest, because NTCP has been identified as a receptor for the hepatitis B and D virus.

Cysteine 96 of Ntcp is responsible for NO-mediated inhibition of taurocholate uptake.

PubMed

Ramasamy, Umadevi; Anwer, M Sawkat; Schonhoff, Christopher M

2013-10-01

The Na(+) taurocholate (TC) cotransporting polypeptide Ntcp/NTCP mediates TC uptake across the sinusoidal membrane of hepatocytes. Previously, we demonstrated that nitric oxide (NO) inhibits TC uptake through S-nitrosylation of a cysteine residue. Our current aim was to determine which of the eight cysteine residues of Ntcp is responsible for NO-mediated S-nitrosylation and inhibition of TC uptake. Thus, we tested the effect of NO on TC uptake in HuH-7 cells transiently transfected with cysteine-to-alanine mutant Ntcp constructs. Of the eight mutants tested, only C44A Ntcp displayed decreased total and plasma membrane (PM) levels that were also reflected in decreased TC uptake. C266A Ntcp showed a decrease in TC uptake that was not explained by a decrease in total expression or PM localization, indicating that C266 is required for optimal uptake. We speculated that NO would target C266 since a previous report had shown the thiol reactive compound [2-(trimethylammonium) ethyl] methanethiosulfonate bromide (MTSET) inhibits TC uptake by wild-type NTCP but not by C266A NTCP. We confirmed that MTSET targets C266 of Ntcp, but, surprisingly, we found that C266 was not responsible for NO-mediated inhibition of TC uptake. Instead, we found that C96 was targeted by NO since C96A Ntcp was insensitive to NO-mediated inhibition of TC uptake. We also found that wild-type but not C96A Ntcp is S-nitrosylated by NO, suggesting that C96 is important in regulating Ntcp function in response to elevated levels of NO.

Cysteine 96 of Ntcp is responsible for NO-mediated inhibition of taurocholate uptake

PubMed Central

Ramasamy, Umadevi; Anwer, M. Sawkat

2013-01-01

The Na+ taurocholate (TC) cotransporting polypeptide Ntcp/NTCP mediates TC uptake across the sinusoidal membrane of hepatocytes. Previously, we demonstrated that nitric oxide (NO) inhibits TC uptake through S-nitrosylation of a cysteine residue. Our current aim was to determine which of the eight cysteine residues of Ntcp is responsible for NO-mediated S-nitrosylation and inhibition of TC uptake. Thus, we tested the effect of NO on TC uptake in HuH-7 cells transiently transfected with cysteine-to-alanine mutant Ntcp constructs. Of the eight mutants tested, only C44A Ntcp displayed decreased total and plasma membrane (PM) levels that were also reflected in decreased TC uptake. C266A Ntcp showed a decrease in TC uptake that was not explained by a decrease in total expression or PM localization, indicating that C266 is required for optimal uptake. We speculated that NO would target C266 since a previous report had shown the thiol reactive compound [2-(trimethylammonium) ethyl] methanethiosulfonate bromide (MTSET) inhibits TC uptake by wild-type NTCP but not by C266A NTCP. We confirmed that MTSET targets C266 of Ntcp, but, surprisingly, we found that C266 was not responsible for NO-mediated inhibition of TC uptake. Instead, we found that C96 was targeted by NO since C96A Ntcp was insensitive to NO-mediated inhibition of TC uptake. We also found that wild-type but not C96A Ntcp is S-nitrosylated by NO, suggesting that C96 is important in regulating Ntcp function in response to elevated levels of NO. PMID:23886862

The Na+-Taurocholate Cotransporting Polypeptide Traffics with the Epidermal Growth Factor Receptor

PubMed Central

Wang, Xintao; Wang, Pijun; Wang, Wenjun; Murray, John W.; Wolkoff, Allan W.

2015-01-01

Na+-taurocholate cotransporting polypeptide (ntcp) mediates uptake of bile acids as well as serving as the receptor for hepatitis B virus in human liver. Previous studies showed that ntcp traffics on microtubules between the cell surface and endocytic vesicles. Specific inhibition of protein kinase C (PKC)ζ resulted in loss of microtubule-based motility of these vesicles in vitro and in living cells. The aim of the present study was to characterize the PKCζ target. Incubation of ntcp-containing endocytic vesicles with γ-32P-ATP revealed a 180 kDa phosphoglycoprotein that was identified as the EGF receptor (EGFR). Surface biotinylation of HuH7 cells expressing GFP-ntcp revealed substantially reduced trafficking of ntcp to the cell surface with EGFR knockdown. Microtubule-based motility of ntcp-containing endocytic vesicles was also significantly reduced when they were not associated with EGFR. Ntcp was also found to undergo cellular redistribution upon stimulation of cells with EGF, consistent with a model in which ntcp and EGF-EGFR internalize into common endocytic vesicles from which they segregate, trafficking EGF-EGFR to lysosomes and recycling ntcp to the plasma membrane. EGF regulation of ntcp trafficking may play a heretofore unanticipated role in subcellular targeting of ntcp ligands such as hepatitis B. PMID:26650232

Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).

PubMed

Dong, Zhongqi; Ekins, Sean; Polli, James E

2013-03-04

The hepatic bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP) is less well characterized than its ileal paralog, the apical sodium dependent bile acid transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were (a) to identify FDA approved drugs that inhibit human NTCP, (b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and (c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe (Ki = 25.0 μM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations.

A Substrate Pharmacophore for the Human Sodium Taurocholate Co-transporting Polypeptide

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2014-01-01

Human Sodium Taurocholate Co-transporting Polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition. PMID:25448570

Quantitative NTCP Pharmacophore and Lack of Association between DILI and NTCP Inhibition

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2014-01-01

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. PMID:25220493

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition.

PubMed

Dong, Zhongqi; Ekins, Sean; Polli, James E

2015-01-23

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors.

PubMed

Choi, Min-Koo; Shin, Ho Jung; Choi, Young-Lim; Deng, Jian-Wei; Shin, Jae-Gook; Song, Im-Sook

2011-01-01

The purpose of this study was to investigate the effect of genetic variations in organic anion-transporting polypeptide 1B1 (OATP1B1) and Na(+)/taurocholate co-transporting polypeptide (NTCP) on the uptake of various statins having different affinities for these transporters. The functional activities and simultaneous expression of NTCP and OATP1B1 were confirmed by the uptake of taurocholate and estrone-3-sulphate as representative substrates for NTCP and OATP1B1, respectively, and by an immunofluorescence analysis. The substrate specificities of NTCP and OATP1B1 for statins and the effects of genetic variations on the uptake of rosuvastatin, pitavastatin, and atorvastatin were measured. Based on the K(m) values and intrinsic clearances of the three statins, pitavastatin was taken up more efficiently than rosuvastatin and atorvastatin by OATP1B1. Consequently, the cellular accumulation of pitavastatin was modulated according to the genetic variation of OATP1B1 (OATP1B1*15), rather than NTCP*2. In contrast, NTCP*2 displayed greater transport of atorvastatin and rosuvastatin, compared with NTCP wild type. Thus, the measurements of decreased rosuvastatin and atorvastatin transport by OATP1B1*15 were confounded by the presence of NTCP and its genetic variant, NTCP*2. In conclusion, the functional consequences of genetic variants of NTCP and OATP1B1 may be different for various statins, depending on the substrate specificity of the OATP1B1 and NTCP transporters.

Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP.

PubMed

Schonhoff, Christopher M; Ramasamy, Umadevi; Anwer, M Sawkat

2011-02-01

The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na(+)-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na(+)-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Using a human hepatoma cell line stably expressing NTCP (HuH-NTCP), we performed experiments with the NO donors sodium nitroprusside and S-nitrosocysteine and demonstrated that NO inhibits TC uptake in these cells. Kinetic analyses revealed that NO significantly decreased the V(max) but not the K(m) of TC uptake by NTCP, indicating noncompetitive inhibition. NO decreased the amount of NTCP in the plasma membrane, providing a molecular mechanism for the noncompetitive inhibition of TC uptake. One way that NO can modify protein function is through a posttranslational modification known as S-nitrosylation: the binding of NO to cysteine thiols. Using a biotin switch technique we observed that NTCP is S-nitrosylated under conditions in which NO inhibits TC uptake. Moreover, dithiothreitol reversed NO-mediated inhibition of TC uptake and S-nitrosylation of NTCP, indicating that NO inhibits TC uptake via modification of cysteine thiols. In addition, NO treatment led to a decrease in Ntcp phosphorylation. Taken together these results indicate that the inhibition of TC uptake by NO involves S-nitrosylation of NTCP.

PKCzeta is required for microtubule-based motility of vesicles containing the ntcp transporter.

PubMed

Sarkar, Souvik; Bananis, Eustratios; Nath, Sangeeta; Anwer, M Sawkat; Wolkoff, Allan W; Murray, John W

2006-08-01

Intracellular trafficking regulates the abundance and therefore activity of transporters present at the plasma membrane. The transporter, Na+-taurocholate co-transporting polypeptide (ntcp), is increased at the plasma membrane upon treatment of cells with cAMP, for which microtubules (MTs) are required and the PI3K pathway and PKCzeta have been implicated. However, trafficking of ntcp on MTs has not been demonstrated directly and the regulation and intracellular localization of ntcp is not well understood. Here, we utilize in vitro and whole-cell immunofluorescence microscopy assays to demonstrate that ntcp is present on intracellular vesicles that bind MTs and move bidirectionally, using kinesin-1 and dynein. These vesicles co-localize with markers for recycling endosomes and early but not late endosomes. They frequently undergo fission, providing a mechanism for the exclusion of ntcp from late endosomes. PI(3,4,5)P3 activates PKCzeta and enhances motility of the ntcp vesicles and overcomes the partial inhibition produced by a PI3-kinase inhibitor. Specific inhibition of PKCzeta blocks the motility of ntcp-containing vesicles but has no effect on late vesicles as shown both in vitro and in living cells transfected with ntcp-GFP. These data indicate that PKCzeta is required specifically for the intracellular movement of vesicles that contain the ntcp transporter.

Regulation of hepatic bile acid transporters Ntcp and Bsep expression.

PubMed

Cheng, Xingguo; Buckley, David; Klaassen, Curtis D

2007-12-03

Sodium-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) are two key transporters for hepatic bile acid uptake and excretion. Alterations in Ntcp and Bsep expression have been reported in pathophysiological conditions. In the present study, the effects of age, gender, and various chemicals on the regulation of these two transporters were characterized in mice. Ntcp and Bsep mRNA levels in mouse liver were low in the fetus, but increased to its highest expression at parturition. After birth, mouse Ntcp and Bsep mRNA decreased by more than 50%, and then gradually increased to adult levels by day 30. Expression of mouse Ntcp mRNA and protein exhibit higher levels in female than male livers. No gender difference exists in BSEP/Bsep expression in human and mouse livers. Hormone replacements conducted in gonadectomized, hypophysectomized, and lit/lit mice indicate that female-predominant Ntcp expression in mouse liver is due to the inhibitory effect of male-pattern GH secretion, but not sex hormones. Ntcp and Bsep expression are in general resistant to induction by a large battery of microsomal enzyme inducers. Administration of cholestyramine increased Ntcp, whereas chenodeoxycholic acid (CDCA) increased Bsep mRNA expression. In conclusion, mouse Ntcp and Bsep are regulated by age, gender, cholestyramine, and bile acid, but resistant to induction by most microsomal enzyme inducers.

Evaluation of a mixed beam therapy for post-mastectomy breast cancer patients: bolus electron conformal therapy combined with intensity modulated photon radiotherapy and volumetric modulated photon arc therapy.

PubMed

Zhang, Rui; Heins, David; Sanders, Mary; Guo, Beibei; Hogstrom, Kenneth

2018-05-10

The purpose of this study was to assess the potential benefits and limitations of a mixed beam therapy, which combined bolus electron conformal therapy (BECT) with intensity modulated photon radiotherapy (IMRT) and volumetric modulated photon arc therapy (VMAT), for left-sided post-mastectomy breast cancer patients. Mixed beam treatment plans were produced for nine post-mastectomy radiotherapy (PMRT) patients previously treated at our clinic with VMAT alone. The mixed beam plans consisted of 40 Gy to the chest wall area using BECT, 40 Gy to the supraclavicular area using parallel opposed IMRT, and 10 Gy to the total planning target volume (PTV) by optimizing VMAT on top of the BECT+IMRT dose distribution. The treatment plans were created in a commercial treatment planning system (TPS), and all plans were evaluated based on PTV coverage, dose homogeneity index (DHI), conformity index (CI), dose to organs at risk (OARs), normal tissue complication probability (NTCP), and secondary cancer complication probability (SCCP). The standard VMAT alone planning technique was used as the reference for comparison. Both techniques produced clinically acceptable PMRT plans but with a few significant differences: VMAT showed significantly better CI (0.70 vs. 0.53, p < 0.001) and DHI (0.12 vs. 0.20, p < 0.001) over mixed beam therapy. For normal tissues, mixed beam therapy showed better OAR sparing and significantly reduced NTCP for cardiac mortality (0.23% vs. 0.80%, p = 0.01) and SCCP for contralateral breast (1.7% vs. 3.1% based on linear model, and 1.2% vs. 1.9% based on linear-exponential model, p < 0.001 in both cases), but showed significantly higher mean (50.8 Gy vs. 49.3 Gy, p < 0.001) and maximum skin doses (59.7 Gy vs. 53.3 Gy, p < 0.001) compared with VMAT. Patients with more tissue (minimum distance between the distal PTV surface and lung approximately > 0.5 cm and volume of tissue between the distal PTV surface and heart or lung approximately > 250 cm 3 ) between distal PTV surface and lung may benefit the most from mixed beam therapy. This work has demonstrated that mixed beam therapy (BECT+IMRT : VMAT = 4 : 1) produces clinically acceptable plans having reduced OAR doses and risks of side effects compared with VMAT. Even though VMAT alone produces more homogenous and conformal dose distributions, mixed beam therapy remains as a viable option for treating post-mastectomy patients, possibly leading to reduced normal tissue complications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression.

PubMed

Tsukuda, Senko; Watashi, Koichi; Iwamoto, Masashi; Suzuki, Ryosuke; Aizaki, Hideki; Okada, Maiko; Sugiyama, Masaya; Kojima, Soichi; Tanaka, Yasuhito; Mizokami, Masashi; Li, Jisu; Tong, Shuping; Wakita, Takaji

2015-02-27

Sodium taurocholate cotransporting polypeptide (NTCP) is an entry receptor for hepatitis B virus (HBV) and is regarded as one of the determinants that confer HBV permissiveness to host cells. However, how host factors regulate the ability of NTCP to support HBV infection is largely unknown. We aimed to identify the host signaling that regulated NTCP expression and thereby permissiveness to HBV. Here, a cell-based chemical screening method identified that Ro41-5253 decreased host susceptibility to HBV infection. Pretreatment with Ro41-5253 inhibited the viral entry process without affecting HBV replication. Intriguingly, Ro41-5253 reduced expression of both NTCP mRNA and protein. We found that retinoic acid receptor (RAR) regulated the promoter activity of the human NTCP (hNTCP) gene and that Ro41-5253 repressed the hNTCP promoter by antagonizing RAR. RAR recruited to the hNTCP promoter region, and nucleotides -112 to -96 of the hNTCP was suggested to be critical for RAR-mediated transcriptional activation. HBV susceptibility was decreased in pharmacologically RAR-inactivated cells. CD2665 showed a stronger anti-HBV potential and disrupted the spread of HBV infection that was achieved by continuous reproduction of the whole HBV life cycle. In addition, this mechanism was significant for drug development, as antagonization of RAR blocked infection of multiple HBV genotypes and also a clinically relevant HBV mutant that was resistant to nucleoside analogs. Thus, RAR is crucial for regulating NTCP expression that determines permissiveness to HBV infection. This is the first demonstration showing host regulation of NTCP to support HBV infection. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Heterogeneous accumulation of fluorescent bile acids in primary rat hepatocytes does not correlate with their homogenous expression of ntcp.

PubMed

Murray, John W; Thosani, Amar J; Wang, Pijun; Wolkoff, Allan W

2011-07-01

Sodium taurocholate-cotransporting polypeptide (ntcp) is considered to be a major determinant of bile acid uptake into hepatocytes. However, the regulation of ntcp and the degree that it participates in the accumulation of specific substrates are not well understood. We utilized fluorescent bile acid derivatives and direct quantitation of fluorescent microscopy images to examine the regulation of ntcp and its role in the cell-to-cell variability of fluorescent bile acid accumulation. Primary-cultured rat hepatocytes rapidly accumulated the fluorescent bile acids, chenodeoxycholylglycylamidofluorescein (CDCGamF), 7-β- nitrobenzoxadiazole 3-α hydroxy 5-β cholan-24-oic acid (NBD-CA), and cholyl-glycylamido-fluorescein (CGamF). However, in stably transfected HeLa cells, ntcp preferred CDCGamF, whereas the organic anion transporter, organic anion transporting polypeptide 1 (oatp1a1), preferred NBD-CA, and neither ntcp nor oatp1a1 showed strong accumulation of CGamF by these methods. Ntcp-mediated transport of CDCGamF was inhibited by taurocholate, cyclosporin, actin depolymerization, and an inhibitor of atypical PKC-ζ. The latter two agents altered the cellular distribution of ntcp as visualized in ntcp-green fluorescent protein-transfected cells. Although fluorescent bile acid accumulation was reproducible by the imaging assays, individual cells showed variable accumulation that was not attributable to changes in membrane permeability or cell viability. In HeLa cells, this was accounted for by variable levels of ntcp, whereas, in hepatocytes, ntcp expression was uniform, and low accumulation was seen in a large portion of cells despite the presence of ntcp. These studies indicate that single-cell imaging can provide insight into previously unrecognized details of anion transport in the complex environment of polarized hepatocytes.

Dysregulation of Retinoic Acid Receptor Diminishes Hepatocyte Permissiveness to Hepatitis B Virus Infection through Modulation of Sodium Taurocholate Cotransporting Polypeptide (NTCP) Expression*

PubMed Central

Tsukuda, Senko; Watashi, Koichi; Iwamoto, Masashi; Suzuki, Ryosuke; Aizaki, Hideki; Okada, Maiko; Sugiyama, Masaya; Kojima, Soichi; Tanaka, Yasuhito; Mizokami, Masashi; Li, Jisu; Tong, Shuping; Wakita, Takaji

2015-01-01

Sodium taurocholate cotransporting polypeptide (NTCP) is an entry receptor for hepatitis B virus (HBV) and is regarded as one of the determinants that confer HBV permissiveness to host cells. However, how host factors regulate the ability of NTCP to support HBV infection is largely unknown. We aimed to identify the host signaling that regulated NTCP expression and thereby permissiveness to HBV. Here, a cell-based chemical screening method identified that Ro41-5253 decreased host susceptibility to HBV infection. Pretreatment with Ro41-5253 inhibited the viral entry process without affecting HBV replication. Intriguingly, Ro41-5253 reduced expression of both NTCP mRNA and protein. We found that retinoic acid receptor (RAR) regulated the promoter activity of the human NTCP (hNTCP) gene and that Ro41-5253 repressed the hNTCP promoter by antagonizing RAR. RAR recruited to the hNTCP promoter region, and nucleotides −112 to −96 of the hNTCP was suggested to be critical for RAR-mediated transcriptional activation. HBV susceptibility was decreased in pharmacologically RAR-inactivated cells. CD2665 showed a stronger anti-HBV potential and disrupted the spread of HBV infection that was achieved by continuous reproduction of the whole HBV life cycle. In addition, this mechanism was significant for drug development, as antagonization of RAR blocked infection of multiple HBV genotypes and also a clinically relevant HBV mutant that was resistant to nucleoside analogs. Thus, RAR is crucial for regulating NTCP expression that determines permissiveness to HBV infection. This is the first demonstration showing host regulation of NTCP to support HBV infection. PMID:25550158

Heterogeneous accumulation of fluorescent bile acids in primary rat hepatocytes does not correlate with their homogenous expression of ntcp

PubMed Central

Thosani, Amar J.; Wang, Pijun; Wolkoff, Allan W.

2011-01-01

Sodium taurocholate-cotransporting polypeptide (ntcp) is considered to be a major determinant of bile acid uptake into hepatocytes. However, the regulation of ntcp and the degree that it participates in the accumulation of specific substrates are not well understood. We utilized fluorescent bile acid derivatives and direct quantitation of fluorescent microscopy images to examine the regulation of ntcp and its role in the cell-to-cell variability of fluorescent bile acid accumulation. Primary-cultured rat hepatocytes rapidly accumulated the fluorescent bile acids, chenodeoxycholylglycylamidofluorescein (CDCGamF), 7-β- nitrobenzoxadiazole 3-α hydroxy 5-β cholan-24-oic acid (NBD-CA), and cholyl-glycylamido-fluorescein (CGamF). However, in stably transfected HeLa cells, ntcp preferred CDCGamF, whereas the organic anion transporter, organic anion transporting polypeptide 1 (oatp1a1), preferred NBD-CA, and neither ntcp nor oatp1a1 showed strong accumulation of CGamF by these methods. Ntcp-mediated transport of CDCGamF was inhibited by taurocholate, cyclosporin, actin depolymerization, and an inhibitor of atypical PKC-ζ. The latter two agents altered the cellular distribution of ntcp as visualized in ntcp-green fluorescent protein-transfected cells. Although fluorescent bile acid accumulation was reproducible by the imaging assays, individual cells showed variable accumulation that was not attributable to changes in membrane permeability or cell viability. In HeLa cells, this was accounted for by variable levels of ntcp, whereas, in hepatocytes, ntcp expression was uniform, and low accumulation was seen in a large portion of cells despite the presence of ntcp. These studies indicate that single-cell imaging can provide insight into previously unrecognized details of anion transport in the complex environment of polarized hepatocytes. PMID:21474652

Interleukin 6 inhibits HBV entry through NTCP down regulation.

PubMed

Bouezzedine, Fidaa; Fardel, Olivier; Gripon, Philippe

2015-07-01

Hepatitis B virus (HBV) infection is a major public health problem. Recently, the human liver bile acid transporter Na(+)/taurocholate cotransporting polypeptide (NTCP) has been identified as an HBV specific receptor. NTCP expression is known to be strongly regulated by IL-6. This study was aimed at characterizing the effect of IL-6 on HBV entry. HBV entry was inhibited by up to 90% when cells were pretreated with IL-6 as shown by a strong inhibition of long term HBsAg secretion. This effect was confirmed by showing a severe reduction of intracellular HBV cccDNA. In parallel, we observed a 98% decrease in NTCP mRNA steady state level and an 80% reduction in NTCP-mediated taurocholate uptake. IL-6-mediated inhibition of NTCP-mediated taurocholate uptake and viral entry exhibited similar dose-dependence and kinetics while restoration of NTCP expression suppressed the inhibitory effect of IL-6. NTCP-mediated HBV entry is therefore markedly inhibited by IL-6. Copyright © 2015 Elsevier Inc. All rights reserved.

Protein kinase Cδ differentially regulates cAMP-dependent translocation of NTCP and MRP2 to the plasma membrane

PubMed Central

Park, Se Won; Schonhoff, Christopher M.; Webster, Cynthia R. L.

2012-01-01

Cyclic AMP stimulates translocation of Na+/taurocholate cotransporting polypeptide (NTCP) from the cytosol to the sinusoidal membrane and multidrug resistance-associated protein 2 (MRP2) to the canalicular membrane. A recent study suggested that protein kinase Cδ (PKCδ) may mediate cAMP-induced translocation of Ntcp and Mrp2. In addition, cAMP has been shown to stimulate NTCP translocation in part via Rab4. The aim of this study was to determine whether cAMP-induced translocation of NTCP and MRP2 require kinase activity of PKCδ and to test the hypothesis that cAMP-induced activation of Rab4 is mediated via PKCδ. Studies were conducted in HuH-NTCP cells (HuH-7 cells stably transfected with NTCP). Transfection of cells with wild-type PKCδ increased plasma membrane PKCδ and NTCP and increased Rab4 activity. Paradoxically, overexpression of kinase-dead dominant-negative PKCδ also increased plasma membrane PKCδ and NTCP as well as Rab4 activity. Similar results were obtained in PKCδ knockdown experiments, despite a decrease in total PKCδ. These results raised the possibility that plasma membrane localization rather than kinase activity of PKCδ is necessary for NTCP translocation and Rab4 activity. This hypothesis was supported by results showing that rottlerin, which has previously been shown to inhibit cAMP-induced membrane translocation of PKCδ and NTCP, inhibited cAMP-induced Rab4 activity. In addition, LY294002 (a phosphoinositide-3-kinase inhibitor), which has been shown to inhibit cAMP-induced NTCP translocation, also inhibited cAMP-induced PKCδ translocation. In contrast to the results with NTCP, cAMP-induced MRP2 translocation was inhibited in cells transfected with DN-PKCδ and small interfering RNA PKCδ. Taken together, these results suggest that the plasma membrane localization rather than kinase activity of PKCδ plays an important role in cAMP-induced NTCP translocation and Rab4 activity, whereas the kinase activity of PKCδ is necessary for cAMP-induced MRP2 translocation. PMID:22744337

Protein kinase Cδ differentially regulates cAMP-dependent translocation of NTCP and MRP2 to the plasma membrane.

PubMed

Park, Se Won; Schonhoff, Christopher M; Webster, Cynthia R L; Anwer, M Sawkat

2012-09-01

Cyclic AMP stimulates translocation of Na(+)/taurocholate cotransporting polypeptide (NTCP) from the cytosol to the sinusoidal membrane and multidrug resistance-associated protein 2 (MRP2) to the canalicular membrane. A recent study suggested that protein kinase Cδ (PKCδ) may mediate cAMP-induced translocation of Ntcp and Mrp2. In addition, cAMP has been shown to stimulate NTCP translocation in part via Rab4. The aim of this study was to determine whether cAMP-induced translocation of NTCP and MRP2 require kinase activity of PKCδ and to test the hypothesis that cAMP-induced activation of Rab4 is mediated via PKCδ. Studies were conducted in HuH-NTCP cells (HuH-7 cells stably transfected with NTCP). Transfection of cells with wild-type PKCδ increased plasma membrane PKCδ and NTCP and increased Rab4 activity. Paradoxically, overexpression of kinase-dead dominant-negative PKCδ also increased plasma membrane PKCδ and NTCP as well as Rab4 activity. Similar results were obtained in PKCδ knockdown experiments, despite a decrease in total PKCδ. These results raised the possibility that plasma membrane localization rather than kinase activity of PKCδ is necessary for NTCP translocation and Rab4 activity. This hypothesis was supported by results showing that rottlerin, which has previously been shown to inhibit cAMP-induced membrane translocation of PKCδ and NTCP, inhibited cAMP-induced Rab4 activity. In addition, LY294002 (a phosphoinositide-3-kinase inhibitor), which has been shown to inhibit cAMP-induced NTCP translocation, also inhibited cAMP-induced PKCδ translocation. In contrast to the results with NTCP, cAMP-induced MRP2 translocation was inhibited in cells transfected with DN-PKCδ and small interfering RNA PKCδ. Taken together, these results suggest that the plasma membrane localization rather than kinase activity of PKCδ plays an important role in cAMP-induced NTCP translocation and Rab4 activity, whereas the kinase activity of PKCδ is necessary for cAMP-induced MRP2 translocation.

Functional Data Analysis in NTCP Modeling: A New Method to Explore the Radiation Dose-Volume Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benadjaoud, Mohamed Amine, E-mail: mohamedamine.benadjaoud@gustaveroussy.fr; Université Paris sud, Le Kremlin-Bicêtre; Institut Gustave Roussy, Villejuif

2014-11-01

Purpose/Objective(s): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. Methods and Materials: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principalmore » components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). Results: The incidence rate of grade ≥2 RB was 14%. V{sub 65Gy} was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. Conclusion: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.« less

NTCP-Reconstituted In Vitro HBV Infection System.

PubMed

Sun, Yinyan; Qi, Yonghe; Peng, Bo; Li, Wenhui

2017-01-01

Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a functional receptor for hepatitis B virus (HBV). Expressing human NTCP in human hepatoma HepG2 cells (HepG2-NTCP) renders these cells susceptible for HBV infection. The HepG2-NTCP stably transfected cell line provides a much-needed and easily accessible platform for studying the virus. HepG2-NTCP cells could also be used to identify chemicals targeting key steps of the virus life cycle including HBV covalent closed circular (ccc) DNA, and enable the development of novel antivirals against the infection.Many factors may contribute to the efficiency of HBV infection on HepG2-NTCP cells, with clonal differences among cell line isolates, the source of viral inoculum, and infection medium among the most critical ones. Here, we provide detailed protocols for efficient HBV infection of HepG2-NTCP cells in culture; generation and selection of single cell clones of HepG2-NTCP; production of infectious HBV virion stock through DNA transfection of recombinant plasmid that enables studying primary clinical HBV isolates; and assessing the infection with immunostaining of HBV antigens and Southern blot analysis of HBV cccDNA.

A geometric model for evaluating the effects of inter-fraction rectal motion during prostate radiotherapy

NASA Astrophysics Data System (ADS)

Pavel-Mititean, Luciana M.; Rowbottom, Carl G.; Hector, Charlotte L.; Partridge, Mike; Bortfeld, Thomas; Schlegel, Wolfgang

2004-06-01

A geometric model is presented which allows calculation of the dosimetric consequences of rectal motion in prostate radiotherapy. Variations in the position of the rectum are measured by repeat CT scanning during the courses of treatment of five patients. Dose distributions are calculated by applying the same conformal treatment plan to each imaged fraction and rectal dose-surface histograms produced. The 2D model allows isotropic expansion and contraction in the plane of each CT slice. By summing the dose to specific volume elements tracked by the model, composite dose distributions are produced that explicitly include measured inter-fraction motion for each patient. These are then used to estimate effective dose-surface histograms (DSHs) for the entire treatment. Results are presented showing the magnitudes of the measured target and rectal motion and showing the effects of this motion on the integral dose to the rectum. The possibility of using such information to calculate normal tissue complication probabilities (NTCP) is demonstrated and discussed.

Viral Entry of Hepatitis B and D Viruses and Bile Salts Transportation Share Common Molecular Determinants on Sodium Taurocholate Cotransporting Polypeptide

PubMed Central

Yan, Huan; Peng, Bo; Liu, Yang; Xu, Guangwei; He, Wenhui; Ren, Bijie; Jing, Zhiyi; Sui, Jianhua

2014-01-01

ABSTRACT The liver bile acids transporter sodium taurocholate cotransporting polypeptide (NTCP) is responsible for the majority of sodium-dependent bile salts uptake by hepatocytes. NTCP also functions as a cellular receptor for viral entry of hepatitis B virus (HBV) and hepatitis D virus (HDV) through a specific interaction between NTCP and the pre-S1 domain of HBV large envelope protein. However, it remains unknown if these two functions of NTCP are independent or if they interfere with each other. Here we show that binding of the pre-S1 domain to human NTCP blocks taurocholate uptake by the receptor; conversely, some bile acid substrates of NTCP inhibit HBV and HDV entry. Mutations of NTCP residues critical for bile salts binding severely impair viral infection by HDV and HBV; to a lesser extent, the residues important for sodium binding also inhibit viral infection. The mutation S267F, corresponding to a single nucleotide polymorphism (SNP) found in about 9% of the East Asian population, renders NTCP without either taurocholate transporting activity or the ability to support HBV or HDV infection in cell culture. These results demonstrate that molecular determinants critical for HBV and HDV entry overlap with that for bile salts uptake by NTCP, indicating that viral infection may interfere with the normal function of NTCP, and bile acids and their derivatives hold the potential for further development into antiviral drugs. IMPORTANCE Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), are important human pathogens. Available therapeutics against HBV are limited, and there is no drug that is clinically available for HDV infection. A liver bile acids transporter (sodium taurocholate cotransporting polypeptide [NTCP]) critical for maintaining homeostasis of bile acids serves as a functional receptor for HBV and HDV. We report here that the NTCP-binding lipopeptide that originates from the first 47 amino acids of the pre-S1 domain of the HBV L protein blocks taurocholate transport. Some bile salts dose dependently inhibit HBV and HDV infection mediated by NTCP; molecular determinants of NTCP critical for HBV and HDV entry overlap with that for bile acids transport. This work advances our understanding of NTCP-mediated HBV and HDV infection in relation to NTCP's physiological function. Our results also suggest that bile acids or their derivatives hold potential for development into novel drugs against HBV and HDV infection. PMID:24390325

Structure Activity Relationship for FDA Approved Drugs as Inhibitors of the Human Sodium Taurocholate Co-transporting Polypeptide (NTCP)

PubMed Central

Dong, Zhongqi; Ekins, Sean; Polli, James E.

2013-01-01

The hepatic bile acid uptake transporter Sodium Taurocholate Cotransporting Polypeptide (NTCP) is less well characterized than its ileal paralog, the Apical Sodium Dependent Bile Acid Transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were a) to identify FDA approved drugs that inhibit human NTCP, b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki =11.9 μM) and ezetimibe (Ki = 25.0 μM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e. more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP’s possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations. PMID:23339484

Vectorial transport of bile salts across MDCK cells expressing both rat Na+-taurocholate cotransporting polypeptide and rat bile salt export pump.

PubMed

Mita, Sachiko; Suzuki, Hiroshi; Akita, Hidetaka; Stieger, Bruno; Meier, Peter J; Hofmann, Alan F; Sugiyama, Yuichi

2005-01-01

Bile salts are predominantly taken up by hepatocytes via the basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP/SLC10A1) and secreted into the bile by the bile salt export pump (BSEP/ABCB11). In the present study, we transfected rat Ntcp and rat Bsep into polarized Madin-Darby canine kidney cells and characterized the transport properties of these cells for eight bile salts. Immunohistochemical staining demonstrated that Ntcp was expressed at the basolateral domains, whereas Bsep was expressed at the apical domains. Basal-to-apical transport of taurocholate across the monolayer expressing only Ntcp and that coexpressing Ntcp/Bsep was observed, whereas the flux across the monolayer of control and Bsep-expressing cells was symmetrical. Basal-to-apical transport of taurocholate across Ntcp/Bsep-coexpressing monolayers was significantly higher than that across monolayers expressing only Ntcp. Kinetic analysis of this vectorial transport of taurocholate gave an apparent K(m) value of 13.9 +/- 4.7 microM for cells expressing Ntcp alone, which is comparable with 22.2 +/- 4.5 microM for cells expressing both Ntcp and Bsep and V(max) values of 15.8 +/- 4.2 and 60.8 +/- 9.0 pmol.min(-1).mg protein(-1) for Ntcp alone and Ntcp and Bsep-coexpressing cells, respectively. Transcellular transport of cholate, glycocholate, taurochenodeoxycholate, chenodeoxycholate, glycochenodeoxycholate, tauroursodeoxycholate, ursodeoxycholate, and glycoursodeoxycholate, but not that of lithocholate was also observed across the double transfectant. This double-expressing system can be used as a model to clarify vectorial transport of bile salts across hepatocytes under physiological conditions.

Absolute measurement of species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) and its modulation in cultured hepatocytes.

PubMed

Qiu, Xi; Bi, Yi-An; Balogh, Larissa M; Lai, Yurong

2013-09-01

Species differences among membrane transporters can be remarkable and difficult to properly assess by conventional methods. Herein, we employed the first use of stable isotope labeling in mammals or stable isotope-labeled peptides combined with mass spectrometry to identify species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) protein expression in liver tissue and to characterize the modulation of protein expression in sandwich-cultured human (SCHH) and rat hepatocytes (SCRH). The lower limit of quantification was established to be 5 fmol on column with a standard curve that was linear up to 2000 fmol. The accuracy and precision were evaluated with three quality control samples and known amounts of synthetic proteotypic peptides that were spiked into the membrane protein extracts. The overall relative error and coefficient of variation were less than 10%. The expression of Ntcp in mouse and rat was significant higher than that in human (five-fold) and monkey (two-fold) and ranked as mouse > rat > monkey > human. In the cultured hepatocytes, although significant downregulation of Ntcp expression in SCRH at day 5 after the culture was detected, NTCP expression in SCHH was comparable to the suspension hepatocytes. The results suggested that NTCP/Ntcp modulation in cultured hepatocytes is species specific. Copyright © 2013 Wiley Periodicals, Inc.

The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

NASA Astrophysics Data System (ADS)

Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.

2008-11-01

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 ± 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.

Dosimetric consequences of the parotid glands using CT-to-CBCT deformable registration during IMRT for late stage head and neck cancers

NASA Astrophysics Data System (ADS)

Conill, Annette L.

Patients receiving Intensity Modulated Radiation Therapy (IMRT) for late stage head and neck (HN) cancer often experience anatomical changes due to weight loss, tumor regression, and positional changes of normal anatomy (1). As a result, the actual dose delivered may vary from the original treatment plan. The purpose of this study was (a) to evaluate the dosimetric consequences of the parotid glands during the course of treatment, and (b) to determine if there would be an optimal timeframe for replanning. Nineteen locally advanced HN cancer patients underwent definitive IMRT. Each patient received an initial computerized tomography simulation (CT-SIM) scan and weekly cone beam computerized tomography (CBCT) scans. A Deformable Image Registration (DIR) was performed between the CT-SIM and CBCT of the parotid glands and Planning Target Volumes (PTVs) using the Eclipse treatment planning system (TPS) and the Velocity deformation software. A recalculation of the dose was performed on the weekly CBCTs using the original monitor units. The parameters for evaluation of our method were: the changes in volume of the PTVs and parotid glands, the dose coverage of the PTVs, the lateral displacement in the Center of Mass (COM), the mean dose, and Normal Tissue Complication Probability (NTCP) of the parotid glands. The studies showed a reduction of the volume in the PTVs and parotids, a medial displacement in COM, and alterations of the mean dose to the parotid glands as compared to the initial plans. Differences were observed for the dose volume coverage of the PTVs and NTCP of the parotid gland values between the initial plan and our proposed method utilizing deformable registration-based dose calculations.

WE-F-304-04: Radiosurgery for Vestibular Schwannomas: Tumor Control Probability Analyses and Recommended Reporting Standards

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soltys, S.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

Screening and verifying potential NTCP inhibitors from herbal medicinal ingredients using the LLC-PK1 cell model stably expressing human NTCP.

PubMed

Shen, Zhuo-Wei; Luo, Meng-Yue; Hu, Hai-Hong; Zhou, Hui; Jiang, Hui-Di; Yu, Lu-Shan; Zeng, Su

2016-07-01

NTCP is specifically expressed on the basolateral membrane of hepatocytes, participating in the enterohepatic circulation of bile salts, especially conjugated bile salts, to maintain bile salts homeostasis. In addition, recent studies have found that NTCP is a functional receptor of HBV and HDV. Therefore, it is important to study the interaction between drugs and NTCP and identify the inhibitors/substrates of NTCP. In the present study, a LLC-PK1 cell model stably expressing human NTCP was established, which was simple and suitable for high throughput screening, and utilized to screen and verify the potential inhibitors of NTCP from 102 herbal medicinal ingredients. The results showed that ginkgolic acid (GA) (13 : 0), GA (15 : 1), GA (17 : 1), erythrosine B, silibinin, and emodin have inhibitory effects on NTCP uptake of TCNa in a concentration-dependent manner. Among them, GA (13 : 0) and GA (15 : 1) exhibited the stronger inhibitory effects, with IC50 values being less than 8.3 and 13.5 μmol·L(-1), respectively, than the classical inhibitor, cyclosporin A (CsA) (IC50 = 20.33 μmol·L(-1)). Further research demonstrated that GA (13 : 0), GA (15 : 1), GA (17 : 1), silibinin, and emodin were not substrates of NTCP. These findings might contribute to a better understanding of the disposition of the herbal ingredients in vivo, especially in biliary excretion. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep.

PubMed

Mita, Sachiko; Suzuki, Hiroshi; Akita, Hidetaka; Hayashi, Hisamitsu; Onuki, Reiko; Hofmann, Alan F; Sugiyama, Yuichi

2006-03-01

Na(+)-taurocholate-cotransporting peptide (NTCP)/SLC10A1 and bile salt export pump (BSEP)/ABCB11 synergistically play an important role in the transport of bile salts by the hepatocyte. In this study, we transfected human NTCP and BSEP or rat Ntcp and Bsep into LLC-PK1 cells, a cell line devoid of bile salts transporters. Transport by these cells was characterized with a focus on substrate specificity between rats and humans. The basal to apical flux of taurocholate across NTCP- and BSEP-expressing LLC-PK1 monolayers was 10 times higher than that in the opposite direction, whereas the flux across the monolayer of control and NTCP or BSEP single-expressing cells did not show any vectorial transport. The basal to apical flux of taurocholate was saturated with a K(m) value of 20 microM. Vectorial transcellular transport was also observed for cholate, chenodeoxycholate, ursodeoxycholate, their taurine and glycine conjugates, and taurodeoxycholate and glycodeoxycholate, whereas no transport of lithocholate was detected. To evaluate the respective functions of NTCP and BSEP and to compare them with those of rat Ntcp and Bsep, we calculated the clearance by each transporter in this system. A good correlation in the clearance of the examined bile salts (cholate, chenodeoxycholate, ursodeoxycholate, and their taurine or glycine conjugates) was observed between transport by human and that of rat transporters in terms of their rank order: for NTCP, taurine conjugates > glycine conjugates > unconjugated bile salts, and for BSEP, unconjugated bile salts and glycine conjugates > taurine conjugates. In conclusion, the substrate specificity of human and rat NTCP and BSEP appear to be very similar at least for monovalent bile salts under physiological conditions.

Interaction of fluvastatin with the liver-specific Na+ -dependent taurocholate cotransporting polypeptide (NTCP).

PubMed

Greupink, Rick; Dillen, Lieve; Monshouwer, Mario; Huisman, Maarten T; Russel, Frans G M

2011-11-20

It has been reported that polymorphisms in the organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) result in decreased hepatic uptake of simvastatin carboxy acid, the active metabolite of simvastatin. This is not the case for fluvastatin and it has been hypothesized that for this drug other hepatic uptake pathways exist. Here, we studied whether Na(+)-dependent taurocholate co-transporting polypeptide (NTCP, SLC10A1) can be an alternative hepatic uptake route for fluvastatin. Chinese Hamster Ovary cells transfected with human NTCP (CHO-NTCP) were used to investigate the inhibitory effect of fluvastatin and other statins on [(3)H]-taurocholic acid uptake ([(3)H]-TCA). Statin uptake by CHO-NTCP and cryopreserved human hepatocytes was assessed via LC-MS/MS. Fluvastatin appeared to be a potent and competitive inhibitor of [(3)H]-TCA uptake (IC(50) of 40μM), pointing to an interaction at the level of the bile acid binding pocket of NTCP. The inhibitory action of other statins was also studied, which revealed that statin inhibitory potency increased with molecular descriptors of lipophilicity: calculated logP (r(2)=0.82, p=0.034), logD(7.4) (r(2)=0.77, p=0.0001). Studies in CHO-NTCP cells showed that fluvastatin was indeed an NTCP substrate (K(m) 250±30μM, V(max) 1340±50ng/mg total cell protein/min). However, subsequent studies revealed that at clinically relevant plasma concentrations, NTCP contributed minimally to overall accumulation in human hepatocytes. In conclusion, fluvastatin interacts with NTCP at the level of the bile acid binding pocket and is an NTCP substrate. However, under normal conditions, NTCP-mediated uptake of this drug seems not to be a significant hepatocellular uptake pathway. Copyright © 2011 Elsevier B.V. All rights reserved.

Modification of Three Amino Acids in Sodium Taurocholate Cotransporting Polypeptide Renders Mice Susceptible to Infection with Hepatitis D Virus In Vivo

PubMed Central

He, Wenhui; Cao, Zhiliang; Mao, Fengfeng; Ren, Bijie; Li, Yunfei; Li, Dan; Li, Huiyu; Peng, Bo; Yan, Huan; Qi, Yonghe; Sun, Yinyan; Wang, Fengchao

2016-01-01

ABSTRACT Sodium taurocholate cotransporting polypeptide (NTCP) was identified as a functional receptor for hepatitis D virus (HDV) and its helper hepatitis B virus (HBV). In cultured cell lines, HDV infection through mouse NTCP is restricted by residues 84 to 87 of the receptor. This study shows that mice with these three amino acids altered their corresponding human residues (H84R, T86K, and S87N) in endogenous mouse NTCP support de novo HDV infection in vivo. HDV infection was documented by the presence of replicative forms of HDV RNA and HDV proteins in liver cells at day 6 after viral inoculation. Monoclonal antibody specifically binding to the motif centered on K86 in NTCP partially inhibited HDV infection. These studies demonstrated specific interaction between the receptor and the viral envelopes in vivo and established a novel mouse model with minimal genetic manipulation for studying HDV infection. The model will also be useful for evaluating entry inhibitors against HDV and its helper HBV. IMPORTANCE NTCP was identified as a functional receptor for both HDV and HBV in cell cultures. We recently showed that neonatal C57BL/6 transgenic (Tg) mice exogenously expressing human NTCP (hNTCP-Tg) in liver support transient HDV infection. In this study, we introduced alterations of three amino acids in the endogenous NTCP of FVB mice through genome editing. The mice with the humanized NTCP residues (H84R, T86K, and S87N) are susceptible to HDV infection, and the infection can be established in both neonatal and adult mice with this editing. We also developed a monoclonal antibody specifically targeting the region of NTCP centered on lysine residue 86, and it can differentiate the modified mouse NTCP from that of the wild type and partially inhibited HDV infection. These studies shed new light on NTCP-mediated HDV infection in vivo, and the NTCP-modified mice provide a useful animal model for studying HDV infection and evaluating antivirals against the infection. PMID:27466423

Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP.

PubMed

Donkers, Joanne M; Zehnder, Benno; van Westen, Gerard J P; Kwakkenbos, Mark J; IJzerman, Adriaan P; Oude Elferink, Ronald P J; Beuers, Ulrich; Urban, Stephan; van de Graaf, Stan F J

2017-11-10

The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC 50 5.1 µM), zafirlukast (IC 50 6.5 µM), TRIAC (IC 50 6.9 µM), and sulfasalazine (IC 50 9.6 µM). Chicago sky blue 6B (IC 50 7.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.

Hepatocyte nuclear factor-4alpha is a central transactivator of the mouse Ntcp gene.

PubMed

Geier, Andreas; Martin, Ina V; Dietrich, Christoph G; Balasubramaniyan, Natarajan; Strauch, Sonja; Suchy, Frederick J; Gartung, Carsten; Trautwein, Christian; Ananthanarayanan, Meenakshisundaram

2008-08-01

Sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake system for conjugated bile acids. Deletions of hepatocyte nuclear factor (HNF)-1alpha and retinoid X receptor-alpha:retinoic acid receptor-alpha binding sites in the mouse 5'-flanking region corresponding to putatively central regulatory elements of rat Ntcp do not significantly reduce promoter activity. We hypothesized that HNF-4alpha, which is increasingly recognized as a central regulator of hepatocyte function, may directly transactivate mouse (mNtcp). A 1.1-kb 5'-upstream region including the mouse Ntcp promoter was cloned and compared with the rat promoter. In contrast to a moderate 3.5-fold activation of mNtcp by HNF-1alpha, HNF-4alpha cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4alpha consensus site at -345/-326 and -335/-316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1alpha but shows a 50-fold enhanced activity upon cotransfection with HNF-4alpha. Gel mobility shift assays demonstrated a complex of the HNF-4alpha-element formed with liver nuclear extracts that was blocked by an HNF-4alpha specific antibody. HNF-4alpha binding was confirmed by chromatin immunoprecipitation. Using Hepa 1-6 cells, HNF-4alpha-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4alpha via a conserved distal cis-element independently of HNF-1alpha.

Patient- and therapy-related factors associated with the incidence of xerostomia in nasopharyngeal carcinoma patients receiving parotid-sparing helical tomotherapy.

PubMed

Lee, Tsair-Fwu; Liou, Ming-Hsiang; Ting, Hui-Min; Chang, Liyun; Lee, Hsiao-Yi; Wan Leung, Stephen; Huang, Chih-Jen; Chao, Pei-Ju

2015-08-20

We investigated the incidence of moderate to severe patient-reported xerostomia among nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT) and identified patient- and therapy-related factors associated with acute and chronic xerostomia toxicity. The least absolute shrinkage and selection operator (LASSO) normal tissue complication probability (NTCP) models were developed using quality-of-life questionnaire datasets from 67 patients with NPC. For acute toxicity, the dosimetric factors of the mean doses to the ipsilateral submandibular gland (Dis) and the contralateral submandibular gland (Dcs) were selected as the first two significant predictors. For chronic toxicity, four predictive factors were selected: age, mean dose to the oral cavity (Doc), education, and T stage. The substantial sparing data can be used to avoid xerostomia toxicity. We suggest that the tolerance values corresponded to a 20% incidence of complications (TD20) for Dis = 39.0 Gy, Dcs = 38.4 Gy, and Doc = 32.5 Gy, respectively, when mean doses to the parotid glands met the QUANTEC 25 Gy sparing guidelines. To avoid patient-reported xerostomia toxicity, the mean doses to the parotid gland, submandibular gland, and oral cavity have to meet the sparing tolerance, although there is also a need to take inherent patient characteristics into consideration.

Protons in head-and-neck cancer: bridging the gap of evidence.

PubMed

Ramaekers, Bram L T; Grutters, Janneke P C; Pijls-Johannesma, Madelon; Lambin, Philippe; Joore, Manuela A; Langendijk, Johannes A

2013-04-01

To use Normal Tissue Complication Probability (NTCP) models and comparative planning studies to explore the (cost-)effectiveness of swallowing sparing intensity modulated proton radiotherapy (IMPT) compared with swallowing sparing intensity modulated radiotherapy with photons (IMRT) in head and neck cancer (HNC). A Markov model was constructed to examine and compare the costs and quality-adjusted life years (QALYs) of the following strategies: (1) IMPT for all patients; (2) IMRT for all patients; and (3) IMPT if efficient. The assumption of equal survival for IMPT and IMRT in the base case analysis was relaxed in a sensitivity analysis. Intensity modulated proton radiation therapy and IMRT for all patients yielded 6.620 and 6.520 QALYs and cost €50,989 and €41,038, respectively. Intensity modulated proton radiation therapy if efficient yielded 6.563 QALYs and cost €43,650. The incremental cost-effectiveness ratio of IMPT if efficient versus IMRT for all patients was €60,278 per QALY gained. In the sensitivity analysis, IMRT was more effective (0.967 QALYs) and less expensive (€8218) and thus dominated IMPT for all patients. Cost-effectiveness analysis based on normal tissue complication probability models and planning studies proved feasible and informative and enables the analysis of individualized strategies. The increased effectiveness of IMPT does not seem to outweigh the higher costs for all head-and-neck cancer patients. However, when assuming equal survival among both modalities, there seems to be value in identifying those patients for whom IMPT is cost-effective. Copyright © 2013 Elsevier Inc. All rights reserved.

First clinical implementation of the Capri applicator

PubMed Central

2014-01-01

This study was to assess the Capri applicator for patients with endometrial cancer undergoing high‐radiation dose treatments following external‐beam radiation therapy. The Capri applicator is an inflatable vaginal cylinder with multiple channels. It is used to tailor the dose distribution to an asymmetric vaginal disease, and better spare organs at risk. Five patients with high‐risk endometrial cancer were selected for this study. The patients were treated with a high dose of radiation using the Capri applicator: daily fraction of 7 Gy was prescribed for a total dose of 21 Gy. The treatment plans included radiobiological parameters such as equivalent uniform dose (EUD), normal tissue complication probability (NTCP), and tumor control probability (TCP). Based on the dose‐volume histograms (DVH), we also calculated four quality factors: conformity index (CI), dose homogeneity index (DHI), dose nonuniformity index (DNR), and overdose index (OI). The TCP values range from 82.26% to 95.92%. Very low values of NTCP were observed for the bladder and rectum. The EUDs to organs at risk ranged from 4.65 Gy to 18.22 Gy for the bladder, and from 3.41 Gy from to 6.56 Gy for the rectum. The mean CI was 1.05(SD=0.0008). The mean DNR was 0.10(range0.0−0.295,SD=0.100). The mean OI was 0.019(SD=0.028). The DHIs were in the range of 1.0−0.754(mean0.886,SD=0.116). The use of a multichannel vaginal cylinder may not only help cover extensive vaginal disease, but also reduce the dose to the rectum. This dosimetric analysis shows that rectal doses could be reduced using a multichannel cylinder. However, the dose delivered to the bladder based on EUD calculation may be higher than that obtained with other methods. Each patient must be evaluated independently to determine if a multichannel treatment is appropriate. Clinical followup will show whether this rectal dose sparing translates into a real toxicity improvement. PACS number: 3.6.96.0 PMID:24423857

TU-EF-304-11: Therapeutic Benefits of Collimation in Spot Scanning Proton Therapy in the Treatment of Brain Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moignier, A; Gelover, E; Wang, D

Purpose: A dynamic collimation system (DCS) based on two orthogonal pairs of mobile trimmer blades has recently been proposed to reduce the lateral penumbra in spot scanning proton therapy (SSPT). The purpose of this work is to quantify the therapeutic benefit of using the DCS for SSPT of brain cancer by comparing un-collimated and collimated treatment plans. Methods: Un-collimated and collimated brain treatment plans were created for five patients, previously treated with SSPT, using an in-house treatment planning system capable of modeling collimated and un-collimated beamlets. Un-collimated plans reproduced the clinically delivered plans in terms of target coverage and organ-at-riskmore » (OAR) sparing, whereas collimated plans were re-optimized to improve the organ-at-risk sparing while maintaining target coverage. Physical and biological comparison metrics such as dose distribution conformity, mean and maximum doses, normal tissue complication probability (NTCP) and risk of secondary brain cancer were used to evaluate the plans. Results: The DCS systematically improved the dose distribution conformity while preserving the target coverage. The average reduction of the mean dose to the 10-mm ring surrounding the target and the healthy brain were 7.1% (95% CI: 4.2%–9.9%; p<0.01) and 14.3% (95% CI: 7.8%–20.8%; p<0.01), respectively. This yielded an average reduction of 12.0% (95% CI: 8.2%–15.7%; p<0.01) for the brain necrosis NTCP using the Flickinger model, and 14.2% (95% CI: 7.7%–20.8%; p<0.01) for the risk of secondary brain cancer. The average maximum dose reductions for the brainstem, chiasm, optic nerves, cochleae and pituitary gland when comparing un-collimated and collimated plans were 14.3%, 10.4%, 11.2%, 13.0%, 12.9% and 3.4%, respectively. Evaluating individual plans using the Lyman-Kutcher-Burman NTCP model also yielded improvements. Conclusion: The lateral penumbra reduction performed by the DCS increases the normal tissue sparing capabilities of SSPT for brain tumor treatment while preserving the target coverage. This research was financially supported by Ion Beam Applications S.A. (IBA, Louvain-La-Neuve, Belgium)« less

Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor

PubMed Central

Zong, Li; Sureau, Camille; Barker, Luke; Wands, Jack R.; Tong, Shuping

2016-01-01

ABSTRACT Cell culture (cc)-derived hepatitis B virus (HBV) can infect differentiated HepaRG cells, but efficient infection requires addition of polyethylene glycol (PEG) during inoculation. Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor enabled ccHBV infection of NTCP reconstituted HepG2 cells, although very little hepatitis B surface antigen (HBsAg) is produced. We found infection by patient serum-derived HBV (sHBV), which required purification of viral particles through ultracentrifugation or PEG precipitation, was PEG independent and much more efficient in HepaRG cells than in HepG2/NTCP cells. In contrast to hepatitis B e antigen (HBeAg), HBsAg was not a reliable marker of productive sHBV infection at early time points. A low HBsAg/HBeAg ratio by ccHBV-infected HepG2/NTCP cells was attributable to dimethyl sulfoxide (DMSO) in culture medium, NTCP overexpression, and HBV genotype D. HepG2/NTCP cells released more viral antigens than HepG2 cells after HBV genome delivery by adeno-associated virus, and stable expression of NTCP in a ccHBV producing cell line increased viral mRNAs, proteins, replicative DNA, and covalently closed circular DNA. NTCP protein expression in HepG2/NTCP cells, despite being driven by the cytomegalovirus promoter, was markedly increased by DMSO treatment. This at least partly explains ability of DMSO to promote ccHBV infection in such cell lines. In conclusion, NTCP appeared inefficient to mediate infection by serum-derived HBV. It could promote HBV RNA transcription while inhibiting HBsAg secretion. Efficient PEG-independent sHBV infection of HepaRG cells permits comparative studies of diverse clinical HBV isolates and will help identify additional factors on virion surface promoting attachment to hepatocytes. IMPORTANCE Currently in vitro infection with hepatitis B virus (HBV) depends on cell culture-derived HBV inoculated in the presence of polyethylene glycol. We found patient serum-derived HBV could efficiently infect differentiated HepaRG cells independent of polyethylene glycol, which represents a more physiological infection system. Serum-derived HBV has poor infectivity in HepG2 cells reconstituted with sodium taurocholate cotransporting polypeptide (NTCP), the currently accepted HBV receptor. Moreover, HepG2/NTCP cells secreted very little hepatitis B surface antigen after infection with cell culture-derived HBV, which was attributed to NTCP overexpression, genotype D virus, and dimethyl sulfoxide added to culture medium. NTCP could promote HBV RNA transcription, protein expression, and DNA replication in HepG2 cells stably transfected with HBV DNA, while dimethyl sulfoxide could increase NTCP protein level despite transcriptional control by a cytomegalovirus promoter. Therefore, this study revealed several unusual features of NTCP as an HBV receptor and established conditions for efficient serum virus infection in vitro. PMID:27384660

Radiobiological characterization of post-lumpectomy focal brachytherapy with lipid nanoparticle-carried radionuclides

NASA Astrophysics Data System (ADS)

Hrycushko, Brian A.; Gutierrez, Alonso N.; Goins, Beth; Yan, Weiqiang; Phillips, William T.; Otto, Pamela M.; Bao, Ande

2011-02-01

Post-operative radiotherapy has commonly been used for early stage breast cancer to treat residual disease. The primary objective of this work was to characterize, through dosimetric and radiobiological modeling, a novel focal brachytherapy technique which uses direct intracavitary infusion of β-emitting radionuclides (186Re/188Re) carried by lipid nanoparticles (liposomes). Absorbed dose calculations were performed for a spherical lumpectomy cavity with a uniformly injected activity distribution using a dose point kernel convolution technique. Radiobiological indices were used to relate predicted therapy outcome and normal tissue complication of this technique with equivalent external beam radiotherapy treatment regimens. Modeled stromal damage was used as a measure of the inhibition of the stimulatory effect on tumor growth driven by the wound healing response. A sample treatment plan delivering 50 Gy at a therapeutic range of 2.0 mm for 186Re-liposomes and 5.0 mm for 188Re-liposomes takes advantage of the dose delivery characteristics of the β-emissions, providing significant EUD (58.2 Gy and 72.5 Gy for 186Re and 188Re, respectively) with a minimal NTCP (0.046%) of the healthy ipsilateral breast. Modeling of kidney BED and ipsilateral breast NTCP showed that large injected activity concentrations of both radionuclides could be safely administered without significant complications.

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate*

PubMed Central

Sommerfeld, Annika; Mayer, Patrick G. K.; Cantore, Miriam; Häussinger, Dieter

2015-01-01

In perfused rat liver, hepatocyte shrinkage induces a Fyn-dependent retrieval of the bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane (Cantore, M., Reinehr, R., Sommerfeld, A., Becker, M., and Häussinger, D. (2011) J. Biol. Chem. 286, 45014–45029) leading to cholestasis. However little is known about the effects of hyperosmolarity on short term regulation of the Na+-taurocholate cotransporting polypeptide (Ntcp), the major bile salt uptake system at the sinusoidal membrane of hepatocytes. The aim of this study was to analyze hyperosmotic Ntcp regulation and the underlying signaling events. Hyperosmolarity induced a significant retrieval of Ntcp from the basolateral membrane, which was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes but not of c-Src. Hyperosmotic internalization of Ntcp was sensitive to SU6656 and PP-2, suggesting that Fyn mediates Ntcp retrieval from the basolateral membrane. Hyperosmotic internalization of Ntcp was also found in livers from wild-type mice but not in p47phox knock-out mice. Tauroursodeoxycholate (TUDC) and cAMP reversed hyperosmolarity-induced Fyn activation and triggered re-insertion of the hyperosmotically retrieved Ntcp into the membrane. This was associated with dephosphorylation of the Ntcp on serine residues. Insertion of Ntcp by TUDC was sensitive to the integrin inhibitory hexapeptide GRGDSP and inhibition of protein kinase A. TUDC also reversed the hyperosmolarity-induced retrieval of bile salt export pump from the canalicular membrane. These findings suggest a coordinated and oxidative stress- and Fyn-dependent retrieval of sinusoidal and canalicular bile salt transport systems from the corresponding membranes. Ntcp insertion was also identified as a novel target of β1-integrin-dependent TUDC action, which is frequently used in the treatment of cholestatic liver disease. PMID:26306036

Regulation of plasma membrane localization of the Na+-taurocholate cotransporting polypeptide (Ntcp) by hyperosmolarity and tauroursodeoxycholate.

PubMed

Sommerfeld, Annika; Mayer, Patrick G K; Cantore, Miriam; Häussinger, Dieter

2015-10-02

In perfused rat liver, hepatocyte shrinkage induces a Fyn-dependent retrieval of the bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane (Cantore, M., Reinehr, R., Sommerfeld, A., Becker, M., and Häussinger, D. (2011) J. Biol. Chem. 286, 45014-45029) leading to cholestasis. However little is known about the effects of hyperosmolarity on short term regulation of the Na(+)-taurocholate cotransporting polypeptide (Ntcp), the major bile salt uptake system at the sinusoidal membrane of hepatocytes. The aim of this study was to analyze hyperosmotic Ntcp regulation and the underlying signaling events. Hyperosmolarity induced a significant retrieval of Ntcp from the basolateral membrane, which was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes but not of c-Src. Hyperosmotic internalization of Ntcp was sensitive to SU6656 and PP-2, suggesting that Fyn mediates Ntcp retrieval from the basolateral membrane. Hyperosmotic internalization of Ntcp was also found in livers from wild-type mice but not in p47(phox) knock-out mice. Tauroursodeoxycholate (TUDC) and cAMP reversed hyperosmolarity-induced Fyn activation and triggered re-insertion of the hyperosmotically retrieved Ntcp into the membrane. This was associated with dephosphorylation of the Ntcp on serine residues. Insertion of Ntcp by TUDC was sensitive to the integrin inhibitory hexapeptide GRGDSP and inhibition of protein kinase A. TUDC also reversed the hyperosmolarity-induced retrieval of bile salt export pump from the canalicular membrane. These findings suggest a coordinated and oxidative stress- and Fyn-dependent retrieval of sinusoidal and canalicular bile salt transport systems from the corresponding membranes. Ntcp insertion was also identified as a novel target of β1-integrin-dependent TUDC action, which is frequently used in the treatment of cholestatic liver disease. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.

PubMed

Pan, Wei; Song, Im-Sook; Shin, Ho-Jung; Kim, Min-Hye; Choi, Yeong-Lim; Lim, Su-Jeong; Kim, Woo-Young; Lee, Sang-Seop; Shin, Jae-Gook

2011-06-01

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP.

PubMed

Iwamoto, Masashi; Watashi, Koichi; Tsukuda, Senko; Aly, Hussein Hassan; Fukasawa, Masayoshi; Fujimoto, Akira; Suzuki, Ryosuke; Aizaki, Hideki; Ito, Takayoshi; Koiwai, Osamu; Kusuhara, Hiroyuki; Wakita, Takaji

2014-01-17

Hepatitis B virus (HBV) entry has been analyzed using infection-susceptible cells, including primary human hepatocytes, primary tupaia hepatocytes, and HepaRG cells. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) membrane transporter was reported as an HBV entry receptor. In this study, we established a strain of HepG2 cells engineered to overexpress the human NTCP gene (HepG2-hNTCP-C4 cells). HepG2-hNTCP-C4 cells were shown to be susceptible to infection by blood-borne and cell culture-derived HBV. HBV infection was facilitated by pretreating cells with 3% dimethyl sulfoxide permitting nearly 50% of the cells to be infected with HBV. Knockdown analysis suggested that HBV infection of HepG2-hNTCP-C4 cells was mediated by NTCP. HBV infection was blocked by an anti-HBV surface protein neutralizing antibody, by compounds known to inhibit NTCP transporter activity, and by cyclosporin A and its derivatives. The infection assay suggested that cyclosporin B was a more potent inhibitor of HBV entry than was cyclosporin A. Further chemical screening identified oxysterols, oxidized derivatives of cholesterol, as inhibitors of HBV infection. Thus, the HepG2-hNTCP-C4 cell line established in this study is a useful tool for the identification of inhibitors of HBV infection as well as for the analysis of the molecular mechanisms of HBV infection. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.

PubMed

Verrier, Eloi R; Colpitts, Che C; Bach, Charlotte; Heydmann, Laura; Zona, Laetitia; Xiao, Fei; Thumann, Christine; Crouchet, Emilie; Gaudin, Raphaël; Sureau, Camille; Cosset, François-Loïc; McKeating, Jane A; Pessaux, Patrick; Hoshida, Yujin; Schuster, Catherine; Zeisel, Mirjam B; Baumert, Thomas F

2016-10-25

Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity.

PubMed

Shimura, Satomi; Watashi, Koichi; Fukano, Kento; Peel, Michael; Sluder, Ann; Kawai, Fumihiro; Iwamoto, Masashi; Tsukuda, Senko; Takeuchi, Junko S; Miyake, Takeshi; Sugiyama, Masaya; Ogasawara, Yuki; Park, Sam-Yong; Tanaka, Yasuhito; Kusuhara, Hiroyuki; Mizokami, Masashi; Sureau, Camille; Wakita, Takaji

2017-04-01

The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC 50 . Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy.

PubMed

Zhang, Jin; Fu, Lei-Lei; Tian, Mao; Liu, Hao-Qiu; Li, Jing-Jing; Li, Yan; He, Jun; Huang, Jian; Ouyang, Liang; Gao, Hui-Yuan; Wang, Jin-Hui

2015-03-01

Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of three and four-field radiotherapy technique and the effect of laryngeal shield on vocal and spinal cord radiation dose in radiotherapy of non-laryngeal head and neck tumors

NASA Astrophysics Data System (ADS)

Pour, Noushin Hassan; Farajollahi, Alireza; Jamali, Masoud; Zeinali, Ahad; Jangjou, Amir Ghasemi

2018-03-01

Introduction: Due to the effect of radiation on both the tumor and the surrounding normal tissues, the side effects of radiation in normal tissues are expected. One of the important complications in the head and neck radiotherapy is the doses reached to the larynx and spinal cord of patients with non-laryngeal head and neck tumors. Materials and Methods: In this study, CT scan images of 25 patients with non-laryngeal tumors including; lymph nodes, tongue, oropharynx and nasopharynx were used. A three-field and a four-field treatment planning with and without laryngeal shield in 3D CRT technique were planned for each patient. Subsequently, the values of Dmin, Dmean, Dmax and Dose Volume Histogram from the treatment planning system and NTCP values of spinal cord and larynx were calculated with BIOPLAN and MATLAB software for all patients. Results: Statistical results showed that mean values of doses of larynx in both three and four-field methods were significantly different between with and without shield groups. Comparison of absorbed dose didn't show any difference between the three and four field methods (P>0.05). Using Shield, just the mean and minimum doses of spinal cord decreased in both three and four fields. The NTCP of the spinal cord and larynx by three and four-field methods with shield in the LKB and EUD models significantly are less than that of the three and four fields without shields, and in the four-field method NTCP of larynx is less than three radiation field. Conclusion: The results of this study indicate that there is no significant difference in doses reached to larynx and spinal cord between the treatments techniques, but laryngeal shield reduce dose and NTCP values in larynx considerably.

Homologue gene of bile acid transporters ntcp, asbt, and ost-alpha in rainbow trout Oncorhynchus mykiss: tissue expression, effect of fasting, and response to bile acid administration.

PubMed

Murashita, Koji; Yoshiura, Yasutoshi; Chisada, Shin-Ichi; Furuita, Hirofumi; Sugita, Tsuyoshi; Matsunari, Hiroyuki; Iwashita, Yasuro; Yamamoto, Takeshi

2014-04-01

Bile acid transporters belonging to the SLC10A protein family, Na+ taurocholate cotransporting polypeptide (NTCP or SLC10A1), apical sodium-dependent bile salt transporter (ASBT or SLC10A2), and organic solute transporter alpha (Ost-alpha) have been known to play critical roles in the enterohepatic circulation of bile acids in mammals. In this study, ntcp, asbt, and ost-alpha-1/-2 cDNA were cloned, their tissue distributions were characterized, and the effects of fasting and bile acid administration on their expression were examined in rainbow trout Oncorhynchus mykiss. The structural characteristics of Ntcp, Asbt, and Ost-alpha were well conserved in trout, and three-dimensional structure analysis showed that Ntcp and Asbt were similar to each other. Tissue distribution analysis revealed that trout asbt was primarily expressed in the hindgut, while ntcp expression occurred in the brain, and ost-alpha-1/-2 was mainly expressed in the liver or ovary. Although asbt and ost-alpha-1 mRNA levels in the gut increased in response to fasting for 4 days, ost-alpha-1 expression in the liver decreased. Similarly, bile acid administration increased asbt and ost-alpha-1 expression levels in the gut, while those of ntcp and ost-alpha-2 in the liver decreased. These results suggested that the genes asbt, ntcp, and ost-alpha are involved in bile acid transport in rainbow trout.

Kinetic characterization of bile salt transport by human NTCP (SLC10A1).

PubMed

Jani, Márton; Beéry, Erzsébet; Heslop, Teresa; Tóth, Beáta; Jagota, Bhavana; Kis, Emese; Kevin Park, B; Krajcsi, Peter; Weaver, Richard J

2018-02-01

The transport of bile acids facilitated by NTCP is an important factor in establishing bile flow. In this study, we examine the kinetics associated with human NTCP-dependent transport of two quantitatively important bile acids comprising the human bile acid pool, chenodeoxycholic acid and glycine-chenodeoxycholate, and secondary bile salt, 3-sulfo-glycolithocholate of potential toxicological significance. The study employed human NTCP overexpressing Chinese Hamster Ovary cells and results compared with taurocholate, a prototypical bile salt commonly used in transporter studies. GCDC and 3S-GLC but not CDCA were transported by NTCP. The efficient uptake of GCDC, TCA and 3S-GLC by NTCP enabled the determination of kinetics. GCDC displayed a lower K M (0.569±0.318μM) than TCA (6.44±3.83μM) and 3S-GLC (3.78±1.17μM). The apparent CL int value for GCDC was 20-fold greater (153±53μl/mg protein/min) than the apparent CL int for TCA (6.92±4.72μl/mg protein/min) and apparent CL int for 3S-GLC (8.05±1.33μl/mg protein/min). These kinetic results provide important complementary data on the substrate selectivity and specificity of NTCP to transport bile acids. NTCP transports GCDC with greater efficiency than TCA and has the same efficacy for 3S-GLC and TCA. Copyright © 2017. Published by Elsevier Ltd.

Patient- and therapy-related factors associated with the incidence of xerostomia in nasopharyngeal carcinoma patients receiving parotid-sparing helical tomotherapy

PubMed Central

Lee, Tsair-Fwu; Liou, Ming-Hsiang; Ting, Hui-Min; Chang, Liyun; Lee, Hsiao-Yi; Wan Leung, Stephen; Huang, Chih-Jen; Chao, Pei-Ju

2015-01-01

We investigated the incidence of moderate to severe patient-reported xerostomia among nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT) and identified patient- and therapy-related factors associated with acute and chronic xerostomia toxicity. The least absolute shrinkage and selection operator (LASSO) normal tissue complication probability (NTCP) models were developed using quality-of-life questionnaire datasets from 67 patients with NPC. For acute toxicity, the dosimetric factors of the mean doses to the ipsilateral submandibular gland (Dis) and the contralateral submandibular gland (Dcs) were selected as the first two significant predictors. For chronic toxicity, four predictive factors were selected: age, mean dose to the oral cavity (Doc), education, and T stage. The substantial sparing data can be used to avoid xerostomia toxicity. We suggest that the tolerance values corresponded to a 20% incidence of complications (TD20) for Dis = 39.0 Gy, Dcs = 38.4 Gy, and Doc = 32.5 Gy, respectively, when mean doses to the parotid glands met the QUANTEC 25 Gy sparing guidelines. To avoid patient-reported xerostomia toxicity, the mean doses to the parotid gland, submandibular gland, and oral cavity have to meet the sparing tolerance, although there is also a need to take inherent patient characteristics into consideration. PMID:26289304

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency: Identification of a novel SLC10A1 mutation in two unrelated infants presenting with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia

PubMed Central

Qiu, Jian-Wu; Deng, Mei; Cheng, Ying; Atif, Raza-Muhammad; Lin, Wei-Xia; Guo, Li; Li, Hua; Song, Yuan-Zong

2017-01-01

Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c.800C>T (p.S267F) and c.263T>C (p.I88T). On genetic analysis of the two family trios, the latter missense variant was detected in trans with the former, a reported loss-of-function variant. Having not been reported in any databases, the c.263T>C (p.I88T) variant demonstrated an allele frequency of 0.67% (1/150) in healthy controls. Moreover, this variant involved a relatively conservative amino acid, and was predicted to be pathogenic or deleterious by changing the conformation of the NTCP molecule. In conclusion, the novel variant c.263T>C (p.I88T) in this study enriched the SLC10A1 mutation spectrum; the clinical findings lent support to the primary role of NTCP in hepatic bile acid clearance, and suggested that NTCP deficiency might be a contributing factor for the development of neonatal indirect hyperbilirubinemia. PMID:29290974

From DCPD to NTCP: The long journey towards identifying a functional hepatitis B virus receptor

PubMed Central

2015-01-01

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection. PMID:26523264

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency: Identification of a novel SLC10A1 mutation in two unrelated infants presenting with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia.

PubMed

Qiu, Jian-Wu; Deng, Mei; Cheng, Ying; Atif, Raza-Muhammad; Lin, Wei-Xia; Guo, Li; Li, Hua; Song, Yuan-Zong

2017-12-05

Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c.800C>T (p.S267F) and c.263T>C (p.I88T). On genetic analysis of the two family trios, the latter missense variant was detected in trans with the former, a reported loss-of-function variant. Having not been reported in any databases, the c.263T>C (p.I88T) variant demonstrated an allele frequency of 0.67% (1/150) in healthy controls. Moreover, this variant involved a relatively conservative amino acid, and was predicted to be pathogenic or deleterious by changing the conformation of the NTCP molecule. In conclusion, the novel variant c.263T>C (p.I88T) in this study enriched the SLC10A1 mutation spectrum; the clinical findings lent support to the primary role of NTCP in hepatic bile acid clearance, and suggested that NTCP deficiency might be a contributing factor for the development of neonatal indirect hyperbilirubinemia.

From DCPD to NTCP: the long journey towards identifying a functional hepatitis B virus receptor.

PubMed

Li, Jisu; Tong, Shuping

2015-09-01

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection.

Bladder radiotherapy treatment: A retrospective comparison of 3-dimensional conformal radiotherapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pasciuti, Katia, E-mail: k.pasciuti@virgilio.it; Kuthpady, Shrinivas; Anderson, Anne

To examine tumor's and organ's response when different radiotherapy plan techniques are used. Ten patients with confirmed bladder tumors were first treated using 3-dimensional conformal radiotherapy (3DCRT) and subsequently the original plans were re-optimized using the intensity-modulated radiation treatment (IMRT) and volumetric-modulated arc therapy (VMAT)-techniques. Targets coverage in terms of conformity and homogeneity index, TCP, and organs' dose limits, including integral dose analysis were evaluated. In addition, MUs and treatment delivery times were compared. Better minimum target coverage (1.3%) was observed in VMAT plans when compared to 3DCRT and IMRT ones confirmed by a statistically significant conformity index (CI) results.more » Large differences were observed among techniques in integral dose results of the femoral heads. Even if no statistically significant differences were reported in rectum and tissue, a large amount of energy deposition was observed in 3DCRT plans. In any case, VMAT plans provided better organs and tissue sparing confirmed also by the normal tissue complication probability (NTCP) analysis as well as a better tumor control probability (TCP) result. Our analysis showed better overall results in planning using VMAT techniques. Furthermore, a total time reduction in treatment observed among techniques including gantry and collimator rotation could encourage using the more recent one, reducing target movements and patient discomfort.« less

On the new metrics for IMRT QA verification.

PubMed

Garcia-Romero, Alejandro; Hernandez-Vitoria, Araceli; Millan-Cebrian, Esther; Alba-Escorihuela, Veronica; Serrano-Zabaleta, Sonia; Ortega-Pardina, Pablo

2016-11-01

The aim of this work is to search for new metrics that could give more reliable acceptance/rejection criteria on the IMRT verification process and to offer solutions to the discrepancies found among different conventional metrics. Therefore, besides conventional metrics, new ones are proposed and evaluated with new tools to find correlations among them. These new metrics are based on the processing of the dose-volume histogram information, evaluating the absorbed dose differences, the dose constraint fulfillment, or modified biomathematical treatment outcome models such as tumor control probability (TCP) and normal tissue complication probability (NTCP). An additional purpose is to establish whether the new metrics yield the same acceptance/rejection plan distribution as the conventional ones. Fifty eight treatment plans concerning several patient locations are analyzed. All of them were verified prior to the treatment, using conventional metrics, and retrospectively after the treatment with the new metrics. These new metrics include the definition of three continuous functions, based on dose-volume histograms resulting from measurements evaluated with a reconstructed dose system and also with a Monte Carlo redundant calculation. The 3D gamma function for every volume of interest is also calculated. The information is also processed to obtain ΔTCP or ΔNTCP for the considered volumes of interest. These biomathematical treatment outcome models have been modified to increase their sensitivity to dose changes. A robustness index from a radiobiological point of view is defined to classify plans in robustness against dose changes. Dose difference metrics can be condensed in a single parameter: the dose difference global function, with an optimal cutoff that can be determined from a receiver operating characteristics (ROC) analysis of the metric. It is not always possible to correlate differences in biomathematical treatment outcome models with dose difference metrics. This is due to the fact that the dose constraint is often far from the dose that has an actual impact on the radiobiological model, and therefore, biomathematical treatment outcome models are insensitive to big dose differences between the verification system and the treatment planning system. As an alternative, the use of modified radiobiological models which provides a better correlation is proposed. In any case, it is better to choose robust plans from a radiobiological point of view. The robustness index defined in this work is a good predictor of the plan rejection probability according to metrics derived from modified radiobiological models. The global 3D gamma-based metric calculated for each plan volume shows a good correlation with the dose difference metrics and presents a good performance in the acceptance/rejection process. Some discrepancies have been found in dose reconstruction depending on the algorithm employed. Significant and unavoidable discrepancies were found between the conventional metrics and the new ones. The dose difference global function and the 3D gamma for each plan volume are good classifiers regarding dose difference metrics. ROC analysis is useful to evaluate the predictive power of the new metrics. The correlation between biomathematical treatment outcome models and the dose difference-based metrics is enhanced by using modified TCP and NTCP functions that take into account the dose constraints for each plan. The robustness index is useful to evaluate if a plan is likely to be rejected. Conventional verification should be replaced by the new metrics, which are clinically more relevant.

NTCP opens the door for hepatitis B virus infection.

PubMed

Yan, Huan; Liu, Yang; Sui, Jianhua; Li, Wenhui

2015-09-01

A liver bile acids transporter, sodium taurocholate cotransporting polypeptide (NTCP, encoded by SLC10A1) was recently identified as a functional receptor for hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). NTCP-complemented human hepatoma HepG2 cells (HepG2-NTCP) were shown to support infection of HBV and HDV in vitro, providing a much-needed and convenient cell culture system for the viruses. Identification of NTCP as a functional receptor for HBV has significantly advanced our understanding of the viral life cycle and opened new opportunities for developing anti-HBV interventions. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B". Copyright © 2015 Elsevier B.V. All rights reserved.

Quantitative analysis of normal tissue effects in the clinic (QUANTEC) guideline validation using quality of life questionnaire datasets for parotid gland constraints to avoid causing xerostomia during head-and-neck radiotherapy.

PubMed

Lee, Tsair-Fwu; Fang, Fu-Min

2013-03-01

To perform a validation test of the quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines against quality of life (QoL) questionnaire datasets collected prospectively from patients with head and neck (HN) cancers, including HN squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC). QoL questionnaire datasets from 95 patients with NPC and 142 with HNSCC were analyzed separately. The European Organization for Research and Treatment of Cancer H&N35 QoL questionnaire was used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate to severe xerostomia 3 and 12 months after the completion of RT, and excluded patients with grade 3(+) xerostomia at the baseline. The Lyman-Kutcher-Burman normal tissue complication probability (NTCP) model was used to describe the incidence of xerostomia. Negative predictive values (NPVs) were used to determine the rate of correctly predicting the lack of complications. NTCP fitted parameters were TD₅₀=37.8 Gy (CI: 29.1-46.9 Gy), m=0.59 (CI: 0.48-0.80) and TD50=43.9 Gy (CI: 33.2-52.8 Gy), m=0.48 (CI: 0.37-0.76) at the 3-month and 12-month time points, respectively. For QUANTEC validation, HN and HNSCC data validation gave similar results at 3 months; at mean doses to the spared parotid of ≤20 and ≤25 Gy, the QoL dataset showed approximately 22% and 28% rates of xerostomia, respectively. At 12 months, the rates of xerostomia were approximately 13% and 19%, respectively. For NPC cases, the dataset showed approximately 0% and 33% (∼67% NPV) rates of xerostomia at 3 months. At 12 months, both rates of xerostomia were approximately 0% (∼100% NPV), which differed significantly from the results for the HNSCC cohort. The QoL datasets validated the QUANTEC guidelines and suggested that the modified QUANTEC 20/20-Gy spared-gland guideline is suitable for clinical use in HNSCC cohorts to effectively avoid xerostomia, and the QUANTEC 25-Gy guideline is justified for NPC cohorts. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moteabbed, Maryam, E-mail: mmoteabbed@partners.org; Yock, Torunn I.; Depauw, Nicolas

Purpose: This study aimed to assess the clinical impact of spot size and the addition of apertures and range compensators on the treatment quality of pencil beam scanning (PBS) proton therapy and to define when PBS could improve on passive scattering proton therapy (PSPT). Methods and Materials: The patient cohort included 14 pediatric patients treated with PSPT. Six PBS plans were created and optimized for each patient using 3 spot sizes (∼12-, 5.4-, and 2.5-mm median sigma at isocenter for 90- to 230-MeV range) and adding apertures and compensators to plans with the 2 larger spots. Conformity and homogeneity indices,more » dose-volume histogram parameters, equivalent uniform dose (EUD), normal tissue complication probability (NTCP), and integral dose were quantified and compared with the respective PSPT plans. Results: The results clearly indicated that PBS with the largest spots does not necessarily offer a dosimetric or clinical advantage over PSPT. With comparable target coverage, the mean dose (D{sub mean}) to healthy organs was on average 6.3% larger than PSPT when using this spot size. However, adding apertures to plans with large spots improved the treatment quality by decreasing the average D{sub mean} and EUD by up to 8.6% and 3.2% of the prescribed dose, respectively. Decreasing the spot size further improved all plans, lowering the average D{sub mean} and EUD by up to 11.6% and 10.9% compared with PSPT, respectively, and eliminated the need for beam-shaping devices. The NTCP decreased with spot size and addition of apertures, with maximum reduction of 5.4% relative to PSPT. Conclusions: The added benefit of using PBS strongly depends on the delivery configurations. Facilities limited to large spot sizes (>∼8 mm median sigma at isocenter) are recommended to use apertures to reduce treatment-related toxicities, at least for complex and/or small tumors.« less

Modeling and optimization of a time-resolved proton radiographic imaging system for proton cancer treatment

NASA Astrophysics Data System (ADS)

Han, Bin

This dissertation describes a research project to test the clinical utility of a time-resolved proton radiographic (TRPR) imaging system by performing comprehensive Monte Carlo simulations of a physical device coupled with realistic lung cancer patient anatomy defined by 4DCT for proton therapy. A time-resolved proton radiographic imaging system was modeled through Monte Carlo simulations. A particle-tracking feature was employed to evaluate the performance of the proton imaging system, especially in its ability to visualize and quantify proton range variations during respiration. The Most Likely Path (MLP) algorithm was developed to approximate the multiple Coulomb scattering paths of protons for the purpose of image reconstruction. Spatial resolution of ˜ 1 mm and range resolution of 1.3% of the total range were achieved using the MLP algorithm. Time-resolved proton radiographs of five patient cases were reconstructed to track tumor motion and to calculate water equivalent length variations. By comparing with direct 4DCT measurement, the accuracy of tumor tracking was found to be better than 2 mm in five patient cases. Utilizing tumor tracking information to reduce margins to the planning target volume, a gated treatment plan was compared with un-gated treatment plan. The equivalent uniform dose (EUD) and the normal tissue complication probability (NTCP) were used to quantify the gain in the quality of treatments. The EUD of the OARs was found to be reduced up to 11% and the corresponding NTCP of organs at risk (OARs) was found to be reduced up to 16.5%. These results suggest that, with image guidance by proton radiography, dose to OARs can be reduced and the corresponding NTCPs can be significantly reduced. The study concludes that the proton imaging system can accurately track the motion of the tumor and detect the WEL variations, leading to potential gains in using image-guided proton radiography for lung cancer treatments.

Effect of induction chemotherapy on estimated risk of radiation pneumonitis in bulky non–small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amin, Neha P., E-mail: npamin@gmail.com; Miften, Moyed; Thornton, Dale

2013-10-01

Patients with bulky non–small cell lung cancer (NSCLC) may be at a high risk for radiation pneumonitis (RP) if treated with up-front concurrent chemoradiation. There is limited information about the effect of induction chemotherapy on the volume of normal lung subsequently irradiated. This study aims to estimate the reduction in risk of RP in patients with NSCLC after receiving induction chemotherapy. Between 2004 and 2009, 25 patients with Stage IV NSCLC were treated with chemotherapy alone (no surgery or radiation therapy [RT]) and had computed tomography (CT) scans before and after 2 cycles of chemotherapy. Simulated RT plans were createdmore » for the prechemotherapy and postchemotherapy scans so as to deliver 60 Gy to the thoracic disease in patients who had either a >20% volumetric increase or decrease in gross tumor volume (GTV) from chemotherapy. The prechemotherapy and postchemotherapy scans were analyzed to compare the percentage of lung volume receiving≥20 Gy (V20), mean lung dose (MLD), and normal tissue complication probability (NTCP). Eight patients (32%) had a GTV reduction >20%, 2 (8%) had GTV increase >20%, and 15 (60%) had stable GTV. In the 8 responders, there was an absolute median GTV decrease of 88.1 cc (7.3 to 351.6 cc) or a 48% (20% to 62%) relative reduction in tumor burden. One had >20% tumor progression during chemotherapy, yet had an improvement in dosimetric parameters postchemotherapy. Among these 9 patients, the median decrease in V20, MLD, and NTCP was 2.6% (p<0.01), 2.1 Gy (p<0.01), and 5.6% (p<0.01), respectively. Less than one-third of patients with NSCLC obtain >20% volumetric tumor reduction from chemotherapy alone. Even with that amount of volumetric reduction, the 5% reduced risk of RP was only modest and did not convert previously ineligible patients to safely receive definitive thoracic RT.« less

Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: Investigating dose-volume relationships and role for inverse planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tho, Lye Mun; Glegg, Martin; Paterson, Jennifer

2006-10-01

Purpose: The relationship between volume of irradiated small bowel (VSB) and acute toxicity in rectal cancer radiotherapy is poorly quantified, particularly in patients receiving concurrent preoperative chemoradiotherapy. Using treatment planning data, we studied a series of such patients. Methods and Materials: Details of 41 patients with locally advanced rectal cancer were reviewed. All received 45 Gy in 25 fractions over 5 weeks, 3-4 fields three-dimensional conformal radiotherapy with daily 5-fluorouracil and folinic acid during Weeks 1 and 5. Toxicity was assessed prospectively in a weekly clinic. Using computed tomography planning software, the VSB was determined at 5 Gy dose intervalsmore » (V{sub 5}, V{sub 1}, etc.). Eight patients with maximal VSB had dosimetry and radiobiological modeling outcomes compared between inverse and conformal three-dimensional planning. Results: VSB correlated strongly with diarrheal severity at every dose level (p < 0.03), with strongest correlation at lowest doses. Median VSB differed significantly between patients experiencing Grade 0-1 and Grade 2-4 diarrhea (p {<=} 0.05). No correlation was found with anorexia, nausea, vomiting, abdominal cramps, age, body mass index, sex, tumor position, or number of fields. Analysis of 8 patients showed that inverse planning reduced median dose to small bowel by 5.1 Gy (p = 0.008) and calculated late normal tissue complication probability (NTCP) by 67% (p = 0.016). We constructed a model using mathematical analysis to predict for acute diarrhea occurring at V{sub 5} and V{sub 15}. Conclusions: A strong dose-volume relationship exists between VSB and acute diarrhea at all dose levels during preoperative chemoradiotherapy. Our constructed model may be useful in predicting toxicity, and this has been derived without the confounding influence of surgical excision on bowel function. Inverse planning can reduce calculated dose to small bowel and late NTCP, and its clinical role warrants further investigation.« less

Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients.

PubMed

Pastore, Francesco; Conson, Manuel; D'Avino, Vittoria; Palma, Giuseppe; Liuzzi, Raffaele; Solla, Raffaele; Farella, Antonio; Salvatore, Marco; Cella, Laura; Pacelli, Roberto

2016-01-01

Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001]. Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.

Incorporating Single-nucleotide Polymorphisms Into the Lyman Model to Improve Prediction of Radiation Pneumonitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L., E-mail: sltucker@mdanderson.org; Li Minghuan; Xu Ting

2013-01-01

Purpose: To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-{beta}, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). Methods and Materials: Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGF{beta}, TNF{alpha}, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk ofmore » severe (grade {>=}3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. Results: Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGF{beta}, VEGF, TNF{alpha}, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGF{beta}, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. Conclusions: This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs.« less

Comparative analysis of SmartArc‐based dual arc volumetric‐modulated arc radiotherapy (VMAT) versus intensity‐modulated radiotherapy (IMRT) for nasopharyngeal carcinoma

PubMed Central

Chao, Pei‐Ju; Ting, Hui‐Min; Lo, Su‐Hua; Wang, Yu‐Wen; Tuan, Chiu‐Ching; Fang, Fu‐Min

2011-01-01

The purpose of this study was to evaluate and quantify the planning performance of SmartArc‐based volumetric‐modulated arc radiotherapy (VMAT) versus fixed‐beam intensity‐modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) using a sequential mode treatment plan. The plan quality and performance of dual arc‐VMAT (DA‐VMAT) using the Pinnacle3 Smart‐Arc system (clinical version 9.0; Philips, Fitchburg, WI, USA) were evaluated and compared with those of seven‐field (7F)‐IMRT in 18 consecutive NPC patients. Analysis parameters included the conformity index (CI) and homogeneity index (HI) for the planning target volume (PTV), maximum and mean dose, normal tissue complication probability (NTCP) for the specified organs at risk (OARs), and comprehensive quality index (CQI) for an overall evaluation in the 11 OARs. Treatment delivery time, monitor units per fraction (MU/fr), and gamma (Γ3mm,3%) evaluations were also analyzed. DA‐VMAT achieved similar target coverage and slightly better homogeneity than conventional 7F‐IMRT with a similar CI and HI. NTCP values were only significantly lower in the left parotid gland (for xerostomia) for DA‐VMAT plans. The mean value of CQI at 0.98±0.02 indicated a 2% benefit in sparing OARs by DA‐VMAT. The MU/fr used and average delivery times appeared to show improved efficiencies in DA‐VMAT. Each technique demonstrated high accuracy in dose delivery in terms of a high‐quality assurance (QA) passing rate (>98%) of the (Γ3mm,3%) criterion. The major difference between DA‐VMAT and 7F‐IMRT using a sequential mode for treating NPC cases appears to be improved efficiency, resulting in a faster delivery time and the use of fewer MU/fr. PACS number: 87.53.Tf, 87.55.x, 87.55.D, 87.55.dk PMID:22089015

Primary biliary acids inhibit hepatitis D virus (HDV) entry into human hepatoma cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP).

PubMed

Veloso Alves Pereira, Isabel; Buchmann, Bettina; Sandmann, Lisa; Sprinzl, Kathrin; Schlaphoff, Verena; Döhner, Katinka; Vondran, Florian; Sarrazin, Christoph; Manns, Michael P; Pinto Marques Souza de Oliveira, Cláudia; Sodeik, Beate; Ciesek, Sandra; von Hahn, Thomas

2015-01-01

The sodium-taurocholate cotransporting polypeptide (NTCP) is both a key bile acid (BA) transporter mediating uptake of BA into hepatocytes and an essential receptor for hepatitis B virus (HBV) and hepatitis D virus (HDV). In this study we aimed to characterize to what extent and through what mechanism BA affect HDV cell entry. HuH-7 cells stably expressing NTCP (HuH-7/NTCP) and primary human hepatocytes (PHH) were infected with in vitro generated HDV particles. Infectivity in the absence or presence of compounds was assessed using immunofluorescence staining for HDV antigen, standard 50% tissue culture infectious dose (TCID50) assays and quantitative PCR. Addition of primary conjugated and unconjugated BA resulted in a dose dependent reduction in the number of infected cells while secondary, tertiary and synthetic BA had a lesser effect. This effect was observed both in HuH-7/NTCP and in PHH. Other replication cycle steps such as replication and particle assembly and release were unaffected. Moreover, inhibitory BA competed with a fragment from the large HBV envelope protein for binding to NTCP-expressing cells. Conversely, the sodium/BA-cotransporter function of NTCP seemed not to be required for HDV infection since infection was similar in the presence or absence of a sodium gradient across the plasma membrane. When chenodeoxycolic acid (15 mg per kg body weight) was administered to three chronically HDV infected individuals over a period of up to 16 days there was no change in serum HDV RNA. Primary BA inhibit NTCP-mediated HDV entry into hepatocytes suggesting that modulation of the BA pool may affect HDV infection of hepatocytes.

WE-F-304-00: Outcomes of Hypofractionated Treatments - Results of the WGSBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

WE-F-304-03: Optic Nerve/Chiasm Hypofractionated SRS/SRT Dose Tolerance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milano, M.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

WE-F-304-02: Recurrent HNC Treated with SBRT: TCP-Based Outcome Estimates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clump, D.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

WE-F-304-01: Overview of the Working Group On Stereotactic Body Radiation Therapy (WGSBRT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yorke, E.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe andmore » effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.« less

Quantitative assessment of the contribution of sodium-dependent taurocholate co-transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin, pitavastatin and fluvastatin.

PubMed

Bi, Yi-an; Qiu, Xi; Rotter, Charles J; Kimoto, Emi; Piotrowski, Mary; Varma, Manthena V; Ei-Kattan, Ayman F; Lai, Yurong

2013-11-01

Hepatic uptake transport is often the rate-determining step in the systemic clearance of drugs. The ability to predict uptake clearance and to determine the contribution of individual transporters to overall hepatic uptake is therefore critical in assessing the potential pharmacokinetic and pharmacodynamic variability associated with drug-drug interactions and pharmacogenetics. The present study revisited the interaction of statin drugs, including pitavastatin, fluvastatin and rosuvastatin, with the sodium-dependent taurocholate co-transporting polypeptide (NTCP) using gene transfected cell models. In addition, the uptake clearance and the contribution of NTCP to the overall hepatic uptake were assessed using in vitro hepatocyte models. Then NTCP protein expression was measured by a targeted proteomics transporter quantification method to confirm the presence and stability of NTCP expression in suspended and cultured hepatocyte models. It was concluded that NTCP-mediated uptake contributed significantly to active hepatic uptake in hepatocyte models for all three statins. However, the contribution of NTCP-mediated uptake to the overall active hepatic uptake was compound-dependent and varied from about 24% to 45%. Understanding the contribution of individual transporter proteins to the overall hepatic uptake and its functional variability when other active hepatic uptake pathways are interrupted could improve the current prediction practice used to assess the pharmacokinetic variability due to drug-drug interactions, pharmacogenetics and physiopathological conditions in humans. Copyright © 2013 John Wiley & Sons, Ltd.

A Dosimetric Model of Duodenal Toxicity After Stereotactic Body Radiotherapy for Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murphy, James D.; Christman-Skieller, Claudia; Kim, Jeff

2010-12-01

Introduction: Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT. Methods and Materials: Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V{sub 5} (volume of duodenum that received 5 Gy), V{sub 10}, V{sub 15}, V{sub 20}, V{sub 25}, and D{sub max} (maximum dose to 1 cm{sup 3}). Normal tissue complication probabilitymore » (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models. Results: The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V{sub 10}-V{sub 25} and D{sub max} all correlated significantly with duodenal toxicity (p < 0.05). In particular, V{sub 15} {>=} 9.1 cm{sup 3} and V{sub 15} < 9.1 cm{sup 3} yielded duodenal toxicity rates of 52% and 11%, respectively (p = 0.002); V{sub 20} {>=} 3.3 cm{sup 3} and V{sub 20} < 3.3 cm{sup 3} gave toxicity rates of 52% and 11%, respectively (p = 0.002); and D{sub max} {>=} 23 Gy and D{sub max} < 23 Gy gave toxicity rates of 49% and 12%, respectively (p = 0.004). Lyman NTCP model optimization generated the coefficients m = 0.23, n = 0.12, and TD{sub 50} = 24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p = 0.001). Conclusions: Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies.« less

Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP)

PubMed Central

Watashi, Koichi; Sluder, Ann; Daito, Takuji; Matsunaga, Satoko; Ryo, Akihide; Nagamori, Shushi; Iwamoto, Masashi; Nakajima, Syo; Tsukuda, Senko; Borroto-Esoda, Katyna; Sugiyama, Masaya; Tanaka, Yasuhito; Kanai, Yoshikatsu; Kusuhara, Hiroyuki; Mizokami, Masashi; Wakita, Takaji

2014-01-01

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM. Conclusion: This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. (Hepatology 2014;59:1726–1737) PMID:24375637

Taurolithocholate-induced MRP2 retrieval involves MARCKS phosphorylation by protein kinase Cϵ in HUH-NTCP Cells.

PubMed

Schonhoff, Christopher M; Webster, Cynthia R L; Anwer, M Sawkat

2013-07-01

Taurolithocholate (TLC) acutely inhibits the biliary excretion of multidrug-resistant associated protein 2 (Mrp2) substrates by inducing Mrp2 retrieval from the canalicular membrane, whereas cyclic adenosine monophosphate (cAMP) increases plasma membrane (PM)-MRP2. The effect of TLC may be mediated via protein kinase Cϵ (PKCϵ). Myristoylated alanine-rich C kinase substrate (MARCKS) is a membrane-bound F-actin crosslinking protein and is phosphorylated by PKCs. MARCKS phosphorylation has been implicated in endocytosis, and the underlying mechanism appears to be the detachment of phosphorylated myristoylated alanine-rich C kinase substrate (pMARCKS) from the membrane. The aim of the present study was to test the hypothesis that TLC-induced MRP2 retrieval involves PKCϵ-mediated MARCKS phosphorylation. Studies were conducted in HuH7 cells stably transfected with sodium taurocholate cotransporting polypeptide (HuH-NTCP cells) and in rat hepatocytes. TLC increased PM-PKCϵ and decreased PM-MRP2 in both HuH-NTCP cells and hepatocytes. cAMP did not affect PM-PKCϵ and increased PM-MRP2 in these cells. In HuH-NTCP cells, dominant-negative (DN) PKCϵ reversed TLC-induced decreases in PM-MRP2 without affecting cAMP-induced increases in PM-MRP2. TLC, but not cAMP, increased MARCKS phosphorylation in HuH-NTCP cells and hepatocytes. TLC and phorbol myristate acetate increased cytosolic pMARCKS and decreased PM-MARCKS in HuH-NTCP cells. TLC failed to increase MARCKS phosphorylation in HuH-NTCP cells transfected with DN-PKCϵ, and this suggested PKCϵ-mediated phosphorylation of MARCKS by TLC. In HuH-NTCP cells transfected with phosphorylation-deficient MARCKS, TLC failed to increase MARCKS phosphorylation or decrease PM-MRP2. Taken together, these results support the hypothesis that TLC-induced MRP2 retrieval involves TLC-mediated activation of PKCϵ followed by MARCKS phosphorylation and consequent detachment of MARCKS from the membrane. Copyright © 2013 American Association for the Study of Liver Diseases.

Genetic variants in NTCP exon gene are associated with HBV infection status in a Chinese Han population.

PubMed

Wu, Wennan; Zeng, Yongbin; Lin, Jinpiao; Wu, Yingying; Chen, Tianbin; Xun, Zhen; Ou, Qishui

2018-04-01

Sodium taurocholate co-transporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids. Recently, NTCP was identified as a hepatitis B virus (HBV) receptor. The aim of this study is to investigate the association of NTCP polymorphisms with HBV clinical outcomes and investigate the relationship between NTCP polymorphisms and the serum bile acid level in a Chinese Han population. The single nucleotide polymorphisms rs2296651 and rs4646285 were genotyped in 1619 Chinese Han individuals. Improved multiple ligase detection reaction was utilized to genotype. The level of bile acids was measured by the enzymatic cycling method. Quantitative polymerase chain reaction analysis was carried out to analyze the potential function. In logistic regression analysis, the frequency of rs2296651 (S267F) CT genotype was higher in HBV immune recovery and healthy control groups than in the chronic HBV infection group (P = 0.001 and P < 0.001, respectively). Patients who carried allele T showed a higher bile acid level than patients who did not carry allele T (P = 0.009). The rs4646285 AA genotype was more common in the immune recovery group than in the chronic HBV infection group (P = 0.011). No difference in serum bile acid was detected between the rs4646285 wild-type patients and mutant-type patients. Quantitative reverse transcription-polymerase chain reaction showed the NTCP mRNA levels were lower in rs4646285 variants than wild types. NTCP gene polymorphisms may be associated with the natural course of HBV infection in a Chinese Han population. The S267F variant may be a protective factor to resist chronic hepatitis B progression which showed a higher bile acid level in Chinese Han chronic HBV infection patients. The rs4646285 variants could influence the expression of NTCP at the level of transcription, and ultimately may be associated with HBV infection immune recovery. © 2017 The Japan Society of Hepatology.

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter

PubMed Central

Yu, Dongke; Zhang, Han; Lionarons, Daniel A.; Boyer, James L.

2017-01-01

The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea. The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA (Km = 92.4 µM) and scymnol sulfate (Ki = 31 µM), compared with hNTCP (TCA, Km = 5.4 µM; Scymnol sulfate, Ki = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. PMID:28077388

Radiobiologically optimized couch shift: A new localization paradigm using cone-beam CT for prostate radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Yimei, E-mail: yhuang2@hfhs.org; Gardner, Stephen J.; Wen, Ning

2015-10-15

Purpose: To present a novel positioning strategy which optimizes radiation delivery by utilizing radiobiological response knowledge and evaluate its use during prostate external beam radiotherapy. Methods: Five patients with low or intermediate risk prostate cancer were evaluated retrospectively in this IRB-approved study. For each patient, a VMAT plan with one 358° arc was generated on the planning CT (PCT) to deliver 78 Gy in 39 fractions. Five representative pretreatment cone beam CTs (CBCT) were selected for each patient. The CBCT images were registered to PCT by a human observer, which consisted of an initial automated registration with three degrees-of-freedom, followedmore » by manual adjustment for agreement at the prostate/rectal wall interface. To determine the optimal treatment position for each CBCT, a search was performed centering on the observer-matched position (OM-position) utilizing a score function based on radiobiological and dosimetric indices (EUD{sub prostate}, D99{sub prostate}, NTCP{sub rectum}, and NTCP{sub bladder}) for the prostate, rectum, and bladder. We termed the optimal treatment position the radiobiologically optimized couch shift position (ROCS-position). Results: The dosimetric indices, averaged over the five patients’ treatment plans, were (mean ± SD) 79.5 ± 0.3 Gy (EUD{sub prostate}), 78.2 ± 0.4 Gy (D99{sub prostate}), 11.1% ± 2.7% (NTCP{sub rectum}), and 46.9% ± 7.6% (NTCP{sub bladder}). The corresponding values from CBCT at the OM-positions were 79.5 ± 0.6 Gy (EUD{sub prostate}), 77.8 ± 0.7 Gy (D99{sub prostate}), 12.1% ± 5.6% (NTCP{sub rectum}), and 51.6% ± 15.2% (NTCP{sub bladder}), respectively. In comparison, from CBCT at the ROCS-positions, the dosimetric indices were 79.5 ± 0.6 Gy (EUD{sub prostate}), 77.3 ± 0.6 Gy (D99{sub prostate}), 8.0% ± 3.3% (NTCP{sub rectum}), and 46.9% ± 15.7% (NTCP{sub bladder}). Excessive NTCP{sub rectum} was observed on Patient 5 (19.5% ± 6.6%) corresponding to localization at OM-position, compared to the planned value of 11.7%. This was mitigated with radiobiologically optimized localization, resulting in a reduced NTCP{sub rectum} value of 11.3% ± 3.5%. Overall, the treatment position optimization resulted in similar target dose coverage with reduced risk to rectum. Conclusions: These encouraging results illustrate the potential advantage of applying radiobiologically optimized correction for online image-guided radiotherapy of prostate patients.« less

SU-C-BRB-05: Determining the Adequacy of Auto-Contouring Via Probabilistic Assessment of Ensuing Treatment Plan Metrics in Comparison with Manual Contours

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nourzadeh, H; Watkins, W; Siebers, J

Purpose: To determine if auto-contour and manual-contour—based plans differ when evaluated with respect to probabilistic coverage metrics and biological model endpoints for prostate IMRT. Methods: Manual and auto-contours were created for 149 CT image sets acquired from 16 unique prostate patients. A single physician manually contoured all images. Auto-contouring was completed utilizing Pinnacle’s Smart Probabilistic Image Contouring Engine (SPICE). For each CT, three different 78 Gy/39 fraction 7-beam IMRT plans are created; PD with drawn ROIs, PAS with auto-contoured ROIs, and PM with auto-contoured OARs with the manually drawn target. For each plan, 1000 virtual treatment simulations with different sampledmore » systematic errors for each simulation and a different sampled random error for each fraction were performed using our in-house GPU-accelerated robustness analyzer tool which reports the statistical probability of achieving dose-volume metrics, NTCP, TCP, and the probability of achieving the optimization criteria for both auto-contoured (AS) and manually drawn (D) ROIs. Metrics are reported for all possible cross-evaluation pairs of ROI types (AS,D) and planning scenarios (PD,PAS,PM). Bhattacharyya coefficient (BC) is calculated to measure the PDF similarities for the dose-volume metric, NTCP, TCP, and objectives with respect to the manually drawn contour evaluated on base plan (D-PD). Results: We observe high BC values (BC≥0.94) for all OAR objectives. BC values of max dose objective on CTV also signify high resemblance (BC≥0.93) between the distributions. On the other hand, BC values for CTV’s D95 and Dmin objectives are small for AS-PM, AS-PD. NTCP distributions are similar across all evaluation pairs, while TCP distributions of AS-PM, AS-PD sustain variations up to %6 compared to other evaluated pairs. Conclusion: No significant probabilistic differences are observed in the metrics when auto-contoured OARs are used. The prostate auto-contour needs improvement to achieve clinically equivalent plans.« less

Dosimetric effects of patient rotational setup errors on prostate IMRT treatments

NASA Astrophysics Data System (ADS)

Fu, Weihua; Yang, Yong; Li, Xiang; Heron, Dwight E.; Saiful Huq, M.; Yue, Ning J.

2006-10-01

The purpose of this work is to determine dose delivery errors that could result from systematic rotational setup errors (ΔΦ) for prostate cancer patients treated with three-phase sequential boost IMRT. In order to implement this, different rotational setup errors around three Cartesian axes were simulated for five prostate patients and dosimetric indices, such as dose-volume histogram (DVH), tumour control probability (TCP), normal tissue complication probability (NTCP) and equivalent uniform dose (EUD), were employed to evaluate the corresponding dosimetric influences. Rotational setup errors were simulated by adjusting the gantry, collimator and horizontal couch angles of treatment beams and the dosimetric effects were evaluated by recomputing the dose distributions in the treatment planning system. Our results indicated that, for prostate cancer treatment with the three-phase sequential boost IMRT technique, the rotational setup errors do not have significant dosimetric impacts on the cumulative plan. Even in the worst-case scenario with ΔΦ = 3°, the prostate EUD varied within 1.5% and TCP decreased about 1%. For seminal vesicle, slightly larger influences were observed. However, EUD and TCP changes were still within 2%. The influence on sensitive structures, such as rectum and bladder, is also negligible. This study demonstrates that the rotational setup error degrades the dosimetric coverage of target volume in prostate cancer treatment to a certain degree. However, the degradation was not significant for the three-phase sequential boost prostate IMRT technique and for the margin sizes used in our institution.

Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.

PubMed

Nkongolo, Shirin; Ni, Yi; Lempp, Florian A; Kaufman, Christina; Lindner, Thomas; Esser-Nobis, Katharina; Lohmann, Volker; Mier, Walter; Mehrle, Stefan; Urban, Stephan

2014-04-01

Chronic hepatitis B and hepatitis D are global health problems caused by the human hepatitis B and hepatitis D virus. The myristoylated preS1 domain of the large envelope protein mediates specific binding to hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP). NTCP is a bile salt transporter known to be inhibited by cyclosporin A. This study aimed to characterize the effect of cyclosporin A on HBV/HDV infection. HepaRG cells, primary human hepatocytes, and susceptible NTCP-expressing hepatoma cell lines were applied for infection experiments. The mode of action of cyclosporin A was studied by comparing the effect of different inhibitors, cyclophilin A/B/C-silenced cell lines as well as NTCP variants and mutants. Bile salt transporter and HBV receptor functions were investigated by taurocholate uptake and quantification of HBVpreS binding. Cyclosporin A inhibited hepatitis B and D virus infections during and--less pronounced--prior to virus inoculation. Binding of HBVpreS to NTCP was blocked by cyclosporin A concentrations at 8 μM. An NTCP variant deficient in HBVpreS binding but competent for bile salt transport showed resistance to cyclosporin A. Silencing of cyclophilins A/B/C did not abrogate transporter and receptor inhibition. In contrast, tacrolimus, a cyclophilin-independent calcineurin inhibitor, was inactive. HBV and HDV entry via sodium taurocholate co-transporting polypeptide is inhibited by cyclosporin A. The interaction between the drug and the viral receptor is direct and overlaps with a functional binding site of the preS1 domain, which mediates viral entry. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

HBV life cycle is restricted in mouse hepatocytes expressing human NTCP.

PubMed

Li, Hanjie; Zhuang, Qiuyu; Wang, Yuze; Zhang, Tianying; Zhao, Jinghua; Zhang, Yali; Zhang, Junfang; Lin, Yi; Yuan, Quan; Xia, Ningshao; Han, Jiahuai

2014-03-01

Recent studies have revealed that human sodium taurocholate cotransporting polypeptide (SLC10A1 or NTCP) is a functional cellular receptor for hepatitis B virus (HBV). However, whether human NTCP can support HBV infection in mouse hepatocyte cell lines has not been clarified. Because an HBV-permissible mouse model would be helpful for the study of HBV pathogenesis, it is necessary to investigate whether human NTCP supports the susceptibility of mouse hepatocyte cell lines to HBV. The results show that exogenous human NTCP expression can render non-susceptible HepG2 (human), Huh7 (human), Hepa1-6 (mouse), AML-12 (mouse) cell lines and primary mouse hepatocyte (PMH) cells susceptible to hepatitis D virus (HDV) which employs HBV envelope proteins. However, human NTCP could only introduce HBV susceptibility in human-derived HepG2 and Huh7 cells, but not in mouse-derived Hepa1-6, AML-12 or PMH cells. These data suggest that although human NTCP is a functional receptor that mediates HBV infection in human cells, it cannot support HBV infection in mouse hepatocytes. Our study indicated that the restriction of HBV in mouse hepatocytes likely occurs after viral entry but prior to viral transcription. We have excluded the role of mouse hepatocyte nuclear factors in the restriction of the HBV life cycle and showed that knockdown or inhibition of Sting, TBK1, IRF3 or IRF7, the components of the anti-viral signaling pathways, had no effect on HBV infection in mouse hepatocytes. Therefore, murine restriction factors that limit HBV infection need to be identified before a HBV-permissible mouse line can be created.

Na+/Taurocholate Cotransporting Polypeptide and Apical Sodium-Dependent Bile Acid Transporter Are Involved in the Disposition of Perfluoroalkyl Sulfonates in Humans and Rats

PubMed Central

Zhao, Wen; Zitzow, Jeremiah D.; Ehresman, David J.; Chang, Shu-Ching; Butenhoff, John L.; Forster, Jameson; Hagenbuch, Bruno

2015-01-01

Among the perfluoroalkyl sulfonates (PFASs), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) have half-lives of several years in humans, mainly due to slow renal clearance and potential hepatic accumulation. Both compounds undergo enterohepatic circulation. To determine whether transporters involved in the enterohepatic circulation of bile acids are also involved in the disposition of PFASs, uptake of perfluorobutane sulfonate (PFBS), PFHxS, and PFOS was measured using freshly isolated human and rat hepatocytes in the absence or presence of sodium. The results demonstrated sodium-dependent uptake for all 3 PFASs. Given that the Na+/taurocholate cotransporting polypeptide (NTCP) and the apical sodium-dependent bile salt transporter (ASBT) are essential for the enterohepatic circulation of bile acids, transport of PFASs was investigated in stable CHO Flp-In cells for human NTCP or HEK293 cells transiently expressing rat NTCP, human ASBT, and rat ASBT. The results demonstrated that both human and rat NTCP can transport PFBS, PFHxS, and PFOS. Kinetics with human NTCP revealed Km values of 39.6, 112, and 130 µM for PFBS, PFHxS, and PFOS, respectively. For rat NTCP Km values were 76.2 and 294 µM for PFBS and PFHxS, respectively. Only PFOS was transported by human ASBT whereas rat ASBT did not transport any of the tested PFASs. Human OSTα/β was also able to transport all 3 PFASs. In conclusion, these results suggest that the long half-live and the hepatic accumulation of PFOS in humans are at least, in part, due to transport by NTCP and ASBT. PMID:26001962

Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver

PubMed Central

Nakabori, Tasuku; Hikita, Hayato; Murai, Kazuhiro; Nozaki, Yasutoshi; Kai, Yugo; Makino, Yuki; Saito, Yoshinobu; Tanaka, Satoshi; Wada, Hiroshi; Eguchi, Hidetoshi; Takahashi, Takeshi; Suemizu, Hiroshi; Sakamori, Ryotaro; Hiramatsu, Naoki; Tatsumi, Tomohide; Takehara, Tetsuo

2016-01-01

Sodium taurocholate cotransporting polypeptide (NTCP) is a recently discovered hepatitis B virus (HBV) receptor. In the present study, we used TK-NOG mice with a humanized liver to examine the impact of endogenous NTCP expression on HBV infection. Upon inoculation with HBV, these mice exhibited clear viremia in 2 weeks, and serum HBV DNA levels gradually increased. The frequency of HBsAg-positive hepatocytes in the liver was 5.1 ± 0.6% at 2 weeks and increased with increasing HBV DNA levels, reaching 92.9 ± 2.8% at 10 to 12 weeks. In vivo siRNA-mediated NTCP knockdown before and after HBV inoculation significantly suppressed the levels of HBV replication and the frequency of HBsAg-positive hepatocytes at 2 weeks, whereas NTCP knockdown 13 weeks after infection did not affect these parameters. Similar to the humanized mouse livers in the early phase of HBV infection, human liver samples from chronic hepatitis B patients, especially those treated with nucleos(t)ide analogues, contained a considerable number of hepatocytes that were negative for the anti-HBs antibody. In conclusion, NTCP inhibition prevents the spread of HBV-infected hepatocytes in mice with a humanized liver. NTCP-targeted therapy has potential for regulating HBV infection in patients with chronic hepatitis B. PMID:27278060

Spinoculation Enhances HBV Infection in NTCP-Reconstituted Hepatocytes.

PubMed

Yan, Ran; Zhang, Yongmei; Cai, Dawei; Liu, Yuanjie; Cuconati, Andrea; Guo, Haitao

2015-01-01

Hepatitis B virus (HBV) infection and its sequelae remain a major public health burden, but both HBV basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the HBV receptor. We herein report that we established a NTCP-complemented HepG2 cell line (HepG2-NTCP12) that supports HBV infection, albeit at a low infectivity level following the reported infection procedures. In our attempts to optimize the infection conditions, we found that the centrifugation of HepG2-NTCP12 cells during HBV inoculation (termed "spinoculation") significantly enhanced the virus infectivity. Moreover, the infection level gradually increased with accelerated speed of spinoculation up to 1,000g tested. However, the enhancement of HBV infection was not significantly dependent upon the duration of centrifugation. Furthermore, covalently closed circular (ccc) DNA was detected in infected cells under optimized infection condition by conventional Southern blot, suggesting a successful establishment of HBV infection after spinoculation. Finally, the parental HepG2 cells remained uninfected under HBV spinoculation, and HBV entry inhibitors targeting NTCP blocked HBV infection when cells were spinoculated, suggesting the authentic virus entry mechanism is unaltered under centrifugal inoculation. Our data suggest that spinoculation could serve as a standard protocol for enhancing the efficiency of HBV infection in vitro.

Spinoculation Enhances HBV Infection in NTCP-Reconstituted Hepatocytes

PubMed Central

Yan, Ran; Zhang, Yongmei; Cai, Dawei; Liu, Yuanjie; Cuconati, Andrea; Guo, Haitao

2015-01-01

Hepatitis B virus (HBV) infection and its sequelae remain a major public health burden, but both HBV basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the HBV receptor. We herein report that we established a NTCP-complemented HepG2 cell line (HepG2-NTCP12) that supports HBV infection, albeit at a low infectivity level following the reported infection procedures. In our attempts to optimize the infection conditions, we found that the centrifugation of HepG2-NTCP12 cells during HBV inoculation (termed “spinoculation”) significantly enhanced the virus infectivity. Moreover, the infection level gradually increased with accelerated speed of spinoculation up to 1,000g tested. However, the enhancement of HBV infection was not significantly dependent upon the duration of centrifugation. Furthermore, covalently closed circular (ccc) DNA was detected in infected cells under optimized infection condition by conventional Southern blot, suggesting a successful establishment of HBV infection after spinoculation. Finally, the parental HepG2 cells remained uninfected under HBV spinoculation, and HBV entry inhibitors targeting NTCP blocked HBV infection when cells were spinoculated, suggesting the authentic virus entry mechanism is unaltered under centrifugal inoculation. Our data suggest that spinoculation could serve as a standard protocol for enhancing the efficiency of HBV infection in vitro. PMID:26070202

In silico analysis and experimental validation of azelastine hydrochloride (N4) targeting sodium taurocholate co-transporting polypeptide (NTCP) in HBV therapy.

PubMed

Fu, L-L; Liu, J; Chen, Y; Wang, F-T; Wen, X; Liu, H-Q; Wang, M-Y; Ouyang, L; Huang, J; Bao, J-K; Wei, Y-Q

2014-08-01

The aim of this study was to explore sodium taurocholate co-transporting polypeptide (NTCP) exerting its function with hepatitis B virus (HBV) and its targeted candidate compounds, in HBV therapy. Identification of NTCP as a novel HBV target for screening candidate small molecules, was used by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro virological examination, q-PCR, western blotting and cytotoxicity studies were used for validating efficacy of the candidate compound. We used the phylogenetic analysis of NTCP and constructed its protein-protein network. Also, we screened compounds from Drugbank and ZINC, among which five were validated for their authentication in HepG 2.2.15 cells. Then, we selected compound N4 (azelastine hydrochloride) as the most potent of them. This showed good inhibitory activity against HBsAg (IC50 = 7.5 μm) and HBeAg (IC50 = 3.7 μm), as well as high SI value (SI = 4.68). Further MD simulation results supported good interaction between compound N4 and NTCP. In silico analysis and experimental validation together demonstrated that compound N4 can target NTCP in HepG2.2.15 cells, which may shed light on exploring it as a potential anti-HBV drug. © 2014 John Wiley & Sons Ltd.

Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP).

PubMed

Watashi, Koichi; Sluder, Ann; Daito, Takuji; Matsunaga, Satoko; Ryo, Akihide; Nagamori, Shushi; Iwamoto, Masashi; Nakajima, Syo; Tsukuda, Senko; Borroto-Esoda, Katyna; Sugiyama, Masaya; Tanaka, Yasuhito; Kanai, Yoshikatsu; Kusuhara, Hiroyuki; Mizokami, Masashi; Wakita, Takaji

2014-05-01

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM. This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. Copyright © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.

Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

PubMed Central

Yan, Huan; Zhong, Guocai; Xu, Guangwei; He, Wenhui; Jing, Zhiyi; Gao, Zhenchao; Huang, Yi; Qi, Yonghe; Peng, Bo; Wang, Haimin; Fu, Liran; Song, Mei; Chen, Pan; Gao, Wenqing; Ren, Bijie; Sun, Yinyan; Cai, Tao; Feng, Xiaofeng; Sui, Jianhua; Li, Wenhui

2012-01-01

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001 PMID:23150796

The effects of small field dosimetry on the biological models used in evaluating IMRT dose distributions

NASA Astrophysics Data System (ADS)

Cardarelli, Gene A.

The primary goal in radiation oncology is to deliver lethal radiation doses to tumors, while minimizing dose to normal tissue. IMRT has the capability to increase the dose to the targets and decrease the dose to normal tissue, increasing local control, decrease toxicity and allow for effective dose escalation. This advanced technology does present complex dose distributions that are not easily verified. Furthermore, the dose inhomogeneity caused by non-uniform dose distributions seen in IMRT treatments has caused the development of biological models attempting to characterize the dose-volume effect in the response of organized tissues to radiation. Dosimetry of small fields can be quite challenging when measuring dose distributions for high-energy X-ray beams used in IMRT. The proper modeling of these small field distributions is essential in reproducing accurate dose for IMRT. This evaluation was conducted to quantify the effects of small field dosimetry on IMRT plan dose distributions and the effects on four biological model parameters. The four biological models evaluated were: (1) the generalized Equivalent Uniform Dose (gEUD), (2) the Tumor Control Probability (TCP), (3) the Normal Tissue Complication Probability (NTCP) and (4) the Probability of uncomplicated Tumor Control (P+). These models are used to estimate local control, survival, complications and uncomplicated tumor control. This investigation compares three distinct small field dose algorithms. Dose algorithms were created using film, small ion chamber, and a combination of ion chamber measurements and small field fitting parameters. Due to the nature of uncertainties in small field dosimetry and the dependence of biological models on dose volume information, this examination quantifies the effects of small field dosimetry techniques on radiobiological models and recommends pathways to reduce the errors in using these models to evaluate IMRT dose distributions. This study demonstrates the importance of valid physical dose modeling prior to the use of biological modeling. The success of using biological function data, such as hypoxia, in clinical IMRT planning will greatly benefit from the results of this study.

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter.

PubMed

Yu, Dongke; Zhang, Han; Lionarons, Daniel A; Boyer, James L; Cai, Shi-Ying

2017-04-01

The Na + -dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na + -dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [ 3 H]TCA uptake assay revealed that skSlc10a1 functioned as a Na + -dependent transporter, but with low affinity for TCA ( K m = 92.4 µM) and scymnol sulfate ( K i = 31 µM), compared with hNTCP (TCA, K m = 5.4 µM; Scymnol sulfate, K i = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na + -dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. Copyright © 2017 the American Physiological Society.

SU-F-J-11: Radiobiologically Optimized Patient Localization During Prostate External Beam Localization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Y; Gardner, S; Liu, C

2016-06-15

Purpose: To present a novel positioning strategy which optimizes radiation delivery with radiobiological response knowledge, and to evaluate its application during prostate external beam radiotherapy. Methods: Ten patients with low or intermediate risk prostate cancer were evaluated retrospectively in this IRB-approved study. For each patient, a VMAT plan was generated on the planning CT (PCT) to deliver 78 Gy in 39 fractions with PTV = prostate + 7 mm margin, except for 5mm in the posterior direction. Five representative pretreatment CBCT images were selected for each patient, and prostate, rectum, and bladder were delineated on all CBCT images. Each CBCTmore » was auto-registered to the corresponding PCT. Starting from this auto-matched position (AM-position), a search for optimal treatment position was performed utilizing a score function based on radiobiological and dosimetric indices (D98-DTV, NTCP-rectum, and NTCP-bladder) for the daily target volume (DTV), rectum, and bladder. DTV was defined as prostate + 4 mm margin to account for intra-fraction motion as well as contouring variability on CBCT. We termed the optimal treatment position the radiobiologically optimized couch shift position (ROCS-position). Results: The indices, averaged over the 10 patients’ treatment plans, were (mean±SD): 77.7±0.2 Gy (D98-PTV), 12.3±2.7% (NTCP-rectum), and 53.2±11.2% (NTCP-bladder). The corresponding values calculated on all 50 CBCT images at the AM-positions were 72.9±11.3 Gy (D98-DTV), 15.8±6.4% (NTCP-rectum), and 53.0±21.1% (NTCP-bladder), respectively. In comparison, calculated on CBCT at the ROCS-positions, the indices were 77.0±2.1 Gy (D98-DTV), 12.1±5.7% (NTCP-rectum), and 60.7±16.4% (NTCP-bladder). Compared to autoregistration, ROCS-optimization recovered dose coverage to target volume and lowered the risk to rectum. Moreover, NTCPrectum for one patient remained high after ROCS-optimization and therefore could potentially benefit from adaptive planning. Conclusion: These encouraging results illustrate the potential utility of applying radiobiologically optimized correction for online image-guided radiotherapy of prostate patients.« less

Lung Size and the Risk of Radiation Pneumonitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Briere, Tina Marie, E-mail: tmbriere@mdanderson.org; Krafft, Shane; Liao, Zhongxing

2016-02-01

Purpose: The purpose of this study was to identify patient populations treated for non-small cell lung cancer (NSCLC) who may be more at risk of radiation pneumonitis. Methods and Materials: A total of 579 patients receiving fractionated 3D conformal or intensity modulated radiation therapy (IMRT) for NSCLC were included in the study. Statistical analysis was performed to search for cohorts of patients with higher incidences of radiation pneumonitis. In addition to conventional risk factors, total and spared lung volumes were analyzed. The Lyman-Kutcher-Burman (LKB) and cure models were then used to fit the incidence of radiation pneumonitis as a functionmore » of lung dose and other factors. Results: Total lung volumes with a sparing of less than 1854 cc at 40 Gy were associated with a significantly higher incidence of radiation pneumonitis at 6 months (38% vs 12% for patients with larger volumes, P<.001). This patient cohort was overwhelmingly female and represented 22% of the total female population of patients and nearly 30% of the cases of radiation pneumonitis. An LKB fit to normal tissue complication probability (NTCP) including volume as a dose modifying factor resulted in a dose that results in a 50% probability of complication for the smaller spared volume cohort that was 9 Gy lower than the fit to all mean lung dose data and improved the ability to predict radiation pneumonitis (P<.001). Using an effective dose parameter of n=0.42 instead of mean lung dose further improved the LKB fit. Fits to the data using the cure model produced similar results. Conclusions: Spared lung volume should be considered when treating NSCLC patients. Separate dose constraints based on smaller spared lung volume should be considered. Smaller spared lung volume patients should be followed closely for signs of radiation pneumonitis.« less

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PubMed

Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

2011-05-01

To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma.

PubMed

Wang, Peng; Mo, Ruidong; Lai, Rongtao; Xu, Yumin; Lu, Jie; Zhao, Gangde; Liu, Yuhan; Cao, Zhujun; Wang, Xiaolin; Li, Ziqiang; Lin, Lanyi; Zhou, Huijuan; Cai, Wei; Wang, Hui; Bao, Shisan; Xiang, Xiaogang; Xie, Qing

2017-12-01

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p <0.001; 0.34(0.21-0.55), p =0.001; or 0.46(0.25-0.83), p =0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p =0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p =0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p =0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma

PubMed Central

Xu, Yumin; Lu, Jie; Zhao, Gangde; Liu, Yuhan; Cao, Zhujun; Wang, Xiaolin; Li, Ziqiang; Lin, Lanyi; Zhou, Huijuan; Cai, Wei; Wang, Hui; Bao, Shisan; Xiang, Xiaogang; Xie, Qing

2017-01-01

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC. PMID:29285260

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, L; Wang, H; Kuang, Y

Purpose: To investigate the utility of {sup 18}F-choline positron emission tomography (PET) scans guidance for SBRT dose painting in patients with prostate cancer and its impact on tumor control probability (TCP) and normal tissue complication probability (NTCP). Methods: Twenty seven patients with localized prostate cancer who had {sup 18}F-choline PET/CT scan prior to treatment were included. A pair of nested intraprostatic dominant lesion (IDL) contours (IDL{sub suv60%} and IDL{sub suv70%}) were generated for each patient based on 60% and 70% of maximum prostate uptake on the {sup 18}F-choline PET images. GTV{sub reg} was delineated on prostate according to the glandmore » boundary seen on CT images. The PTVs (PTV{sub suv60%} and PTV{sub suv70%}) were defined as respective IDLs with a 3-mm margin posteriorly and 5 mm in all other dimensions. Two 5-fraction SBRT plans using VMAT technique along with 10 MV FFF beams, plan{sub 36Gy} and plan{sub 50–55Gy}, were generated for each patient. All plans included a dose of 36.25 Gy prescribed to PTV{sub reg}. The Plan{sub 50–55Gy} also included a simultaneous boost dose of 50 Gy and 55 Gy prescribed to the PTV{sub suv60%} and PTV{sub suv70%}, respectively. The utility of {sup 18}F-Choline PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The TCP and NTCP calculated by radiological models were also compared between two plans for each patient. Results: In all 54 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 50–55Gy} had a significantly higher dose in PTV{sub suv60%} and PTV{sub suv70%} than those in Plan{sub 36Gy} (p < 0.05), respectively, while still maintaining a safe OAR sparing profile. In addition, plan{sub 50–55Gy} had significantly higher TCP than plan{sub 36Gy}. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-choline PET-guided radiation boost dose up to 55 Gy into a SBRT plan is technically feasible. This work was supported in part by Congressionally Directed Medical Research Programs Prostate Cancer Research Program grant PC04130, National Institutes of Health/National Cancer Institute grant R41CA110121, and the UNLV Lincy Endowed Assistant Professorship.« less

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

PubMed

Wennberg, Berit M; Baumann, Pia; Gagliardi, Giovanna; Nyman, Jan; Drugge, Ninni; Hoyer, Morten; Traberg, Anders; Nilsson, Kristina; Morhed, Elisabeth; Ekberg, Lars; Wittgren, Lena; Lund, Jo-Åsmund; Levin, Nina; Sederholm, Christer; Lewensohn, Rolf; Lax, Ingmar

2011-05-01

In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

Brazil: balance of the National Tobacco Control Policy in the last decade and dilemmas.

PubMed

Cavalcante, Tânia Maria; Pinho, Mariana Coutinho Marques de; Perez, Cristina de Abreu; Teixeira, Ana Paula Leal; Mendes, Felipe Lacerda; Vargas, Rosa Rulff; Carvalho, Alexandre Octávio Ribeiro de; Rangel, Erica Cavalcanti; Almeida, Liz Maria de

2017-09-21

Since 2005, Brazil has been a Party of the World Health Organization Framework Convention on Tobacco Control, an international treaty whose measures are the foundation of the National Tobacco-Control Policy (NTCP), of Brazil. The results evidence a significant decrease in the prevalence of smokers and in tobacco-related morbidity and mortality. These results, however, could have been even better if there wasn't the interference of the tobacco supply chain (TSC), controlled by transnational corporations, which has become more intense over the last 10 years. These companies made Brazil not only a repository for tobacco, but also for economic and political power capable of threatening NTCP achievements. This Essay recounts the development of NTCP and the tobacco supply chain modus operandi to hamper it, and discusses how the strengthening of policies to promote alternative crops for tobacco could shield NTCP from such interference.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheng, Y; Ge, Y; Yuan, L

Purpose: To investigate the impact of outliers on knowledge modeling in radiation therapy, and develop a systematic workflow for identifying and analyzing geometric and dosimetric outliers using pelvic cases. Methods: Four groups (G1-G4) of pelvic plans were included: G1 (37 prostate cases), G2 (37 prostate plus lymph node cases), and G3 (37 prostate bed cases) are all clinical IMRT cases. G4 are 10 plans outside G1 re-planned with dynamic-arc to simulate dosimetric outliers. The workflow involves 2 steps: 1. identify geometric outliers, assess impact and clean up; 2. identify dosimetric outliers, assess impact and clean up.1. A baseline model wasmore » trained with all G1 cases. G2/G3 cases were then individually added to the baseline model as geometric outliers. The impact on the model was assessed by comparing leverage statistic of inliers (G1) and outliers (G2/G3). Receiver-operating-characteristics (ROC) analysis was performed to determine optimal threshold. 2. A separate baseline model was trained with 32 G1 cases. Each G4 case (dosimetric outliers) was then progressively added to perturb this model. DVH predictions were performed using these perturbed models for remaining 5 G1 cases. Normal tissue complication probability (NTCP) calculated from predicted DVH were used to evaluate dosimetric outliers’ impact. Results: The leverage of inliers and outliers was significantly different. The Area-Under-Curve (AUC) for differentiating G2 from G1 was 0.94 (threshold: 0.22) for bladder; and 0.80 (threshold: 0.10) for rectum. For differentiating G3 from G1, the AUC (threshold) was 0.68 (0.09) for bladder, 0.76 (0.08) for rectum. Significant increase in NTCP started from models with 4 dosimetric outliers for bladder (p<0.05), and with only 1 dosimetric outlier for rectum (p<0.05). Conclusion: We established a systematic workflow for identifying and analyzing geometric and dosimetric outliers, and investigated statistical metrics for detecting. Results validated the necessity for outlier detection and clean-up to enhance model quality in clinical practice. Research Grant: Varian master research grant.« less

The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity.

PubMed

Guo, Yao Xue; Xu, Xue Fei; Zhang, Qi Zhi; Li, Chun; Deng, Ye; Jiang, Pei; He, Lei Yan; Peng, Wen Xing

2015-01-01

Co-treatment of isoniazid (INH) and rifampicin (RFP) is well known for clinically apparent liver injury. However, the mechanism of INH/RFP-induced liver injury is controversial. Emerging evidence shows links between inhibition of bile acids transporters and drug-induced liver injury (DILI). The present study investigates whether sodium taurocholate cotransporting polypeptide (NTCP/Ntcp; SLC10A1) and bile salt export pump (BSEP/Bsep; ABCB11) are involved in the anti-tuberculosis medicines induced liver injury. ICR female mice were intragastrically treated with INH (50 or 100 mg/kg), RFP (100 or 200 mg/kg), or the combination of INH/RFP (50 + 100 mg/kg or 100 + 200 mg/kg) for 14 consecutive days. Liver histopathological examination, serum biochemical and liver malondialdehyde tests were evaluated. Apparent histopathological alterations and hepatic oxidative stress showed in INH (100 mg/kg), RFP (200 mg/kg) and their combination group. The hepatoxic effect was also indicated by increased serum biomarkers, such as aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBil), total bilirubin (TBil) and total bile acids (TBA). Both doses of INH/RFP administration significantly down-regulated the expression of Ntcp and Bsep in liver. Furthermore, the combination of INH and RFP displayed stronger effect on the expression of Ntcp compared with the corresponding dose of INH or RFP alone. In conclusion, down-regulated expression of hepatic Ntcp and Bsep might play an important role in the development of INH and RFP induced liver injury.

The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis.

PubMed

Cherrington, Nathan J; Estrada, Teresa E; Frisk, Harrison A; Canet, Mark J; Hardwick, Rhiannon N; Dvorak, Bohuslav; Lux, Katie; Halpern, Melissa D

2013-01-01

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants and is characterized by an extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. We have previously shown that, during the development of experimental NEC, the liver plays an important role in regulating inflammation in the ileum, and accumulation of ileal bile acids (BA) along with dysregulation of ileal BA transporters contributes to ileal damage. Given these findings, we speculated that hepatic BA transporters would also be altered in experimental NEC. Using both rat and mouse models of NEC, levels of Cyp7a1, Cyp27a1, and the hepatic BA transporters Bsep, Ntcp, Oatp2, Oatp4, Mrp2, and Mrp3 were investigated. In addition, levels of hepatic BA transporters were also determined when the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-18, which are both elevated in NEC, are neutralized during disease development. Ntcp and Mrp2 were decreased in NEC, but elevated ileal BA levels were not responsible for these reductions. However, neutralization of TNF-α normalized Ntcp, whereas removal of IL-18 normalized Mrp2 levels. These data show that the hepatic transporters Ntcp and Mrp2 are downregulated, whereas Cyp27a1 is increased in rodent models of NEC. Furthermore, increased levels of TNF-α and IL-18 in experimental NEC may play a role in the regulation of Ntcp and Mrp2, respectively. These data suggest the gut-liver axis should be considered when therapeutic modalities for NEC are developed.

Comparison of doses and NTCP to risk organs with enhanced inspiration gating and free breathing for left-sided breast cancer radiotherapy using the AAA algorithm.

PubMed

Edvardsson, Anneli; Nilsson, Martin P; Amptoulach, Sousana; Ceberg, Sofie

2015-04-10

The purpose of this study was to investigate the potential dose reduction to the heart, left anterior descending (LAD) coronary artery and the ipsilateral lung for patients treated with tangential and locoregional radiotherapy for left-sided breast cancer with enhanced inspiration gating (EIG) compared to free breathing (FB) using the AAA algorithm. The radiobiological implication of such dose sparing was also investigated. Thirty-two patients, who received tangential or locoregional adjuvant radiotherapy with EIG for left-sided breast cancer, were retrospectively enrolled in this study. Each patient was CT-scanned during FB and EIG. Similar treatment plans, with comparable target coverage, were created in the two CT-sets using the AAA algorithm. Further, the probability of radiation induced cardiac mortality and pneumonitis were calculated using NTCP models. For tangential treatment, the median V25Gy for the heart and LAD was decreased for EIG from 2.2% to 0.2% and 40.2% to 0.1% (p < 0.001), respectively, whereas there was no significant difference in V20Gy for the ipsilateral lung (p = 0.109). For locoregional treatment, the median V25Gy for the heart and LAD was decreased for EIG from 3.3% to 0.2% and 51.4% to 5.1% (p < 0.001), respectively, and the median ipsilateral lung V20Gy decreased from 27.0% for FB to 21.5% (p = 0.020) for EIG. The median excess cardiac mortality probability decreased from 0.49% for FB to 0.02% for EIG (p < 0.001) for tangential treatment and from 0.75% to 0.02% (p < 0.001) for locoregional treatment. There was no significant difference in risk of radiation pneumonitis for tangential treatment (p = 0.179) whereas it decreased for locoregional treatment from 6.82% for FB to 3.17% for EIG (p = 0.004). In this study the AAA algorithm was used for dose calculation to the heart, LAD and left lung when comparing the EIG and FB techniques for tangential and locoregional radiotherapy of breast cancer patients. The results support the dose and NTCP reductions reported in previous studies where dose calculations were performed using the pencil beam algorithm.

Investigation of whether in-room CT-based adaptive intracavitary brachytherapy for uterine cervical cancer is robust against interfractional location variations of organs and/or applicators

PubMed Central

Oku, Yoshifumi; Arimura, Hidetaka; Nguyen, Tran Thi Thao; Hiraki, Yoshiyuki; Toyota, Masahiko; Saigo, Yasumasa; Yoshiura, Takashi; Hirata, Hideki

2016-01-01

This study investigates whether in-room computed tomography (CT)-based adaptive treatment planning (ATP) is robust against interfractional location variations, namely, interfractional organ motions and/or applicator displacements, in 3D intracavitary brachytherapy (ICBT) for uterine cervical cancer. In ATP, the radiation treatment plans, which have been designed based on planning CT images (and/or MR images) acquired just before the treatments, are adaptively applied for each fraction, taking into account the interfractional location variations. 2D and 3D plans with ATP for 14 patients were simulated for 56 fractions at a prescribed dose of 600 cGy per fraction. The standard deviations (SDs) of location displacements (interfractional location variations) of the target and organs at risk (OARs) with 3D ATP were significantly smaller than those with 2D ATP (P < 0.05). The homogeneity index (HI), conformity index (CI) and tumor control probability (TCP) in 3D ATP were significantly higher for high-risk clinical target volumes than those in 2D ATP. The SDs of the HI, CI, TCP, bladder and rectum D2cc, and the bladder and rectum normal tissue complication probability (NTCP) in 3D ATP were significantly smaller than those in 2D ATP. The results of this study suggest that the interfractional location variations give smaller impacts on the planning evaluation indices in 3D ATP than in 2D ATP. Therefore, the 3D plans with ATP are expected to be robust against interfractional location variations in each treatment fraction. PMID:27296250

Present developments in reaching an international consensus for a model-based approach to particle beam therapy.

PubMed

Prayongrat, Anussara; Umegaki, Kikuo; van der Schaaf, Arjen; Koong, Albert C; Lin, Steven H; Whitaker, Thomas; McNutt, Todd; Matsufuji, Naruhiro; Graves, Edward; Mizuta, Masahiko; Ogawa, Kazuhiko; Date, Hiroyuki; Moriwaki, Kensuke; Ito, Yoichi M; Kobashi, Keiji; Dekura, Yasuhiro; Shimizu, Shinichi; Shirato, Hiroki

2018-03-01

Particle beam therapy (PBT), including proton and carbon ion therapy, is an emerging innovative treatment for cancer patients. Due to the high cost of and limited access to treatment, meticulous selection of patients who would benefit most from PBT, when compared with standard X-ray therapy (XRT), is necessary. Due to the cost and labor involved in randomized controlled trials, the model-based approach (MBA) is used as an alternative means of establishing scientific evidence in medicine, and it can be improved continuously. Good databases and reasonable models are crucial for the reliability of this approach. The tumor control probability and normal tissue complication probability models are good illustrations of the advantages of PBT, but pre-existing NTCP models have been derived from historical patient treatments from the XRT era. This highlights the necessity of prospectively analyzing specific treatment-related toxicities in order to develop PBT-compatible models. An international consensus has been reached at the Global Institution for Collaborative Research and Education (GI-CoRE) joint symposium, concluding that a systematically developed model is required for model accuracy and performance. Six important steps that need to be observed in these considerations include patient selection, treatment planning, beam delivery, dose verification, response assessment, and data analysis. Advanced technologies in radiotherapy and computer science can be integrated to improve the efficacy of a treatment. Model validation and appropriately defined thresholds in a cost-effectiveness centered manner, together with quality assurance in the treatment planning, have to be achieved prior to clinical implementation.

Hepatitis B virus infection in Taiwan: The role of NTCP rs2296651 variant in relation to sex.

PubMed

Nfor, O N; Wu, M-F; Debnath, T; Lee, C-T; Lee, W; Liu, W-H; Tantoh, D M; Hsu, S-Y; Liaw, Y-P

2018-04-16

Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) infection. NTCP rs2296651 is believed to be an Asian-specific variant responsible for HBV susceptibility. We investigated the relationship between rs2296651 and HBV infection in Taiwan based on stratification by gender and menopausal status. We recruited 10 017 Taiwan Biobank participants aged 30-70 years with complete genetic data and sociodemographic information. Gender-stratified multivariate logistic regression models were used to determine the relationship between NTCP variant and HBV infection. Among individuals with HBV infection, the genotype frequencies of GG, AG and AA in women were 0.85, 0.15 and 0 while those in men were 0.82, 0.18 and 0, respectively. The multivariate-adjusted odds ratios (OR) of HBV infection were 0.77 (95% CI 0.59-0.10) in women and 0.98 (95% CI 0.79-1.20) in men. The adjusted OR was 0.87 (CI 0.63-1.19) in premenopausal and 0.59 (0.36-0.97) in postmenopausal women. We found that genetic variation in the HBV receptor gene (NTCP) was significantly associated with a decreased risk of HBV infection in Taiwanese women. © 2018 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.

Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes.

PubMed

Hartman, J Craig; Brouwer, Kenneth; Mandagere, Arun; Melvin, Lawrence; Gorczynski, Richard

2010-06-01

To evaluate potential mechanisms of clinical hepatotoxicity, 4 endothelin receptor antagonists (ERAs) were examined for substrate activity and inhibition of hepatic uptake and efflux transporters in sandwich-cultured human hepatocytes. The 4 transporters studied were sodium-dependent taurocholate cotransporter (NTCP), organic anion transporter (OATP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2). ERA transporter inhibition was examined using the substrates taurocholate (for NTCP and BSEP), [(3)H]estradiol-17beta-D-glucuronide (for OATP), and [2-D-penicillamine, 5-D-penicillamine]enkephalin (for MRP2). ERA substrate activity was evaluated using probe inhibitors ritonavir (OATP and BSEP), bromosulfalein (OATP), erythromycin (P-glycoprotein), probenecid (MRP2 and OATP), and cyclosporin (NTCP). ERAs were tested at 2, 20, and 100 micromol*L-1 for inhibition and at 2 micromol*L-1 as substrates. OATP, NTCP, or BSEP transport activity was not reduced by ambrisentan or darusentan. Bosentan and sitaxsentan attenuated NTCP transport at higher concentrations. Only sitaxsentan decreased OATP transport (52%), and only bosentan reduced BSEP transport (78%). MRP2 transport activity was unaltered. OATP inhibitors decreased influx of all ERAs. Darusentan influx was least affected (84%-100% of control), whereas bosentan was most affected (32%-58% of control). NTCP did not contribute to influx of ERAs. Only bosentan and darusentan were shown as substrates for both BSEP and P-glycoprotein efflux. All ERAs tested were substrates for at least one hepatic transporter. Bosentan and sitaxsentan, but not ambrisentan and darusentan, inhibited human hepatic transporters, which provides a potential mechanism for the increased hepatotoxicity observed for these agents in the clinical setting.

SU-E-J-97: Pretreatment Test and Post-Treatment Evaluation for Iso-NTCP Dose Guided Adapive Radiotherapy (DGART), Experience with Prostate Cancer Patients Treated with Rectal Balloons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, J; Thomas Jefferson UniversityHospital, Philadelphia, PA; Hardcastle, N

Purpose: To explore the feasibility of pretreatment test for iso-NTCP DGART and to compare the pretreatment test results with post-treatment evaluations. Methods: NTCP here refers to late rectal wall toxicity only and is calculated with the ring rectal wall DVH. Simulation for one time iso- NTCP DGART starts after half of the total dose was done for 10 patients to investigate if TCP gains could be achieved. Six patients were treated using a 12-fraction 4.3Gy technique and four using 16-fraction 3.63Gy technique. For each of the 12-fraction cases a VMAT plan was generated in Pinnacle3™ using the daily CT obtainedmore » prior to the 6th fraction. A pretreatment simulation was performed using only the first 6 daily CTs. The idea is to add the 6 original plan delivered doses with 6 DGART plan delivered doses by deformable dose accumulation (DDA) on each of the first 6 CTs, resulting in 6 rectal wall doses (RWDs) and NTCPs. The 95% confidence interval (95%CI) for the 6 NTCPs were computed.The posttreatment evaluation was done by: a) copy the DGART plan to 6 CTs for fraction 7–12 and calculate the 6 actual DGART delivered fractional doses; b) sum the 6 actual DGART doses with the 6 original plan delivered doses by DDA on each of the 12 CTs resulting in 12 post-treatment RWDs and NTCPs; c) boxplot the 12 post-treatment NTCPs. Results: Target dose gain is 0.76–1.93 Gy. The 95%CI widths of the pretreatment tests NTCPs were 1.1–2.7%. For 5 patients, the planned NTCP fell within the 95%CI. For 4 patients, the planned NTCP was lower than the 95%CI lines. Post-treatment results show that for 7 patients, the upper quartile was within the 95%CI; for 2 patients, the upper quartile were higher than the 95%CI. Conclusion: The pretreatment test yields conservative prediction of the actual delivered NTCP.« less

SU-F-J-187: The Statistical NTCP and TCP Models in the Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, S; Frometa, T; Pyakuryal, A

2016-06-15

Purpose: The statistical models (SM) are typically used as a subjective description of a population for which there is only limited sample data, and especially in cases where the relationship between variables is known. The normal tissue complications and tumor control are frequently stochastic effects in the Radiotherapy (RT). Based on probabilistic treatments, it recently has been formulated new NTCP and TCP models for the RT. Investigating the particular requirements for their clinical use in the proton therapy (PT) is the goal of this work. Methods: The SM can be used as phenomenological or mechanistic models. The former way allowsmore » fitting real data and getting theirparameters. In the latter one, we should do efforts for determining the parameters through the acceptable estimations, measurements, and/or simulation experiments. Experimental methodologies for determination of the parameters have been developed from the fraction cells surviving the proton irradiation curves in tumor and OAR, and precise RBE models are used for calculating the variable of effective dose. As the executions of these methodologies have a high costs, so we have developed computer tools enable to perform simulation experiments as complement to limitations of the real ones. Results: The requirements for the use of the SM in the PT, such as validation and improvement of the elaborated and existent methodologies for determining the SM parameters and effective dose respectively, were determined. Conclusion: The SM realistically simulates the main processes in the PT, and for this reason these can be implemented in this therapy, which are simples, computable and they have other advantages over some current models. It has been determined some negative aspects for some currently used probabilistic models in the RT, like the LKB NTCP and others derived from logistic functions; which can be improved with the proposed methods in this study.« less

Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation.

PubMed

Grills, Inga S; Yan, Di; Martinez, Alvaro A; Vicini, Frank A; Wong, John W; Kestin, Larry L

2003-11-01

To systematically evaluate four different techniques of radiation therapy (RT) used to treat non-small-cell lung cancer and to determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage and achieving dose escalation. Treatment planning was performed for 18 patients with Stage I to IIIB inoperable non-small-cell lung cancer using four different RT techniques to treat the primary lung tumor +/- the hilar/mediastinal lymph nodes: (1) Intensity-modulated radiation therapy (IMRT), (2) Optimized three-dimensional conformal RT (3D-CRT) using multiple beam angles, (3) Limited 3D-CRT using only 2 to 3 beams, and (4) Traditional RT using elective nodal irradiation (ENI) to treat the mediastinum. All patients underwent virtual simulation, including a CT scan and (18)fluorodeoxyglucose positron emission tomography scan, fused to the CT to create a composite tumor volume. For IMRT and 3D-CRT, the target included the primary tumor and regional nodes either > or =1.0 cm in short-axis dimension on CT or with increased uptake on PET. For ENI, the target included the primary tumor plus the ipsilateral hilum and mediastinum from the inferior head of the clavicle to at least 5.0 cm below the carina. The goal was to deliver 70 Gy to > or =99% of the planning target volume (PTV) in 35 daily fractions (46 Gy to electively treated mediastinum) while meeting multiple normal-tissue dose constraints. Heterogeneity correction was applied to all dose calculations (maximum allowable heterogeneity within PTV 30%). Pulmonary and esophageal constraints were as follows: lung V(20) < or =25%, mean lung dose < or =15 Gy, esophagus V(50) < or =25%, mean esophageal dose < or =25 Gy. At the completion of all planning, the four techniques were contrasted for their ability to achieve the set dose constraints and deliver tumoricidal RT doses. Requiring a minimum dose of 70 Gy within the PTV, we found that IMRT was associated with a greater degree of heterogeneity within the target and, correspondingly, higher mean doses and tumor control probabilities (TCPs), 7%-8% greater than 3D-CRT and 14%-16% greater than ENI. Comparing the treatment techniques in this manner, we found only minor differences between 3D-CRT and IMRT, but clearly greater risks of pulmonary and esophageal toxicity with ENI. The mean lung V(20) was 36% with ENI vs. 23%-25% with the three other techniques, whereas the average mean lung dose was approximately 21.5 Gy (ENI) vs. 15.5 Gy (others). Similarly, the mean esophagus V(50) was doubled with ENI, to 34% rather than 15%-18%. To account for differences in heterogeneity, we also compared the techniques giving each plan a tumor control probability equivalent to that of the optimized 3D-CRT plan delivering 70 Gy. Using this method, IMRT and 3D-CRT offered similar results in node-negative cases (mean lung and esophageal normal-tissue complication probability [NTCP] of approximately 10% and 2%-7%, respectively), but ENI was distinctly worse (mean NTCPs of 29% and 20%). In node-positive cases, however, IMRT reduced the lung V(20) and mean dose by approximately 15% and lung NTCP by 30%, compared to 3D-CRT. Compared to ENI, the reductions were 50% and >100%. Again, for node-positive cases, especially where the gross tumor volume was close to the esophagus, IMRT reduced the mean esophagus V(50) by 40% (vs. 3D-CRT) to 145% (vs. ENI). The esophageal NTCP was at least doubled converting from IMRT to 3D-CRT and tripled converting from IMRT to ENI. Finally, the total number of fractions for each plan was increased or decreased until all outlined normal-tissue constraints were reached/satisfied. While meeting all constraints, IMRT or 3D-CRT increased the deliverable dose in node-negative patients by >200% over ENI. In node-positive patients, IMRT increased the deliverable dose 25%-30% over 3D-CRT and 130%-140% over ENI. The use of 3D-CRT without IMRT increased the deliverable RT dose >80% over ENI. Using a limited number of 3D-CRT beams decreased the lung V(20), mean dose, and NTCP in node-positive patients. The use of 3D-CRT, particul mean dose, and NTCP in node-positive patients. The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the esophagus. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 25%-30% greater than 3D-CRT and 130%-140% greater than ENI. Whereas the possibility of dose escalation is severely limited with ENI, the potential for pulmonary and esophageal toxicity is clearly increased.

The effect of Na+/taurocholate cotransporting polypeptide (NTCP) c.800C > T polymorphism on rosuvastatin pharmacokinetics in Chinese healthy males.

PubMed

Lou, Xiao-Ya; Zhang, Wei; Wang, Guo; Hu, Dong-Li; Guo, Dong; Tan, Zhi-Rong; Zhou, Hong-Hao; Chen, Yao; Bao, Hei-Hua

2014-10-01

This study was designed to investigate the potential association between NTCP c.800C >T polymorphism and rosuvastatin pharmacokinetics in Chinese healthy males. 305 individuals were enrolled to identify NTCP c.800C > T, OATP1B1 c.521T > C and BCRP c.421C > A genotypes by direct sequencing and pyrosequencing methods, respectively. 17 healthy volunteers who were OATP1B1 c.521TT and BCRP c.421CC wild-type homozygotes with different NTCP c.800C > T genotype were selected to participate in this pharmacokinetic study. Nine were NTCP c.800CC wild-type homozygotes and the other eight subjects were carriers with at least one c.800T variant allele (seven subjects with c.800CT genotype and one was homozygote of c.800TT). All the subjects received a single oral dose of 10 mg rosuvastatin. The plasma concentrations of rosuvastatin were measured up to 72 h by a LC-MS method. NTCP c.800C > T genetic polymorphism markedly effected rosuvastatin pharmacokinetics. The AUC(o-72) and AUC(0 --> ∞) in subjects with NTCP c.800CT + TT genotype were 56% (162.64 ± 37.55 vs. 103.99 ± 28.15 ng x h/ml, P = 0.016) and 57% greater (178.51 ± 42.75 vs. 113.60 ± 33.73 ng x h/ml, P = 0.020) than those in the c.800CC wild-type subjects, respectively. In the c.800CT + TT mutant group, the C(max) was about 78% higher than those in c.800CC genotype (14.31 ± 3.63 vs. 8.04 ± 1.72 ng x h/ml, P = 0.004). The oral clearance (CL/F) of rosuvastatin in subjects with the c.800CT+TT genotype was only 63% of those in the c.800CC genotype (58.32 ± 12.16 vs. 93.04 ± 20.61 ng x h/ml, P = 0.009). The half-time (T1/2) and the T(max) had no significant difference between two groups (p = 0.466 and 0.713, respectively). NTCP c.800C > T polymorphism play a critical role in the individual variability of rosuvastatin pharmacokinetics in Chinese healthy males after excluding the impact of OATP1B1 c.521T > C and BCRP c.421C > A polymorphisms.

Effect of S267F variant of NTCP on the patients with chronic hepatitis B.

PubMed

Lee, Hye Won; Park, Hye Jung; Jin, Bora; Dezhbord, Mehrangiz; Kim, Do Young; Han, Kwang-Hyub; Ryu, Wang-Shick; Kim, Seungtaek; Ahn, Sang Hoon

2017-12-15

Sodium taurocholate cotransporting polypeptide (NTCP) was identified as an entry receptor for hepatitis B virus (HBV) infection. The substitution of serine at position 267 of NTCP with phenylalanine (S267F) is an Asian-specific variation that hampers HBV entry in vitro. In this study, we aimed to evaluate the prevalence of S267F polymorphism in Korean patients with chronic hepatitis B (CHB) and its association with disease progression and potential viral evolution in the preS1 domain of HBV. We found that the frequency of the S267F variant of NTCP in CHB patients and controls was 2.7% and 5.7% (P = 0.031), respectively, and that those who had S267F variant were less susceptible to chronic HBV infection. The frequency of the S267F variant in CHB, cirrhosis and hepatocellular carcinoma (HCC) patients was 3.3%, 0.9%, and 3.5%, respectively. Thus, the S267F variant correlated significantly with a lower risk for cirrhosis (P = 0.036). Sequencing preS1 domain of HBV from the patients who had S267F variant revealed no significant sequence change compared to the wild type. In conclusion, the S267F variant of NTCP is clinically associated with a lower risk of chronic HBV infection and cirrhosis development, which implicates suppressing HBV entry could reduce the disease burden.

Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3.

PubMed

Gozalpour, Elnaz; Greupink, Rick; Wortelboer, Heleen M; Bilos, Albert; Schreurs, Marieke; Russel, Frans G M; Koenderink, Jan B

2014-06-02

Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of β-estradiol 17-β-d-glucuronide (E217βG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 μM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 μM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces the inhibition of NTCP but decreases the inhibition of OATP1B1 and OATP1B3. To investigate whether DLCs can be translocated, we quantified their uptake in transporter-expressing cells by LC-MS. We demonstrated that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates of OATP1B3. No transport was observed for the other compounds in any of the studied transporters. In summary, this work provides a step toward an improved understanding of the interaction of DLCs with three major hepatic uptake transporters. Ultimately, this can be of use in the development of DLCs that are less prone to transporter-mediated drug-drug interactions.

Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.

PubMed

Ödén, Jakob; Eriksson, Kjell; Toma-Dasu, Iuliana

2017-03-01

A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction, and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions. Photon and proton dose plans were created for three generic prostate cancer cases. Three BED 3Gy equivalent schedules were studied, 78, 57.2, and 42.8 Gy in 39, 15, and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LET d ) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs, and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was reoptimized for each proton plan based on the LET d distribution, to achieve a homogeneous RBE-weighted target dose when applying a specific RBE model and still fulfill the clinical goals for the rectum and bladder. All the photon and proton plans assuming RBE = 1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2 Gy(RBE), whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The reoptimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE. Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2 Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by reoptimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively. © 2017 American Association of Physicists in Medicine.

NTCP and Beyond: Opening the Door to Unveil Hepatitis B Virus Entry

PubMed Central

Watashi, Koichi; Urban, Stephan; Li, Wenhui; Wakita, Takaji

2014-01-01

Chronic hepatitis B virus (HBV) infection, affecting approximately 240 million people worldwide, is a major public health problem that elevates the risk of developing liver cirrhosis and hepatocellular carcinoma. Given that current anti-HBV drugs are limited to interferon-based regimens and nucleos(t)ide analogs, the development of new anti-HBV agents is urgently needed. The viral entry process is generally an attractive target implicated in antiviral strategies. Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important determinants of viral entry have been achieved. Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as an HBV entry receptor and enabled the establishment of a susceptible cell line that can efficiently support HBV infection. This finding will allow a deeper understanding of the requirements for efficient HBV infection, including the elucidation of the molecular entry mechanism. In addition, pharmacological studies suggest that NTCP is able to serve as a therapeutic target. This article summarizes our current knowledge on the mechanisms of HBV entry and the role of NTCP in this process. PMID:24557582

NTCP and beyond: opening the door to unveil hepatitis B virus entry.

PubMed

Watashi, Koichi; Urban, Stephan; Li, Wenhui; Wakita, Takaji

2014-02-19

Chronic hepatitis B virus (HBV) infection, affecting approximately 240 million people worldwide, is a major public health problem that elevates the risk of developing liver cirrhosis and hepatocellular carcinoma. Given that current anti-HBV drugs are limited to interferon-based regimens and nucleos(t)ide analogs, the development of new anti-HBV agents is urgently needed. The viral entry process is generally an attractive target implicated in antiviral strategies. Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important determinants of viral entry have been achieved. Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as an HBV entry receptor and enabled the establishment of a susceptible cell line that can efficiently support HBV infection. This finding will allow a deeper understanding of the requirements for efficient HBV infection, including the elucidation of the molecular entry mechanism. In addition, pharmacological studies suggest that NTCP is able to serve as a therapeutic target. This article summarizes our current knowledge on the mechanisms of HBV entry and the role of NTCP in this process.

A genetic variant of the NTCP gene is associated with HBV infection status in a Chinese population.

PubMed

Yang, Jingmin; Yang, Yuan; Xia, Mingying; Wang, Lianghui; Zhou, Weiping; Yang, Yajun; Jiang, Yueming; Wang, Hongyang; Qian, Ji; Jin, Li; Wang, Xiaofeng

2016-03-12

To investigate whether genetic variants of the HBV receptor gene NTCP are associated with HBV infection in the Han Chinese population. We sequenced the entire 23 kb NTCP gene from 111 HBeAg-positive HBsAg carriers (PSE group), 110 HBeAg-negative HBsAg carriers (PS group), and 110 control subjects. Then, we performed association analyses of suggestively significant SNPs with HBV infection in 1075 controls, 1936 PSs and 639 PSEs. In total, 109 rare variants (74 novel) and 38 single nucleotide polymorphisms (SNPs, one novel) were screened. Of the seven non-synonymous rare variants, six were singletons and one was a double hit. All three damaging rare singletons presented exclusively in the PSE group. Of the five SNPs validated in all 3650 subjects, the T allele of rs4646287 was significantly decreased (p = 0.002) in the PS group (10.1%) and PSE group (8.1%) compared to the controls (10.9%) and was decreased to 7.4% in the PSE hepatocellular carcinoma (HCC) subgroup. Additionally, rs4646287-T was associated with a 0.68-fold (95% CI = 0.51-0.89, p = 0.006) decreased risk of PSE compared with the controls. The NTCP mRNA level was lower in HCC tissues in "CT + TT" carriers than in "CC" carriers. We found a genetic variant (rs4646287) located in intron 1 of NTCP that may be associated with increased risk of HBV infection in Han Chinese.

Characterization of ursodeoxycholic and norursodeoxycholic acid as substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and NTCP.

PubMed

König, Jörg; Klatt, Sabine; Dilger, Karin; Fromm, Martin F

2012-08-01

Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock-out mice. Uptake of UDCA and norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA are substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and Na(+) -taurocholate co-transporting polypeptide (NTCP), which are localized in the basolateral membrane of hepatocytes. Uptake of [(3) H]UDCA and [(14) C]norUDCA into Human embryonic kidney (HEK) cells stably expressing OATP1B1, OATP1B3, OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter-transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1-, OATP1B3- and OATP2B1-mediated UDCA and norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK-NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34-fold. NorUDCA was not significantly transported by NTCP. The low uptake rates suggest that OATP1B1, OATP1B3, OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and norUDCA in human beings. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

SU-D-204-03: Comparison of Patient Positioning Methods Through Modeling of Acute Rectal Toxicity in Intensity Modulated Radiation Therapy for Prostate Cancer. Does Quality of Data Matter More Than the Quantity?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, X; Fatyga, M; Vora, S

Purpose: To determine if differences in patient positioning methods have an impact on the incidence and modeling of grade >=2 acute rectal toxicity in prostate cancer patients who were treated with Intensity Modulated Radiation Therapy (IMRT). Methods: We compared two databases of patients treated with radiation therapy for prostate cancer: a database of 79 patients who were treated with 7 field IMRT and daily image guided positioning based on implanted gold markers (IGRTdb), and a database of 302 patients who were treated with 5 field IMRT and daily positioning using a trans-abdominal ultrasound system (USdb). Complete planning dosimetry was availablemore » for IGRTdb patients while limited planning dosimetry, recorded at the time of planning, was available for USdb patients. We fit Lyman-Kutcher-Burman (LKB) model to IGRTdb only, and Univariate Logistic Regression (ULR) NTCP model to both databases. We perform Receiver Operating Characteristics analysis to determine the predictive power of NTCP models. Results: The incidence of grade >= 2 acute rectal toxicity in IGRTdb was 20%, while the incidence in USdb was 54%. Fits of both LKB and ULR models yielded predictive NTCP models for IGRTdb patients with Area Under the Curve (AUC) in the 0.63 – 0.67 range. Extrapolation of the ULR model from IGRTdb to planning dosimetry in USdb predicts that the incidence of acute rectal toxicity in USdb should not exceed 40%. Fits of the ULR model to the USdb do not yield predictive NTCP models and their AUC is consistent with AUC = 0.5. Conclusion: Accuracy of a patient positioning system affects clinically observed toxicity rates and the quality of NTCP models that can be derived from toxicity data. Poor correlation between planned and clinically delivered dosimetry may lead to erroneous or poorly performing NTCP models, even if the number of patients in a database is large.« less

Characterisation of the hepatitis B virus cross-species transmission pattern via Na+/taurocholate co-transporting polypeptides from 11 New World and Old World primate species.

PubMed

Müller, Simon F; König, Alexander; Döring, Barbara; Glebe, Dieter; Geyer, Joachim

2018-01-01

The hepatic Na+/taurocholate co-transporting polypeptide (NTCP in man, Ntcp in animals) is the high-affinity receptor for the hepatitis B (HBV) and hepatitis D (HDV) viruses. Species barriers for human HBV/HDV within the order Primates were previously attributed to Ntcp sequence variations that disable virus-receptor interaction. However, only a limited number of primate Ntcps have been analysed so far. In the present study, a total of 11 Ntcps from apes, Old and New World monkeys were cloned and expressed in vitro to characterise their interaction with HBV and HDV. All Ntcps showed intact bile salt transport. Human NTCP as well as the Ntcps from the great apes chimpanzee and orangutan showed transport-competing binding of HBV derived myr-preS1-peptides. In contrast, all six Ntcps from the group of Old World monkeys were insensitive to HBV myr-preS1-peptide binding and HBV/HDV infection. This is basically predetermined by the amino acid arginine at position 158 of all studied Old World monkey Ntcps. An exchange from arginine to glycine (as present in humans and great apes) at this position (R158G) alone was sufficient to achieve full transport-competing HBV myr-preS1-peptide binding and susceptibility for HBV/HDV infection. New World monkey Ntcps showed higher sequence heterogeneity, but in two cases with 158G showed transport-competing HBV myr-preS1-peptide binding, and in one case (Saimiri sciureus) even susceptibility for HBV/HDV infection. In conclusion, amino acid position 158 of NTCP/Ntcp is sufficient to discriminate between the HBV/HDV susceptible group of humans and great apes (158G) and the non-susceptible group of Old World monkeys (158R). In the case of the phylogenetically more distant New World monkey Ntcps amino acid 158 plays a significant, but not exclusive role.

The interface between the national tuberculosis control programme and district hospitals in Cameroon: missed opportunities for strengthening the local health system -a multiple case study.

PubMed

Keugoung, Basile; Macq, Jean; Buve, Anne; Meli, Jean; Criel, Bart

2013-03-22

Tuberculosis remains a major public health problem in sub-Saharan Africa. District hospitals (DHs) play a central role in district-based health systems, and their relation with vertical programmes is very important. Studies on the impact of vertical programmes on DHs are rare. This study aims to fill this gap. Its purpose is to analyse the interaction between the National Tuberculosis Control Programme (NTCP) and DHs in Cameroon, especially its effects on the human resources, routine health information system (HIS) and technical capacity at the hospital level. We used a multiple case study methodology. From the Adamaoua Region, we selected two DHs, one public and one faith-based. We collected qualitative and quantitative data through document reviews, semi-structured interviews with district and regional staff, and observations in the two DHs. The NTCP trained and supervised staff, designed and provided tuberculosis data collection and reporting tools, and provided anti-tuberculosis drugs, reagents and microscopes to DHs. However, these interventions were limited to the hospital units designated as Tuberculosis Diagnostic and Treatment Centres and to staff dedicated to tuberculosis control activities. The NTCP installed a parallel HIS that bypassed the District Health Services. The DH that performs well in terms of general hospital care and that is well managed was successful in tuberculosis control. Based on the available resources, the two hospitals adapt the organisation of tuberculosis control to their settings. The management teams in charge of the District Health Services are not involved in tuberculosis control. In our study, we identified several opportunities to strengthen the local health system that have been missed by the NTCP and the health system managers. Well-managed DHs perform better in terms of tuberculosis control than DHs that are not well managed. The analysis of the effects of the NTCP on the human resources, HIS and technical capacity of DHs indicates that the NTCP supports, rather than strengthens, the local health system. Moreover, there is potential for this support to be enhanced. Positive synergies between the NTCP and district health systems can be achieved if opportunities to strengthen the district health system are seized. The question remains, however, of why managers do not take advantage of the opportunities to strengthen the health system.

Analysis of hepatitis B virus preS1 variability and prevalence of the rs2296651 polymorphism in a Spanish population

PubMed Central

Casillas, Rosario; Tabernero, David; Gregori, Josep; Belmonte, Irene; Cortese, Maria Francesca; González, Carolina; Riveiro-Barciela, Mar; López, Rosa Maria; Quer, Josep; Esteban, Rafael; Buti, Maria; Rodríguez-Frías, Francisco

2018-01-01

AIM To determine the variability/conservation of the domain of hepatitis B virus (HBV) preS1 region that interacts with sodium-taurocholate cotransporting polypeptide (hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism (S267F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection (CHB) (n = 41, 73% Caucasians), patients with resolved HBV infection (n = 100, 100% Caucasians) and an HBV-uninfected control group (n = 105, 100% Caucasians). Variability/conservation of the amino acid (aa) sequences of the NTCP-interacting domain, (aa 2-48 in viral genotype D) and a highly conserved preS1 domain associated with virion morphogenesis (aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis. RESULTS The HBV preS1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21 (in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCP-interacting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies (25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms (34% vs 27.3%), according to consensus sequences from GenBank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable (limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant. CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null. PMID:29456407

The interface between the national tuberculosis control programme and district hospitals in Cameroon: missed opportunities for strengthening the local health system –a multiple case study

PubMed Central

2013-01-01

Background Tuberculosis remains a major public health problem in sub-Saharan Africa. District hospitals (DHs) play a central role in district-based health systems, and their relation with vertical programmes is very important. Studies on the impact of vertical programmes on DHs are rare. This study aims to fill this gap. Its purpose is to analyse the interaction between the National Tuberculosis Control Programme (NTCP) and DHs in Cameroon, especially its effects on the human resources, routine health information system (HIS) and technical capacity at the hospital level. Methods We used a multiple case study methodology. From the Adamaoua Region, we selected two DHs, one public and one faith-based. We collected qualitative and quantitative data through document reviews, semi-structured interviews with district and regional staff, and observations in the two DHs. Results The NTCP trained and supervised staff, designed and provided tuberculosis data collection and reporting tools, and provided anti-tuberculosis drugs, reagents and microscopes to DHs. However, these interventions were limited to the hospital units designated as Tuberculosis Diagnostic and Treatment Centres and to staff dedicated to tuberculosis control activities. The NTCP installed a parallel HIS that bypassed the District Health Services. The DH that performs well in terms of general hospital care and that is well managed was successful in tuberculosis control. Based on the available resources, the two hospitals adapt the organisation of tuberculosis control to their settings. The management teams in charge of the District Health Services are not involved in tuberculosis control. In our study, we identified several opportunities to strengthen the local health system that have been missed by the NTCP and the health system managers. Conclusion Well-managed DHs perform better in terms of tuberculosis control than DHs that are not well managed. The analysis of the effects of the NTCP on the human resources, HIS and technical capacity of DHs indicates that the NTCP supports, rather than strengthens, the local health system. Moreover, there is potential for this support to be enhanced. Positive synergies between the NTCP and district health systems can be achieved if opportunities to strengthen the district health system are seized. The question remains, however, of why managers do not take advantage of the opportunities to strengthen the health system. PMID:23521866

Potential benefits of dosimetric VMAT tracking verified with 3D film measurements.

PubMed

Crijns, Wouter; Defraene, Gilles; Van Herck, Hans; Depuydt, Tom; Haustermans, Karin; Maes, Frederik; Van den Heuvel, Frank

2016-05-01

To evaluate three different plan adaptation strategies using 3D film-stack dose measurements of both focal boost and hypofractionated prostate VMAT treatments. The adaptation strategies (a couch shift, geometric tracking, and dosimetric tracking) were applied for three realistic intrafraction prostate motions. A focal boost (35 × 2.2 and 35 × 2.7 Gy) and a hypofractionated (5 × 7.25 Gy) prostate VMAT plan were created for a heterogeneous phantom that allows for internal prostate motion. For these plans geometric tracking and dosimetric tracking were evaluated by ionization chamber (IC) point dose measurements (zero-D) and measurements using a stack of EBT3 films (3D). The geometric tracking applied translations, rotations, and scaling of the MLC aperture in response to realistic prostate motions. The dosimetric tracking additionally corrected the monitor units to resolve variations due to difference in depth, tissue heterogeneity, and MLC-aperture. The tracking was based on the positions of four fiducial points only. The film measurements were compared to the gold standard (i.e., IC measurements) and the planned dose distribution. Additionally, the 3D measurements were converted to dose volume histograms, tumor control probability, and normal tissue complication probability parameters (DVH/TCP/NTCP) as a direct estimate of clinical relevance of the proposed tracking. Compared to the planned dose distribution, measurements without prostate motion and tracking showed already a reduced homogeneity of the dose distribution. Adding prostate motion further blurs the DVHs for all treatment approaches. The clinical practice (no tracking) delivered the dose distribution inside the PTV but off target (CTV), resulting in boost dose errors up to 10%. The geometric and dosimetric tracking corrected the dose distribution's position. Moreover, the dosimetric tracking could achieve the planned boost DVH, but not the DVH of the more homogeneously irradiated prostate. A drawback of both the geometric and dosimetric tracking was a reduced MLC blocking caused by the rotational component of the MLC aperture corrections. Because of the used CTV to PTV margins and the high doses in the considered fractionation schemes, the TCP differed less than 0.02 from the planned value for all targets and all correction methods. The rectal NTCP constraints, however, could not be realized using any of these methods. The geometric and dosimetric tracking use only a limited input, but they deposit the dose distribution with higher geometric accuracy than the clinical practice. The latter case has boost dose errors up to 10%. The increased accuracy has a modest impact [Δ(NT)CP < 0.02] because of the applied margins and the high dose levels used. To allow further margin reduction tracking methods are vital. The proposed methodology could further be improved by implementing a rotational correction using collimator rotations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crijns, Wouter, E-mail: wouter.crijns@uzleuven.be; Depuydt, Tom; Haustermans, Karin

Purpose: To evaluate three different plan adaptation strategies using 3D film-stack dose measurements of both focal boost and hypofractionated prostate VMAT treatments. The adaptation strategies (a couch shift, geometric tracking, and dosimetric tracking) were applied for three realistic intrafraction prostate motions. Methods: A focal boost (35 × 2.2 and 35 × 2.7 Gy) and a hypofractionated (5 × 7.25 Gy) prostate VMAT plan were created for a heterogeneous phantom that allows for internal prostate motion. For these plans geometric tracking and dosimetric tracking were evaluated by ionization chamber (IC) point dose measurements (zero-D) and measurements using a stack of EBT3more » films (3D). The geometric tracking applied translations, rotations, and scaling of the MLC aperture in response to realistic prostate motions. The dosimetric tracking additionally corrected the monitor units to resolve variations due to difference in depth, tissue heterogeneity, and MLC-aperture. The tracking was based on the positions of four fiducial points only. The film measurements were compared to the gold standard (i.e., IC measurements) and the planned dose distribution. Additionally, the 3D measurements were converted to dose volume histograms, tumor control probability, and normal tissue complication probability parameters (DVH/TCP/NTCP) as a direct estimate of clinical relevance of the proposed tracking. Results: Compared to the planned dose distribution, measurements without prostate motion and tracking showed already a reduced homogeneity of the dose distribution. Adding prostate motion further blurs the DVHs for all treatment approaches. The clinical practice (no tracking) delivered the dose distribution inside the PTV but off target (CTV), resulting in boost dose errors up to 10%. The geometric and dosimetric tracking corrected the dose distribution’s position. Moreover, the dosimetric tracking could achieve the planned boost DVH, but not the DVH of the more homogeneously irradiated prostate. A drawback of both the geometric and dosimetric tracking was a reduced MLC blocking caused by the rotational component of the MLC aperture corrections. Because of the used CTV to PTV margins and the high doses in the considered fractionation schemes, the TCP differed less than 0.02 from the planned value for all targets and all correction methods. The rectal NTCP constraints, however, could not be realized using any of these methods. Conclusions: The geometric and dosimetric tracking use only a limited input, but they deposit the dose distribution with higher geometric accuracy than the clinical practice. The latter case has boost dose errors up to 10%. The increased accuracy has a modest impact [Δ(NT)CP < 0.02] because of the applied margins and the high dose levels used. To allow further margin reduction tracking methods are vital. The proposed methodology could further be improved by implementing a rotational correction using collimator rotations.« less

SU-E-J-172: Bio-Physical Effects of Patients Set-Up Errors According to Whole Breast Irradiation Techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, S; Suh, T; Park, S

2015-06-15

Purpose: The dose-related effects of patient setup errors on biophysical indices were evaluated for conventional wedge (CW) and field-in-field (FIF) whole breast irradiation techniques. Methods: The treatment plans for 10 patients receiving whole left breast irradiation were retrospectively selected. Radiobiological and physical effects caused by dose variations were evaluated by shifting the isocenters and gantry angles of the treatment plans. Dose-volume histograms of the planning target volume (PTV), heart, and lungs were generated, and conformity index (CI), homogeneity index (HI), tumor control probability (TCP), and normal tissue complication probability (NTCP) were determined. Results: For “isocenter shift plan” with posterior direction,more » the D95 of the PTV decreased by approximately 15% and the TCP of the PTV decreased by approximately 50% for the FIF technique and by 40% for the CW; however, the NTCPs of the lungs and heart increased by about 13% and 1%, respectively, for both techniques. Increasing the gantry angle decreased the TCPs of the PTV by 24.4% (CW) and by 34% (FIF). The NTCPs for the two techniques differed by only 3%. In case of CW, the CIs and HIs were much higher than that of the FIF in all cases. It had a significant difference between two techniques (p<0.01). According to our results, however, the FIF had more sensitive response by set up errors rather than CW in bio-physical aspects. Conclusions: The radiobiological-based analysis can detect significant dosimetric errors then, can provide a practical patient quality assurance method to guide the radiobiological and physical effects.« less

Sci-Fri PM: Radiation Therapy, Planning, Imaging, and Special Techniques - 03: The Potential Benefit Of Esophageal Sparing During Palliative Radiotherapy For Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Granton, Patrick V.; Palma, David A.; Louie, Alexa

Puropose: Palliative radiotherapy is an effective technique to alleviate systems of disease burden in late-stage lung cancer patients. Previous randomized controlled studies demonstrated a survival benefit in patients with good performance status at radiation doses of 35Gy10 or greater but with an increased incidence of esophagitis. The objective of this planning study was to assess the potential impact of esophageal-sparing IMRT (ES-IMRT) compared to the current standard of care using parallel-opposed pair beams (POP). Methods: In this study, 15 patients with lung cancer treated to a dose of 30Gy in 10 fractions between August 2015 and January 2016 were identified.more » Radiation treatment plans were optimized using ES-IMRT by limiting the max esophagus point dose to 24Gy. Using published Lyman-Kutcher-Burman normal tissue complication probabilities (LKB-NTCP) models, both plans were evaluated for the likelihood of esophagitis (≥ grade 2) and pneumonitis (≥ grade 2). Results: Using ES-IMRT, the median esophageal and lung mean doses reduced from 16 and 8Gy to 7 and 7Gy, respectively. Using the LKB models, the theoretical probability of symptomatic esophagitis and pneumonitis reduced from 13 to 1%, and from 5 to 3%, respectively. The median NTD mean for the GTV and PTV of the clinically approved POP plans compared to the ES-IMRT plans were similar. Conclusions: Advanced radiotherapy techniques such as ES-IMRT may have clinical utility in reducing treatment-related toxicity in advanced lung cancer patients. Our data suggests that the rate of esophagitis can be reduced without compromising tumour control.« less

Intentional avoidance of the esophagus using intensity modulated radiation therapy to reduce dysphagia after palliative thoracic radiation.

PubMed

Granton, Patrick V; Palma, David A; Louie, Alexander V

2017-01-26

Palliative thoracic radiotherapy is an effective technique to alleviate symptoms of disease burden in advanced-stage lung cancer patients. Previous randomized controlled studies demonstrated a survival benefit in patients with good performance status at radiation doses of 35Gy 10 or greater but with an increased incidence of esophagitis. The objective of this planning study was to assess the potential impact of esophageal-sparing IMRT (ES-IMRT) compared to the current standard of care using parallel-opposed pair beams (POP). In this study, 15 patients with lung cancer treated to a dose of 30Gy in 10 fractions between August 2015 and January 2016 were identified. Radiation treatment plans were optimized using ES-IMRT by limiting the max esophagus point dose to 24Gy. Using published Lyman-Kutcher-Burman normal tissue complication probabilities (LKB-NTCP) models, both plans were evaluated for the likelihood of esophagitis (≥ grade 2) and pneumonitis (≥ grade 2). Using ES-IMRT, the median esophageal and lung mean doses reduced from 16 and 8Gy to 7 and 7Gy, respectively. Using the LKB models, the theoretical probability of symptomatic esophagitis and pneumonitis reduced from 13 to 2%, and from 5 to 3%, respectively. The median normalize total dose (NTD mean) accounting for fraction size for the GTV and PTV of the clinically approved POP plans compared to the ES-IMRT plans were similar. Advanced radiotherapy techniques such as ES-IMRT may have clinical utility in reducing treatment-related toxicity in advanced lung cancer patients. Our data suggests that the rate of esophagitis can be reduced without compromising local control.

Investigation of whether in-room CT-based adaptive intracavitary brachytherapy for uterine cervical cancer is robust against interfractional location variations of organs and/or applicators.

PubMed

Oku, Yoshifumi; Arimura, Hidetaka; Nguyen, Tran Thi Thao; Hiraki, Yoshiyuki; Toyota, Masahiko; Saigo, Yasumasa; Yoshiura, Takashi; Hirata, Hideki

2016-11-01

This study investigates whether in-room computed tomography (CT)-based adaptive treatment planning (ATP) is robust against interfractional location variations, namely, interfractional organ motions and/or applicator displacements, in 3D intracavitary brachytherapy (ICBT) for uterine cervical cancer. In ATP, the radiation treatment plans, which have been designed based on planning CT images (and/or MR images) acquired just before the treatments, are adaptively applied for each fraction, taking into account the interfractional location variations. 2D and 3D plans with ATP for 14 patients were simulated for 56 fractions at a prescribed dose of 600 cGy per fraction. The standard deviations (SDs) of location displacements (interfractional location variations) of the target and organs at risk (OARs) with 3D ATP were significantly smaller than those with 2D ATP (P < 0.05). The homogeneity index (HI), conformity index (CI) and tumor control probability (TCP) in 3D ATP were significantly higher for high-risk clinical target volumes than those in 2D ATP. The SDs of the HI, CI, TCP, bladder and rectum D 2cc , and the bladder and rectum normal tissue complication probability (NTCP) in 3D ATP were significantly smaller than those in 2D ATP. The results of this study suggest that the interfractional location variations give smaller impacts on the planning evaluation indices in 3D ATP than in 2D ATP. Therefore, the 3D plans with ATP are expected to be robust against interfractional location variations in each treatment fraction. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

The Benefits of Including Clinical Factors in Rectal Normal Tissue Complication Probability Modeling After Radiotherapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Defraene, Gilles, E-mail: gilles.defraene@uzleuven.be; Van den Bergh, Laura; Al-Mamgani, Abrahim

2012-03-01

Purpose: To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial. Methods and Materials: Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including themore » most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits. Results: Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011-0.013) clinical factor was 'previous abdominal surgery.' As second significant (p = 0.012-0.016) factor, 'cardiac history' was included in all three rectal bleeding fits, whereas including 'diabetes' was significant (p = 0.039-0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003-0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D{sub 50}. Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints. Conclusions: Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly.« less

An MLE method for finding LKB NTCP model parameters using Monte Carlo uncertainty estimates

NASA Astrophysics Data System (ADS)

Carolan, Martin; Oborn, Brad; Foo, Kerwyn; Haworth, Annette; Gulliford, Sarah; Ebert, Martin

2014-03-01

The aims of this work were to establish a program to fit NTCP models to clinical data with multiple toxicity endpoints, to test the method using a realistic test dataset, to compare three methods for estimating confidence intervals for the fitted parameters and to characterise the speed and performance of the program.

Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy.

PubMed

Dean, Jamie A; Wong, Kee H; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

2016-07-01

Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

An investigation of the impact of variations of DVH calculation algorithms on DVH dependant radiation therapy plan evaluation metrics

NASA Astrophysics Data System (ADS)

Kennedy, A. M.; Lane, J.; Ebert, M. A.

2014-03-01

Plan review systems often allow dose volume histogram (DVH) recalculation as part of a quality assurance process for trials. A review of the algorithms provided by a number of systems indicated that they are often very similar. One notable point of variation between implementations is in the location and frequency of dose sampling. This study explored the impact such variations can have on DVH based plan evaluation metrics (Normal Tissue Complication Probability (NTCP), min, mean and max dose), for a plan with small structures placed over areas of high dose gradient. Dose grids considered were exported from the original planning system at a range of resolutions. We found that for the CT based resolutions used in all but one plan review systems (CT and CT with guaranteed minimum number of sampling voxels in the x and y direction) results were very similar and changed in a similar manner with changes in the dose grid resolution despite the extreme conditions. Differences became noticeable however when resolution was increased in the axial (z) direction. Evaluation metrics also varied differently with changing dose grid for CT based resolutions compared to dose grid based resolutions. This suggests that if DVHs are being compared between systems that use a different basis for selecting sampling resolution it may become important to confirm that a similar resolution was used during calculation.

EUCLID: an outcome analysis tool for high-dimensional clinical studies

NASA Astrophysics Data System (ADS)

Gayou, Olivier; Parda, David S.; Miften, Moyed

2007-03-01

Treatment management decisions in three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) are usually made based on the dose distributions in the target and surrounding normal tissue. These decisions may include, for example, the choice of one treatment over another and the level of tumour dose escalation. Furthermore, biological predictors such as tumour control probability (TCP) and normal tissue complication probability (NTCP), whose parameters available in the literature are only population-based estimates, are often used to assess and compare plans. However, a number of other clinical, biological and physiological factors also affect the outcome of radiotherapy treatment and are often not considered in the treatment planning and evaluation process. A statistical outcome analysis tool, EUCLID, for direct use by radiation oncologists and medical physicists was developed. The tool builds a mathematical model to predict an outcome probability based on a large number of clinical, biological, physiological and dosimetric factors. EUCLID can first analyse a large set of patients, such as from a clinical trial, to derive regression correlation coefficients between these factors and a given outcome. It can then apply such a model to an individual patient at the time of treatment to derive the probability of that outcome, allowing the physician to individualize the treatment based on medical evidence that encompasses a wide range of factors. The software's flexibility allows the clinicians to explore several avenues to select the best predictors of a given outcome. Its link to record-and-verify systems and data spreadsheets allows for a rapid and practical data collection and manipulation. A wide range of statistical information about the study population, including demographics and correlations between different factors, is available. A large number of one- and two-dimensional plots, histograms and survival curves allow for an easy visual analysis of the population. Several visual and analytical methods are available to quantify the predictive power of the multivariate regression model. The EUCLID tool can be readily integrated with treatment planning and record-and-verify systems.

EUCLID: an outcome analysis tool for high-dimensional clinical studies.

PubMed

Gayou, Olivier; Parda, David S; Miften, Moyed

2007-03-21

Treatment management decisions in three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) are usually made based on the dose distributions in the target and surrounding normal tissue. These decisions may include, for example, the choice of one treatment over another and the level of tumour dose escalation. Furthermore, biological predictors such as tumour control probability (TCP) and normal tissue complication probability (NTCP), whose parameters available in the literature are only population-based estimates, are often used to assess and compare plans. However, a number of other clinical, biological and physiological factors also affect the outcome of radiotherapy treatment and are often not considered in the treatment planning and evaluation process. A statistical outcome analysis tool, EUCLID, for direct use by radiation oncologists and medical physicists was developed. The tool builds a mathematical model to predict an outcome probability based on a large number of clinical, biological, physiological and dosimetric factors. EUCLID can first analyse a large set of patients, such as from a clinical trial, to derive regression correlation coefficients between these factors and a given outcome. It can then apply such a model to an individual patient at the time of treatment to derive the probability of that outcome, allowing the physician to individualize the treatment based on medical evidence that encompasses a wide range of factors. The software's flexibility allows the clinicians to explore several avenues to select the best predictors of a given outcome. Its link to record-and-verify systems and data spreadsheets allows for a rapid and practical data collection and manipulation. A wide range of statistical information about the study population, including demographics and correlations between different factors, is available. A large number of one- and two-dimensional plots, histograms and survival curves allow for an easy visual analysis of the population. Several visual and analytical methods are available to quantify the predictive power of the multivariate regression model. The EUCLID tool can be readily integrated with treatment planning and record-and-verify systems.

Volumetric-modulated arc therapy vs c-IMRT in esophageal cancer: A treatment planning comparison

PubMed Central

Yin, Li; Wu, Hao; Gong, Jian; Geng, Jian-Hao; Jiang, Fan; Shi, An-Hui; Yu, Rong; Li, Yong-Heng; Han, Shu-Kui; Xu, Bo; Zhu, Guang-Ying

2012-01-01

AIM: To compare the volumetric-modulated arc therapy (VMAT) plans with conventional sliding window intensity-modulated radiotherapy (c-IMRT) plans in esophageal cancer (EC). METHODS: Twenty patients with EC were selected, including 5 cases located in the cervical, the upper, the middle and the lower thorax, respectively. Five plans were generated with the eclipse planning system: three using c-IMRT with 5 fields (5F), 7 fields (7F) and 9 fields (9F), and two using VMAT with a single arc (1A) and double arcs (2A). The treatment plans were designed to deliver a dose of 60 Gy to the planning target volume (PTV) with the same constrains in a 2.0 Gy daily fraction, 5 d a week. Plans were normalized to 95% of the PTV that received 100% of the prescribed dose. We examined the dose-volume histogram parameters of PTV and the organs at risk (OAR) such as lungs, spinal cord and heart. Monitor units (MU) and normal tissue complication probability (NTCP) of OAR were also reported. RESULTS: Both c-IMRT and VMAT plans resulted in abundant dose coverage of PTV for EC of different locations. The dose conformity to PTV was improved as the number of field in c-IMRT or rotating arc in VMAT was increased. The doses to PTV and OAR in VMAT plans were not statistically different in comparison with c-IMRT plans, with the following exceptions: in cervical and upper thoracic EC, the conformity index (CI) was higher in VMAT (1A 0.78 and 2A 0.8) than in c-IMRT (5F 0.62, 7F 0.66 and 9F 0.73) and homogeneity was slightly better in c-IMRT (7F 1.09 and 9F 1.07) than in VMAT (1A 1.1 and 2A 1.09). Lung V30 was lower in VMAT (1A 12.52 and 2A 12.29) than in c-IMRT (7F 14.35 and 9F 14.81). The humeral head doses were significantly increased in VMAT as against c-IMRT. In the middle and lower thoracic EC, CI in VMAT (1A 0.76 and 2A 0.74) was higher than in c-IMRT (5F 0.63 Gy and 7F 0.67 Gy), and homogeneity was almost similar between VMAT and c-IMRT. V20 (2A 21.49 Gy vs 7F 24.59 Gy and 9F 24.16 Gy) and V30 (2A 9.73 Gy vs 5F 12.61 Gy, 7F 11.5 Gy and 9F 11.37 Gy) of lungs in VMAT were lower than in c-IMRT, but low doses to lungs (V5 and V10) were increased. V30 (1A 48.12 Gy vs 5F 59.2 Gy, 7F 58.59 Gy and 9F 57.2 Gy), V40 and V50 of heart in VMAT was lower than in c-IMRT. MUs in VMAT plans were significantly reduced in comparison with c-IMRT, maximum doses to the spinal cord and mean doses of lungs were similar between the two techniques. NTCP of spinal cord was 0 for all cases. NTCP of lungs and heart in VMAT were lower than in c-IMRT. The advantage of VMAT plan was enhanced by doubling the arc. CONCLUSION: Compared with c-IMRT, VMAT, especially the 2A, slightly improves the OAR dose sparing, such as lungs and heart, and reduces NTCP and MU with a better PTV coverage. PMID:23066322

Volumetric-modulated arc therapy vs. c-IMRT in esophageal cancer: a treatment planning comparison.

PubMed

Yin, Li; Wu, Hao; Gong, Jian; Geng, Jian-Hao; Jiang, Fan; Shi, An-Hui; Yu, Rong; Li, Yong-Heng; Han, Shu-Kui; Xu, Bo; Zhu, Guang-Ying

2012-10-07

To compare the volumetric-modulated arc therapy (VMAT) plans with conventional sliding window intensity-modulated radiotherapy (c-IMRT) plans in esophageal cancer (EC). Twenty patients with EC were selected, including 5 cases located in the cervical, the upper, the middle and the lower thorax, respectively. Five plans were generated with the eclipse planning system: three using c-IMRT with 5 fields (5F), 7 fields (7F) and 9 fields (9F), and two using VMAT with a single arc (1A) and double arcs (2A). The treatment plans were designed to deliver a dose of 60 Gy to the planning target volume (PTV) with the same constrains in a 2.0 Gy daily fraction, 5 d a week. Plans were normalized to 95% of the PTV that received 100% of the prescribed dose. We examined the dose-volume histogram parameters of PTV and the organs at risk (OAR) such as lungs, spinal cord and heart. Monitor units (MU) and normal tissue complication probability (NTCP) of OAR were also reported. Both c-IMRT and VMAT plans resulted in abundant dose coverage of PTV for EC of different locations. The dose conformity to PTV was improved as the number of field in c-IMRT or rotating arc in VMAT was increased. The doses to PTV and OAR in VMAT plans were not statistically different in comparison with c-IMRT plans, with the following exceptions: in cervical and upper thoracic EC, the conformity index (CI) was higher in VMAT (1A 0.78 and 2A 0.8) than in c-IMRT (5F 0.62, 7F 0.66 and 9F 0.73) and homogeneity was slightly better in c-IMRT (7F 1.09 and 9F 1.07) than in VMAT (1A 1.1 and 2A 1.09). Lung V30 was lower in VMAT (1A 12.52 and 2A 12.29) than in c-IMRT (7F 14.35 and 9F 14.81). The humeral head doses were significantly increased in VMAT as against c-IMRT. In the middle and lower thoracic EC, CI in VMAT (1A 0.76 and 2A 0.74) was higher than in c-IMRT (5F 0.63 Gy and 7F 0.67 Gy), and homogeneity was almost similar between VMAT and c-IMRT. V20 (2A 21.49 Gy vs. 7F 24.59 Gy and 9F 24.16 Gy) and V30 (2A 9.73 Gy vs. 5F 12.61 Gy, 7F 11.5 Gy and 9F 11.37 Gy) of lungs in VMAT were lower than in c-IMRT, but low doses to lungs (V5 and V10) were increased. V30 (1A 48.12 Gy vs. 5F 59.2 Gy, 7F 58.59 Gy and 9F 57.2 Gy), V40 and V50 of heart in VMAT was lower than in c-IMRT. MUs in VMAT plans were significantly reduced in comparison with c-IMRT, maximum doses to the spinal cord and mean doses of lungs were similar between the two techniques. NTCP of spinal cord was 0 for all cases. NTCP of lungs and heart in VMAT were lower than in c-IMRT. The advantage of VMAT plan was enhanced by doubling the arc. Compared with c-IMRT, VMAT, especially the 2A, slightly improves the OAR dose sparing, such as lungs and heart, and reduces NTCP and MU with a better PTV coverage.

Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy.

PubMed

Miura, Takuya; Kimura, Norihisa; Yamada, Toshiyuki; Shimizu, Takeshi; Nanashima, Naoki; Yamana, Daisuke; Hakamada, Kenichi; Tsuchida, Shigeki

2011-08-01

To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model. Male Sprague-Dawley rats were subjected to 90% hepatectomy, and tissues were harvested at 0, 1, 3, and 7 days for microarray analysis, quantitative real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry to examine the expression of multidrug resistance protein 4 (Mrp4), bile salt export pump (Bsep), and sodium-dependent taurocholate cotransporting polypeptide (Ntcp). Persistently elevated levels of serum bile acids were observed at days 3 and 7. RT-PCR and Western blotting indicated that the expression of Mrp4, a bile acid export pump located in the basolateral membrane, was increased at day 3. The expression of Ntcp, a transporter used to uptake bile acids from the sinusoids, was significantly decreased throughout the period. The levels of Bsep, an export pump localized to the canalicular membrane, were unchanged. Immunohistochemistry revealed the localization of Mrp4 and Bsep in the basolateral and canalicular membranes, respectively. On the other hand, at days 3 and 7, Ntcp was localized in the cytoplasm and was hardly detected in the basolateral membrane. These results suggested that the sustained repression and translocation of Ntcp and the expression of Mrp4 at the basolateral membrane seem to be responsible for the high blood bile acids levels after massive hepatectomy. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Clinical implications in the use of the PBC algorithm versus the AAA by comparison of different NTCP models/parameters

PubMed Central

2013-01-01

Purpose Retrospective analysis of 3D clinical treatment plans to investigate qualitative, possible, clinical consequences of the use of PBC versus AAA. Methods The 3D dose distributions of 80 treatment plans at four different tumour sites, produced using PBC algorithm, were recalculated using AAA and the same number of monitor units provided by PBC and clinically delivered to each patient; the consequences of the difference on the dose-effect relations for normal tissue injury were studied by comparing different NTCP model/parameters extracted from a review of published studies. In this study the AAA dose calculation is considered as benchmark data. The paired Student t-test was used for statistical comparison of all results obtained from the use of the two algorithms. Results In the prostate plans, the AAA predicted lower NTCP value (NTCPAAA) for the risk of late rectal bleeding for each of the seven combinations of NTCP parameters, the maximum mean decrease was 2.2%. In the head-and-neck treatments, each combination of parameters used for the risk of xerostemia from irradiation of the parotid glands involved lower NTCPAAA, that varied from 12.8% (sd=3.0%) to 57.5% (sd=4.0%), while when the PBC algorithm was used the NTCPPBC’s ranging was from 15.2% (sd=2.7%) to 63.8% (sd=3.8%), according the combination of parameters used; the differences were statistically significant. Also NTCPAAA regarding the risk of radiation pneumonitis in the lung treatments was found to be lower than NTCPPBC for each of the eight sets of NTCP parameters; the maximum mean decrease was 4.5%. A mean increase of 4.3% was found when the NTCPAAA was calculated by the parameters evaluated from dose distribution calculated by a convolution-superposition (CS) algorithm. A markedly different pattern was observed for the risk relating to the development of pneumonitis following breast treatments: the AAA predicted higher NTCP value. The mean NTCPAAA varied from 0.2% (sd = 0.1%) to 2.1% (sd = 0.3%), while the mean NTCPPBC varied from 0.1% (sd = 0.0%) to 1.8% (sd = 0.2%) depending on the chosen parameters set. Conclusions When the original PBC treatment plans were recalculated using AAA with the same number of monitor units provided by PBC, the NTCPAAA was lower than the NTCPPBC, except for the breast treatments. The NTCP is strongly affected by the wide-ranging values of radiobiological parameters. PMID:23826854

Clinical implications in the use of the PBC algorithm versus the AAA by comparison of different NTCP models/parameters.

PubMed

Bufacchi, Antonella; Nardiello, Barbara; Capparella, Roberto; Begnozzi, Luisa

2013-07-04

Retrospective analysis of 3D clinical treatment plans to investigate qualitative, possible, clinical consequences of the use of PBC versus AAA. The 3D dose distributions of 80 treatment plans at four different tumour sites, produced using PBC algorithm, were recalculated using AAA and the same number of monitor units provided by PBC and clinically delivered to each patient; the consequences of the difference on the dose-effect relations for normal tissue injury were studied by comparing different NTCP model/parameters extracted from a review of published studies. In this study the AAA dose calculation is considered as benchmark data. The paired Student t-test was used for statistical comparison of all results obtained from the use of the two algorithms. In the prostate plans, the AAA predicted lower NTCP value (NTCPAAA) for the risk of late rectal bleeding for each of the seven combinations of NTCP parameters, the maximum mean decrease was 2.2%. In the head-and-neck treatments, each combination of parameters used for the risk of xerostemia from irradiation of the parotid glands involved lower NTCPAAA, that varied from 12.8% (sd=3.0%) to 57.5% (sd=4.0%), while when the PBC algorithm was used the NTCPPBC's ranging was from 15.2% (sd=2.7%) to 63.8% (sd=3.8%), according the combination of parameters used; the differences were statistically significant. Also NTCPAAA regarding the risk of radiation pneumonitis in the lung treatments was found to be lower than NTCPPBC for each of the eight sets of NTCP parameters; the maximum mean decrease was 4.5%. A mean increase of 4.3% was found when the NTCPAAA was calculated by the parameters evaluated from dose distribution calculated by a convolution-superposition (CS) algorithm. A markedly different pattern was observed for the risk relating to the development of pneumonitis following breast treatments: the AAA predicted higher NTCP value. The mean NTCPAAA varied from 0.2% (sd = 0.1%) to 2.1% (sd = 0.3%), while the mean NTCPPBC varied from 0.1% (sd = 0.0%) to 1.8% (sd = 0.2%) depending on the chosen parameters set. When the original PBC treatment plans were recalculated using AAA with the same number of monitor units provided by PBC, the NTCPAAA was lower than the NTCPPBC, except for the breast treatments. The NTCP is strongly affected by the wide-ranging values of radiobiological parameters.

SU-F-T-104: Determining the NTCP Parameters of Pharyngeal Constrictors and Proximal Esophagus for Radiation Induced Swallowing Problems Recorded Six Months After Radiation Therapy for Head and Neck Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mavroidis, P; Price, A; Kostich, M

Purpose: To estimate the radiobiological parameters of four NTCP models that describe the dose-response relations of pharyngeal constrictors and proximal esophagus regarding the severity of patient reported swallowing problems 6 months post chemo-radiotherapy. To identify the section/structure that best correlates with the manifestation of the clinical endpoints. Finally, to compare the goodness-of-fit of those models. Methods: Forty-three patients were treated on a prospective multi-institutional phase II study for oropharyngeal squamous cell carcinoma. All the patients received 60 Gy IMRT and they reported symptoms using the novel patient reported outcome version of the CTCAE. We derived the individual patient dosimetric datamore » of superior, medium and inferior sections of pharyngeal constrictors (SPC, MPC and IPC), superior and inferior sections of esophagus (SES and IES) as separate structures as well as combinations. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), Logit and Relative Logit (RL) NTCP models were used to fit the patient data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC) and the Odds Ratio methods. Results: The AUC values were highest for the SPC for Grade ≥ 2 (0.719 for the RS and RL models, and 0.716 for LKB and Logit). For Grade ≥ 1, the respective values were 0.699 for RS, LKB and Logit and 0.676 for RL. For MPC the AUC values varied between 0.463–0.477, for IPC between 0.396–0.458, for SES between 0.556–0.613 and for IES between 0.410–0.519. The Odds Ratio for the SPC was 15.6 (1.7–146.4) for RS, LKB and Logit for NTCP of 55%. Conclusion: All the examined NTCP models could fit the clinical data with similar accuracy. The SPC appear to correlate best with the clinical endpoints of swallowing problems. A prospective study could establish the use of NTCP values of SPC as a constraint in treatment planning.« less

SU-D-204-05: Fitting Four NTCP Models to Treatment Outcome Data of Salivary Glands Recorded Six Months After Radiation Therapy for Head and Neck Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mavroidis, P; Price, A; Kostich, M

Purpose: To estimate the radiobiological parameters of four popular NTCP models that describe the dose-response relations of salivary glands to the severity of patient reported dry mouth 6 months post chemo-radiotherapy. To identify the glands, which best correlate with the manifestation of those clinical endpoints. Finally, to evaluate the goodness-of-fit of the NTCP models. Methods: Forty-three patients were treated on a prospective multiinstitutional phase II study for oropharyngeal squamous cell carcinoma. All the patients received 60 Gy IMRT and they reported symptoms using the novel patient reported outcome version of the CTCAE. We derived the individual patient dosimetric data ofmore » the parotid and submandibular glands (SMG) as separate structures as well as combinations. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), Logit and Relative Logit (RL) NTCP models were used to fit the patients data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC) and the Odds Ratio methods. Results: The AUC values were highest for the contralateral parotid for Grade ≥ 2 (0.762 for the LKB, RS, Logit and 0.753 for the RL). For the salivary glands the AUC values were: 0.725 for the LKB, RS, Logit and 0.721 for the RL. For the contralateral SMG the AUC values were: 0.721 for LKB, 0.714 for Logit and 0.712 for RS and RL. The Odds Ratio for the contralateral parotid was 5.8 (1.3–25.5) for all the four NTCP models for the radiobiological dose threshold of 21Gy. Conclusion: It was shown that all the examined NTCP models could fit the clinical data well with very similar accuracy. The contralateral parotid gland appears to correlated best with the clinical endpoints of severe/very severe dry mouth. An EQD2Gy dose of 21Gy appears to be a safe threshold to be used as a constraint in treatment planning.« less

Effect of Yin-Zhi-Huang on up-regulation of Oatp2, Ntcp, and Mrp2 proteins in estrogen-induced rat cholestasis.

PubMed

Zhang, Guoqiang; Zhou, Yan; Rao, Zhi; Qin, Hongyan; Wei, Yuhui; Ren, Jiangxia; Zhou, Liting; Wu, Xin'an

2015-03-01

Yin-Zhi-Huang (YZH), a prescription of traditional Chinese medicine, is widely used to treat neonatal jaundice or cholestasis. This study investigates the regulatory effect of YZH on the localization and expression of organic anion transporting polypeptides 2 (Oatp2), Na(+)-taurocholate co-transporting polypeptide (Ntcp), multidrug-resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) in estrogen-induced cholestasis rats. Cholestasis model rats were induced via subcutaneous injection of estradiol benzoate (EB, 5 mg/kg/d) for 5 d. Other EB-induced rats were treated with saline (2 ml) or YZH (1.5 g/kg, two times a day) for 7, 14, and 21 d. The biochemical and pathologic examinations were performed. Moreover, the localization and expression of Oatp2, Ntcp, Mrp2, and Bsep were determined by immunohistochemisty and Western blotting, respectively. YZH treatment could significantly decrease the serum total bile acids (TBA) (4.9 ± 0.6-2.8 ± 0.8) and direct bilirubin (DBIL) (2.6 ± 0.7-1.0 ± 0.1) levels, improve the histological disorganization, and, respectively, increase the expression of Oatp2 and Ntcp by 46% and 28% compared with saline-treated (p < 0.05) rats at 14 d. The expression of Mrp2 increased by 45% was observed in YZH treated compared with saline-treated (p < 0.05) rats at 7 d. However, there was a little change in the expression of Bsep (p > 0.05) after YZH treatment for 7, 14, and 21 d. In conclusion, the therapeutic effect of YZH to cholestasis could be attributed to the regulation of Oatp2, Ntcp, Mrp2, and Bsep.

Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study.

PubMed

Thanapirom, Kessarin; Suksawatamnuay, Sirinporn; Sukeepaisarnjaroen, Wattana; Treeprasertsuk, Sombat; Tanwandee, Tawesak; Charatcharoenwitthaya, Phunchai; Thongsawat, Satawat; Leerapun, Apinya; Piratvisuth, Teerha; Boonsirichan, Rattana; Bunchorntavakul, Chalermrat; Pattanasirigool, Chaowalit; Pornthisarn, Bubpha; Tuntipanichteerakul, Supoj; Sripariwuth, Ekawee; Jeamsripong, Woramon; Sanpajit, Theeranun; Poovorawan, Yong; Komolmit, Piyawat

2018-01-01

Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection. A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL). Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients. The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.

Systems Development in a Complex Stakeholder Environment: NTCP Chronicle 2.0

PubMed Central

Callahan, Christopher P.; Petersen, Lisa

2003-01-01

The CDC’s National Tobacco Control Program (NTCP) is developing its Chronicle 2.0 online grant application and progress reporting system. 51 CDC-funded state tobacco control programs currently use Chronicle in its 1.0 version to facilitate the collection of state data supporting progress on key performance measures. This poster highlights the application development process for Chronicle 2.0 and presents lessons learned. PMID:14728306

A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction.

PubMed

Saso, Wakana; Tsukuda, Senko; Ohashi, Hirofumi; Fukano, Kento; Morishita, Ryo; Matsunaga, Satoko; Ohki, Mio; Ryo, Akihide; Park, Sam-Yong; Suzuki, Ryosuke; Aizaki, Hideki; Muramatsu, Masamichi; Sureau, Camille; Wakita, Takaji; Matano, Tetsuro; Watashi, Koichi

2018-06-22

Current anti-hepatitis B virus (HBV) agents have limited effect in curing HBV infection, and thus novel anti-HBV agents with different modes of action are in demand. In this study, we applied AlphaScreen assay to high-throughput screening of small molecules inhibiting the interaction between HBV large surface antigen (LHBs) and the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP). From the chemical screening, we identified that rapamycin, an immunosuppressant, strongly inhibited the LHBs-NTCP interaction. Rapamycin inhibited hepatocyte infection with HBV without significant cytotoxicity. This activity was due to impaired attachment of the LHBs preS1 domain to cell surface. Pretreatment of target cells with rapamycin remarkably reduced their susceptibility to preS1 attachment, while rapamycin pretreatment to preS1 did not affect its attachment activity, suggesting that rapamycin targets the host side. In support of this, a surface plasmon resonance analysis showed a direct interaction of rapamycin with NTCP. Consistently, rapamycin also prevented hepatitis D virus infection, whose entry into cells is also mediated by NTCP. We also identified two rapamycin derivatives, everolimus and temsirolimus, which possessed higher anti-HBV potencies than rapamycin. Thus, this is the first report for application of AlphaScreen technology that monitors a viral envelope-receptor interaction to identify viral entry inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4alpha and PGC1alpha.

PubMed

Dietrich, Christoph G; Martin, Ina V; Porn, Anne C; Voigt, Sebastian; Gartung, Carsten; Trautwein, Christian; Geier, Andreas

2007-09-01

Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.

Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1.

PubMed

Grosser, Gary; Döring, Barbara; Ugele, Bernhard; Geyer, Joachim; Kulling, Sabine E; Soukup, Sebastian T

2015-12-01

Soy isoflavones (IF) are phytoestrogens, which interact with estrogen receptors. They are extensively metabolized by glucuronosyltransferases and sulfotransferases, leading to the modulation of their estrogenic activity. It can be assumed that this biotransformation also has a crucial impact on the uptake of IF by active or passive cellular transport mechanisms, but little is known about the transport of IF phase II metabolites into the cell. Therefore, transport assays for phase II metabolites of daidzein (DAI) were carried out using HEK293 cell lines transfected with five human candidate carriers, i.e., organic anion transporter OAT4, sodium-dependent organic anion transporter (SOAT), Na(+)-taurocholate cotransporting polypeptide (NTCP), apical sodium-dependent bile acid transporter ASBT, and organic anion transporting polypeptide OATP2B1. Cellular uptake was monitored by UHPLC-DAD. DAI monosulfates were transported by the carriers NTCP and SOAT in a sodium-dependent manner, while OAT4-HEK293 cells revealed a partly sodium-dependent transport for these compounds. In contrast, DAI-7,4'-disulfate was only taken up by NTCP-HEK293 cells. DAI-7-glucuronide, but not DAI-4'-glucuronide, was transported exclusively by OATP2B1 in a sodium-independent manner. DAI-7-glucuronide-4'-sulfate, DAI-7-glucoside, and DAI were no substrate of any of the tested carriers. In addition, the inhibitory potency of the DAI metabolites toward estrone-sulfate (E1S) uptake of the above-mentioned carriers was determined. In conclusion, human SOAT, NTCP, OATP2B1, and OAT4 were identified as carriers for the DAI metabolites. Several metabolites were able to inhibit carrier-dependent E1S uptake. These findings might contribute to a better understanding of the bioactivity of IF especially in case of hormone-related cancers.

Critical Role of PPAR-α in Perfluorooctanoic Acid– and Perfluorodecanoic Acid–Induced Downregulation of Oatp Uptake Transporters in Mouse Livers

PubMed Central

Cheng, Xingguo; Klaassen, Curtis D.

2008-01-01

Perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) have been detected globally in wildlife and humans. Data from a gene array indicate that PFOA decreases organic anion transporting polypeptides (Oatps) in liver. Na+-taurocholate cotransporting polypeptide (Ntcp) and Oatp1a1, 1a4, and 1b2 are major transporters responsible for uptake of bile acids (BAs) and other organic compounds into liver. The purpose of the present study was to determine the effects of two perfluorinated fatty acids, PFOA and PFDA, on mRNA and protein expression of hepatic uptake transporters Oatps and Ntcp, and to determine the underlying regulatory mechanisms by using peroxisome proliferator-activated receptor alpha (PPAR-α), constitutive androstane receptor, pregnane-X receptor, NF-E2–related factor 2, and farnesoid X receptor-null mouse models. After 2 days following a single i.p. administration, PFOA did not alter serum BA concentrations, but PFDA increased serum BA concentrations 300%. Furthermore, PFOA decreased mRNA and protein expression of Oatp1a1, 1a4, and 1b2, but not Ntcp in mouse liver. In contrast, PFDA decreased mRNA and protein expression of all four transporters, and decreased the mRNA expression in a dose-dependent manner, with the decrease of Oatp1a4 occurring at lower doses than the other three transporters. Multiple mechanisms are likely involved in the down-regulation of mouse Oatps and Ntcp by PFDA. By using the various transcription factor-null mice, PPAR-α was shown to play a central role in the down-regulation of Oatp1a1, 1a4, 1b2, and Ntcp by PFDA. The current studies provide important insight into understanding the mechanisms by which PFDA regulate the expression of hepatic uptake transporters. In conclusion, PFOA and PFDA decrease mouse liver uptake transporters primarily via activation of PPAR-α. PMID:18703564

Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients Treated With Intensity-Modulated Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazan, Jose G.; Luxton, Gary; Mok, Edward C.

2012-11-01

Purpose: To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT). Methods and Materials: We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade {>=}3 HT (HT3+) and hematologic event (HE), defined as any grade {>=}2 HT with a modification in chemotherapy dose. Normal tissue complication probabilitymore » (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters. Results: Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD{sub 50} = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose {>=}30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors. Conclusions: LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively.« less

SU-C-BRA-01: 18F-NaF PET/CT-Directed Dose Escalation in Stereotactic Body Radiotherapy for Spine Oligometastases From Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, L; University of Nevada, Las Vegas, Las Vegas, NV; Zhang, W

2015-06-15

Purpose: To investigate the technical feasibility of SBRT dose painting using {sup 18}F-NaF positron emission tomography (PET) scans guidance in patients with spine oligometastases from prostate cancer. Methods: As a proof of concept, six patients with 14 spine oligometastatic lesions from prostate cancer who had {sup 18}F-NaF PET/CT scan prior to treatment were retrospectively included. GTV{sub reg} was delineated according to the regular tumor boundary shown on PET and/or CT images; and GTV{sub MATV} was contoured based on a net metabolically active tumor volume (MATV) defined by 60% of the SUV{sub max} values on {sup 18}F-NaF PET images. The PTVsmore » (PTV{sub reg} and PTV{sub MATV}) were defined as respective GTVs (plus involved entire vertebral body for PTV{sub reg}) with a 3-mm isotropic expansion margin. Three 1-fraction SBRT plans using VMAT technique along with 10 MV FFF beams (Plan{sub 24Gy}, Plan{sub 24–27Gy}, and Plan{sub 24–30Gy}) were generated for each patient. All plans included a dose of 24 Gy prescribed to PTV{sub reg}. The Plan{sub 24–27Gy} and Plan{sub 24–30Gy} also included a simultaneous boost dose of 27 Gy or 30 Gy prescribed to the PTV{sub MATV}, respectively. The feasibility of 18F-NaF PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The normal tissue complication probabilities (NTCP) calculated by radiological models were also compared between the plans. Results: In all 33 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 24–27Gy} and Plan{sub 24–30Gy} had a significantly higher dose in PTV{sub MATV} than Plan{sub 24Gy} (p < 0.05), respectively, while maintaining a similar OAR sparing profile and NTCP values. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-NaF PET-guided radiation boost dose up to 30 Gy into a SBRT plan is technically feasible. The relationship between local control and normal tissue toxicity in SBRT dose painting should be validated in clinical trials.« less

Mixed effects of OATP1B1, BCRP and NTCP polymorphisms on the population pharmacokinetics of pravastatin in healthy volunteers.

PubMed

Lu, Xue-Feng; Zhou, Yang; Bi, Kai-Shun; Chen, Xiao-Hui

2016-09-01

1. Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non-linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well. 2. Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p < 0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p < 0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%. 3. There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.01 < p < 0.05), whereas rs11045819 (OATP1B1), rs1061018 (BCRP) and rs61745930 (NTCP) genotypes do not appear to be associated with pravastatin pharmacokinetics based on the population model (p > 0.05). 4. The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics.

Poster - 47: A parametrized prediction model of rectal toxicity in focal SBRT of low risk prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stevens, Todd; Bauman, Glenn

There has been a recent trend towards watchful waiting in place of intervention for early stage prostate cancer (CaP). However, this approach can allow for disease progression, and subsequent whole-gland therapies such as prostatectomy and whole gland irradiation can result in functional deficits or rectal toxicities or both. A controversial alternative approach for this patient cohort is the use of focal therapy, where the treatment is focussed on an identified dominant index lesion (DIL). This work aims to investigate the treatment parameters for focal SBRT of the prostate under which clinically acceptable rectal NTCP levels can be achieved. For eachmore » of 25 low risk CaP patients, a hypothetical 2 cc DIL was modeled in the right-posterior quadrant of the prostate, and was used to build a PTV as the target for SBRT simulation. An SBRT prescriptions of 41 Gy and 37 Gy in 5 fractions were chosen, corresponding to the boost levels used in previous CaP dose escalation studies. DVH data were exported and used to calculate rectal NTCP values based on the Lyman-Kutcher-Burman (LKB) model using the QUANTEC reccommended model parameters. Rectal NTCP dependence on DIL-to-rectum separation, dose level, and DIL volume were investigated. The final goal of this ongoing work is to create a map of the maximum allowable prescription dose for a given patient geometry that achieves a clinically acceptable rectal NTCP level.« less

WE-H-BRA-02: Radiobiological Modeling of Tumor Control Probability (TCP) and Radiation-Induced Pneumonitis (RP) for Lung Cancer Patients Treated with Monte Carlo-Based Lung SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Sood, S; Shen, X

2016-06-15

Purpose: To present radiobiological modeling of TCP using tumor size-adjusted BED(s-BED)and PTV(D99) to lung SBRT patients treated with X-ray Voxel Monte Carlo(XVMC) algorithm, apply parameterized Lyman-NTCP model to predict grade-2 RP and subsequently, compare with clinical outcomes/observations. Methods: Dosimetric parameters and clinical follow-up for XVMC-based lung-SBRT patients were retrospectively evaluated. Patients were treated at Novalis-TX with hybrid(2 non-coplanar partial-arcs plus 3–6 static-beams)plan using HD-MLC/6MV-SRS-beam.For TCP,s-BED modelling was utilized: TCP=EXP[sBED-TCD50]/k/(1.0+EXP[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy and s-BED was defined as BED10 minus 10 times the tumor diameter(in centimeters)by Ohri et al.(IJROBP,2012). For 2-yr local-control, we used more-realistic MC-computed PTVD99 as amore » predictive parameter, s-BED(D99).Due to relatively shorter median follow-up interval(12-months),Kaplan-Meier curves were generated to estimate 2-yr observed local-control and compared to predicted-rate by TCP modeling. For NTCP, we employed parameterized Lyman-NTCP model utilizing normal-lung DVH and α/β=3Gy fitted to predict grade-2 RP after lung-SBRT. Results: Total 108 patients (137 tumors) treated for 35–70Gy in 3–5 fractions, either primary-lung(n=74)or metastatic-lung(n=53)tumors were included.F or the given prescription dose with MC-computed MUs, 2-yr local-control rates with s-BED(D99) was 87±8%. Kaplan-Meier generated observed local-control rate at 2-yr was 87.5%,suggesting that PTV(D99) could be a potential predictor (p-value=0.38). Observed vs predicted TCP for primary-lung tumors and metastatic tumors were 97% vs 88±7% and 94% vs 86±9%.NTCP model predicted well for symptomatic-RP with predicted vs observed (3±5% vs 2%). Radiographic and clinically significant RP was observed in 13% and 2% of patients. Higher rates of radiographic change were observed in patients who received >50Gy compared to ≤50Gy(24% vs 10%). Conclusion: Utilizing MC-computed PTVD99, our TCP results were well correlated with clinical outcome. The predicted grade-2 RP rate was comparable to clinical observations. Clinical application of these radiobiological models may potentially allow for target dose escalation and/or lung-toxicity reduction. Further validation of these radiobiological models with longer follow up interval for large cohorts of lung-SBRT patients is anticipated.« less

Transport of the placental estriol precursor 16α-hydroxy-dehydroepiandrosterone sulfate (16α-OH-DHEAS) by stably transfected OAT4-, SOAT-, and NTCP-HEK293 cells.

PubMed

Schweigmann, H; Sánchez-Guijo, A; Ugele, B; Hartmann, K; Hartmann, M F; Bergmann, M; Pfarrer, C; Döring, B; Wudy, S A; Petzinger, E; Geyer, J; Grosser, G

2014-09-01

16α-Hydroxy-dehydroepiandrosterone sulfate (16α-OH-DHEAS) mainly originates from the fetus and serves as precursor for placental estriol biosynthesis. For conversion of 16α-OH-DHEAS to estriol several intracellular enzymes are required. However, prior to enzymatic conversion, 16α-OH-DHEAS must enter the cells by carrier mediated transport. To identify these carriers, uptake of 16α-OH-DHEAS by the candidate carriers organic anion transporter OAT4, sodium-dependent organic anion transporter SOAT, Na(+)-taurocholate cotransporting polypeptide NTCP, and organic anion transporting polypeptide OATP2B1 was measured in stably transfected HEK293 cells by LC-MS-MS. Furthermore, the study aimed to localize SOAT in the human placenta. Stably transfected OAT4-HEK293 cells revealed a partly sodium-dependent transport for 16α-OH-DHEAS with an apparent Km of 23.1 ± 5.1 μM and Vmax of 485.0 ± 39.1 pmol/mg protein/min, while stably transfected SOAT- and NTCP-HEK293 cells showed uptake only under sodium conditions with Km of 319.0 ± 59.5 μM and Vmax of 1465.8 ± 118.8 pmol/mg protein/min for SOAT and Km of 51.4 ± 9.9 μM and Vmax of 1423.3 ± 109.6 pmol/mg protein/min for NTCP. In contrast, stably transfected OATP2B1-HEK293 cells did not transport 16α-OH-DHEAS at all. Immunohistochemical studies and in situ hybridization of formalin fixed and paraffin embedded sections of human late term placenta showed expression of SOAT in syncytiotrophoblasts, predominantly at the apical membrane as well as in the vessel endothelium. In conclusion, OAT4, SOAT, and NTCP were identified as carriers for the estriol precursor 16α-OH-DHEAS. At least SOAT and OAT4 seem to play a functional role for the placental estriol synthesis as both are expressed in the syncytiotrophoblast of human placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

Live Cell Imaging Confocal Microscopy Analysis of HBV Myr-PreS1 Peptide Binding and Uptake in NTCP-GFP Expressing HepG2 Cells.

PubMed

König, Alexander; Glebe, Dieter

2017-01-01

To obtain basic knowledge about specific molecular mechanisms involved in the entry of pathogens into cells is the basis for establishing pharmacologic substances blocking initial viral binding, infection, and subsequent viral spread. Lack of information about key cellular factors involved in the initial steps of HBV infection has hampered the characterization of HBV binding and entry for decades. However, recently, the liver-specific sodium-dependent taurocholate cotransporting polypeptide (NTCP) has been discovered as a functional receptor for HBV and HDV, thus opening the field for new concepts of basic binding and entry of HBV and HDV. Here, we describe practical issues of a basic in vitro assay system to examine kinetics and mechanisms of receptor-dependent HBV binding, uptake, and intracellular trafficking by live-cell imaging confocal microscopy. The assay system is comprised of HepG2 cells expressing a NTCP-GFP fusion-protein and chemically synthesized, fluorophore-labeled part of HBV surface protein, spanning the first N-terminal 48 amino acids of preS1 of the large hepatitis B virus surface protein.

Analysis of plastome and chondriome genome types in potato somatic hybrids from Solanum tuberosum × Solanum etuberosum.

PubMed

Tiwari, Jagesh K; Chandel, Poonam; Singh, Bir Pal; Bhardwaj, Vinay

2014-01-01

Cytoplasm types of the potato somatic hybrids from Solanum tuberosum × Solanum etuberosum were analysed using chloroplast (cp) and mitochondrial (mt) organelle genomes-specific markers. Of the 29 markers (15 cpDNA and 14 mtDNA) amplified in the 26 genotypes, 5 cpDNA (H3, NTCP4, NTCP8, NTCP9, and ALC1/ALC3) and 13 mtDNA markers showed polymorphism. The cluster analysis based on the mtDNA markers detected higher diversity compared with the cpDNA markers. Presence of new mtDNA fragments of the markers, namely, T11-2, Nsm1, pumD, Nsm3, and Nsm4, were observed, while monomorphic loci revealed highly conserved genomic regions in the somatic hybrids. The study revealed that the somatic hybrids had diverse cytoplasm types consisting predominantly of T-, W-, and C-, with a few A- and S-type cp genomes; and α-, β-, and γ-type mt genomes. Somatic hybridization has unique potential to widen the cytoplasm types of the cultivated gene pools from wild species through introgression by breeding methods.

Age-dependent activity of the uptake transporters Ntcp and Oatp1b2 in male rat hepatocytes: from birth till adulthood.

PubMed

Fattah, Sarinj; Augustijns, Patrick; Annaert, Pieter

2015-01-01

Recognition of the role of hepatic drug transporters in elimination of xenobiotics continues to grow. Hepatic uptake transporters, such as hepatic isoforms of the organic anion-transporting polypeptide (Oatp) family as well as the bile acid transporter Na(+)-taurocholate cotransporting polypeptide (Ntcp) have been studied extensively both at the mRNA and protein expression levels in adults. However, in pediatric/juvenile populations, there continues to be a knowledge gap about the functional activity of these transporters. Therefore, the aim of this study was to examine the functional maturation of Ntcp and Oatp isoforms as major hepatic transporters. Hepatocytes were freshly isolated from rats aged between birth and 8 weeks. Transporter activities were assessed by measuring the initial uptake rates of known substrates: taurocholate (TCA) for Ntcp and sodium fluorescein (NaFluo) for Oatp. Relative to adult values, uptake clearance of TCA in hepatocytes from rats aged 0, 1, 2, 3, and 4 weeks reached 19, 43, 22, 46, and 63%, respectively. In contrast, Oatp-mediated NaFluo uptake showed a considerably slower developmental pattern: uptake clearance of NaFluo in hepatocytes from rats aged 0, 1, 2, 3, 4, and 6 weeks were 24, 20, 19, 8, 19, and 64%, respectively. Maturation of NaFluo uptake activity correlated with the previously reported ontogeny of Oatp1b2 mRNA expression, confirming the role of Oatp1b2 for NaFluo uptake in rat liver. The outcome of this project will help in understanding and predicting age-dependent drug exposure in juvenile animals and will eventually support safe and more effective drug therapies for children. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer

NASA Astrophysics Data System (ADS)

González, S. J.; Pozzi, E. C. C.; Monti Hughes, A.; Provenzano, L.; Koivunoro, H.; Carando, D. G.; Thorp, S. I.; Casal, M. R.; Bortolussi, S.; Trivillin, V. A.; Garabalino, M. A.; Curotto, P.; Heber, E. M.; Santa Cruz, G. A.; Kankaanranta, L.; Joensuu, H.; Schwint, A. E.

2017-10-01

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson’s correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

PubMed

González, S J; Pozzi, E C C; Monti Hughes, A; Provenzano, L; Koivunoro, H; Carando, D G; Thorp, S I; Casal, M R; Bortolussi, S; Trivillin, V A; Garabalino, M A; Curotto, P; Heber, E M; Santa Cruz, G A; Kankaanranta, L; Joensuu, H; Schwint, A E

2017-10-03

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

NASA Astrophysics Data System (ADS)

Rutkowska, Eva; Baker, Colin; Nahum, Alan

2010-04-01

A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

Scintigraphic assessment of salivary function after intensity-modulated radiotherapy for head and neck cancer: correlations with parotid dose and quality of life.

PubMed

Chen, Wen-Cheng; Lai, Chia-Hsuan; Lee, Tsair-Fwu; Hung, Chao-Hsiung; Liu, Kuo-Chi; Tsai, Ming-Fong; Wang, Wen-Hung; Chen, Hungcheng; Fang, Fu-Ming; Chen, Miao-Fen

2013-01-01

We investigated salivary function using quantitative scintigraphy and sought to identify functional correlations between parotid dose and quality of life (QoL) for head and neck cancer (HNC) patients receiving intensity-modulated radiotherapy (IMRT). Between August, 2007 and June, 2008, 31 patients treated IMRT for HNC were enrolled in this prospective study. Salivary excretion function (SEF) was previously measured by salivary scintigraphy at annual intervals for 2 years after IMRT. A dose-volume histogram of each parotid gland was calculated, and the normal tissue complication probability (NTCP) was used to determine the tolerance dose. QoL was longitudinally assessed by the EORTC QLQ-C30 and H&N35 questionnaires prior to RT, and at one, three, 12 and 24 months after RT. A significant correlation was found between the reduction of SEF and the mean parotid dose measured at 1 year (correlation coefficient, R(2)=0.651) and 2 years (R(2)=0.310) after IMRT (p<0.001). The TD(50) of the parotid gland at 1 year after IMRT is 43.6 Gy, comparable to results from western countries. We further found that contralateral parotid and submandibular gland function preservation was correlated with reduced sticky saliva and a better QoL compared to the functional preservation of both parotid glands, as determined by the EORTC QLQ-H&N35 questionnaire. A significant correlation was found between the reduction of SEF and the mean parotid dose. Preservation of contralateral parotid and submandibular gland function predicts a better QoL compared to preservation of the function of both parotid glands. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluation of the clinical usefulness of modulated arc treatment

NASA Astrophysics Data System (ADS)

Lee, Young Kyu; Jang, Hong Seok; Kim, Yeon Sil; Choi, Byung Ock; Kang, Young-Nam; Nam, Sang Hee; Park, Hyeong Wook; Kim, Shin Wook; Shin, Hun Joo; Lee, Jae Choon; Kim, Ji Na; Park, Sung Kwang; Kim, Jin Young

2015-07-01

The purpose of this study is to evaluate the clinical usefulness of modulated arc (mARC) treatment techniques. The mARC treatment plans for non-small-cell lung cancer (NSCLC) patients were made in order to verify the clinical usefulness of mARC. A pre-study was conducted to find the best plan condition for mARC treatment, and the usefulness of the mARC treatment plan was evaluated by comparing it with other Arc treatment plans such as tomotherapy and RapidArc plans. In the case of mARC, the optimal condition for the mARC plan was determined by comparing the dosimetric performance of the mARC plans developed by using various parameters, which included the photon energy (6 MV, 10 MV), the optimization point angle (6°- 10°intervals), and the total number of segments (36 - 59 segments). The best dosimetric performance of mARC was observed at a 10 MV photon energy, a point angle 6 degrees, and 59 segments. The treatment plans for the three different techniques were compared by using the following parameters: the conformity index (CI), homogeneity index (HI), the target coverage, the dose to the OARs, the number of monitor units (MU), the beam on time, and the normal tissue complication probability (NTCP). As a result, the three different treatment techniques showed similar target coverages. The mARC plan had the lowest V20 (volume of lung receiving > 20 Gy) and MU per fraction compared with both the RapidArc and the tomotherapy plans. The mARC plan reduced the beam on time as well. Therefore, the results of this study provide satisfactory evidence that the mARC technique can be considered as a useful clinical technique for radiation treatment.

Comparison of the extent of hippocampal sparing according to the tilt of a patient's head during WBRT using linear accelerator-based IMRT and VMAT.

PubMed

Moon, Sun Young; Yoon, Myonggeun; Chung, Mijoo; Chung, Weon Kuu; Kim, Dong Wook

2016-05-01

In this paper, we report the results of our investigation into whole brain radiotherapy (WBRT) using linear accelerator-based intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in lung cancer patients with a high risk of metastasis to the brain. Specifically, we assessed the absorbed dose and the rate of adverse effects for several organs at risk (OAR), including the hippocampus, according to the tilt of a patient's head. We arbitrarily selected five cases where measurements were made with the patients' heads tilted forward and five cases without such tilt. We set the entire brain as the planning target volume (PTV), and the hippocampi, the lenses, the eyes, and the cochleae as the main OAR, and formulated new plans for IMRT (coplanar, non-coplanar) and VMAT (coplanar, non-coplanar). Using the dose-volume histogram (DVH), we calculated and compared the effective uniform dose (EUD), normal tissue complication probability (NTCP) of the OAR and the mean and the maximum doses of hippocampus. As a result, if the patient tilted the head forward when receiving the Linac-based treatment, for the same treatment effect in the PTV, we confirmed that a lower dose entered the OAR, such as the hippocampus, eye, lens, and cochlea. Moreover, the damage to the hippocampus was expected to be the least when receiving coplanar VMAT with the head tilted forward. Accordingly, if patients tilt their heads forward when undergoing Linac-based WBRT, we anticipate that a smaller dose would be transmitted to the OAR, resulting in better quality of life following treatment. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Use of convolution/superposition-based treatment planning system for dose calculations in the kilovoltage energy range

NASA Astrophysics Data System (ADS)

Alaei, Parham

2000-11-01

A number of procedures in diagnostic radiology and cardiology make use of long exposures to x rays from fluoroscopy units. Adverse effects of these long exposure times on the patients' skin have been documented in recent years. These include epilation, erythema, and, in severe cases, moist desquamation and tissue necrosis. Potential biological effects from these exposures to other organs include radiation-induced cataracts and pneumonitis. Although there have been numerous studies to measure or calculate the dose to skin from these procedures, there have only been a handful of studies to determine the dose to other organs. Therefore, there is a need for accurate methods to measure the dose in tissues and organs other than the skin. This research was concentrated in devising a method to determine accurately the radiation dose to these tissues and organs. The work was performed in several stages: First, a three dimensional (3D) treatment planning system used in radiation oncology was modified and complemented to make it usable with the low energies of x rays used in diagnostic radiology. Using the system for low energies required generation of energy deposition kernels using Monte Carlo methods. These kernels were generated using the EGS4 Monte Carlo system of codes and added to the treatment planning system. Following modification, the treatment planning system was evaluated for its accuracy of calculations in low energies within homogeneous and heterogeneous media. A study of the effects of lungs and bones on the dose distribution was also performed. The next step was the calculation of dose distributions in humanoid phantoms using this modified system. The system was used to calculate organ doses in these phantoms and the results were compared to those obtained from other methods. These dose distributions can subsequently be used to create dose-volume histograms (DVHs) for internal organs irradiated by these beams. Using this data and the concept of normal tissue complication probability (NTCP) developed for radiation oncology, the risk of future complications in a particular organ can be estimated.

niSWAP and NTCP gates realized in a circuit QED system

NASA Astrophysics Data System (ADS)

Essammouni, K.; Chouikh, A.; Said, T.; Bennai, M.

Based on superconducting qubit coupled to a resonator driven by a strong microwave field, we propose a method to implement two quantum logic gates (niSWAP and NTCP gates) of one qubit simultaneously controlling n qubits selected from N qubits in a circuit QED (1 < n < N) by introducing qubit-qubit interaction. The interaction between the qubits and the circuit QED can be achieved by tuning the gate voltage and the external flux. The operation times of the logic gates are much smaller than the decoherence time and dephasing time. Moreover, the numerical simulation under the influence of the gates operations shows that the scheme could be achieved efficiently with presently available techniques.

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liebl, Jakob, E-mail: jakob.liebl@medaustron.at; Francis H. Burr Proton Therapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Therapeutic Radiology and Oncology, Medical University of Graz, 8036 Graz

2014-09-15

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patientmore » positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R{sup 2} < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe.« less

SU-G-TeP3-11: Radiobiological-Cum-Dosimetric Quality Assurance of Complex Radiotherapy Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paudel, N; Narayanasamy, G; Zhang, X

2016-06-15

Purpose: Dosimetric gamma-analysis used for QA of complex radiotherapy plans tests the dosimetric equivalence of a delivered plan with the treatment planning system (TPS) optimized plan. It does not examine whether a dosimetric difference results in any radiobiological difference. This study introduces a method to test the radiobiological and dosimetric equivalence between a delivered and the TPS optimized plan. Methods: Six head and neck and seven lung cancer VMAT or IMRT plans optimized for patient treatment were calculated and delivered to an ArcCheck phantom. ArcCheck measured dose distributions were compared with the TPS calculated dose distributions using a 2-D gamma-analysis.more » Dose volume histograms (DVHs) for various patient structures were obtained by using measured data in 3DVH software and compared against the TPS calculated DVHs using 3-D gamma analysis. DVH data were used in the Poisson model to calculate tumor control probability (TCP) for the treatment targets and in the sigmoid dose response model to calculate normal tissue complication probability (NTCP) for the normal structures. Results: Two-D and three-D gamma passing rates among six H&N patient plans differed by 0 to 2.7% and among seven lung plans by 0.1 to 4.5%. Average ± SD TCPs based on measurement and TPS were 0.665±0.018 and 0.674±0.044 for H&N, and 0.791±0.027 and 0.733±0.031 for lung plans, respectively. Differences in NTCPs were usually negligible. The differences in dosimetric results, TCPs and NTCPs were insignificant. Conclusion: The 2-D and 3-D gamma-analysis based agreement between measured and planned dose distributions may indicate their dosimetric equivalence. Small and insignificant differences in TCPs and NTCPs based on measured and planned dose distributions indicate the radiobiological equivalence between the measured and optimized plans. However, patient plans showing larger differences between 2-D and 3-D gamma-analysis can help us make a more definite conclusion through our ongoing research with a larger number of patients.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, E; Yuan, F; Templeton, A

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on themore » targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.« less

SU-D-BRB-05: Quantum Learning for Knowledge-Based Response-Adaptive Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

El Naqa, I; Ten, R

Purpose: There is tremendous excitement in radiotherapy about applying data-driven methods to develop personalized clinical decisions for real-time response-based adaptation. However, classical statistical learning methods lack in terms of efficiency and ability to predict outcomes under conditions of uncertainty and incomplete information. Therefore, we are investigating physics-inspired machine learning approaches by utilizing quantum principles for developing a robust framework to dynamically adapt treatments to individual patient’s characteristics and optimize outcomes. Methods: We studied 88 liver SBRT patients with 35 on non-adaptive and 53 on adaptive protocols. Adaptation was based on liver function using a split-course of 3+2 fractions with amore » month break. The radiotherapy environment was modeled as a Markov decision process (MDP) of baseline and one month into treatment states. The patient environment was modeled by a 5-variable state represented by patient’s clinical and dosimetric covariates. For comparison of classical and quantum learning methods, decision-making to adapt at one month was considered. The MDP objective was defined by the complication-free tumor control (P{sup +}=TCPx(1-NTCP)). A simple regression model represented state-action mapping. Single bit in classical MDP and a qubit of 2-superimposed states in quantum MDP represented the decision actions. Classical decision selection was done using reinforcement Q-learning and quantum searching was performed using Grover’s algorithm, which applies uniform superposition over possible states and yields quadratic speed-up. Results: Classical/quantum MDPs suggested adaptation (probability amplitude ≥0.5) 79% of the time for splitcourses and 100% for continuous-courses. However, the classical MDP had an average adaptation probability of 0.5±0.22 while the quantum algorithm reached 0.76±0.28. In cases where adaptation failed, classical MDP yielded 0.31±0.26 average amplitude while the quantum approach averaged a more optimistic 0.57±0.4, but with high phase fluctuations. Conclusion: Our results demonstrate that quantum machine learning approaches provide a feasible and promising framework for real-time and sequential clinical decision-making in adaptive radiotherapy.« less

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

PubMed Central

Liebl, Jakob; Paganetti, Harald; Zhu, Mingyao; Winey, Brian A.

2014-01-01

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patient positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R2 < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe. PMID:25186386

Prostate volumetric‐modulated arc therapy: dosimetry and radiobiological model variation between the single‐arc and double‐arc technique

PubMed Central

Jiang, Runqing

2013-01-01

This study investigates the dosimetry and radiobiological model variation when a second photon arc was added to prostate volumetric‐modulated arc therapy (VMAT) using the single‐arc technique. Dosimetry and radiobiological model comparison between the single‐arc and double‐arc prostate VMAT plans were performed on five patients with prostate volumes ranging from 29−68.1 cm3. The prescription dose was 78 Gy/39 fractions and the photon beam energy was 6 MV. Dose‐volume histogram, mean and maximum dose of targets (planning and clinical target volume) and normal tissues (rectum, bladder and femoral heads), dose‐volume criteria in the treatment plan (D99% of PTV; D30%,D50%,V17Gy and V35Gy of rectum and bladder; D5% of femoral heads), and dose profiles along the vertical and horizontal axis crossing the isocenter were determined using the single‐arc and double‐arc VMAT technique. For comparison, the monitor unit based on the RapidArc delivery method, prostate tumor control probability (TCP), and rectal normal tissue complication probability (NTCP) based on the Lyman‐Burman‐Kutcher algorithm were calculated. It was found that though the double‐arc technique required almost double the treatment time than the single‐arc, the double‐arc plan provided a better rectal and bladder dose‐volume criteria by shifting the delivered dose in the patient from the anterior–posterior direction to the lateral. As the femoral head was less radiosensitive than the rectum and bladder, the double‐arc technique resulted in a prostate VMAT plan with better prostate coverage and rectal dose‐volume criteria compared to the single‐arc. The prostate TCP of the double‐arc plan was found slightly increased (0.16%) compared to the single‐arc. Therefore, when the rectal dose‐volume criteria are very difficult to achieve in a single‐arc prostate VMAT plan, it is worthwhile to consider the double‐arc technique. PACS number: 87.55.D‐, 87.55.dk, 87.55.K‐, 87.55.Qr

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

PubMed Central

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID:23635256

Online adaptation and verification of VMAT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crijns, Wouter, E-mail: wouter.crijns@uzleuven.be; Defraene, Gilles; Depuydt, Tom

2015-07-15

Purpose: This work presents a method for fast volumetric modulated arc therapy (VMAT) adaptation in response to interfraction anatomical variations. Additionally, plan parameters extracted from the adapted plans are used to verify the quality of these plans. The methods were tested as a prostate class solution and compared to replanning and to their current clinical practice. Methods: The proposed VMAT adaptation is an extension of their previous intensity modulated radiotherapy (IMRT) adaptation. It follows a direct (forward) planning approach: the multileaf collimator (MLC) apertures are corrected in the beam’s eye view (BEV) and the monitor units (MUs) are corrected usingmore » point dose calculations. All MLC and MU corrections are driven by the positions of four fiducial points only, without need for a full contour set. Quality assurance (QA) of the adapted plans is performed using plan parameters that can be calculated online and that have a relation to the delivered dose or the plan quality. Five potential parameters are studied for this purpose: the number of MU, the equivalent field size (EqFS), the modulation complexity score (MCS), and the components of the MCS: the aperture area variability (AAV) and the leaf sequence variability (LSV). The full adaptation and its separate steps were evaluated in simulation experiments involving a prostate phantom subjected to various interfraction transformations. The efficacy of the current VMAT adaptation was scored by target mean dose (CTV{sub mean}), conformity (CI{sub 95%}), tumor control probability (TCP), and normal tissue complication probability (NTCP). The impact of the adaptation on the plan parameters (QA) was assessed by comparison with prediction intervals (PI) derived from a statistical model of the typical variation of these parameters in a population of VMAT prostate plans (n = 63). These prediction intervals are the adaptation equivalent of the tolerance tables for couch shifts in the current clinical practice. Results: The proposed adaptation of a two-arc VMAT plan resulted in the intended CTV{sub mean} (Δ ≤ 3%) and TCP (ΔTCP ≤ 0.001). Moreover, the method assures the intended CI{sub 95%} (Δ ≤ 11%) resulting in lowered rectal NTCP for all cases. Compared to replanning, their adaptation is faster (13 s vs 10 min) and more intuitive. Compared to the current clinical practice, it has a better protection of the healthy tissue. Compared to IMRT, VMAT is more robust to anatomical variations, but it is also less sensitive to the different correction steps. The observed variations of the plan parameters in their database included a linear dependence on the date of treatment planning and on the target radius. The MCS is not retained as QA metric due to a contrasting behavior of its components (LSV and AAV). If three out of four plan parameters (MU, EqFS, AAV, and LSV) need to lie inside a 50% prediction interval (3/4—50%PI), all adapted plans will be accepted. In contrast, all replanned plans do not meet this loose criterion, mainly because they have no connection to the initially optimized and verified plan. Conclusions: A direct (forward) VMAT adaptation performs equally well as (inverse) replanning but is faster and can be extended to real-time adaptation. The prediction intervals for the machine parameters are equivalent to the tolerance tables for couch shifts in the current clinical practice. A 3/4—50%PI QA criterion accepts all the adapted plans but rejects all the replanned plans.« less

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

PubMed

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

2013-05-01

Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.

Single Vesicle Analysis of Endocytic Fission on Microtubules In Vitro

PubMed Central

Wolkoff, Allan W.

2016-01-01

Following endocytosis, internalized molecules are found within intracellular vesicles and tubules that move along the cytoskeleton and undergo fission, as demonstrated here using primary cultured rat hepatocytes. Although the use of depolymerizing drugs has shown that the cytoskeleton is not required to segregate endocytic protein, many studies suggest that the cytoskeleton is involved in the segregation of protein in normal cells. To investigate whether cytoskeletal-based movement results in the segregation of protein, we tracked the contents of vesicles during in vitro microscopy assays. These studies showed that the addition of ATP causes fission of endocytic contents along microtubules, resulting in the segregation of proteins that are targeted for different cellular compartments. The plasma membrane proteins, sodium (Na+) taurocholate cotransporting polypeptide (ntcp) and transferrin receptor, segregated from asialoorosomucoid (ASOR), an endocytic ligand that is targeted for degradation. Epidermal growth factor receptor, which is degraded, and the asialoglycoprotein receptor, which remains partially bound to ASOR, segregated less efficiently from ASOR. Vesicles containing ntcp and transferrin receptor had reduced fission in the absence of ASOR, suggesting that fission is regulated to allow proteins to segregate. A single round of fission resulted in 6.5-fold purification of ntcp from ASOR, and 25% of the resulting vesicles were completely depleted of the endocytic ligand. PMID:18284582

Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus

PubMed Central

Kaneko, Shun; Kakinuma, Sei; Asahina, Yasuhiro; Kamiya, Akihide; Miyoshi, Masato; Tsunoda, Tomoyuki; Nitta, Sayuri; Asano, Yu; Nagata, Hiroko; Otani, Satoshi; Kawai-Kitahata, Fukiko; Murakawa, Miyako; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin; Nakauchi, Hiromitsu; Nishitsuji, Hironori; Ujino, Saneyuki; Shimotohno, Kunitada; Iwamoto, Masashi; Watashi, Koichi; Wakita, Takaji; Watanabe, Mamoru

2016-01-01

Hepatitis B virus (HBV) is not eradicated by current antiviral therapies due to persistence of HBV covalently closed circular DNA (cccDNA) in host cells, and thus development of novel culture models for productive HBV infection is urgently needed, which will allow the study of HBV cccDNA eradication. To meet this need, we developed culture models of HBV infection using human induced pluripotent stem cell-derived hepatocyte lineages, including immature proliferating hepatic progenitor-like cell lines (iPS-HPCs) and differentiated hepatocyte-like cells (iPS-Heps). These cells were susceptible to HBV infection, produced HBV particles, and maintained innate immune responses. The infection efficiency of HBV in iPS-HPCs predominantly depended on the expression levels of sodium taurocholate cotransporting polypeptide (NTCP), and was low relative to iPS-Heps: however, long-term culture of iPS-Heps was difficult. To provide a model for HBV persistence, iPS-HPCs overexpressing NTCP were established. The long-term persistence of HBV cccDNA was detected in iPS-HPCs overexpressing NTCP, and depended on the inhibition of the Janus-kinase signaling pathway. In conclusion, this study provides evidence that iPS-derived hepatic cell lines can be utilized for novel HBV culture models with genetic variation to investigate the interactions between HBV and host cells and the development of anti-HBV strategies. PMID:27386799

Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via NTCP-dependent uptake of enveloped virus particles.

PubMed

Tu, Thomas; Budzinska, Magdalena A; Vondran, Florian W R; Shackel, Nicholas A; Urban, Stephan

2018-02-07

Chronic infection by the Hepatitis B Virus (HBV) is the major contributor to liver disease worldwide. Though HBV replicates via a nuclear episomal DNA (cccDNA), integration of HBV DNA into the host cell genome is regularly observed in the liver of infected patients. While reported as a pro-oncogenic alteration, the mechanism(s) and timing of HBV DNA integration are not well-understood, chiefly due to the lack of in vitro infection models that have detectable integration events. Here, we have established an in vitro system in which integration can be reliably detected following HBV infection. We measured HBV DNA integration using inverse nested PCR in primary human hepatocytes, HepaRG-NTCP, HepG2-NTCP, and Huh7-NTCP cells after HBV infection. Integration was detected in all cell types at a rate of >1 per 10000 cells, with the most consistent detection in Huh7-NTCP cells. Integration rate remained stable between 3 and 9 days post-infection. HBV DNA integration was efficiently blocked by treatment with 200nM of the HBV entry inhibitor Myrcludex B, but not with 10μM Tenofovir, 100U Interferon alpha, or 1μM of the capsid assembly inhibitor GLS4. This suggests integration of HBV DNA occurs immediately after infection of hepatocytes and is likely independent of de novo HBV replication in this model. Site analysis revealed that HBV DNA integrations were distributed over the entire human genome. Further, integrated HBV DNA sequences were consistent with double-stranded linear HBV DNA being the major precursor. Thus, we have established an in vitro system to interrogate the mechanisms of HBV DNA integration. Importance Hepatitis B Virus (HBV) is a common blood-borne pathogen and, following a chronic infection, can cause liver cancer and liver cirrhosis. Integration of HBV DNA into the host genome occurs in all known members of the hepadnaviridae family, despite this form not being necessary for viral replication. HBV DNA integration has been reported to drive liver cancer formation and persistence of virus infection. However, when and the mechanism(s) by which HBV DNA integration occurs is not clear. Here, we have developed and characterized an in vitro system to reliably detect HBV DNA integrations that result from a true HBV infection event and that closely resemble those found in patient tissues. Using this model, we show that integration already occurs when the infection is first established. Importantly, we provide here a system to analyze molecular factors involved in HBV integration, which can be used to develop strategies to halt its formation. Copyright © 2018 American Society for Microbiology.

Concentrating Solar Power Projects - Dadri ISCC Plant | Concentrating Solar

Science.gov Websites

Fresnel reflector Turbine Capacity: Gross: 14.0 MW Status: Under construction Start Year: 2017 Do you have , 2016 Start Production: September 2017 Participants Developer(s): Frenell Owner(s) (%): NTCP EPC

The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies.

PubMed

van Leeuwen, C M; Oei, A L; Crezee, J; Bel, A; Franken, N A P; Stalpers, L J A; Kok, H P

2018-05-16

Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinically, the LQ model is mainly used to estimate equivalent radiotherapy schedules (e.g. calculate the equivalent dose in 2 Gy fractions, EQD 2 ), but increasingly also to predict tumour control probability (TCP) and normal tissue complication probability (NTCP) using logistic models. The selection of accurate LQ parameters α, β and α/β is pivotal for a reliable estimate of radiation response. The aim of this review is to provide an overview of published values for the LQ parameters of human tumours as a guideline for radiation oncologists and radiation researchers to select appropriate radiobiological parameter values for LQ modelling in clinical radiotherapy. We performed a systematic literature search and found sixty-four clinical studies reporting α, β and α/β for tumours. Tumour site, histology, stage, number of patients, type of LQ model, radiation type, TCP model, clinical endpoint and radiobiological parameter estimates were extracted. Next, we stratified by tumour site and by tumour histology. Study heterogeneity was expressed by the I 2 statistic, i.e. the percentage of variance in reported values not explained by chance. A large heterogeneity in LQ parameters was found within and between studies (I 2  > 75%). For the same tumour site, differences in histology partially explain differences in the LQ parameters: epithelial tumours have higher α/β values than adenocarcinomas. For tumour sites with different histologies, such as in oesophageal cancer, the α/β estimates correlate well with histology. However, many other factors contribute to the study heterogeneity of LQ parameters, e.g. tumour stage, type of LQ model, TCP model and clinical endpoint (i.e. survival, tumour control and biochemical control). The value of LQ parameters for tumours as published in clinical radiotherapy studies depends on many clinical and methodological factors. Therefore, for clinical use of the LQ model, LQ parameters for tumour should be selected carefully, based on tumour site, histology and the applied LQ model. To account for uncertainties in LQ parameter estimates, exploring a range of values is recommended.

Total marrow irradiation using Helical TomoTherapy

NASA Astrophysics Data System (ADS)

Garcia-Fernandez, Lourdes Maria

Clinical dose response data of human tumours are limited or restricted to a radiation dose range determined by the level of toxicity to the normal tissues. This is the case for the most common disseminated plasma cell neoplasm, multiple myeloma, where the maximum dose deliverable to the entire bony skeleton using a standard total body irradiation (TBI) technique is limited to about 12 Gy. This study is part of scientific background of a phase I/II dose escalation clinical trial for multiple myeloma using image-guided intensity modulated radiotherapy (IG-IMRT) to deliver high dose to the entire volume of bone marrow with Helical TomoTherapy (HT). This relatively new technology can deliver highly conformal dose distributions to complex target shapes while reducing the dose to critical normal tissues. In this study tools for comparing and predicting the effectiveness of different approaches to total marrow irradiation (TMI) using HT were provided. The expected dose response for plasma cell neoplasms was computed and a radiobiological evaluation of different treatment cohorts in a dose escalating study was performed. Normal tissue complication probability (NTCP) and tumour control probability (TCP) models were applied to an actual TMI treatment plan for a patient and the implications of using different longitudinal field widths were assessed. The optimum dose was ˜39 Gy for which a predicted tumour control of 95% (+/-3%) was obtained, with a predicted 3% (0, 8%) occurrence of radiation pneumonitis. Tissue sparing was seen by using smaller field widths only in the organs of the head. This suggests it would be beneficial to use the small fields in the head only since using small fields for the whole treatment would lead to long treatment times. In TMI it may be necessary to junction two longitudinally adjacent treatment volumes to form a contiguous planning target volume PTV. For instance, this is the case when a different SUP-INF spatial resolution is required or when the PTV length exceeds the bed travel distance. In this work, the dosimetric challenges associated with junctioning longitudinally adjacent PTVs with HT were analyzed and the feasibility of PTV junctioning was demonstrated. The benefits of spatially dividing or splitting the treatment into a few sub-treatments along the longitudinal direction were also investigated.

Intensity Modulated Radiation Therapy Dose Painting for Localized Prostate Cancer Using {sup 11}C-choline Positron Emission Tomography Scans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Joe H.; University of Melbourne, Victoria; Lim Joon, Daryl

Purpose: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using {sup 11}C-choline positron emission tomography PET scans in patients with localized prostate cancer. Methods and Materials: This was an RT planning study of 8 patients with prostate cancer who had {sup 11}C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV{sub 60%} and SUV{sub 70%}). Three IMRT plans were generated for each patient: PLAN{sub 78}, which consisted of whole-prostate radiation therapy to 78more » Gy; PLAN{sub 78-90}, which consisted of whole-prostate RT to 78 Gy, a boost to the SUV{sub 60%} to 84 Gy, and a further boost to the SUV{sub 70%} to 90 Gy; and PLAN{sub 72-90}, which consisted of whole-prostate RT to 72 Gy, a boost to the SUV{sub 60%} to 84 Gy, and a further boost to the SUV{sub 70%} to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP{sub PET}) and on prostatectomy-defined volumes (TCP{sub path}), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. Results: All plans for all patients reached prescription doses while adhering to dose constraints. TCP{sub PET} values for PLAN{sub 78}, PLAN{sub 78-90}, and PLAN{sub 72-90} were 65%, 97%, and 96%, respectively. TCP{sub path} values were 71%, 97%, and 89%, respectively. Both PLAN{sub 78-90} and PLAN{sub 72-90} had significantly higher TCP{sub PET} (P=.002 and .001) and TCP{sub path} (P<.001 and .014) values than PLAN{sub 78}. PLAN{sub 78-90} and PLAN{sub 72-90} were not significantly different in terms of TCP{sub PET} or TCP{sub path}. There were no significant differences in rectal NTCPs between the 3 plans. Conclusions: IMRT dose painting for localized prostate cancer using {sup 11}C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs.« less

Effects of Trichostatin A on drug uptake transporters in primary rat hepatocyte cultures

PubMed Central

Ramboer, Eva; Rogiers, Vera; Vanhaecke, Tamara; Vinken, Mathieu

2015-01-01

The present study was set up to investigate the effects of Trichostatin A (TSA), a prototypical epigenetic modifier, on the expression and activity of hepatic drug uptake transporters in primary cultured rat hepatocytes. To this end, the expression of the sinusoidal transporters sodium-dependent taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 4 (Oatp4) was monitored by real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunoblotting. The activity of the uptake transporters was analyzed using radiolabeled substrates and chemical inhibitors. Downregulation of the expression and activity of Oatp4 and Ntcp was observed as a function of the cultivation time and could not be counteracted by TSA. In conclusion, the epigenetic modifier TSA does not seem to exert a positive effect on the expression and activity of the investigated uptake transporters in primary rat hepatocyte cultures. PMID:26648816

Atlas Based Segmentation and Mapping of Organs at Risk from Planning CT for the Development of Voxel-Wise Predictive Models of Toxicity in Prostate Radiotherapy

NASA Astrophysics Data System (ADS)

Acosta, Oscar; Dowling, Jason; Cazoulat, Guillaume; Simon, Antoine; Salvado, Olivier; de Crevoisier, Renaud; Haigron, Pascal

The prediction of toxicity is crucial to managing prostate cancer radiotherapy (RT). This prediction is classically organ wise and based on the dose volume histograms (DVH) computed during the planning step, and using for example the mathematical Lyman Normal Tissue Complication Probability (NTCP) model. However, these models lack spatial accuracy, do not take into account deformations and may be inappropiate to explain toxicity events related with the distribution of the delivered dose. Producing voxel wise statistical models of toxicity might help to explain the risks linked to the dose spatial distribution but is challenging due to the difficulties lying on the mapping of organs and dose in a common template. In this paper we investigate the use of atlas based methods to perform the non-rigid mapping and segmentation of the individuals' organs at risk (OAR) from CT scans. To build a labeled atlas, 19 CT scans were selected from a population of patients treated for prostate cancer by radiotherapy. The prostate and the OAR (Rectum, Bladder, Bones) were then manually delineated by an expert and constituted the training data. After a number of affine and non rigid registration iterations, an average image (template) representing the whole population was obtained. The amount of consensus between labels was used to generate probabilistic maps for each organ. We validated the accuracy of the approach by segmenting the organs using the training data in a leave one out scheme. The agreement between the volumes after deformable registration and the manually segmented organs was on average above 60% for the organs at risk. The proposed methodology provides a way to map the organs from a whole population on a single template and sets the stage to perform further voxel wise analysis. With this method new and accurate predictive models of toxicity will be built.

Do Intermediate Radiation Doses Contribute to Late Rectal Toxicity? An Analysis of Data From Radiation Therapy Oncology Group Protocol 94-06

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L., E-mail: sltucker@mdanderson.org; Dong, Lei; Michalski, Jeff M.

2012-10-01

Purpose: To investigate whether the volumes of rectum exposed to intermediate doses, from 30 to 50 Gy, contribute to the risk of Grade {>=}2 late rectal toxicity among patients with prostate cancer receiving radiotherapy. Methods and Materials: Data from 1009 patients treated on Radiation Therapy Oncology Group protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportionmore » of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5 to 85 Gy, and a multivariate Cox proportional hazards model was used to determine which of these parameters were significantly associated with time to Grade {>=}2 late rectal toxicity. Results: Doses <60 Gy had no detectable impact on the fit of the LKB model, as expected on the basis of the small estimate of the volume parameter (n = 0.077). Furthermore, there was no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox proportional hazards model selected V75 as the only value of VDose significantly associated with late rectal toxicity. Conclusions: There is no evidence from these data that intermediate doses influence the risk of Grade {>=}2 late rectal toxicity. Instead, the critical doses for this endpoint seem to be {>=}75 Gy. It is hypothesized that cases of Grade {>=}2 late rectal toxicity occurring among patients with V75 less than approximately 12% may be due to a 'background' level of risk, likely due mainly to biological factors.« less

SU-G-BRC-08: Evaluation of Dose Mass Histogram as a More Representative Dose Description Method Than Dose Volume Histogram in Lung Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, J; Eldib, A; Ma, C

2016-06-15

Purpose: Dose-volume-histogram (DVH) is widely used for plan evaluation in radiation treatment. The concept of dose-mass-histogram (DMH) is expected to provide a more representative description as it accounts for heterogeneity in tissue density. This study is intended to assess the difference between DVH and DMH for evaluating treatment planning quality. Methods: 12 lung cancer treatment plans were exported from the treatment planning system. DVHs for the planning target volume (PTV), the normal lung and other structures of interest were calculated. DMHs were calculated in a similar way as DVHs expect that the voxel density converted from the CT number wasmore » used in tallying the dose histogram bins. The equivalent uniform dose (EUD) was calculated based on voxel volume and mass, respectively. The normal tissue complication probability (NTCP) in relation to the EUD was calculated for the normal lung to provide quantitative comparison of DVHs and DMHs for evaluating the radiobiological effect. Results: Large differences were observed between DVHs and DMHs for lungs and PTVs. For PTVs with dense tumor cores, DMHs are higher than DVHs due to larger mass weighing in the high dose conformal core regions. For the normal lungs, DMHs can either be higher or lower than DVHs depending on the target location within the lung. When the target is close to the lower lung, DMHs show higher values than DVHs because the lower lung has higher density than the central portion or the upper lung. DMHs are lower than DVHs for targets in the upper lung. The calculated NTCPs showed a large range of difference between DVHs and DMHs. Conclusion: The heterogeneity of lung can be well considered using DMH for evaluating target coverage and normal lung pneumonitis. Further studies are warranted to quantify the benefits of DMH over DVH for plan quality evaluation.« less

A Biomechanical Model for Lung Fibrosis in Proton Beam Therapy

NASA Astrophysics Data System (ADS)

King, David J. S.

The physics of protons makes them well-suited to conformal radiotherapy due to the well-known Bragg peak effect. From a proton's inherent stopping power, uncertainty effects can cause a small amount of dose to overflow to an organ at risk (OAR). Previous models for calculating normal tissue complication probabilities (NTCPs) relied on the equivalent uniform dose model (EUD), in which the organ was split into 1/3, 2/3 or whole organ irradiation. However, the problem of dealing with volumes <1/3 of the total volume renders this EUD based approach no longer applicable. In this work the case for an experimental data-based replacement at low volumes is investigated. Lung fibrosis is investigated as an NTCP effect typically arising from dose overflow from tumour irradiation at the spinal base. Considering a 3D geometrical model of the lungs, irradiations are modelled with variable parameters of dose overflow. To calculate NTCPs without the EUD model, experimental data is used from the quantitative analysis of normal tissue effects in the clinic (QUANTEC) data. Additional side projects are also investigated, introduced and explained at various points. A typical radiotherapy course for the patient of 30x2Gy per fraction is simulated. A range of geometry of the target volume and irradiation types is investigated. Investigations with X-rays found the majority of the data point ratios (ratio of EUD values found from calculation based and data based methods) at 20% within unity showing a relatively close agreement. The ratios have not systematically preferred one particular type of predictive method. No Vx metric was found to consistently outperform another. In certain cases there is a good agreement and not in other cases which can be found predicted in the literature. The overall results leads to conclusion that there is no reason to discount the use of the data based predictive method particularly, as a low volume replacement predictive method.

Parotid gland mean dose as a xerostomia predictor in low-dose domains.

PubMed

Gabryś, Hubert Szymon; Buettner, Florian; Sterzing, Florian; Hauswald, Henrik; Bangert, Mark

2017-09-01

Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques. We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves. Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points. Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

In vitro inhibition of OATP-mediated uptake of phalloidin using bile acid derivatives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose

2009-08-15

Hepatocyte uptake of phalloidin is carried out mainly by OATP1B1. We have used this compound as a prototypic substrate and assayed the ability to inhibit OATP-mediated phalloidin transport of four bile acid derivatives (BALU-1, BALU-2, BALU-3 and BALU-4) that showed positive results in preliminary screening. Using Xenopus laevis oocytes for heterologous expression of transporters, BALUs were found to inhibit taurocholic acid (TCA) transport by OATP1B1 (but not OATP1B3) as well as by rat Oatp1a1, Oatp1a4 and Oatp1b2. The study of their ability to inhibit sodium-dependent bile acid transporters revealed that the four BALUs induced an inhibition of rat Asbt-mediated TCAmore » transport, which was similar to TCA-induced self-inhibition. Regarding human NTCP and rat Ntcp, BALU-1 differs from the other three BALUS in its lack of effect on TCA transport by these proteins. Using HPLC-MS/MS and CHO cells stably expressing OATP1B1 the ability of BALU-1 to inhibit the uptake of phalloidin itself by this transporter was confirmed. Kinetic analysis using X. laevis oocytes revealed that BALU-1-induced inhibition of OATP1B1 was mainly due to a competitive mechanism (Ki = 8 {mu}M). In conclusion, BALU-1 may be useful as a pharmacological tool to inhibit the uptake of compounds mainly taken up by OATP1B1 presumably without impairing bile acid uptake by the major carrier accounting for this process, i.e., NTCP.« less

Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes.

PubMed

Zhang, Zhenfeng; Filzmayer, Christina; Ni, Yi; Sültmann, Holger; Mutz, Pascal; Hiet, Marie-Sophie; Vondran, Florian W R; Bartenschlager, Ralf; Urban, Stephan

2018-07-01

Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2 NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5 NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2 NTCP and HepaRG NTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN-β/λ response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus replicative intermediates. An IFN-activated state did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses and therapeutic IFN treatment. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens

2013-05-15

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposedmore » lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.« less

The solute carrier family 10 (SLC10): beyond bile acid transport

PubMed Central

da Silva, Tatiana Claro; Polli, James E.; Swaan, Peter W.

2012-01-01

The solute carrier (SLC) family 10 (SLC10) comprises influx transporters of bile acids, steroidal hormones, various drugs, and several other substrates. Because the seminal transporters of this family, namely, sodium/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2), were primarily bile acid transporters, the term “sodium bile salt cotransporting family” was used for the SLC10 family. However, this notion became obsolete with the finding of other SLC10 members that do not transport bile acids. For example, the sodium-dependent organic anion transporter (SOAT; SLC10A6) transports primarily sulfated steroids. Moreover, NTCP was shown to also transport steroids and xenobiotics, including HMG-CoA inhibitors (statins). The SLC10 family contains four additional members, namely, P3 (SLC10A3; SLC10A3), P4 (SLC10A4; SLC10A4), P5 (SLC10A5; SLC10A5) and SLC10A7 (SLC10A7), several of which were unknown or considered hypothetical until approximately a decade ago. While their substrate specificity remains undetermined, great progress has been made towards their characterization in recent years. SLC10A4 may participate in vesicular storage or exocytosis of neurotransmitters or mastocyte mediators, whereas SLC10A5 and SLC10A7 may be involved in solute transport and SLC10A3 may have a role as a housekeeping protein. Finally, the newly found role of bile acids in glucose and energy homeostasis, via the TGR5 receptor, sheds new light on the clinical relevance of ASBT and NTCP. The present mini-review provides a brief summary of recent progress on members of the SLC10 family. PMID:23506869

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus

PubMed Central

Qi, Yonghe; Gao, Zhenchao; Peng, Bo; Yan, Huan; Tang, Dingbin; Song, Zilin; He, Wenhui; Sun, Yinyan; Guo, Ju-Tao; Li, Wenhui

2016-01-01

Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined. Here we conducted targeted genetic screening in combination with chemical inhibition to identify the cellular DNA polymerase(s) responsible for cccDNA formation, and exploited recombinant HBV with capsid coding deficiency which infects HepG2-NTCP cells with similar efficiency of wild-type HBV to assure cccDNA synthesis is exclusively from de novo HBV infection. We found that DNA polymerase κ (POLK), a Y-family DNA polymerase with maximum activity in non-dividing cells, substantially contributes to cccDNA formation during de novo HBV infection. Depleting gene expression of POLK in HepG2-NTCP cells by either siRNA knockdown or CRISPR/Cas9 knockout inhibited the conversion of rcDNA into cccDNA, while the diminished cccDNA formation in, and hence the viral infection of, the knockout cells could be effectively rescued by ectopic expression of POLK. These studies revealed that POLK is a crucial host factor required for cccDNA formation during a de novo HBV infection and suggest that POLK may be a potential target for developing antivirals against HBV. PMID:27783675

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus.

PubMed

Qi, Yonghe; Gao, Zhenchao; Xu, Guangwei; Peng, Bo; Liu, Chenxuan; Yan, Huan; Yao, Qiyan; Sun, Guoliang; Liu, Yang; Tang, Dingbin; Song, Zilin; He, Wenhui; Sun, Yinyan; Guo, Ju-Tao; Li, Wenhui

2016-10-01

Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined. Here we conducted targeted genetic screening in combination with chemical inhibition to identify the cellular DNA polymerase(s) responsible for cccDNA formation, and exploited recombinant HBV with capsid coding deficiency which infects HepG2-NTCP cells with similar efficiency of wild-type HBV to assure cccDNA synthesis is exclusively from de novo HBV infection. We found that DNA polymerase κ (POLK), a Y-family DNA polymerase with maximum activity in non-dividing cells, substantially contributes to cccDNA formation during de novo HBV infection. Depleting gene expression of POLK in HepG2-NTCP cells by either siRNA knockdown or CRISPR/Cas9 knockout inhibited the conversion of rcDNA into cccDNA, while the diminished cccDNA formation in, and hence the viral infection of, the knockout cells could be effectively rescued by ectopic expression of POLK. These studies revealed that POLK is a crucial host factor required for cccDNA formation during a de novo HBV infection and suggest that POLK may be a potential target for developing antivirals against HBV.

Paeoniflorin ameliorates cholestasis via regulating hepatic transporters and suppressing inflammation in ANIT-fed rats.

PubMed

Zhao, Yanling; He, Xuan; Ma, Xiao; Wen, Jianxia; Li, Pengyan; Wang, Jiabo; Li, Ruisheng; Zhu, Yun; Wei, Shizhang; Li, Haotian; Zhou, Xuelin; Li, Kun; Liu, Honghong; Xiao, Xiaohe

2017-05-01

Paeoniflorin has shown the obvious effect on cholestasis according to our previous research. However, its mechanism has not been absolutely explored yet. This study aims at evaluating the potential effect of paeoniflorin on alpha-naphthylisothiocyanate (ANIT) -induced cholestasis by inhibiting nuclear factor kappa-B (NF-κB) and simultaneously regulating hepatocyte transporters. Cholestasis was induced by administration of ANIT. The effect of paeoniflorin on serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GT), total bile acid (TBA) and histopathology of liver were determined. Liver protein levels of NF-κB, interleukin 1β (IL-1β) and the hepatocyte transporters such as Na + /taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2) and cholesterol 7α-hydroxylase (Cyp7a1) were investigated by western blotting. The results demonstrated that paeoniflorin could decrease serum ALT, AST, ALP, γ-GT, TBIL, DBIL and TBA in ANIT-treated rats. Histological examination revealed that rats treated with paeoniflorin represented fewer neutrophils infiltration, edema and necrosis in liver tissue compared with ANIT rats. Moreover, paeoniflorin significantly reduced the over expressions of NF-κB and IL-1β induced by ANIT in liver tissue. In addition, the relative protein expressions of NTCP, BSEP, MRP2 but not Cyp7a1 were also restored by paeoniflorin. The potential mechanism of paeoniflorin in alleviating ANIT-induced cholestasis seems to be related to reduce the over expressions of NF-κB and hepatocyte transporters such as NTCP, BSEP as well as MRP2. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effect of Cisplatin on Parotid Gland Function in Concomitant Radiochemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hey, Jeremias; Setz, Juergen; Gerlach, Reinhard

2009-12-01

Purpose: To determine the influence of concomitant radiochemotherapy with cisplatin on parotid gland tissue complication probability. Methods and Materials: Patients treated with either radiotherapy (n = 61) or concomitant radiochemotherapy with cisplatin (n = 36) for head-and-neck cancer were prospectively evaluated. The dose and volume distributions of the parotid glands were noted in dose-volume histograms. Stimulated salivary flow rates were measured before, during the 2nd and 6th weeks and at 4 weeks and 6 months after the treatment. The data were fit using the normal tissue complication probability model of Lyman. Complication was defined as a reduction of the salivarymore » flow rate to less than 25% of the pretreatment flow rate. Results: The normal tissue complication probability model parameter TD{sub 50} (the dose leading to a complication probability of 50%) was found to be 32.2 Gy at 4 weeks and 32.1 Gy at 6 months for concomitant radiochemotherapy and 41.1 Gy at 4 weeks and 39.6 Gy at 6 months for radiotherapy. The tolerated dose for concomitant radiochemotherapy was at least 7 to 8 Gy lower than for radiotherapy alone at TD{sub 50}. Conclusions: In this study, the concomitant radiochemotherapy tended to cause a higher probability of parotid gland tissue damage. Advanced radiotherapy planning approaches such as intensity-modulated radiotherapy may be partiticularly important for parotid sparing in radiochemotherapy because of cisplatin-related increased radiosensitivity of glands.« less

Effect of bladder filling on doses to prostate and organs at risk: a treatment planning study

PubMed Central

Liu, Mitchell; Kristensen, Sarah; Gelowitz, Gerald; Berthelet, Eric

2007-01-01

In the present study, we aimed to evaluate effects of bladder filling on dose–volume distributions for bladder, rectum, planning target volume (PTV), and prostate in radiation therapy of prostate cancer. Patients (n=21) were scanned with a full bladder, and after 1 hour, having been allowed to void, with an empty bladder. Radiotherapy plans were generated using a four‐field box technique and dose of 70 Gy in 35 fractions. First, plans obtained for full‐ and empty‐bladder scans were compared. Second, situations in which a patient was planned on full bladder but was treated on empty bladder, and vice versa, were simulated, assuming that patients were aligned to external tattoos. Doses to the prostate [equivalent uniform dose (EUD)], bladder and rectum [effective dose (Deff)], and normal tissue complication probability (NTCP) were compared. Dose to the small bowel was examined. Mean bladder volume was 354.3 cm3 when full and 118.2 cm3 when empty. Median prostate EUD was 70 Gy for plans based on full‐ and empty‐bladder scans alike. The median rectal Deff was 55.6 Gy for full‐bladder anatomy and 56.8 Gy for empty‐bladder anatomy, and the corresponding bladder Deff was 29.0 Gy and 49.3 Gy respectively. In 1 patient, part of the small bowel (7.5 cm3) received more than 50 Gy with full‐bladder anatomy, and in 6 patients, part (2.5 cm3−30 cm3) received more than 50 Gy with empty‐bladder anatomy. Bladder filling had no significant impact on prostate EUD or rectal Deff. A minimal volume of the small bowel received more than 50 Gy in both groups, which is below dose tolerance. The bladder Deff was higher with empty‐bladder anatomy; however, the predicted complication rates were clinically insignificant. When the multileaf collimator pattern was applied in reverse, substantial underdosing of the planning target volume (PTV) was observed, particularly for patients with prostate shifts in excess of 0.5 cm in any one direction. However, the prostate shifts showed no correlation with bladder filling, and therefore the PTV underdosing also cannot be related to bladder filling. For some patients, bladder dose–volume constraints were not fulfilled in the worst‐case scenario—that is, when a patient planned with full bladder consistently arrived for treatment with an empty bladder. PACS numbers: 87.53.‐j, 87.53.Kn, 87.53.Tf PMID:17592448

Comparison of dosimetric and radiobiological parameters on plans for prostate stereotactic body radiotherapy using an endorectal balloon for different dose-calculation algorithms and delivery-beam modes

NASA Astrophysics Data System (ADS)

Kang, Sang-Won; Suh, Tae-Suk; Chung, Jin-Beom; Eom, Keun-Yong; Song, Changhoon; Kim, In-Ah; Kim, Jae-Sung; Lee, Jeong-Woo; Cho, Woong

2017-02-01

The purpose of this study was to evaluate the impact of dosimetric and radiobiological parameters on treatment plans by using different dose-calculation algorithms and delivery-beam modes for prostate stereotactic body radiation therapy using an endorectal balloon. For 20 patients with prostate cancer, stereotactic body radiation therapy (SBRT) plans were generated by using a 10-MV photon beam with flattening filter (FF) and flattening-filter-free (FFF) modes. The total treatment dose prescribed was 42.7 Gy in 7 fractions to cover at least 95% of the planning target volume (PTV) with 95% of the prescribed dose. The dose computation was initially performed using an anisotropic analytical algorithm (AAA) in the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) and was then re-calculated using Acuros XB (AXB V. 11.0.34) with the same monitor units and multileaf collimator files. The dosimetric and the radiobiological parameters for the PTV and organs at risk (OARs) were analyzed from the dose-volume histogram. An obvious difference in dosimetric parameters between the AAA and the AXB plans was observed in the PTV and rectum. Doses to the PTV, excluding the maximum dose, were always higher in the AAA plans than in the AXB plans. However, doses to the other OARs were similar in both algorithm plans. In addition, no difference was observed in the dosimetric parameters for different delivery-beam modes when using the same algorithm to generate plans. As a result of the dosimetric parameters, the radiobiological parameters for the two algorithm plans presented an apparent difference in the PTV and the rectum. The average tumor control probability of the AAA plans was higher than that of the AXB plans. The average normal tissue complication probability (NTCP) to rectum was lower in the AXB plans than in the AAA plans. The AAA and the AXB plans yielded very similar NTCPs for the other OARs. In plans using the same algorithms, the NTCPs for delivery-beam modes showed no differences. This study demonstrated that the dosimetric and the radiobiological parameters for the PTV and the rectum affected the dose-calculation algorithms for prostate SBRT using an endorectal balloon. However, the dosimetric and the radiobiological parameters in the AAA and the AXB plans for other OARs were similar. Furthermore, difference between the dosimetric and the radiobiological parameters for different delivery-beam modes were not found when the same algorithm was used to generate the treatment plan.

Tailoring the operative approach for appendicitis to the patient: a prediction model from national surgical quality improvement program data.

PubMed

Senekjian, Lara; Nirula, Raminder

2013-01-01

Laparoscopic appendectomy (LA) is increasingly being performed in the United States, despite controversy about differences in infectious complication rates compared with open appendectomy (OA). Subpopulations exist in which infectious complication rates, both surgical site and organ space, differ with respect to LA compared with OA. All appendectomies in the National Surgical Quality Improvement Program database were analyzed with respect to surgical site infection (SSI) and organ space infection (OSI). Multivariate logistic regression analysis identified independent predictors of SSI or OSI. Probabilities of SSI or OSI were determined for subpopulations to identify when LA was superior to OA. From 2005 to 2009, there were 61,830 appendectomies performed (77.5% LA), of which 9,998 (16.2%) were complicated (58.7% LA). The risk of SSI was considerably lower for LA in both noncomplicated and complicated appendicitis. Across all ages, body mass index, renal function, and WBCs, LA was associated with a lower probability of SSI. The risk of OSI was considerably greater for LA in both noncomplicated and complicated appendicitis. In complicated appendicitis, OA was associated with a lower probability of OSI in patients with WBC >12 cells × 10(3)/μL. In noncomplicated appendicitis, OA was associated with a lower probability of OSI in patients with a body mass index <37.5 when compared with LA. Subpopulations exist in which OA is superior to LA in terms of OSI, however, SSI is consistently lower in LA patients. Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Radiotherapy of soft tissue sarcomas in dogs.

PubMed

McChesney, S L; Withrow, S J; Gillette, E L; Powers, B E; Dewhirst, M W

1989-01-01

Megavoltage radiotherapy was administered to 42 dogs with soft tissue sarcoma. Acceptable local control of these aggressive tumors was achieved after one year of treatment. Control rates of 48 and 67% were obtained at doses of 45 and 50 gray (Gy), respectively. At 2 years, control rates decreased to 33% at the dose of 50 Gy. Serious complications developed in 4 of 42 dogs at doses of 40 to 50 Gy. The estimated dose with a 50% probability for causing serious complications was 54 Gy, given in 10 fractions. We believe that the large doses per fraction used in this study probably led to an increased probability for necrosis. Hemangiopericytomas seemed to be more responsive than fibrosarcomas. Only 2 of 11 recurrent tumors were controlled with surgery. Good local control was achieved with radiation alone for one year at doses with a low probability for serious complications; however, higher total radiation doses or combined modalities, such as surgery and radiation or radiation and hyperthermia, may be needed for longer-term control.

Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs.

PubMed

Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Müller, Judith; Burckhardt, Gerhard; Hagos, Yohannes

2015-01-01

The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan. Copyright © 2014 Elsevier Ltd. All rights reserved.

Thyroid V30 Predicts Radiation-Induced Hypothyroidism in Patients Treated With Sequential Chemo-Radiotherapy for Hodgkin's Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cella, Laura; Department of Diagnostic Imaging and Radiation Oncology, Federico II University School of Medicine, Naples; Conson, Manuel

Purpose: Hypothyroidism (HT) is a frequent late side effect of Hodgkin's lymphoma (HL) therapy. The purpose of this study is to determine dose-volume constraints that correlate with functional impairment of the thyroid gland in HL patients treated with three-dimensional radiotherapy. Methods and Materials: A total of 61 consecutive patients undergoing antiblastic chemotherapy and involved field radiation treatment (median dose, 32 Gy; range, 30-36 Gy) for HL were retrospectively considered. Their median age was 28 years (range, 14-70 years). Blood levels of thyroid-stimulating hormone (TSH), free triiodo-thyronine (FT3), free thyroxine (FT4), and thyroglobulin antibody (ATG) were recorded basally and at differentmore » times after the end of therapy. For the thyroid gland, normal tissue complication probability (NTCP), dosimetric parameters, and the percentage of thyroid volume exceeding 10, 20, and 30 Gy (V10, V20, and V30) were calculated in all patients. To evaluate clinical and dosimetric factors possibly associated with HT, univariate and multivariate logistic regression analyses were performed. Results: Eight of 61 (13.1%) patients had HT before treatment and were excluded from further evaluation. At a median follow-up of 32 months (range, 6-99 months), 41.5% (22/53) of patients developed HT after treatment. Univariate analyses showed that all dosimetric factors were associated with HT (p < 0.05). On multivariate analysis, the thyroid V30 value was the single independent predictor associated with HT (p = 0.001). This parameter divided the patients into low- vs. high-risk groups: if V30 was {<=} 62.5%, the risk of developing HT was 11.5%, and if V30 was >62.5%, the risk was 70.8% (p < 0.0001). A Cox regression curve stratified by two levels of V30 value was created (odds ratio, 12.6). Conclusions: The thyroid V30 predicts the risk of developing HT after sequential chemo-radiotherapy and defines a useful constraint to consider for more accurate HL treatment planning.« less

TU-AB-BRA-01: Abdominal Synthetic CT Generation in Support of Liver SBRT Dose Calculation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bredfeldt, JS; Liu, L; Feng, M

2016-06-15

Purpose: To demonstrate and validate a technique for generating MRI-derived synthetic CT volumes (MRCTs) in support of adaptive liver SBRT. Methods: Under IRB approval, ten hepatocellular carcinoma patients were scanned using a single MR sequence (T1 Dixon-VIBE), yielding inherently-registered water, fat, and T1-weighted images. Air-containing voxels were identified by intensity thresholding. The envelope of the anterior vertebral bodies was segmented from the fat image by fitting a shape model to vertebral body candidate voxels, then using level sets to expand the contour outward. Fuzzy-C-Means (FCM) was then used to classify each non-air voxel in the image as fat, water, bone,more » or marrow. Bone and marrow only were classified within the vertebral body envelope. The MRCT was created by integrating the product of the FCM class probability with the assigned class density for each voxel. The resulting MRCTs were deformably aligned with planning CTs and 2-ARC SBRT VMAT plans were optimized on the MRCT density maps. Fluence was copied onto the CT density grids and dose recalculated. Results: The MRCTs faithfully reproduced most of the features visible in the corresponding CT image volumes, with exceptions of ribs and posterior spinous processes. The liver, vertebral bodies, kidneys, spleen and cord all had median HU differences of less than 75 between MRCT and CT images. PTV D99% values had an average 0.2% difference (standard deviation: 0.46%) between calculations on MRCT and CT density grids. The maximum difference in dose to 0.1cc of the PTV was 0.25% (std:0.49%). OAR dose differences were similarly small (mean:0.03Gy, std:0.26Gy). The largest normal tissue complication percentage (NTCP) difference was 1.48% (mean:0.06%, std:0.54%). Conclusions: MRCTs from a single abdominal imaging sequence are promising for use in SBRT dose calculation. Future work will focus on extending models to better define bones in the upper abdomen. Supported by NIHR01EB016079 and NIH1L30CA199594-01.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chau, Ricky; Teo, Peter; Kam, Michael

The aim of this study is to evaluate the deficiencies in target coverage and organ protection of 2-dimensional radiation therapy (2DRT) in the treatment of advanced T-stage (T3-4) nasopharyngeal carcinoma (NPC), and assess the extent of improvement that could be achieved with intensity modulated radiation therapy (IMRT), with special reference to of the dose to the planning organ-at-risk volume (PRV) of the brainstem and spinal cord. A dosimetric study was performed on 10 patients with advanced T-stage (T3-4 and N0-2) NPC. Computer tomography (CT) images of 2.5-mm slice thickness of the head and neck were acquired with the patient immobilizedmore » in semi-extended-head position. A 2D plan based on Ho's technique, and an IMRT plan based on a 7-coplanar portals arrangement, were established for each patient. 2DRT was planned with the field borders and shielding drawn on the simulator radiograph with reference to bony landmarks, digitized, and entered into a planning computer for reconstruction of the 3D dose distribution. The 2DRT and IMRT treatment plans were evaluated and compared with respect to the dose-volume histograms (DVHs) of the targets and the organs-at-risk (OARs), tumor control probability (TCP), and normal tissue complication probabilities (NTCPs). With IMRT, the dose coverage of the target was superior to that of 2DRT. The mean minimum dose of the GTV and PTV were increased from 33.7 Gy (2DRT) to 62.6 Gy (IMRT), and 11.9 Gy (2DRT) to 47.8 Gy (IMRT), respectively. The D{sub 95} of the GTV and PTV were also increased from 57.1 Gy (2DRT) to 67 Gy (IMRT), and 45 Gy (2DRT) to 63.6 Gy (IMRT), respectively. The TCP was substantially increased to 78.5% in IMRT. Better protection of the critical normal organs was also achieved with IMRT. The mean maximum dose delivered to the brainstem and spinal cord were reduced significantly from 61.8 Gy (2DRT) to 52.8 Gy (IMRT) and 56 Gy (2DRT) to 43.6 Gy (IMRT), respectively, which were within the conventional dose limits of 54 Gy for brainstem and of 45 Gy for spinal cord. The mean maximum doses deposited on the PRV of the brainstem and spinal cord were 60.7 Gy and 51.6 Gy respectively, which were above the conventional dose limits. For the chiasm, the mean dose maximum and the dose to 5% of its volume were reduced from 64.3 Gy (2DRT) to 53.7 Gy (IMRT) and from 62.8 Gy (2DRT) to 48.7 Gy (IMRT), respectively, and the corresponding NTCP was reduced from 18.4% to 2.1%. For the temporal lobes, the mean dose to 10% of its volume (about 4.6 cc) was reduced from 63.8 Gy (2DRT) to 55.4 Gy (IMRT) and the NTCP was decreased from 11.7% to 3.4%. The therapeutic ratio for T3-4 NPC tumors can be significantly improved with IMRT treatment technique due to improvement both in target coverage and the sparing of the critical normal organ. Although the maximum doses delivered to the brainstem and spinal cord in IMRT can be kept at or below their conventional dose limits, the maximum doses deposited on the PRV often exceed these limits due to the close proximity between the target and OARs. In other words, ideal dosimetric considerations cannot be fulfilled in IMRT planning for T3-4 NPC tumors. A compromise of the maximal dose limit to the PRV of the brainstem and spinal cord would need be accepted if dose coverage to the targets is not to be unacceptably compromised. Dosimetric comparison with 2DRT plans show that these dose limits to PRV were also frequently exceeded in 2DRT plans for locally advanced NPC. A dedicated retrospective study on the incidence of clinical injury to neurological organs in a large series of patients with T3-4 NPC treated by 2DRT may provide useful reference data in exploring how far the PRV dose constraints may be relaxed, to maximize the target coverage without compromising the normal organ function.« less

Survival analysis of cervical cancer using stratified Cox regression

NASA Astrophysics Data System (ADS)

Purnami, S. W.; Inayati, K. D.; Sari, N. W. Wulan; Chosuvivatwong, V.; Sriplung, H.

2016-04-01

Cervical cancer is one of the mostly widely cancer cause of the women death in the world including Indonesia. Most cervical cancer patients come to the hospital already in an advanced stadium. As a result, the treatment of cervical cancer becomes more difficult and even can increase the death's risk. One of parameter that can be used to assess successfully of treatment is the probability of survival. This study raises the issue of cervical cancer survival patients at Dr. Soetomo Hospital using stratified Cox regression based on six factors such as age, stadium, treatment initiation, companion disease, complication, and anemia. Stratified Cox model is used because there is one independent variable that does not satisfy the proportional hazards assumption that is stadium. The results of the stratified Cox model show that the complication variable is significant factor which influent survival probability of cervical cancer patient. The obtained hazard ratio is 7.35. It means that cervical cancer patient who has complication is at risk of dying 7.35 times greater than patient who did not has complication. While the adjusted survival curves showed that stadium IV had the lowest probability of survival.

WE-AB-207B-10: On Spinal Nerve Toxicity from Single-Session SAbR in Pigs and the Translation of Small Animal NTCP Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, B; Medin, P

Purpose: The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose-tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single-session irradiation to the pig spinal nerves exhibit a similar dose-tolerance as that of the spinal cord and that a dose-length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data. Methods: To date, 16 of 25 Yucatan minipigs have received single-session SAbR to a 1.5cm length and 4 ofmore » 25 have received irradiation to a 0.5cm length of left-sided C6-C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose-response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose-response data and to preliminary peripheral nerve response data was evaluated through residual analysis. Results: No rodent-derived dose-response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long-length irradiated spinal cord data well, with the more serial-like models fitting best. Preliminary data on the short-length irradiation suggests no length effect exists, disproving our hypothesis. Conclusion: Direct application of small-animal NTCP models to pig data suggests dose-length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low-to-mid dose levels in the penumbral region will improve this match. This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).« less

The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.

PubMed

Hu, Hui-Han; Liu, Jessica; Lin, Yu-Ling; Luo, Wun-Sheng; Chu, Yu-Ju; Chang, Chia-Lin; Jen, Chin-Lan; Lee, Mei-Hsuan; Lu, Sheng-Nan; Wang, Li-Yu; You, San-Lin; Yang, Hwai-I; Chen, Chien-Jen

2016-09-01

The sodium taurocholate co-transporting polypeptide (NTCP), encoded by SLC10A1, was recently identified as a receptor for HBV. We assessed the association of the p.Ser267Phe variant (rs2296651) with chronic hepatitis B (CHB) serostatus, cirrhosis and hepatocellular carcinoma (HCC) in patients with CHB. The variant was genotyped in 3801 patients with CHB and 3801 matched hepatitis B surface antigen (HBsAg) seronegative individuals. ORs with 95% CIs for the variant's association with CHB, cirrhosis and HCC were estimated using logistic regression. In patients with CHB, the S267F variant was observed in 515 (18.5%) controls, 40 (17.2%) cirrhosis only cases, 49 (13.2%) non-cirrhotic HCC cases, and 52 (12.7%) cirrhotic-HCC cases. After adjustment for known risk factors, S267F was significantly associated with decreased risk for cirrhosis (OR 0.65 (95% CI 0.49 to 0.86), p=0.002) and HCC (OR 0.55 (95% CI 0.42 to 0.72), p<0.001). This association persisted for non-cirrhotic and cirrhotic-HCC. Compared with patients with HBV DNA levels greater than 10(5) copies/mL who carried the GG genotype, patients who had undetectable HBV DNA and the GA or AA genotypes had a 25-fold decreased risk of developing HCC (OR 0.04 (95% CI 0.02 to 0.11), p<0.001). The AA genotype was also associated with HBsAg seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p<0.001). The SLC10A1 (NTCP) S267F variant is independently associated with decreased risk of cirrhosis and HCC, and resistance to CHB infection. Together with serum HBV DNA levels, S267F may help to identify patients with CHB with very low risk of HCC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

SU-E-T-549: Modeling Relative Biological Effectiveness of Protons for Radiation Induced Brain Necrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirkovic, D; Peeler, C; Grosshans, D

Purpose: To develop a model of the relative biological effectiveness (RBE) of protons as a function of dose and linear energy transfer (LET) for induction of brain necrosis using clinical data. Methods: In this study, treatment planning information was exported from a clinical treatment planning system (TPS) and used to construct a detailed Monte Carlo model of the patient and the beam delivery system. The physical proton dose and LET were computed in each voxel of the patient volume using Monte Carlo particle transport. A follow-up magnetic resonance imaging (MRI) study registered to the treatment planning CT was used tomore » determine the region of the necrosis in the brain volume. Both, the whole brain and the necrosis volumes were segmented from the computed tomography (CT) dataset using the contours drawn by a physician and the corresponding voxels were binned with respect to dose and LET. The brain necrosis probability was computed as a function of dose and LET by dividing the total volume of all necrosis voxels with a given dose and LET with the corresponding total brain volume resulting in a set of NTCP-like curves (probability as a function of dose parameterized by LET). Results: The resulting model shows dependence on both dose and LET indicating the weakness of the constant RBE model for describing the brain toxicity. To the best of our knowledge the constant RBE model is currently used in all clinical applications which may Result in increased rate of brain toxicities in patients treated with protons. Conclusion: Further studies are needed to develop more accurate brain toxicity models for patients treated with protons and other heavy ions.« less

Dosimetric treatment course simulation based on a statistical model of deformable organ motion

NASA Astrophysics Data System (ADS)

Söhn, M.; Sobotta, B.; Alber, M.

2012-06-01

We present a method of modeling dosimetric consequences of organ deformation and correlated motion of adjacent organ structures in radiotherapy. Based on a few organ geometry samples and the respective deformation fields as determined by deformable registration, principal component analysis (PCA) is used to create a low-dimensional parametric statistical organ deformation model (Söhn et al 2005 Phys. Med. Biol. 50 5893-908). PCA determines the most important geometric variability in terms of eigenmodes, which represent 3D vector fields of correlated organ deformations around the mean geometry. Weighted sums of a few dominating eigenmodes can be used to simulate synthetic geometries, which are statistically meaningful inter- and extrapolations of the input geometries, and predict their probability of occurrence. We present the use of PCA as a versatile treatment simulation tool, which allows comprehensive dosimetric assessment of the detrimental effects that deformable geometric uncertainties can have on a planned dose distribution. For this, a set of random synthetic geometries is generated by a PCA model for each simulated treatment course, and the dose of a given treatment plan is accumulated in the moving tissue elements via dose warping. This enables the calculation of average voxel doses, local dose variability, dose-volume histogram uncertainties, marginal as well as joint probability distributions of organ equivalent uniform doses and thus of TCP and NTCP, and other dosimetric and biologic endpoints. The method is applied to the example of deformable motion of prostate/bladder/rectum in prostate IMRT. Applications include dosimetric assessment of the adequacy of margin recipes, adaptation schemes, etc, as well as prospective ‘virtual’ evaluation of the possible benefits of new radiotherapy schemes.

Dosimetric treatment course simulation based on a statistical model of deformable organ motion.

PubMed

Söhn, M; Sobotta, B; Alber, M

2012-06-21

We present a method of modeling dosimetric consequences of organ deformation and correlated motion of adjacent organ structures in radiotherapy. Based on a few organ geometry samples and the respective deformation fields as determined by deformable registration, principal component analysis (PCA) is used to create a low-dimensional parametric statistical organ deformation model (Söhn et al 2005 Phys. Med. Biol. 50 5893-908). PCA determines the most important geometric variability in terms of eigenmodes, which represent 3D vector fields of correlated organ deformations around the mean geometry. Weighted sums of a few dominating eigenmodes can be used to simulate synthetic geometries, which are statistically meaningful inter- and extrapolations of the input geometries, and predict their probability of occurrence. We present the use of PCA as a versatile treatment simulation tool, which allows comprehensive dosimetric assessment of the detrimental effects that deformable geometric uncertainties can have on a planned dose distribution. For this, a set of random synthetic geometries is generated by a PCA model for each simulated treatment course, and the dose of a given treatment plan is accumulated in the moving tissue elements via dose warping. This enables the calculation of average voxel doses, local dose variability, dose-volume histogram uncertainties, marginal as well as joint probability distributions of organ equivalent uniform doses and thus of TCP and NTCP, and other dosimetric and biologic endpoints. The method is applied to the example of deformable motion of prostate/bladder/rectum in prostate IMRT. Applications include dosimetric assessment of the adequacy of margin recipes, adaptation schemes, etc, as well as prospective 'virtual' evaluation of the possible benefits of new radiotherapy schemes.

Deep reinforcement learning for automated radiation adaptation in lung cancer.

PubMed

Tseng, Huan-Hsin; Luo, Yi; Cui, Sunan; Chien, Jen-Tzung; Ten Haken, Randall K; Naqa, Issam El

2017-12-01

To investigate deep reinforcement learning (DRL) based on historical treatment plans for developing automated radiation adaptation protocols for nonsmall cell lung cancer (NSCLC) patients that aim to maximize tumor local control at reduced rates of radiation pneumonitis grade 2 (RP2). In a retrospective population of 114 NSCLC patients who received radiotherapy, a three-component neural networks framework was developed for deep reinforcement learning (DRL) of dose fractionation adaptation. Large-scale patient characteristics included clinical, genetic, and imaging radiomics features in addition to tumor and lung dosimetric variables. First, a generative adversarial network (GAN) was employed to learn patient population characteristics necessary for DRL training from a relatively limited sample size. Second, a radiotherapy artificial environment (RAE) was reconstructed by a deep neural network (DNN) utilizing both original and synthetic data (by GAN) to estimate the transition probabilities for adaptation of personalized radiotherapy patients' treatment courses. Third, a deep Q-network (DQN) was applied to the RAE for choosing the optimal dose in a response-adapted treatment setting. This multicomponent reinforcement learning approach was benchmarked against real clinical decisions that were applied in an adaptive dose escalation clinical protocol. In which, 34 patients were treated based on avid PET signal in the tumor and constrained by a 17.2% normal tissue complication probability (NTCP) limit for RP2. The uncomplicated cure probability (P+) was used as a baseline reward function in the DRL. Taking our adaptive dose escalation protocol as a blueprint for the proposed DRL (GAN + RAE + DQN) architecture, we obtained an automated dose adaptation estimate for use at ∼2/3 of the way into the radiotherapy treatment course. By letting the DQN component freely control the estimated adaptive dose per fraction (ranging from 1-5 Gy), the DRL automatically favored dose escalation/de-escalation between 1.5 and 3.8 Gy, a range similar to that used in the clinical protocol. The same DQN yielded two patterns of dose escalation for the 34 test patients, but with different reward variants. First, using the baseline P+ reward function, individual adaptive fraction doses of the DQN had similar tendencies to the clinical data with an RMSE = 0.76 Gy; but adaptations suggested by the DQN were generally lower in magnitude (less aggressive). Second, by adjusting the P+ reward function with higher emphasis on mitigating local failure, better matching of doses between the DQN and the clinical protocol was achieved with an RMSE = 0.5 Gy. Moreover, the decisions selected by the DQN seemed to have better concordance with patients eventual outcomes. In comparison, the traditional temporal difference (TD) algorithm for reinforcement learning yielded an RMSE = 3.3 Gy due to numerical instabilities and lack of sufficient learning. We demonstrated that automated dose adaptation by DRL is a feasible and a promising approach for achieving similar results to those chosen by clinicians. The process may require customization of the reward function if individual cases were to be considered. However, development of this framework into a fully credible autonomous system for clinical decision support would require further validation on larger multi-institutional datasets. © 2017 American Association of Physicists in Medicine.

Ventricular Catheter Systems with Subcutaneous Reservoirs (Ommaya Reservoirs) in Pediatric Patients with Brain Tumors: Infections and Other Complications.

PubMed

Gerber, Nicolas U; Müller, Anna; Bellut, David; Bozinov, Oliver; Berger, Christoph; Grotzer, Michael A

2015-12-01

This study aims to describe complications related to ventricular catheter systems with subcutaneous reservoirs (VCSR) (such as Ommaya reservoirs) in pediatric patients with brain tumors. Retrospective analysis of consecutive patients with a total of 31 VCSR treated at the Children's University Hospital of Zurich, Switzerland. A total of 20 patients with a median age of 3.3 years at VCSR implantation received 31 VCSR. Overall, 19 complications in 11 patients were recorded: 7 patients had a VCSR-related infection with coagulase-negative staphylococci, 4 of these probably as a surgical complication and 3 probably related to VCSR use. Systemic perioperative prophylaxis was administered in 22 cases, and intraventricular vancomycin and gentamicin were given in 8 cases (none of which subsequently developed an infection). Other complications included wound dehiscence, catheter malplacement, and leakage of cerebrospinal fluid. Overall, 17 VCSR were explanted due to complications. Infections were the most frequent VCSR-related complication. In our own institution, the high rate of complications led to the definition of a bundle of measures as a standard operating procedure for VCSR placement and use. Prospective studies in larger patient collectives are warranted to better identify risk factors and evaluate preventive measures such as the administration of perioperative antibiotics and the use of antimicrobial coating of catheters. Georg Thieme Verlag KG Stuttgart · New York.

Cost-effectiveness of cervical spine clearance interventions with litigation and long-term-care implications in obtunded adult patients following blunt injury.

PubMed

Ertel, Audrey E; Robinson, Bryce R H; Eckman, Mark H

2016-11-01

Recent guidelines from the Eastern Association for the Surgery of Trauma conditionally recommend cervical collar removal after a negative cervical computed tomography in obtunded adult blunt trauma patients. Although the rates of missed injury are extremely low, the impact of chronic care costs and litigation upon decision making remains unclear. We hypothesize that the cost-effectiveness of strategies that include additional imaging may contradict current guidelines. A cost-effectiveness analysis was performed for a base-case 40-year-old, obtunded man with a negative computed tomography. Strategies compared included adjunct imaging with cervical magnetic resonance imaging (MRI), collar maintenance for 6 weeks, or removal. Data on the probability for long-term collar complications, spine injury, imaging costs, complications associated with MRI, acute and chronic care, and litigation were obtained from published and Medicare data. Outcomes were expressed as 2014 US dollars and quality-adjusted life-years. Collar removal was more effective and less costly than collar use or MRI (19.99 vs. 19.35 vs. 18.70 quality-adjusted life-years; $675,359 vs. $685,546 vs. $685,848) in the base-case analysis. When the probability of missed cervical injury was greater than 0.04 adjunct imaging with MRI dominated, however, collar removal remained cost-effective until the probability of missed injury exceeded 0.113 at which point collar removal exceeded the $50,000 threshold. Collar removal remained the most cost-effective approach until the probability of complications from collar use was reduced to less than 0.009, at which point collar maintenance became the most cost-effective strategy. Early collar removal dominates all strategies until the risk of complications from MRI positioning is reduced to 0.03 and remained cost-effective even when the probability of complication was reduced to 0. Early collar removal in obtunded adult blunt trauma patients appears to be the most effective and least costly strategy for cervical clearance based on the current literature available. Economic evaluation, level III; therapeutic study, level IV.

Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.

PubMed

Zhu, He; Long, Min-Hui; Wu, Jie; Wang, Meng-Meng; Li, Xiu-Yang; Shen, Hong; Xu, Jin-Di; Zhou, Li; Fang, Zhi-Jun; Luo, Yi; Li, Song-Lin

2015-12-02

Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.

The relationship between diabetes, diabetes-related complications and productive activities among older Europeans.

PubMed

Rodriguez-Sanchez, B; Alessie, R J M; Feenstra, T L; Angelini, V

2018-06-01

To assess the impact of diabetes and diabetes-related complications on two measures of productivity for people in the labour force and out of it, namely "being afraid health limits ability to work before retirement" and "volunteering". Logistic regressions were run to test the impact of diabetes and its complications on the probability of being afraid health limits work and being a formal volunteer. The longitudinal sample for the former outcome includes 53,631 observations, clustered in 34,393 individuals, aged 50-65 years old whereas the latter consists of 45,384 observations, grouped in 29,104 individuals aged 65 and above across twelve European countries taken from the Survey of Health, Ageing and Retirement in Europe, from 2006 to 2013. Diabetes increased the probability of being afraid health limited work by nearly 11% points, adjusted by clinical complications, and reduced the likelihood of being a formal volunteer by 2.7% points, additionally adjusted by mobility problems. We also found that both the probability of being afraid health limits work and the probability of being a formal volunteer increased during and after the crisis. Moreover, having diabetes had a larger effect on being afraid health limits work during the year 2010, possibly related to the financial crisis. Our findings show that diabetes significantly affects the perception of people regarding the effects of their condition on work, increasing the fear that health limits their ability to work, especially during the crisis year 2010, as well as the participation in volunteering work among retired people.

SU-E-T-589: Optimization of Patient Head Angle Position to Spare Hippocampus During the Brain Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheon, G; Kang, Y; Kang, S

Purpose: Hippocampus is one of the important organs which controls emotions, behaviors, movements the memorizing and learning ability. In the conventional head & neck therapy position, it is difficult to perform the hippocampal-sparing brain radiation therapy. The purpose of this study is to investigate optimal head angle which can save the hippocampal-sparing and organ at risk (OAR) in conformal radiation therapy (CRT), Intensity modulation radiation therapy (IMRT) and helical tomotherapy (HT). Methods: Three types of radiation treatment plans, CRT, IMRT and Tomotherapy plans, were performed for 10 brain tumor patients. The image fusion between CT and MRI data were usedmore » in the contour due to the limited delineation of the target and OAR in the CT scan. The optimal condition plan was determined by comparing the dosimetric performance of the each plan with the use of various parameters which include three different techniques (CRT, IMRT, HT) and 4 angle (0, 15, 30, 40 degree). The each treatment plans of three different techniques were compared with the following parameters: conformity index (CI), homogeneity index (HI), target coverage, dose in the OARs, monitor units (MU), beam on time and the normal tissue complication probability (NTCP). Results: HI, CI and target coverage was most excellent in head angle 30 degree among all angle. When compared by modality, target coverage and CI showed good results in IMRT and TOMO than compared to the CRT. HI at the head angle 0 degrees is 1.137±0.17 (CRT), 1.085±0.09 (IMRT) and 1.077±0.06 (HT). HI at the head angle 30 degrees is 1.056±0.08 (CRT), 1.020±0.05 (IMRT) and 1.022±0.07 (HT). Conclusion: The results of our study show that when head angle tilted at 30 degree, target coverage, HI, CI were improved, and the dose delivered to OAR was reduced compared with conventional supine position in brain radiation therapy. This work was supported by the Radiation Technology R&D program (No. 2013M2A2A7043498) and the Mid-career Researcher Program (2014R1A2A1A10050270) through the National Research Foundation of Korea funded by the Ministry of Science, ICT&Future Planning.« less

Distributed Immune Systems for Wireless Network Information Assurance

DTIC Science & Technology

2010-04-26

ratio test (SPRT), where the goal is to optimize a hypothesis testing problem given a trade-off between the probability of errors and the...using cumulative sum (CUSUM) and Girshik-Rubin-Shiryaev (GRSh) statistics. In sequential versions of the problem the sequential probability ratio ...the more complicated problems, in particular those where no clear mean can be established. We developed algorithms based on the sequential probability

Food, mechanic and septic complications in patients enterally nutritioned in home conditions.

PubMed

Kalita, Monika; Majewska, Krystyna; Gradowska, Aleksandra; Karwowska, Katarzyna; Ławiński, Michał

2015-02-03

Home enteral nutrition (HEN for short) allows practically normal living for patients who cannot be fed orally but at the same time do not have to stay in hospitals, which is often found to decrease their mental condition, increase of probability of complications and costs of medical treatment. The aim of the study was to analyze the frequency of nutritional, mechanical and septic complications in patients fed enterally in home conditions. The study performed using retrospective analysis of study results and reports from control visits for patients in the period between 2012-2013. 147 patients fed enterally using HEN method participated in the study, including 70 men and 77 women aged 19 to 99 years (average 65 years). The following type of gastrointestinal tract access was used for patients: PEG in 113 (76.5%), feeding jejunostomy - 21 (1.4%), PEG-PEJ - 5 (3.5%), in case of the remaining 8 patients the nasogastric gavage (5.5%) was used. The most common complication were infections (of gastric tract, skin soft tissue in the region of nutritional fistula entry, in three cases the aspiration pneumonia was diagnosed) found in 55 (49.1%) of cases. Mechanical complications were found out in 29 (25.9% of all complications), nutritional complications were present 28 times, which constituted 25% of all complications. In the studied group of patients with an implemented HEN procedure, septic complications were the most common problem. The longest average nutrition time with PEG-PEJ probably results from the effective protection of the patient against aspiration pneumonia.

Prediction of major complications after hepatectomy using liver stiffness values determined by magnetic resonance elastography.

PubMed

Sato, N; Kenjo, A; Kimura, T; Okada, R; Ishigame, T; Kofunato, Y; Shimura, T; Abe, K; Ohira, H; Marubashi, S

2018-04-23

Liver fibrosis is a risk factor for hepatectomy but cannot be determined accurately before hepatectomy because diagnostic procedures are too invasive. Magnetic resonance elastography (MRE) can determine liver stiffness (LS), a surrogate marker for assessing liver fibrosis, non-invasively. The aim of this study was to investigate whether the LS value determined by MRE is predictive of major complications after hepatectomy. This prospective study enrolled consecutive patients who underwent hepatic resection between April 2013 and August 2016. LS values were measured by imaging shear waves by MRE in the liver before hepatectomy. The primary endpoint was major complications, defined as Clavien-Dindo grade IIIa or above. Logistic regression analysis identified independent predictive factors, from which a logistic model to estimate the probability of major complications was constructed. A total of 96 patients were included in the study. Major complications were observed in 15 patients (16 per cent). Multivariable logistic analysis confirmed that higher LS value (P = 0·021) and serum albumin level (P = 0·009) were independent predictive factors for major complications after hepatectomy. Receiver operating characteristic (ROC) analysis showed that the best LS cut-off value was 4·3 kPa for detecting major complications, comparable to liver fibrosis grade F4, with a sensitivity of 80 per cent and specificity of 82 per cent. A logistic model using the LS value and serum albumin level to estimate the probability of major complications was constructed; the area under the ROC curve for predicting major complications was 0·84. The LS value determined by MRE in patients undergoing hepatectomy was an independent predictive factor for major complications. © 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.

WE-D-BRE-02: BEST IN PHYSICS (THERAPY) - Radiogenomic Modeling of Normal Tissue Toxicities in Prostate Cancer Patients Receiving Hypofractionated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coates, J; Jeyaseelan, K; Ybarra, N

2014-06-15

Purpose: It has been realized that inter-patient radiation sensitivity variability is a multifactorial process involving dosimetric, clinical, and genetic factors. Therefore, we explore a new framework to integrate physical, clinical, and biological data denoted as radiogenomic modeling. In demonstrating the feasibility of this work, we investigate the association of genetic variants (copy number variations [CNVs] and single nucleotide polymorphisms [SNPs]) with radiation induced rectal bleeding (RB) and erectile dysfunction (ED) while taking into account dosimetric and clinical variables in prostate cancer patients treated with curative irradiation. Methods: A cohort of 62 prostate cancer patients who underwent hypofractionated radiotherapy (66 Gymore » in 22 fractions) was retrospectively genotyped for CNV and SNP rs25489 in the xrcc1 DNA repair gene. Dosevolume metrics were extracted from treatment plans of 54 patients who had complete dosimetric profiles. Treatment outcomes were considered to be a Result of functional mapping of radiogenomic input variables according to a logit transformation. Model orders were estimated using resampling by leave-one out cross-validation (LOO-CV). Radiogenomic model performance was evaluated using area under the ROC curve (AUC) and LOO-CV. For continuous univariate dosimetric and clinical variables, Spearmans rank coefficients were calculated and p-values reported accordingly. In the case of binary variables, Chi-squared statistics and contingency table calculations were used. Results: Ten patients were found to have three copies of xrcc1 CNV (RB: χ2=14.6 [p<0.001] and ED: χ2=4.88[p=0.0272]) and twelve had heterozygous rs25489 SNP (RB: χ2=0.278[p=0.599] and ED: χ2=0.112[p=0.732]). LOO-CV identified penile bulb D60 as the only significant QUANTEC predictor (rs=0.312 [p=0.0145]) for ED. Radiogenomic modeling yielded statistically significant, cross-validated NTCP models for RB (rs=0.243[p=0.0443], AUC=0.665) and ED (rs=0.276[p=0.0217], AUC=0.754). Conclusion: The radiogenomic modeling approach presented herein has been shown to identify NTCP models which have increased predictive power. Furthermore, CNVs appears to be useful genetic variants when added to dosimetric NTCP models. This work was partially supported by CIHR grant MOP-114910.« less

SU-E-T-466: Implementation of An Extension Module for Dose Response Models in the TOPAS Monte Carlo Toolkit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramos-Mendez, J; Faddegon, B; Perl, J

2015-06-15

Purpose: To develop and verify an extension to TOPAS for calculation of dose response models (TCP/NTCP). TOPAS wraps and extends Geant4. Methods: The TOPAS DICOM interface was extended to include structure contours, for subsequent calculation of DVH’s and TCP/NTCP. The following dose response models were implemented: Lyman-Kutcher-Burman (LKB), critical element (CE), population based critical volume (CV), parallel-serials, a sigmoid-based model of Niemierko for NTCP and TCP, and a Poisson-based model for TCP. For verification, results for the parallel-serial and Poisson models, with 6 MV x-ray dose distributions calculated with TOPAS and Pinnacle v9.2, were compared to data from the benchmarkmore » configuration of the AAPM Task Group 166 (TG166). We provide a benchmark configuration suitable for proton therapy along with results for the implementation of the Niemierko, CV and CE models. Results: The maximum difference in DVH calculated with Pinnacle and TOPAS was 2%. Differences between TG166 data and Monte Carlo calculations of up to 4.2%±6.1% were found for the parallel-serial model and up to 1.0%±0.7% for the Poisson model (including the uncertainty due to lack of knowledge of the point spacing in TG166). For CE, CV and Niemierko models, the discrepancies between the Pinnacle and TOPAS results are 74.5%, 34.8% and 52.1% when using 29.7 cGy point spacing, the differences being highly sensitive to dose spacing. On the other hand, with our proposed benchmark configuration, the largest differences were 12.05%±0.38%, 3.74%±1.6%, 1.57%±4.9% and 1.97%±4.6% for the CE, CV, Niemierko and LKB models, respectively. Conclusion: Several dose response models were successfully implemented with the extension module. Reference data was calculated for future benchmarking. Dose response calculated for the different models varied much more widely for the TG166 benchmark than for the proposed benchmark, which had much lower sensitivity to the choice of DVH dose points. This work was supported by National Cancer Institute Grant R01CA140735.« less

DVH- and NTCP-based dosimetric comparison of different longitudinal margins for VMAT-IMRT of esophageal cancer.

PubMed

Münch, S; Oechsner, M; Combs, S E; Habermehl, D

2017-08-15

To cover the microscopic tumor spread in squamous cell carcinoma of the esophagus (SCC), longitudinal margins of 3-4 cm are used for radiotherapy (RT) protocols. However, smaller margins of 2-3 cm might be reasonable when advanced diagnostic imaging is integrated into target volume delineation. Purpose of this study was to compare the dose distribution and deposition to the organs at risk (OAR) for different longitudinal margins using a DVH- and NTCP-based approach. Ten patients with SCC of the middle or lower third were retrospectively selected. Three planning target volumes (PTV) with longitudinal margins of 4 cm, 3 cm and 2 cm and an axial margin of 1.5 cm to the gross target volume (GTV) were defined for each patient. For each PTV two treatment plans with total doses of 41.4 Gy (neoadjuvant treatment) and 50.4 Gy (definite treatment) were calculated. Dose to the lungs, heart, myelon and liver were then evaluated and compared between different PTVs. When using a longitudinal margin of 3 cm instead of 4 cm, all dose parameters (Dmin, Dmean, Dmedian and V5-V35), except Dmax could be significantly reduced for the lungs. Regarding the heart, a significant reduction was seen for Dmean and V5, but not for Dmin, Dmax, Dmedian and V10-V35. When comparing a longitudinal margin of 4 cm to a longitudinal margin of 2 cm, a significant difference was calculated for Dmin, Dmean, Dmedian and V5-V35 of the lungs and for Dmax, Dmean and V5-V35 of the heart. Nevertheless, no difference was seen for median heart dose. An additional dose reduction for V10 of the heart was achieved for definite treatment plans when using a longitudinal margin of 3 cm. The NTCP-based risk of pneumonitis was significantly reduced by a margin reduction to 2 cm for neoadjuvant and definite treatment plans. Reduction of longitudinal margins from 4 cm to 3 cm can significantly reduce the dose to lungs and Dmean of the heart. Despite clinical benefit and oncologic outcome remain unclear, reduction of the longitudinal margins might provide the opportunity to reduce side effects of chemoradiation (CRT) for SCC in upcoming studies.

Adaptive volumetric modulated arc treatment planning for esophageal cancers using cone beam computed tomography.

PubMed

Sriram, Padmanaban; Syamkumar, S A; Kumar, J Sam Deva; Prabakar, Sukumar; Dhanabalan, Rajasekaran; Vivekanandan, Nagarajan

2012-10-01

To assess the potential of cone beam CT (CBCT) derived adaptive RapidArc treatment for esophageal cancers in reducing the dose to organs at risk (OAR). Ten patients with esophageal cancer were CT scanned in free breathing pattern. The PTV is generated by adding a 3D margin of 1 cm to the CTV as per ICRU 62 recommendations. The double arc RapidArc plan (Clin_RA) was generated for the PTV. Patients were setup using kV orthogonal images and kV-CBCT scan was acquired daily during first week of therapy, then weekly. These images were exported to the Eclipse TPS. The adaptive CTV which includes tumor and involved nodes was delineated in each CBCT image set for the length of the PTV. The composite CTV from first week CBCT was generated using Boolean union operator and 5 mm margin was added circumferentially to generate adaptive PTV (PTV1). Adaptive RapidArc plan (Adap_RA) was generated. NTCP and DVH of the OARs of the two plans were compared. Similarly, PTV2 was generated from weekly CBCT. PTV2 was evaluated for the coverage of 95% isodose of Adap_RA plan. The PTV1 and PTV2 volumes covered by 95% isodose in adaptive plans were 93.51 ± 1.17% and 94.59 ± 1.43% respectively. The lung V(10Gy,)V(20Gy) and mean dose in Adap_RA plan was reduced by 17.43% (p = 0.0012), 34.64% (p = 0.0019) and 16.50% (p = 0.0002) respectively compared to Clin_RA. The Adap_RA plan reduces the heart D(35%) and mean dose by 17.35% (p = 0.0011) and 17.16% (p = 0.0012). No significant reduction in spinal cord and liver doses were observed. NTCP for the lung (0.42% vs. 0.08%) and heart (1.39% vs. 0.090%) was reduced significantly in adaptive plans. The adaptive re-planning strategy based on the first week CBCT dataset significantly reduces the doses and NTCP to OARs. Copyright © 2011 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Exact Tests for the Rasch Model via Sequential Importance Sampling

ERIC Educational Resources Information Center

Chen, Yuguo; Small, Dylan

2005-01-01

Rasch proposed an exact conditional inference approach to testing his model but never implemented it because it involves the calculation of a complicated probability. This paper furthers Rasch's approach by (1) providing an efficient Monte Carlo methodology for accurately approximating the required probability and (2) illustrating the usefulness…

Modelling duodenum radiotherapy toxicity using cohort dose-volume-histogram data.

PubMed

Holyoake, Daniel L P; Aznar, Marianne; Mukherjee, Somnath; Partridge, Mike; Hawkins, Maria A

2017-06-01

Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data. A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials. Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n=0.070, m=0.46, TD 50(1) [Gy]=183.8, while the values for the model incorporating the individual patient data were n=0.193, m=0.51, TD 50(1) [Gy]=299.1. LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Which factor is most important for occurrence of cutout complications in patients treated with proximal femoral nail antirotation? Retrospective analysis of 298 patients.

PubMed

Turgut, Ali; Kalenderer, Önder; Karapınar, Levent; Kumbaracı, Mert; Akkan, Hasan Ali; Ağuş, Haluk

2016-05-01

Mechanical complications, such as cut-out of the head-neck fixation device, are the most common causes of morbidity after trochanteric femur fracture treatment. The causes of cut-out complications are well defined in patients who are treated with sliding hip screws and biaxial cephalomedullary nails but there are few reports about the patients who are treated with proximal femoral nail antirotation. The purpose of this study was to evaluate the most important factor about occurance of cutout complication and also to evaluate the risks of the combination of each possible factors. Overally 298 patients were enrolled in the study. Medical records were reviewed for patients' age, fracture type, gender, anesthesia type and occurance of cut-out complication. Postoperatively taken radiographs were reviewed for tip-apex distance, obtained collo-diaphyseal angle, the quadrant of the helical blade and Ikuta reduction subgroup. The most important factor (s) and also predicted probability of cut-out complication was calculated for each combination of factors. Cut-out complication was observed in 14 patients (4.7 %). The most important factor about occurrence of the cut-out complication was found as varus reduction (p: 0.01), the second important factor was found as implantation of the helical blade in the improper quadrant (p: 0.02). Tip-apex distance was found as third important factor (p: 0.10). The predicted probability of cut-out complication was calculated as 45.6 % when whole of the four surgeon dependent factors were improperly obtained. Althought obtaining proper tip-apex distance is important to prevent cutout complication in these fractures, if the fracture is not reduced in varus position and helical blade is inserted in the proper quadrant, possibility of cut-out complication is very low even in the patients with high tip-apex distance.

Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease.

PubMed

Chancellor, John R; Padmanabhan, Sriranjani P; Greenough, Thomas C; Sacra, Richard; Ellison, Richard T; Madoff, Lawrence C; Droms, Rebecca J; Hinkle, David M; Asdourian, George K; Finberg, Robert W; Stroher, Ute; Uyeki, Timothy M; Cerón, Olga M

2016-02-01

We report a case of probable Zaire Ebola virus-related ophthalmologic complications in a physician from the United States who contracted Ebola virus disease in Liberia. Uveitis, immune activation, and nonspecific increase in antibody titers developed during convalescence. This case highlights immune phenomena that could complicate management of Ebola virus disease-related uveitis during convalescence.

CT findings of acute cholecystitis and its complications.

PubMed

Shakespear, Jonathan S; Shaaban, Akram M; Rezvani, Maryam

2010-06-01

The purpose of this article is to describe and illustrate the CT findings of acute cholecystitis and its complications. CT findings suggesting acute cholecystitis should be interpreted with caution and should probably serve as justification for further investigation with abdominal ultrasound. CT has a relatively high negative predictive value, and acute cholecystitis is unlikely in the setting of a negative CT. Complications of acute cholecystitis have a characteristic CT appearance and include necrosis, perforation, abscess formation, intraluminal hemorrhage, and wall emphysema.

A Probabilistic Model of Illegal Drug Trafficking Operations in the Eastern Pacific and Caribbean Sea

DTIC Science & Technology

2013-09-01

partner agencies and nations, detects, tracks, and interdicts illegal drug-trafficking in this region. In this thesis, we develop a probability model based...trafficking in this region. In this thesis, we develop a probability model based on intelligence inputs to generate a spatial temporal heat map specifying the...complement and vet such complicated simulation by developing more analytically tractable models. We develop probability models to generate a heat map

MO-D-BRF-01: Pediatric Treatment Planning II: The PENTEC Report On Normal Tissue Complications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Constine, L; Hodgson, D; Bentzen, S

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy may cause debilitating or even fatal ‘late effects’ that are critical to understand, mitigate, or prevent. QUANTEC identified the uncertainties relating to side-effects of adult treatments, but this is more complicated for children in whom a mosaic of tissues develops at different rates and temporal sequences. Childhood cancer survivors have long life expectancy and may develop treatmentinduced secondary cancers and severe organ/tissue injury decades after treatment. Collaborative long-term observational studies and clinical research programs for survivors of pediatric and adolescent cancer provide some dose-responsemore » data for follow-up periods exceeding 40 years. Data analysis is challenging due to the influence of both therapeutic and developmental variables. PENTEC is a group of radiation oncologists, pediatric oncologists, subsepcialty physicians, medical physicists, biomathematic modelers/statisticians, and epidemiologists charged with conducting a critical synthesis of existing literature aiming to: critically analyze radiation dose-volume effects on normal tissue tolerances as a function of age/development in pediatric cancer patients in order to inform treatment planning and improve outcomes for survivors; describe relevant physics issues specific to pediatric radiotherapy; propose dose-volumeoutcome reporting standards to improve the knowledge base to inform future treatment guidelines. PENTEC has developed guidelines for systematic literature reviews, data extraction tolls and data analysis. This education session will discuss:1. Special considerations for normal tissue radiation response of children/adolescents, e.g. the interplay between development and radiotherapy effects.2. Epidemiology of organ/tissue injuries and secondary cancers.3. Exploration of dose-response differences between children and adults4. Methodology for literature review, data mining of outcomes databases, and NTCP or longitudinal modeling of doseresponse. 5. PENTEC goals and timetable. Learning Objectives: Understand important differences between normal tissue effects of radiation therapy in pediatric and adult patients. Be able to identify situations where there is ‘interplay’ between organ development and radiation-induced complications. Identify methods to systematically extract quantitative dose-volumeresponse relationships from existing outcomes databases. Provide guidance for the medical physicist to properly understand, implement, guide and control contemporary technology and applications in pediatric radiation oncology.« less

Advanced reliability methods for structural evaluation

NASA Technical Reports Server (NTRS)

Wirsching, P. H.; Wu, Y.-T.

1985-01-01

Fast probability integration (FPI) methods, which can yield approximate solutions to such general structural reliability problems as the computation of the probabilities of complicated functions of random variables, are known to require one-tenth the computer time of Monte Carlo methods for a probability level of 0.001; lower probabilities yield even more dramatic differences. A strategy is presented in which a computer routine is run k times with selected perturbed values of the variables to obtain k solutions for a response variable Y. An approximating polynomial is fit to the k 'data' sets, and FPI methods are employed for this explicit form.

Elephantiasis Nostras Verrucosa (ENV): a complication of congestive heart failure and obesity.

PubMed

Baird, Drew; Bode, David; Akers, Troy; Deyoung, Zachariah

2010-01-01

Congestive heart failure (CHF) and obesity are common medical conditions that have many complications and an increasing incidence in the United States. Presented here is a case of a disfiguring skin condition that visually highlights the dermatologic consequences of poorly controlled CHF and obesity. This condition will probably become more common as CHF and obesity increase in the US.

[Obesity and heart].

PubMed

Svačina, Štěpán

2014-12-01

Cardiovascular complications of obesity are traditionally considered an important complication of obesity. Obesity itself is probably not direct cause of atherosclerosis or coronary heart disease. This may occur indirectly in metabolic complications of obesity, especially diabetes and metabolic syndrome. However, thrombogenicity potential of obesity contributes to embolism and atherosclerosis development. In cardiology is well-known a phenomenon of obesity paradox when obese patients have better prognosis than thin. This is the case of heart failure and some other cardiovascular diseases. Recently, a new concept has emerged of myokines - hormones from muscle tissue that have extensive protective effects on organism and probably on heart. Whether heart is a source of myokines is uncertain. However, undoubted importance has epicardial and pericardial fatty tissue. The epicardial fatty tissue has mainly protective effects on myocardium. This fatty tissue may produce factors of inflammation affecting the myocardium. Relationship between amount of epicardial fatty tissue and coronary heart disease is rather pathogenic. Currently, it is certain that obesity brings more metabolic and cancer complications than cardiovascular and accurate contribution to pathogenic or protective character of fatty tissue in cardiology requires further research. Nevertheless, the conclusion is that adipose tissue of organism and around the heart may be in some circumstances beneficial.

Integration of second cancer risk calculations in a radiotherapy treatment planning system

NASA Astrophysics Data System (ADS)

Hartmann, M.; Schneider, U.

2014-03-01

Second cancer risk in patients, in particular in children, who were treated with radiotherapy is an important side effect. It should be minimized by selecting an appropriate treatment plan for the patient. The objectives of this study were to integrate a risk model for radiation induced cancer into a treatment planning system which allows to judge different treatment plans with regard to second cancer induction and to quantify the potential reduction in predicted risk. A model for radiation induced cancer including fractionation effects which is valid for doses in the radiotherapy range was integrated into a treatment planning system. From the three-dimensional (3D) dose distribution the 3D-risk equivalent dose (RED) was calculated on an organ specific basis. In addition to RED further risk coefficients like OED (organ equivalent dose), EAR (excess absolute risk) and LAR (lifetime attributable risk) are computed. A risk model for radiation induced cancer was successfully integrated in a treatment planning system. Several risk coefficients can be viewed and used to obtain critical situations were a plan can be optimised. Risk-volume-histograms and organ specific risks were calculated for different treatment plans and were used in combination with NTCP estimates for plan evaluation. It is concluded that the integration of second cancer risk estimates in a commercial treatment planning system is feasible. It can be used in addition to NTCP modelling for optimising treatment plans which result in the lowest possible second cancer risk for a patient.

Smoking, Labor, & Delivery: It's Complicated

Cancer.gov

You probably have mixed feelings about going into labor. On one hand, bringing a new life into the world is really exciting. On the other, it can be really scary to have a baby, especially if this is your first child. Unfortunately, it can be even scarier if you smoke. Research shows that smoking during pregnancy can lead to serious complications for you and your baby during labor and delivery.

Prevalence of cardiovascular and respiratory complications following trauma in patients with obesity.

PubMed

Bell, Teresa; Stokes, Samantha; Jenkins, Peter C; Hatcher, LeRanna; Fecher, Alison M

It is generally accepted that obesity puts patients at an increased risk for cardiovascular and respiratory complications after surgical procedures. However, in the setting of trauma, there have been mixed findings in regards to whether obesity increases the risk for additional complications. The aim of this study was to identify whether obese patients suffer an increased risk of cardiac and respiratory complications following traumatic injury. A retrospective analysis of 275,393 patients was conducted using the 2012 National Trauma Data Bank. Hierarchical regression modeling was performed to determine the probability of experiencing a cardiac or respiratory complication. Patients with obesity were at a significantly higher risk of cardiac and respiratory complications compared to patients without obesity [OR: 1.81; CI: 1.72-1.91]. Prevalence of cardiovascular and respiratory complications for patients with obesity was 12.6% compared to 5.2% for non-obese patients. Obesity is predictive of an increased risk for cardiovascular and respiratory complications following trauma. Copyright © 2017 Elsevier Inc. All rights reserved.

Visceroptosis and the Ehlers-Danlos Syndrome.

PubMed

Kucera, Stephen; Sullivan, Stephen N

2017-11-08

The case of a patient with visceroptosis and Ehlers-Danlos syndrome hypermobility type (RDS-HT) is reported here. The literature on this unusual but probably under-recognized complication is reviewed.

The comparative risk of developing postoperative complications in patients with distal radius fractures following different treatment modalities

PubMed Central

Qiu, Wen-Jun; Li, Yi-Fan; Ji, Yun-Han; Xu, Wei; Zhu, Xiao-Dong; Tang, Xian-Zhong; Zhao, Huan-Li; Wang, Gui-Bin; Jia, Yue-Qing; Zhu, Shi-Cai; Zhang, Feng-Fang; Liu, Hong-Mei

2015-01-01

In this study, we performed a network meta-analysis to compare the outcomes of seven most common surgical procedures to fix DRF, including bridging external fixation, non-bridging external fixation, K-wire fixation, plaster fixation, dorsal plating, volar plating, and dorsal and volar plating. Published studies were retrieved through PubMed, Embase and Cochrane Library databases. The database search terms used were the following keywords and MeSH terms: DRF, bridging external fixation, non-bridging external fixation, K-wire fixation, plaster fixation, dorsal plating, volar plating, and dorsal and volar plating. The network meta-analysis was performed to rank the probabilities of postoperative complication risks for the seven surgical modalities in DRF patients. This network meta-analysis included data obtained from a total of 19 RCTs. Our results revealed that compared to DRF patients treated with bridging external fixation, marked differences in pin-track infection (PTI) rate were found in patients treated with plaster fixation, volar plating, and dorsal and volar plating. Cluster analysis showed that plaster fixation is associated with the lowest probability of postoperative complication in DRF patients. Plaster fixation is associated with the lowest risk for postoperative complications in DRF patients, when compared to six other common DRF surgical methods examined. PMID:26549312

[Influence of Training of Orthopaedic Surgeons on Clinical Outcome after Total Hip Arthroplasty in a High Volume Endoprosthetic Centre].

PubMed

Osmanski-Zenk, Katrin; Finze, Susanne; Lenz, Robert; Bader, Rainer; Mittelmeier, Wolfram

2018-06-26

The study aims to evaluate whether the postoperative outcome and the probability of complications of patients with total hip arthroplasty increases significantly when surgeons in training are in charge, assisted by a high volume surgeon, compared to a highly experienced orthopaedic surgeon, within the context of a high volume hospital certified to EndoCert. 192 patients with a primary hip arthroplasty were included. To assess the outcome, the Harris Hip Score, WOMAC, SF-36 and EuroQol-5D were surveyed pre- and 12 months postoperatively. As complications we considered the quality indicators defined by EndoCert. We found significant improvements in the postoperative score values with the qualifications of the surgeon in charge, even when a high volume surgeon or a surgeon in training was responsible. If a surgeon in training is assisted by a highly experienced surgeon, the risk of complications does not increase, although the operating time was significantly increased. Both the surgeon in training as well as the arthroplasty patient benefit from implementing the EndoCert system, because the postoperative outcome and the complication probability is independent of the qualifcation of the operating orthopaedic surgeon performing total hip arthroplasty when assisted by an experienced surgeon. Georg Thieme Verlag KG Stuttgart · New York.

Follow-up of the original cohort with the Ahmed glaucoma valve implant.

PubMed

Topouzis, F; Coleman, A L; Choplin, N; Bethlem, M M; Hill, R; Yu, F; Panek, W C; Wilson, M R

1999-08-01

To study the long-term results of the Ahmed glaucoma valve implant in patients with complicated glaucoma in whom short-term results have been reported. In this multicenter study, we analyzed the long-term outcome of a cohort of 60 eyes from 60 patients in whom the Ahmed glaucoma valve was implanted. Failure was characterized by at least one of the following: intraocular pressure greater than 21 mm Hg at both of the last two visits less than 6 mm Hg at both of the last two visits, loss of light perception, additional glaucoma surgery, devastating complications, and removal or replacement of the Ahmed glaucoma valve implant. Devastating complications included chronic hypotony, retinal detachment, malignant glaucoma, endophthalmitis, and phthisis bulbi; we also report results that add corneal complications (corneal decompensation or edema, corneal graft failure) as defining a devastating complication. The mean follow-up time for the 60 eyes was 30.5 months (range, 2.1 to 63.5). When corneal complications were included in the definition of failure, 26 eyes (43%) were considered failures. Cumulative probabilities of success at 1, 2, 3, and 4 years were 76%, 68%, 54%, and 45%, respectively. When corneal complications were excluded from the definition of failure, 13 eyes (21.5%) were considered failures. Cumulative probabilities of success at 1, 2, 3, and 4 years were 87%, 82%, 76%, and 76%, respectively. Most of the failures after 12 months of postoperative follow-up were because of corneal complications. The long-term performance of the Ahmed glaucoma valve implant is comparable to other drainage devices. More than 12 months after the implantation of the Ahmed glaucoma valve implant, the most frequent adverse outcome was corneal decompensation or corneal graft failure. These corneal problems may be secondary to the type of eyes that have drainage devices or to the drainage device itself. Further investigation is needed to identify the reasons that corneal problems follow drainage device implantation.

Theoretical Aspects of the Patterns Recognition Statistical Theory Used for Developing the Diagnosis Algorithms for Complicated Technical Systems

NASA Astrophysics Data System (ADS)

Obozov, A. A.; Serpik, I. N.; Mihalchenko, G. S.; Fedyaeva, G. A.

2017-01-01

In the article, the problem of application of the pattern recognition (a relatively young area of engineering cybernetics) for analysis of complicated technical systems is examined. It is shown that the application of a statistical approach for hard distinguishable situations could be the most effective. The different recognition algorithms are based on Bayes approach, which estimates posteriori probabilities of a certain event and an assumed error. Application of the statistical approach to pattern recognition is possible for solving the problem of technical diagnosis complicated systems and particularly big powered marine diesel engines.

Genetic risk profiling and gene signature modeling to predict risk of complications after IPAA.

PubMed

Sehgal, Rishabh; Berg, Arthur; Polinski, Joseph I; Hegarty, John P; Lin, Zhenwu; McKenna, Kevin J; Stewart, David B; Poritz, Lisa S; Koltun, Walter A

2012-03-01

Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD. The aim of this study was to identify single-nucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making. One hundred forty-two IPAA patients were retrospectively classified as "asymptomatic" (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a "severe pouchitis" group (n = 12, ≥ 4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a "Crohn's disease-like" group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 single-nucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These single-nucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication. The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's disease-like complications. In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications.

Comparision of beam data requirements for MLC commissioning on a TPS

NASA Astrophysics Data System (ADS)

Solaiappan, Gopi; Singaravelu, Ganesan; Prakasarao, Aruna; Supe, Sanjay S.

2008-01-01

The treatment planning system (TPS) has become a key element in the radiotherapy process with the introduction of computer tomography (CT) based 3D conformal treatment planning. Commissioning of a MLC on a TPS either for conformal radiotherapy or intensity modulated radiation therapy (IMRT) requires beam data to be generated on a linear accelerator. Most of the TPS require these beam data to be generated with routine collimator jaws. However some TPS demand the data to be provided for MLC shaped fields. This prompted us to investigate whether beam data with jaws differ than that with MLC and whether the jaw based beam data would suffice for the commissioning of a MLC on a TPS. Beam data like percentage depth dose (PDD), cross beam profiles and output factors was acquired for jaws and MLC defined square fields for 6, 10 and 23 MV photon beams. Percentage depth dose and cross beam profiles were acquired with a radiation field analyzer RFA-200, CC13-S ion chambers with active volume of 0.13 cm3 and OmniPro-Accept software from Scanditronix-Wellhofer. A Medtec-TG51 water tank with Max-4000 electrometer and 0.6 cc PTW ionization chamber and a mini phantom from Standard Imaging was utilized for output measurements for millennium-120 MLC (Varian Medical Systems) and SRS diode detector (Scanditronix-Wellhofer) of 0.6 mm diameter of active area and 0.3 mm of active volume thickness for micro-MLC (BrainLab). The difference in PDD in the build-up region for millennium MLC was ±1.0% for 6 MV photons. For 10 MV photons the PDD difference was within ±4.0%. The difference in PDD for 23 MV photons ranged from 0% to 40.0%. PDD difference from build-up depth to about 28 cm was within ±1.0%. Difference in PDD crossed ±1.0% at 30 cm depth for 6 MV photons. The difference in PDD in the build-up region for mMLC was ±8.0% for 6 MV photons. For the smallest field size studied with micro-MLC i.e. 0.6 × 0.6 cm2 difference in PDD was more than ±1.0% in the build-up region and beyond a depth of 8.0 cm. The profiles for jaws and MLC agreed within the umbra region. However in the penumbra region small differences in doses were observed. The collimator scatter factor (Sc), phantom scatter factor (Sp) and output factor values for MLC were different that those for jaws. The differences in beam characteristics could have implication for intensity modulated radiation therapy and stereotactic radiosurgery in terms of dose in the build up region, exit dose, dose to the planning target volume (PTV) and organ at risk (OAR). Impact of these dosimetric differences between jaw and MLC needs to be further studied in terms of dose volume histograms for PTV and OAR and its further impact on tumor control probability (TCP) and normal tissue complication probability (NTCP).

Neuromuscular complications of thyrotoxicosis.

PubMed

Kung, Annie W C

2007-11-01

Thyroid hormones exert multiple effects on the neuromuscular system and the brain, with the most important being their role in stimulating the development and differentiation of the neuromuscular system and brain in foetal and neonatal life. In the presence of hyperthyroidism, muscular and neurological symptoms may be the presenting clinical features of the disease. The frequency and severity of neuromuscular complications vary considerably and are probably related to the degree of hyperthyroidism, although in some patients the neuromuscular dysfunction is caused by associated disorders rather than by hyperthyroidism per se. This update focuses on the most common neurological and muscular disorders that occur in patients with thyrotoxicosis. It is beyond the scope of this paper to discuss thyroid eye disease and cardiac complications, in themselves separate complications of specific myocytes.

Continuous-Time Classical and Quantum Random Walk on Direct Product of Cayley Graphs

NASA Astrophysics Data System (ADS)

Salimi, S.; Jafarizadeh, M. A.

2009-06-01

In this paper we define direct product of graphs and give a recipe for obtaining probability of observing particle on vertices in the continuous-time classical and quantum random walk. In the recipe, the probability of observing particle on direct product of graph is obtained by multiplication of probability on the corresponding to sub-graphs, where this method is useful to determining probability of walk on complicated graphs. Using this method, we calculate the probability of continuous-time classical and quantum random walks on many of finite direct product Cayley graphs (complete cycle, complete Kn, charter and n-cube). Also, we inquire that the classical state the stationary uniform distribution is reached as t → ∞ but for quantum state is not always satisfied.

The role of high fat diet in the development of complications of chronic pancreatitis.

PubMed

Castiñeira-Alvariño, M; Lindkvist, B; Luaces-Regueira, M; Iglesias-García, J; Lariño-Noia, J; Nieto-García, L; Domínguez-Muñoz, J E

2013-10-01

Little is known about risk factors for complications in chronic pancreatitis (CP). High fat diet (HFD) has been demonstrated to aggravate pancreatic injury in animal models. The aim of this study was to investigate the role of HFD in age at diagnosis of CP and probability of CP related complications. A cross-sectional case-case study was performed within a prospectively collected cohort of patients with CP. Diagnosis and morphological severity of CP was established by endoscopic ultrasound. Pancreatic exocrine insufficiency (PEI) was diagnosed by ¹³C mixed triglyceride breath test. Fat intake was assessed by a specific nutritional questionnaire. Odds ratios (OR) for CP related complications were estimated by multivariate logistic regression analysis. 168 patients were included (128 (76.2%) men, mean age 44 years (SD 13.5)). Etiology of CP was alcohol abuse in 89 patients (53.0%), other causes in 30 (17.9%) and idiopathic in the remaining 49 subjects (29.2%). 24 patients (14.3%) had a HFD. 68 patients (40.5%) had continuous abdominal pain, 39 (23.2%) PEI and 43 (25.7%) morphologically severe CP. HFD was associated with an increased probability for continuous abdominal pain (OR = 2.84 (95% CI, 1.06-7.61)), and a younger age at diagnosis (37.0 ± 13.9 versus 45.8 ± 13.0 years, p = 0.03) but not with CP related complications after adjusting for sex, years of follow-up, alcohol and tobacco consumption, etiology and body mass index. Compared with a normal fat diet, HFD is associated with a younger age at diagnosis of CP and continuous abdominal pain, but not with severity and complications of the disease. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Risk-adaptive radiotherapy

NASA Astrophysics Data System (ADS)

Kim, Yusung

Currently, there is great interest in integrating biological information into intensity-modulated radiotherapy (IMRT) treatment planning with the aim of boosting high-risk tumor subvolumes. Selective boosting of tumor subvolumes can be accomplished without violating normal tissue complication constraints using information from functional imaging. In this work we have developed a risk-adaptive optimization-framework that utilizes a nonlinear biological objective function. Employing risk-adaptive radiotherapy for prostate cancer, it is possible to increase the equivalent uniform dose (EUD) by up to 35.4 Gy in tumor subvolumes having the highest risk classification without increasing normal tissue complications. Subsequently, we have studied the impact of functional imaging accuracy, and found on the one hand that loss in sensitivity had a large impact on expected local tumor control, which was maximal when a low-risk classification for the remaining low risk PTV was chosen. While on the other hand loss in specificity appeared to have a minimal impact on normal tissue sparing. Therefore, it appears that in order to improve the therapeutic ratio a functional imaging technique with a high sensitivity, rather than specificity, is needed. Last but not least a comparison study between selective boosting IMRT strategies and uniform-boosting IMRT strategies yielding the same EUD to the overall PTV was carried out, and found that selective boosting IMRT considerably improves expected TCP compared to uniform-boosting IMRT, especially when lack of control of the high-risk tumor subvolumes is the cause of expected therapy failure. Furthermore, while selective boosting IMRT, using physical dose-volume objectives, did yield similar rectal and bladder sparing when compared its equivalent uniform-boosting IMRT plan, risk-adaptive radiotherapy, utilizing biological objective functions, did yield a 5.3% reduction in NTCP for the rectum. Hence, in risk-adaptive radiotherapy the therapeutic ratio can be increased over that which can be achieved with conventional selective boosting IMRT using physical dose-volume objectives. In conclusion, a novel risk-adaptive radiotherapy strategy is proposed and promises increased expected local control for locoregionally advanced tumors with equivalent or better normal tissue sparing.

Nonaggressive obstetric management. An option for some fetal anomalies during the third trimester.

PubMed

Chervenak, F A; McCullough, L B

1989-06-16

Nonaggressive obstetric management was used in 13 cases of anomalous fetuses during the third trimester. Criteria that define these anomalies are (1) a very high probability of a correct diagnosis and (2) either (a) a very high probability of death as an outcome of the anomaly diagnosed or (b) a very high probability of severe and irreversible deficit of cognitive developmental capacity as a result of the anomaly diagnosed. On the basis of two approaches to obstetric ethics, we defend the legitimacy of nonaggressive management of third-trimester pregnancies complicated by fetal anomalies that meet these criteria.

76 FR 21747 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-18

... disease burden and have a high probability of developing diabetes-related complications. However, research... thirteen (the ``Youth Books''). CDC plans to conduct a descriptive evaluation of the Eagle Books and the...

Branch retinal vein thrombosis and visual loss probably associated with pegylated interferon therapy of chronic hepatitis C

PubMed Central

Gonçalves, Luciana Lofego; Farias, Alberto Queiroz; Gonçalves, Patrícia Lofego; D’Amico, Elbio Antonio; Carrilho, Flair José

2006-01-01

Ophthalmological complications with interferon therapy are usually mild and reversible, not requiring the withdrawal of the treatment. We report a case of a patient who had visual loss probably associated with interferon therapy. Chronic hepatitis C virus infection (genotype 1a) was diagnosed in a 33-year old asymptomatic man. His past medical history was unremarkable and previous routine ophthalmologic check-up was normal. Pegylated interferon alpha and ribavirin were started. Three weeks later he reported painless reduction of vision. Ophthalmologic examination showed extensive intraretinal hemorrhages and cotton-wool spots, associated with inferior branch retinal vein thrombosis. Antiviral therapy was immediately discontinued, but one year later he persists with severely decreased visual acuity. This case illustrates the possibility of unpredictable and severe complications during pegylated interferon therapy. PMID:16874884

Newsvendor problem under complete uncertainty: a case of innovative products.

PubMed

Gaspars-Wieloch, Helena

2017-01-01

The paper presents a new scenario-based decision rule for the classical version of the newsvendor problem (NP) under complete uncertainty (i.e. uncertainty with unknown probabilities). So far, NP has been analyzed under uncertainty with known probabilities or under uncertainty with partial information (probabilities known incompletely). The novel approach is designed for the sale of new, innovative products, where it is quite complicated to define probabilities or even probability-like quantities, because there are no data available for forecasting the upcoming demand via statistical analysis. The new procedure described in the contribution is based on a hybrid of Hurwicz and Bayes decision rules. It takes into account the decision maker's attitude towards risk (measured by coefficients of optimism and pessimism) and the dispersion (asymmetry, range, frequency of extremes values) of payoffs connected with particular order quantities. It does not require any information about the probability distribution.

[Quality assessment of microscopic examination in tuberculosis diagnostic laboratories: a preliminary study].

PubMed

Simşek, Hülya; Ceyhan, Ismail; Tarhan, Gülnur; Güner, Uğur

2010-10-01

Recently, the diagnosis of pulmonary tuberculosis (TB) has based on smear microscopy in the Direct Observed Treatment Strategy (DOTS) programme which provides the basis of treatment worldwide. Microscopic detection of AFB (Acid-Fast Bacilli) is one of the main components in the National TB Control Programmes (NTCP). Precision level in microscopy procedures and evaluations are the most important steps for accurate diagnosis of the disease and to initiate proper treatment. Therefore, the external quality assessment (EQA) is the most important implement to provide the reliability and validity of tests. In countries where NTCP are performed, this task is fulfilled by the National Reference Laboratories (NRL) according to the guidelines of the World Health Organization (WHO). For this purpose a pilot study was initiated by the central NRL of Turkey for EQA of AFB smear microscopy as part of the NTCP on January 1, 2005. A total of 5 laboratories of which 2 were district TB laboratories (A, B), 2 were tuberculosis control dispensaries (C, D), 1 was a national reference laboratory (E), participated in this study. Blind re-checking method (re-examination of randomly selected slides) was used for the evaluation, and the slides were sent to the central NRL with 3 months interval, four times a year, selected according to LQAS (Lot Quality Assurance Sampling) guides. In the re-evaluation of the slides, false positivity (FP), false negativity (FN) and quantification errors (QE) were noted. Laboratory A, sent totally 525 slides between January 1, 2005 and April 1, 2008. In the result of re-checking, 514 (97.9%) slides were found concordant, and 11 (2.1%) were discordant (10 FP, 1 FN). Laboratory B, participated in the study between October 1, 2005 and July 1, 2006 and of the 67 re-examined slides, 60 (89.5%) were concordant and 7 (10.5%) were discordant (2 FP, 0 FN, 5 QE). Laboratory C, sent 235 slides between January 1, 2005 and April 1, 2006; of them 218 (92.8%) were detected as compatible and 17 (7.2%) slides were incompatible (4 FP, 9 FN, 4 QE). Laboratory D, participated in QC for only once between January 1, 2008 and April 1, 2008; and all the 50 slides were found compatible, with no FP, FN and QE. Laboratory E, was included in the study between January 1, 2005 and January 1, 2008 and of the 696 re-checked slides, 690 (99.1%) were reported as compatible and 6 (0.9%) were incompatible (3 FN, 3 QE). Following EQA, on-site evaluation of the laboratories with major errors, was performed and necessary adjustments and training were done. In conclusion, external quality control measures for AFB microscopy is crucial and essential for the tuberculosis laboratory performances for accurate and reliable results.

Individual bile acids have differential effects on bile acid signaling in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Peizhen, E-mail: songacad@gmail.com; Rockwell, Cheryl E., E-mail: rockwelc@msu.edu; Cui, Julia Yue, E-mail: juliacui@uw.edu

2015-02-15

Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In themore » liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and pharmacological concentrations of BAs. - Highlights: • All four major bile acids in humans activate the FXR in liver and intestine. • These bile acids decreased the mRNA of the bile acid synthetic enzymes Cyp7a1 and Cyp8b1. • These BAs did not alter the mRNA or protein of the conjugated BA transporters (Ntcp and Bsep). • Cholic acid and deoxycholic acid are more potent activators of FXR than chenodeoxycholic acid and lithocholic acid.« less

Complications of acromegaly: thyroid and colon.

PubMed

Tirosh, Amit; Shimon, Ilan

2017-02-01

In acromegaly the long-term exposure to high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels may result in specific complications in different human organs, including the thyroid gland and the colon. We will review here the evidence available regarding the characteristic thyroid and colon complications in acromegaly. This review summarizes the published data observing noncancerous structural abnormalities (thyroid nodules, colonic polyps) and thyroid and colon cancer in patients diagnosed with acromegaly. Thyroid micro-carcinomas are probably over-diagnosed among acromegalic patients. In regard to colon cancer, there is no sufficient data to suggest that colon cancer risk is higher in acromegaly compared to the general population.

Influence of early neurological complications on clinical outcome following lung transplant.

PubMed

Gamez, Josep; Salvado, Maria; Martinez-de La Ossa, Alejandro; Deu, Maria; Romero, Laura; Roman, Antonio; Sacanell, Judith; Laborda, Cesar; Rochera, Isabel; Nadal, Miriam; Carmona, Francesc; Santamarina, Estevo; Raguer, Nuria; Canela, Merce; Solé, Joan

2017-01-01

Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied. We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014. Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients' survival. The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors.

Influence of early neurological complications on clinical outcome following lung transplant

PubMed Central

Salvado, Maria; Martinez-de La Ossa, Alejandro; Deu, Maria; Romero, Laura; Roman, Antonio; Sacanell, Judith; Laborda, Cesar; Rochera, Isabel; Nadal, Miriam; Carmona, Francesc; Santamarina, Estevo; Raguer, Nuria; Canela, Merce; Solé, Joan

2017-01-01

Background Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied. Methods We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014. Results Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients’ survival. Conclusions The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors. PMID:28301586

Complications associated with brachytherapy alone or with laser in lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khanavkar, B.; Stern, P.; Alberti, W.

1991-05-01

Relatively little has been reported about destruction through brachytherapy of mucosa-perforating and extraluminary tumors with probable large vessel involvement causing major hemorrhagic or fistular complications. We report 12 patients subjected to laser and brachytherapy for centrally occluding lung cancer, whom we have periodically followed up from June 1986 until they died. Although all laser procedures were free from complications, necrotic cavitation in five cases, two of which were accompanied by large bronchoesophageal fistulas, and massive fatal hemoptysis occurred in six. Minor complications included radiation mucositis (two), noncritical mucosal scarring (two), and cough (four). Characteristics that will identify patients at riskmore » of developing fatal hemoptysis and fistulas should be better defined by imaging and endoscopic techniques. In such cases, modifying the protocol or using alternative procedures should be considered. Minor complications, such as cough, can be avoided by using topical steroid therapy (eg, beclomethasone dipropionate).« less

Safety profile and complications of autologous limbal conjunctival transplantation for primary pterygium

PubMed Central

Prabhakar, Srinivasapuram Krishnachary

2014-01-01

Purpose Primary pterygium is a fibrovascular proliferation over the nasal cornea, probably resulting from the limbal stem cell deficiency. Intraoperative mitomycin-C application seems to associate with reduced recurrences, however produced ocular surface problems and vision threatening complications. The present clinical study investigated the safety profile of autologous limbal conjunctival transplantation in terms of recurrence rate, as the main outcome measure and complications as the secondary outcome. Methods The present study was randomised, interventional and prospective clinical study conducted from a tertiary Hospital. Pterygium excision was performed with limbal conjunctival autograft availed from the affected eye. Secondary pterygia resulting from inflammation, trauma and other diseases were excluded. Patients were followed up for 18 months for recurrence and other complications. Microsoft Office Excel 2007 was used for statistical analysis. Results A total of 71 eyes of sixty-eight patients with primary pterygia included between November 2007 and October 2010. The study recruited 35 (51%) males and 33 (49%) females with mean age of 36.9 with ±12.82 years standard deviation (mean, SD) ranging from 19 to 75 years. Age grouped by range intervals categorised into six groups. Pterygium was diagnosed in 32 (45%) right eyes and 39 (55%) left eyes. There were 65 (91.55%) nasal and 4 (5.63%) temporal pterygium and no case of double head pterygia found. Average horizontal extension of the pterygium measured was 1.67 mm (±4.23) from the apex to the corneal limbus. Graft oedema in 1 (0.71%) patient, graft bleed in 2 (1.42%) cases and 1 (0.72%) case of granuloma observed. No recurrences encountered during 18 months follow up. Conclusions Pterygium occurred predominantly in the younger population group 36.9 mm (±12.82) probably due to the increased outdoor activity with high exposure to sunlight and dusty atmosphere. Absence of recurrences was probably attributable to the smaller pterygium size of 1.67 mm (±4.23), use of the autologous limbal conjunctival graft and treatable intra and post operative complications successfully. PMID:25473341

On Voxel based Iso-Tumor Control Probabilty and Iso-Complication Maps for Selective Boosting and Selective Avoidance Intensity Modulated Radiotherapy.

PubMed

Kim, Yusung; Tomé, Wolfgang A

2008-01-01

Voxel based iso-Tumor Control Probability (TCP) maps and iso-Complication maps are proposed as a plan-review tool especially for functional image-guided intensity-modulated radiotherapy (IMRT) strategies such as selective boosting (dose painting) and conformal avoidance IMRT. The maps employ voxel-based phenomenological biological dose-response models for target volumes and normal organs. Two IMRT strategies for prostate cancer, namely conventional uniform IMRT delivering an EUD = 84 Gy (equivalent uniform dose) to the entire PTV and selective boosting delivering an EUD = 82 Gy to the entire PTV, are investigated, to illustrate the advantages of this approach over iso-dose maps. Conventional uniform IMRT did yield a more uniform isodose map to the entire PTV while selective boosting did result in a nonuniform isodose map. However, when employing voxel based iso-TCP maps selective boosting exhibited a more uniform tumor control probability map compared to what could be achieved using conventional uniform IMRT, which showed TCP cold spots in high-risk tumor subvolumes despite delivering a higher EUD to the entire PTV. Voxel based iso-Complication maps are presented for rectum and bladder, and their utilization for selective avoidance IMRT strategies are discussed. We believe as the need for functional image guided treatment planning grows, voxel based iso-TCP and iso-Complication maps will become an important tool to assess the integrity of such treatment plans.

Clinical and sonographic risk factors and complications of shoulder dystocia - a case-control study with parity and gestational age matched controls.

PubMed

Parantainen, Jukka; Palomäki, Outi; Talola, Nina; Uotila, Jukka

2014-06-01

To examine the clinical risk factors and complications of shoulder dystocia today and to evaluate ultrasound methods predicting it. Retrospective, matched case-control study at a University Hospital with 5000 annual deliveries. The study population consisted of 152 deliveries complicated by shoulder dystocia over a period of 8.5 years (January 2004-June 2012) and 152 controls matched for gestational age and parity. The data was collected from the medical records of mothers and children and analyzed by conditional logistic regression. Incidences and odds ratios were calculated for risk factors and complications. Antenatal ultrasound data was analyzed when available by conditional logistic regression to test for significant differences between study groups. Birthweight (OR 12.1 for ≥4000 g; 95% CI 4.18-35.0) and vacuum extraction (OR 3.98; 95% CI 1.25-12.7) remained the most significant clinical risk factors. Only a trend of an association of pregestational or gestational diabetes was noticed (OR 1.87; 95% CI 0.997-3.495, probability of type II error 51%). Of the complications of shoulder dystocia the incidence of brachial plexus palsies was high (40%). Antenatal ultrasound method based on the difference between abdominal and biparietal diameters had a significant difference between cases and controls. The impact of diabetes as a risk factor has diminished, which may reflect improved screening and treatment. Antenatal ultrasound methods are showing some promise, but the predictive value of ultrasound alone is probably low. Copyright © 2014. Published by Elsevier Ireland Ltd.

Hepatobiliary transporter expression and post-operative jaundice in patients undergoing partial hepatectomy.

PubMed

Bernhardt, Gerwin A; Zollner, Gernot; Cerwenka, Herwig; Kornprat, Peter; Fickert, Peter; Bacher, Heinz; Werkgartner, Georg; Müller, Gabriele; Zatloukal, Kurt; Mischinger, Hans-Jörg; Trauner, Michael

2012-01-01

Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with high morbidity and mortality. Apart from different known factors responsible for the development of post-operative jaundice, little is known about the role of hepatobiliary transport systems in the pathogenesis of post-operative jaundice in humans after liver resection. Two liver tissue samples were taken from 14 patients undergoing liver resection before and after Pringle manoeuvre. Patients were retrospectively divided into two groups according to post-operative bilirubin serum levels. The two groups were analysed comparing the results of hepatobiliary transporter [Na-taurocholate cotransporter (NTCP); multidrug resistance gene/phospholipid export pump(MDR3); bile salt export pump (BSEP); canalicular bile salt export pump (MRP2)], heat shock protein 70 (HSP70) expression as well as the results of routinely taken post-operative liver chemistry tests. Patients with low post-operative bilirubin had lower levels of NTCP, MDR3 and BSEP mRNA compared to those with high bilirubin after Pringle manoeuvre. HSP70 levels were significantly higher after ischaemia-reperfusion (IR) injury in both groups resulting in 4.5-fold median increase. Baseline median mRNA expression of all four transporters prior to Pringle manoeuvre tended to be lower in the low bilirubin group whereas expression of HSP70 was higher in the low bilirubin group compared to the high bilirubin group. Higher mRNA levels of HSP70 in the low bilirubin group could indicate a possible protective effect of high HSP70 levels against IR injury. Although the exact role of hepatobiliary transport systems in the development of post-operative hyper bilirubinemia is not yet completely understood, this study provides new insights into the molecular aspects of post-operative jaundice after liver surgery. © 2011 John Wiley & Sons A/S.

LETTER TO THE EDITOR: Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy

NASA Astrophysics Data System (ADS)

Tsougos, Ioannis; Mavroidis, Panayiotis; Theodorou, Kyriaki; Rajala, J.; Pitkänen, M. A.; Holli, K.; Ojala, A. T.; Hyödynmaa, S.; Järvenpää, Ritva; Lind, Bengt K.; Kappas, Constantin

2006-02-01

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving \\bar{\\bar{D}}|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

Effect of heme oxygenase-1 on the protection of ischemia reperfusion injury of bile duct in rats after liver transplantation.

PubMed

Zhan, Xi; Zhang, Zhiqing; Huang, Hanfei; Zhang, Yujun; Zeng, Zhong

2018-06-01

To investigate the effect of heme oxygenase-1 (HO-1) on the ischemic reperfusion injury (IRI) of bile duct in rat models after liver transplantation. 320 SD rats were equally and randomly divided into 5 groups, which were group A receiving injection of 3×10 8 /pfu/ml adenovirus (adv), group B with donor receiving Adv-HO-1 and recipient receiving Adv-HO-1-siRNA, group C with donor and recipient both receiving Adv-HO-1, group D with donor receiving Adv-HO-1-siRNA and recipient receiving Adv-HO-1, and group E with donor and recipient both receiving Adv-HO-1-siRNA at 24h before liver transplantation. Donor liver was stored in UW liquid at 4°C followed by measuring HO-1 level by western blot before transplantation. On d1, d3, d7 and d14, serum and liver was isolated for analysis of liver function, inflammatory cell infiltration by H&E staining, ultrastructure of liver by transmission electron microscopy as well as the expression of HO-1, Bsep, Mrp2 and Ntcp by western blot. Compared with group D and E, group B and C displayed improved liver function as demonstrated by lower level of ALT, AST, LDH, TBIL, ALP and GGT, increased secretion of TBA and PL as well as expression of transporter proteins (Bsep, Mrp2 and Ntcp), reduced inflammatory cells infiltration and liver injury. Our study demonstrated that overexpression of HO-1 in donor liver can ameliorate the damage to bile duct and liver, and improved liver function, suggesting HO-1 might be a new therapeutic target in the treatment of IRI after liver transplantation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.

PubMed

Ishizawa, Takeaki; Masuda, Koichi; Urano, Yasuteru; Kawaguchi, Yoshikuni; Satou, Shouichi; Kaneko, Junichi; Hasegawa, Kiyoshi; Shibahara, Junji; Fukayama, Masashi; Tsuji, Shingo; Midorikawa, Yutaka; Aburatani, Hiroyuki; Kokudo, Norihiro

2014-02-01

Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

PubMed Central

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P.J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1β). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1β, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity. PMID:19358839

Normal tissue complication probability modeling of radiation-induced hypothyroidism after head-and-neck radiation therapy.

PubMed

Bakhshandeh, Mohsen; Hashemi, Bijan; Mahdavi, Seied Rabi Mehdi; Nikoofar, Alireza; Vasheghani, Maryam; Kazemnejad, Anoshirvan

2013-02-01

To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D(50) estimated from the models was approximately 44 Gy. The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication. Copyright © 2013 Elsevier Inc. All rights reserved.

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

PubMed

Basara, N; Rasche, F-M; Schwalenberg, T; Wickenhauser, C; Maier, M; Ivovic, J; Niederwieser, D; Lindner, T H

2010-01-01

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor.

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

PubMed Central

Basara, N.; Rasche, F.-M.; Schwalenberg, T.; Wickenhauser, C.; Maier, M.; Ivovic, J.; Niederwieser, D.; Lindner, T. H.

2010-01-01

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor. PMID:20936157

Esophageal Perforation After Transesophageal Echocardiogram.

PubMed

Shapira, Michael Y.; Hirshberg, Boaz; Agid, Ronit; Zuckerman, Elena; Caraco, Yoseph

1999-02-01

Esophageal rupture after transesophageal echocardiogram (TEE) is a rare but life-threatening complication. Risk factors for perforation include spasm or hypertrophy of the cricopharyngeal sphincter, cervical arthritis, forward and left lateral bending of the distal esophagus, and esophageal disease such as inflammation or neoplasm. We present the case of a 80-year-old woman who developed perforation of her esophagus after TEE. Prior irradiation to the chest due to treatment for breast cancer and subsequent fibrosis probably contributed to this complication. Physicians referring patients for a TEE and physicians performing this procedure should be aware for the risk of perforation. The identification of risk factors and gentle maneuvering of the probe may prevent this severe, life-threatening complication.

Postoperative complications of contemporary open and robot-assisted laparoscopic radical prostatectomy using standardized reporting systems.

PubMed

Pompe, Raisa S; Beyer, Burkhard; Haese, Alexander; Preisser, Felix; Michl, Uwe; Steuber, Thomas; Graefen, Markus; Huland, Hartwig; Karakiewicz, Pierre I; Tilki, Derya

2018-05-04

To analyze time trends and contemporary rates of postoperative complications after RP and to compare the complication profile of ORP and RALP using standardized reporting systems. Retrospective analysis of 13,924 RP patients in a single institution (2005 to 2015). Complications were collected during hospital stay and via standardized questionnaire 3 months after and grouped into eight schemes. Since 2013, the revised Clavien-Dindo classification was used (n = 4,379). Annual incidence rates of different complications were graphically displayed. Multivariable logistic regression analyses compared complications between ORP and RALP after inverse probability of treatment weighting (IPTW). After introduction of standardized classification systems, complication rates have increased with a contemporary rate of 20.6% (2013 - 2015). While minor Clavien-Dindo grades represented the majority (I: 10.6%; II: 7.9%), severe complications (grades IV-V) were rare (<1%). In logistic regression analyses after IPTW, RALP was associated with less blood loss, shorter catheterization time and lower risk for Clavien-Dindo grade II and III complications. Our results emphasize the importance of standardized reporting systems for quality control and comparison across approaches or institutions. Contemporary complication rates in a high volume center remain low and are most frequently minor Clavien-Dindo grades. RALP had a slightly better complication profile compared to ORP. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Spontaneous hemothorax: a rare complication of neurofibromatosis type 1].

PubMed

Fdil, Soumia; Bouchikhi, Saad; Bourkadi, Jamal-Eddine

2017-01-01

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen's disease is an autosomal dominant genetic disorder. It is the most common of phacomatoses. Pulmonary complications have been rarely described in the literature. Vascular complications have been reported in 3.6% of patients. We here report the case of a 38-year old female patient, followed-up for neurofibromatosis type 1, admitted to the Emergency Department with hemorrhagic shock. Clinical examination showed several coffee-with-milk colored spots, many plexiform neurofibromas, left-sided pleural effusion syndrome. Pleural puncture objectified coagulable haemorrhagic fluid. The patient received transfusion and emergency chest drainage. Patient's assessment was completed by angioscanner which showed no pulmonary embolism or other associated lesions. Spontaneous hemothorax is a rare and severe complication of neurofibromatosis. It is probably due to vascular injury caused by this disease.

[Gastroplasty: complications and their prevention].

PubMed

Schlienger, J L; Meyer, L; Rohr, S; Pradignac, A; Perrin, A E; Meyer, C; Simon, C

2003-02-01

Bariatric surgery is now frequently proposed for the treatment of morbid or complicated obesity since the introduction of minimally invasive laparoscopic anti-obesity operations such as the adjustable silicone gastric binding gastroplasty. However this reversible procedure in not always as safe as presumed and the results in weight loss may be sometimes disappointing. Side effects are common and early or late complications occured in more than 20% out of the patients. They are favoured by post operative eating disorders. Nutritional consequences are probably underestimated and are not limited to uncomfortable digestive symptoms. Some deficiencies in micronutriments have been described. The worsening of previous eating disorders or psychosocial abnormalities are not seldom. Gastroplasty is not an harmless procedure. A good selection in patients, a regular follow up, nutritional advices and psychosocial management by a multidisciplinar team are required to reduce complications after gastroplasty.

Cost-Effectiveness Analysis of Universal Influenza Vaccination: Application of Susceptible-Infectious-Complication-Recovery Model.

PubMed

Yang, Kuen-Cheh; Hung, Hui-Fang; Chen, Meng-Kan; Chen, Li-Sheng; Fann, Jean Ching-Yuan; Chiu, Sherry Yueh-Hsia; Yen, Amy-Ming Fang; Huang, Kuo-Chin; Chen, Hsiu-Hsi; Wang, Sen-Te

2018-06-12

Despite the fact that vaccination is an effective primary prevention strategy for containing influenza outbreak, health policymakers show great concern over enormous costs involved in universal immunization particularly when resources are limited. We conducted a two-arm cost-effectiveness analysis (CEA) that takes into account the aspect of herd immunity, using a study cohort that was composed of 100,000 residents with the make-up of demographic characteristics identical to those of the underlying population in Taipei County, Taiwan, during the epidemic influenza season of 2001-2002. The parameters embedded in the dynamic process of infection were estimated by the application of the newly proposed susceptible-infection-complication-recovery model to the empirical data in order to compute the number of deaths and complications averted due to universal vaccination compared to non-vaccination. Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curve (CEAC) given maximum amount of willingness-to-pay (WTP) were calculated to delineate the results of the two-arm CEA. Incremental costs involved in the vaccinated group as opposed to the unvaccinated group was $1,195 for reducing one additional complication and $805 for averting one additional death, allowing for herd immunity. The corresponding figures were higher for the results without considering herd immunity. Given the ceiling ratio of willingness-to-pay (WTP) equal to $10,000 (approximately two-thirds of the GDP), the probability of being cost-effective for vaccination was 100% and 96.7% for averting death and complications, respectively. Universal vaccination against seasonal influenza was very cost-effective particularly when herd immunity is considered. The probability of being cost-effective was almost certain given the maximum amount of WTP within two-thirds of the GDP. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

On Voxel based Iso-Tumor Control Probabilty and Iso-Complication Maps for Selective Boosting and Selective Avoidance Intensity Modulated Radiotherapy

PubMed Central

Kim, Yusung; Tomé, Wolfgang A.

2010-01-01

Summary Voxel based iso-Tumor Control Probability (TCP) maps and iso-Complication maps are proposed as a plan-review tool especially for functional image-guided intensity-modulated radiotherapy (IMRT) strategies such as selective boosting (dose painting) and conformal avoidance IMRT. The maps employ voxel-based phenomenological biological dose-response models for target volumes and normal organs. Two IMRT strategies for prostate cancer, namely conventional uniform IMRT delivering an EUD = 84 Gy (equivalent uniform dose) to the entire PTV and selective boosting delivering an EUD = 82 Gy to the entire PTV, are investigated, to illustrate the advantages of this approach over iso-dose maps. Conventional uniform IMRT did yield a more uniform isodose map to the entire PTV while selective boosting did result in a nonuniform isodose map. However, when employing voxel based iso-TCP maps selective boosting exhibited a more uniform tumor control probability map compared to what could be achieved using conventional uniform IMRT, which showed TCP cold spots in high-risk tumor subvolumes despite delivering a higher EUD to the entire PTV. Voxel based iso-Complication maps are presented for rectum and bladder, and their utilization for selective avoidance IMRT strategies are discussed. We believe as the need for functional image guided treatment planning grows, voxel based iso-TCP and iso-Complication maps will become an important tool to assess the integrity of such treatment plans. PMID:21151734

Breeding for polled dairy cows versus dehorning: Preliminary cost assessments & discussion

USDA-ARS?s Scientific Manuscript database

Dairy producers today face costs associated with dehorning heifers, including labor, equipment, and medications. Further, costs associated with decreased feed intake immediately following dehorning and possible complications requiring a veterinarian or antibiotics occur with some probability. The ob...

Bivariate categorical data analysis using normal linear conditional multinomial probability model.

PubMed

Sun, Bingrui; Sutradhar, Brajendra

2015-02-10

Bivariate multinomial data such as the left and right eyes retinopathy status data are analyzed either by using a joint bivariate probability model or by exploiting certain odds ratio-based association models. However, the joint bivariate probability model yields marginal probabilities, which are complicated functions of marginal and association parameters for both variables, and the odds ratio-based association model treats the odds ratios involved in the joint probabilities as 'working' parameters, which are consequently estimated through certain arbitrary 'working' regression models. Also, this later odds ratio-based model does not provide any easy interpretations of the correlations between two categorical variables. On the basis of pre-specified marginal probabilities, in this paper, we develop a bivariate normal type linear conditional multinomial probability model to understand the correlations between two categorical variables. The parameters involved in the model are consistently estimated using the optimal likelihood and generalized quasi-likelihood approaches. The proposed model and the inferences are illustrated through an intensive simulation study as well as an analysis of the well-known Wisconsin Diabetic Retinopathy status data. Copyright © 2014 John Wiley & Sons, Ltd.

The value of fine needle aspiration and cytologic examination of impalpable complicated breast cysts.

PubMed

Tez, Selda; Dener, Cenap; Köktener, Aslý; Caydere, Muzaffer; Tez, Mesut

2008-01-01

The purpose of the study was to evaluate the utility of fine needle aspiration--FNA and cytologic analysis of impalpable complicated breast cysts. We rewieved the imaging findings, aspiration, cytology and biopsy results and followup imaging findings of 246 complicated cysts in 166 women retrospectively. FNA was performed in 169 out of the 246 complicated cysts. Thirtyone lesions were followed-up with US. Surgical biopsy was performed from five lesions. No malignant cells (137 cysts), insufficient cellular material (17 cysts), atypical cells (4 cysts) were seen in cytological examination of the aspirates. None of these lesions were found to represent malignancy at the time of surgical excision and during follow-up. Impalpable complicated breast cysts may be classified as probably benign and can be managed with follow-up imaging studies instead of intervention. Routine cytologic examination is unnecessary if the fluid is not bloody (Tab. 2, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

INCLUDING TRANSITION PROBABILITIES IN NEST SURVIVAL ESTIMATION: A MAYFIELD MARKOV CHAIN

EPA Science Inventory

This manuscript is primarily an exploration of the statistical properties of nest-survival estimates for terrestrial songbirds. The Mayfield formulation described herein should allow researchers to test for complicated effects of stressors on daily survival and overall success, i...

Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

NASA Astrophysics Data System (ADS)

Barón-Aznar, C.; Moreno-Jiménez, S.; Celis, M. A.; Lárraga-Gutiérrez, J. M.; Ballesteros-Zebadúa, P.

2008-08-01

Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScansoftware, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

Application of thoracic endovascular aortic repair (TEVAR) in treating dwarfism with Stanford B aortic dissection: A case report.

PubMed

Qiu, Jian; Cai, Wenwu; Shu, Chang; Li, Ming; Xiong, Qinggen; Li, Quanming; Li, Xin

2018-04-01

To apply thoracic endovascular aortic repair (TEVAR) to treat dwarfism complicated with Stanford B aortic dissection. In this report, we presented a 63-year-old male patient of dwarfism complicated with Stanford B aortic dissection successfully treated with TEVAR. He was diagnosed with dwarfism complicated with Stanford B aortic dissection. After conservative treatment, the male patient underwent TEVAR at 1 week after hospitalization. After operation, he presented with numbness and weakness of his bilateral lower extremities, and these symptoms were significantly mitigated after effective treatment. At 1- and 3-week after TEVAR, the aorta status was maintained stable and restored. The patient obtained favorable clinical prognosis and was smoothly discharged. During subsequent follow-up, he remained physically stable. TEVAR is probably an option for treating dwarfism complicated with Stanford B aortic dissection, which remains to be validated by subsequent studies with larger sample size.

Using the Reliability Theory for Assessing the Decision Confidence Probability for Comparative Life Cycle Assessments.

PubMed

Wei, Wei; Larrey-Lassalle, Pyrène; Faure, Thierry; Dumoulin, Nicolas; Roux, Philippe; Mathias, Jean-Denis

2016-03-01

Comparative decision making process is widely used to identify which option (system, product, service, etc.) has smaller environmental footprints and for providing recommendations that help stakeholders take future decisions. However, the uncertainty problem complicates the comparison and the decision making. Probability-based decision support in LCA is a way to help stakeholders in their decision-making process. It calculates the decision confidence probability which expresses the probability of a option to have a smaller environmental impact than the one of another option. Here we apply the reliability theory to approximate the decision confidence probability. We compare the traditional Monte Carlo method with a reliability method called FORM method. The Monte Carlo method needs high computational time to calculate the decision confidence probability. The FORM method enables us to approximate the decision confidence probability with fewer simulations than the Monte Carlo method by approximating the response surface. Moreover, the FORM method calculates the associated importance factors that correspond to a sensitivity analysis in relation to the probability. The importance factors allow stakeholders to determine which factors influence their decision. Our results clearly show that the reliability method provides additional useful information to stakeholders as well as it reduces the computational time.

[Graft-versus-host disease, a rare complication of lung transplantation].

PubMed

Morisse-Pradier, H; Nove-Josserand, R; Philit, F; Senechal, A; Berger, F; Callet-Bauchu, E; Traverse-Glehen, A; Maury, J-M; Grima, R; Tronc, F; Mornex, J-F

2016-02-01

Graft-versus-host disease (GVHD) is a classic and frequent multisystemic complication of bone marrow allografts. It has also been reported after the transplantation of solid organs such as the liver or gut. Recent cases of GVHD have been reported after lung and heart-lung transplant. Skin, liver, gastrointestinal tract and bone marrow are the organ preferentially affected by GVHD. Corticosteroid is the first line treatment of GVHD. The prognosis reported in solid organ transplants is poor with infectious complications favoured by immunosuppressive therapy. In this article, we report a case of a patient with cystic fibrosis who presented a probable GVHD 18 months after a lung transplant and a literature review of similar cases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Metachronous Lung Cancer: Clinical Characteristics and Effects of Surgical Treatment.

PubMed

Rzechonek, Adam; Błasiak, Piotr; Muszczyńska-Bernhard, Beata; Pawełczyk, Konrad; Pniewski, Grzegorz; Ornat, Maciej; Grzegrzółka, Jędrzej; Brzecka, Anna

2018-01-01

The occurrence of a second lung tumor after surgical removal of lung cancer usually indicates a lung cancer metastasis, but sometimes a new lesion proves to be a new primary lung cancer, i.e., metachronous lung cancer. The goal of the present study was to conduct a clinical evaluation of patients with metachronous lung cancer and lung cancer metastasis, and to compare the early and distant outcomes of surgical treatment in both cancer types. There were 26 age-matched patients with lung cancer metastases and 23 patients with metachronous lung cancers, who underwent a second lung cancer resection. We evaluated the histological type of a resected cancer, the extent of thoracosurgery, the frequency of early postoperative complications, and the probability of 5-year survival after the second operation. The findings were that metachronous lung cancer was adenocarcinoma in 52% of patients, with a different histopathological pattern from that of the primary lung cancer in 74% of patients. In both cancer groups, mechanical resections were the most common surgery type (76% of all cases), with anatomical resections such as segmentectomy, lobectomy, or pneumectomy being much rarer conducted. The incidence of early postoperative complications in metachronous lung cancer and lung cancer metastasis (30% vs. 31%, respectively) and the probability of 5-year survival after resection of either cancer tumor (60.7% vs. 50.9%, respectively) were comparable. In conclusion, patients undergoing primary lung cancer surgery require a long-term follow-up due to the risk of metastatic or metachronous lung cancer. The likelihood of metachronous lung cancer and pulmonary lung cancer metastases, the incidence of postoperative complications, and the probability of 5-year survival after resection of metachronous lung cancer or lung cancer metastasis are similar.

Diagnosis of Exclusion: A Case Report of Probable Glatiramer Acetate-Induced Eosinophilic Myocarditis

PubMed Central

Michaud, Christopher J.; Bockheim, Heather M.; Daum, Timothy E.

2014-01-01

Importance. Medication-induced eosinophilia is an acknowledged, often self-limiting occurrence. Glatiramer acetate, a biologic injection used in the management of relapsing-remitting multiple sclerosis, is widely regarded as a safe and effective medication and lists eosinophilia as an infrequent side effect in its package insert. Contrary to reports of transient, benign drug-induced eosinophilia, we describe a case of probable glatiramer acetate-induced eosinophilia that ultimately culminated in respiratory distress, shock, and eosinophilic myocarditis. Observations. A 59-year-old female was admitted to the hospital after routine outpatient labs revealed leukocytosis (43,000 cells/mm3) with pronounced hypereosinophilia (63%). This patient had been using glatiramer acetate without complication for over 10 years prior to admission. Leukocytosis and hypereosinophilia persisted as a myriad of diagnostic evaluations returned negative, ultimately leading to respiratory depression, shock, and myocarditis. Glatiramer acetate was held for the first time on day 6 of the hospital stay with subsequent resolution of leukocytosis, hypereosinophilia, respiratory distress, and shock. Conclusions and Relevance. Glatiramer acetate was probably the cause of this observed hypereosinophilia and the resulting complications. Reports of glatiramer-induced eosinophilia are rare, and few case reports regarding medication-induced hypereosinophilia describe the severe systemic manifestations seen in this patient. PMID:25105037

Diagnosis of exclusion: a case report of probable glatiramer acetate-induced eosinophilic myocarditis.

PubMed

Michaud, Christopher J; Bockheim, Heather M; Nabeel, Muhammad; Daum, Timothy E

2014-01-01

Importance. Medication-induced eosinophilia is an acknowledged, often self-limiting occurrence. Glatiramer acetate, a biologic injection used in the management of relapsing-remitting multiple sclerosis, is widely regarded as a safe and effective medication and lists eosinophilia as an infrequent side effect in its package insert. Contrary to reports of transient, benign drug-induced eosinophilia, we describe a case of probable glatiramer acetate-induced eosinophilia that ultimately culminated in respiratory distress, shock, and eosinophilic myocarditis. Observations. A 59-year-old female was admitted to the hospital after routine outpatient labs revealed leukocytosis (43,000 cells/mm(3)) with pronounced hypereosinophilia (63%). This patient had been using glatiramer acetate without complication for over 10 years prior to admission. Leukocytosis and hypereosinophilia persisted as a myriad of diagnostic evaluations returned negative, ultimately leading to respiratory depression, shock, and myocarditis. Glatiramer acetate was held for the first time on day 6 of the hospital stay with subsequent resolution of leukocytosis, hypereosinophilia, respiratory distress, and shock. Conclusions and Relevance. Glatiramer acetate was probably the cause of this observed hypereosinophilia and the resulting complications. Reports of glatiramer-induced eosinophilia are rare, and few case reports regarding medication-induced hypereosinophilia describe the severe systemic manifestations seen in this patient.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

PubMed

Harden, Cynthia L; Hopp, Jennifer; Ting, Tricia Y; Pennell, Page B; French, Jacqueline A; Allen Hauser, W; Wiebe, Samuel; Gronseth, Gary S; Thurman, David; Meador, Kimford J; Koppel, Barbara S; Kaplan, Peter W; Robinson, Julian N; Gidal, Barry; Hovinga, Collin A; Wilner, Andrew N; Vazquez, Blanca; Holmes, Lewis; Krumholz, Allan; Finnell, Richard; Le Guen, Claire

2009-05-01

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

Paraplegia after contrast media application: a transient or devastating rare complication? Case report.

PubMed

Mielke, Dorothee; Kallenberg, Kai; Hartmann, Marius; Rohde, Veit

2016-05-01

The authors report the case of a 76-year-old man with a spinal dural arteriovenous fistula. The patient suffered from sudden repeated reversible paraplegia after spinal digital subtraction angiography as well as CT angiography. Neurotoxicity of contrast media (CM) is the most probable cause for this repeated short-lasting paraplegia. Intolerance to toxicity of CM to the vulnerable spinal cord is rare, and probably depends on the individual patient. This phenomenon is transient and can occur after both intraarterial and intravenous CM application.

The Effect of Resident Involvement in Pelvic Prolapse Surgery: A Retrospective Study From a Nationwide Inpatient Sample.

PubMed

Caveney, Maxx; Matthews, Catherine; Mirzazadeh, Majid

The primary aim of this study was to assess the effect of resident involvement on perioperative complication rates in pelvic organ prolapse surgery using the National Surgical Quality Improvement database. All pelvic organ prolapse operations from 2006 to 2012 were identified and dichotomized by resident participation. Preoperative characteristics and 30-day perioperative outcomes were compared using χ and Student t test. To control for nonrandomization of cases, propensity scores representing the probability of resident involvement as a function of a case's comorbidities were calculated. They were then divided into quartiles, and because of equal probabilities for the first and second quartiles, 3 groups were created (Q1/2, Q3, and Q4), followed by substratification and analysis. As a control, complications of transurethral resection of prostate and nephrectomy were dichotomized by resident involvement. We identified 2637 cases. Resident involvement was associated with increased postoperative urinary tract infections, perioperative complications, and procedure length. After stratification by propensity scoring, the following unique findings occurred in each group: in the first group, resident involvement was associated with increased rates of readmission, pulmonary embolism, and sepsis; in the second and third groups, resident involvement was associated with increased rates of superficial surgical site infection. Resident involvement in nephrectomy observed increased perioperative complications and procedural length. In prostate resection, increased procedure lengths and decreased postoperative length of stay were observed. Resident involvement in pelvic organ prolapse surgery was associated with an increased risk of adverse outcomes. A similar effect was seen with nephrectomy but not with a more simple endoscopic urologic procedure.

Outcomes following total laryngectomy for squamous cell carcinoma: one centre experience.

PubMed

Leong, S C; Kartha, S-S; Kathan, C; Sharp, J; Mortimore, S

2012-12-01

To evaluate the clinical outcomes of total laryngectomy (TL), complications and factors affecting survival. Retrospective review of hospital electronic database for head and neck squamous cell carcinoma (SCCa). Large district general hospital in England, United Kingdom. Patients who had TL between January 1994 and January 2008. 5-year disease specific survival (DSS) and disease-free survival (DFS). Seventy-one patients were reviewed, of whom 38 (54%) had laryngeal SCCa and 33 (46%) hypopharyngeal SCCa. The overall mean survival period following TL was 42.4 months. The 5-year DSS and DFS was better for laryngeal SCCa compared to hypopharyngeal SCCa, although not statistically significant (P=0.090, P=0.54 respectively). Patients treated for laryngeal SCCa had a mean survival period of 47.5 months compared to 36.5 months for hypopharyngeal disease. Those who had laryngeal recurrence after primary radiotherapy (RT) demonstrated statistically better survival probability than those who had hypopharyngeal recurrence (P=0.011). Patients without cervical lymphadenopathy had statistically better survival (P=0.049). The most common early complication was related to the cardiorespiratory system. One fatal complication of erosion of the brachiocephalic artery due to the laryngectomy tube was noted. The most common late complication was neopharyngeal stenosis. The commonest cause of death was due to locoregional recurrence, followed by medical co-morbidities. Patients referred to specialised head and neck clinic had a better survival probability than those referred to a general ENT clinic (P=0.37). While there is increasing tendency towards laryngeal conservation, total laryngectomy remains a robust treatment option in selected patients. Copyright © 2012. Published by Elsevier Masson SAS.

Intraoperative and early postoperative complications of manual sutureless cataract extraction.

PubMed

Iqbal, Yasir; Zia, Sohail; Baig Mirza, Aneeq Ullah

2014-04-01

To determine the intraoperative and early postoperative complications of manual sutureless cataract extraction. Case series. Redo Eye Hospital, Rawalpindi, Pakistan, from January 2009 to December 2010. Three hundred patients of cataract through purposive non-probability sampling were selected. The patients underwent manual sutureless cataract surgery (MSCS) by single experienced surgeon and intraoperative complications were documented. The surgical technique was modified to deal with any intraoperative complications accordingly. Patients were examined on the first postoperative day and on the first postoperative week for any postoperative complications. The data was entered in Statistical Package for Social Sciences (SPSS) version 13.0 and the results were calculated in frequencies. Among the 300 cases, 81.3% surgeries went uneventful whereas 18.6% had some complication. The common intraoperative complications were superior button-hole formation in 5%; posterior capsular rent in 5% and premature entry with iris prolapse in 3% cases. Postoperatively, the commonly encountered complications were striate keratopathy in 9.6% and hyphema 9%. At first week follow-up, 4% had striate keratopathy and 0.6% had hyphema. Striate keratopathy resolved with topical medication on subsequent follow-up. A total of 9 cases (3%) underwent second surgery: 2 cases for lens matter wash, 2 cases for hyphema and 5 cases needed suturing of wound for shallow anterior chamber due to wound leak. Superior button-hole formation, posterior capsular rent and premature entry were the common intraoperative complications of MSCS whereas the common early postoperative complications were striate keratopathy and hyphema.

Dose- and LET-painting with particle therapy.

PubMed

Bassler, Niels; Jäkel, Oliver; Søndergaard, Christian Skou; Petersen, Jørgen B

2010-10-01

Tumour hypoxia is one of the limiting factors in obtaining tumour control in radiotherapy. The high-LET region of a beam of heavy charged particles such as carbon ions is located in the distal part of the Bragg peak. A modulated or spread out Bragg peak (SOBP) is a weighted function of several Bragg peaks at various energies, which however results in a dilution of the dose-average LET in the target volume. Here, we investigate the possibility to redistribute the LET by dedicated treatment plan optimisation, in order to maximise LET in the target volume. This may be a strategy to potentially overcome hypoxia along with dose escalation or dose painting. The high-LET region can be shaped in very different ways, while maintaining the distribution of the absorbed dose or biological effective dose. Treatment plans involving only carbon ion beams, show very different LET distributions depending on how the fields are arranged. Alternatively, a LET boost can be applied in multi-modal treatment planning, such as combining carbon ions with protons and/or photons. For such mixed radiation modalities, significant "LET boosts" can be achieved at nearly arbitrary positions within the target volume. Following the general understanding of the relationship between hypoxia, LET and the oxygen enhancement ratio (OER), we conclude, that an additional therapeutic advantage can be achieved by confining the high-LET part of the radiation in hypoxic compartments of the tumour, and applying low-LET radiation to the normoxic tissue. We also anticipate that additional advantages may be achieved by deliberate sparing of normal tissue from high LET regions. Consequently, treatment planning based on simultaneous dose and LET optimisation has a potential to achieve higher tumour control and/or reduced normal tissue control probability (NTCP).

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bakhshandeh, Mohsen; Hashemi, Bijan, E-mail: bhashemi@modares.ac.ir; Mahdavi, Seied Rabi Mehdi

Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-basedmore » treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with {alpha}/{beta} = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D{sub 50} estimated from the models was approximately 44 Gy. Conclusions: The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.« less

Principal Score Methods: Assumptions, Extensions, and Practical Considerations

ERIC Educational Resources Information Center

Feller, Avi; Mealli, Fabrizia; Miratrix, Luke

2017-01-01

Researchers addressing posttreatment complications in randomized trials often turn to principal stratification to define relevant assumptions and quantities of interest. One approach for the subsequent estimation of causal effects in this framework is to use methods based on the "principal score," the conditional probability of belonging…

Mechanical Parametric Oscillations and Waves

ERIC Educational Resources Information Center

Dittrich, William; Minkin, Leonid; Shapovalov, Alexander S.

2013-01-01

Usually parametric oscillations are not the topic of general physics courses. Probably it is because the mathematical theory of this phenomenon is relatively complicated, and until quite recently laboratory experiments for students were difficult to implement. However parametric oscillations are good illustrations of the laws of physics and can be…

Economic considerations of breeding for polled dairy cows versus dehorning in the United States

USDA-ARS?s Scientific Manuscript database

Dairy producers today face labor, equipment, and medical costs associated with dehorning heifers. Further, complications requiring veterinary intervention occur with some probability. The objective of this work is to develop preliminary cost estimates of selecting for polled dairy heifers. Stochasti...

Scientific assessment of accuracy, skill and reliability of ocean probabilistic forecast products.

NASA Astrophysics Data System (ADS)

Wei, M.; Rowley, C. D.; Barron, C. N.; Hogan, P. J.

2016-02-01

As ocean operational centers are increasingly adopting and generating probabilistic forecast products for their customers with valuable forecast uncertainties, how to assess and measure these complicated probabilistic forecast products objectively is challenging. The first challenge is how to deal with the huge amount of the data from the ensemble forecasts. The second one is how to describe the scientific quality of probabilistic products. In fact, probabilistic forecast accuracy, skills, reliability, resolutions are different attributes of a forecast system. We briefly introduce some of the fundamental metrics such as the Reliability Diagram, Reliability, Resolution, Brier Score (BS), Brier Skill Score (BSS), Ranked Probability Score (RPS), Ranked Probability Skill Score (RPSS), Continuous Ranked Probability Score (CRPS), and Continuous Ranked Probability Skill Score (CRPSS). The values and significance of these metrics are demonstrated for the forecasts from the US Navy's regional ensemble system with different ensemble members. The advantages and differences of these metrics are studied and clarified.

Evaluation of high myopia complications prevention program in university freshmen

PubMed Central

Tseng, Gow-Lieng; Chen, Cheng-Yu

2016-01-01

Abstract High myopia is a global eye health problem because of its high incidence of sight-threatening complications. Due to the role of awareness, self-examination, and preventive behavior in prevention of morbidity of high myopia complications, promoting knowledge, capabilities, and attitude of high myopic personnel are required in this regard. In this quasi-experiment study, 31 freshmen with high myopia in a national university were enrolled in 2014. The data were collected by validated and reliable questionnaire based on health belief model (HBM) and self-efficacy theory. The intervention program consisted of 1 educational session lasting 150 minutes by lecturing of high myopia complications, virtual reality experiencing, similarity modeling, and quibbling a film made on high myopia complications preventive concepts. Implementing the educational program showed immediate effect in knowledge, perceived susceptibility, perceived severity, self-efficacy, and preventive behavior intention. While 6 weeks after the educational program, significant increases were observed in cues to action, self-efficacy, and preventive behavior intention. This article provided that, after a single session, there was positive improvement in high myopia complication prevention behavior intention among participants. These positive effects confirmed the efficacy of the education program and will probably induce behavior change. PMID:27749586

Evaluation of high myopia complications prevention program in university freshmen.

PubMed

Tseng, Gow-Lieng; Chen, Cheng-Yu

2016-10-01

High myopia is a global eye health problem because of its high incidence of sight-threatening complications. Due to the role of awareness, self-examination, and preventive behavior in prevention of morbidity of high myopia complications, promoting knowledge, capabilities, and attitude of high myopic personnel are required in this regard.In this quasi-experiment study, 31 freshmen with high myopia in a national university were enrolled in 2014. The data were collected by validated and reliable questionnaire based on health belief model (HBM) and self-efficacy theory. The intervention program consisted of 1 educational session lasting 150 minutes by lecturing of high myopia complications, virtual reality experiencing, similarity modeling, and quibbling a film made on high myopia complications preventive concepts.Implementing the educational program showed immediate effect in knowledge, perceived susceptibility, perceived severity, self-efficacy, and preventive behavior intention. While 6 weeks after the educational program, significant increases were observed in cues to action, self-efficacy, and preventive behavior intention.This article provided that, after a single session, there was positive improvement in high myopia complication prevention behavior intention among participants. These positive effects confirmed the efficacy of the education program and will probably induce behavior change.

Current techniques and outcomes in hysteroscopic sterilization: current evidence, considerations, and complications with hysteroscopic sterilization micro inserts.

PubMed

Casey, James; Cedo-Cintron, Laura; Pearce, Jessica; Yunker, Amanda

2017-08-01

To describe the current data regarding effectiveness, complications, postoperative evaluation, and surgical interventions associated with Essure hysteroscopic sterilization. Hysteroscopic sterilization is a commonly performed procedure that is offered as a well tolerated, effective, outpatient method of permanent sterilization. Over the past several years, concerns have been raised regarding correct placement and postoperative complications. This has led to statements by both the Food and Drug Administration (FDA) in October, 2016 and American Association of Gynecologic Laparoscopists in February, 2017, as a significant portion of women seek removal of these devices. A current black-box warning issued by the FDA in 2016 recommends discussion of 'the probabilities of rates or events' of adverse outcomes associated with Essure placement. Although hysteroscopic sterilization is usually a safe, effective option for permanent contraception, new evidence regarding complications has emphasized the need for proper education and counseling. Appropriate patient selection and knowledge of potential complications is paramount to ensuring patients, and medical providers are well informed and have realistic expectations regarding potential placement and postoperative issues.

Visual Prognosis and Ocular Complications in Herpetic versus HLA-B27- or Ankylosing Spondylitis-associated Anterior Uveitis.

PubMed

Hoeksema, Lisette; Los, Leonoor I

2016-06-01

To investigate the visual prognosis and ocular complications in patients with herpetic versus HLA-B27 associated anterior uveitis (AU). This was a retrospective, observational study conducted at the ophthalmology department of the University Medical Center of Groningen. Sixty-two herpetic and 113 HLA-B27-associated AU patients were included. The main outcome measures were visual acuity and ocular complications. Visual acuity over time was significantly lower in herpetic as compared to HLA-B27 AU, mainly due to corneal scarring. The incidence rate of any ocular complication was higher in herpetic AU compared to HLA-B27-associated AU (0.140/EY versus 0.076/EY, p = <0.001), which was mainly due to glaucoma (0.033/EY versus 0.004/EY, p < 0.001) and cataract (0.059/EY versus 0.023/EY, p < 0.001). The most prominent finding was a worse visual prognosis in herpetic AU, which is probably related to higher prevalence of corneal scarring and glaucoma. In addition, herpetic AU patients have more ocular complications overall.

[Polycystic ovary syndrome: an example of obesity-related cardiovascular complication affecting young women].

PubMed

Orio, Francesco; Cascella, Teresa; Giallauria, Francesco; Palomba, Stefano; De Lorenzo, Anna; Lucci, Rosa; Ambrosino, Elena; Lombardi, Gaetano; Colao, Annamaria; Vigorito, Carlo

2006-03-01

Polycystic ovary syndrome (PCOS) is a good example of obesity-related cardiovascular complication affecting young women. PCOS is not only considered a reproductive problem but rather represents a complex endocrine, multifaceted syndrome with important health implications. Several evidences suggest an increased cardiovascular risk of cardiovascular disease associated with this syndrome, characterized by an impairment of heart structure and function, endothelial dysfunction and lipid abnormalities. All these features, probably linked to insulin-resistance, are often present in obese PCOS patients. Cardiovascular abnormalities represent important long-term sequelae of PCOS that need further investigations.

Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baron-Aznar, C.; Moreno-Jimenez, S.; Celis, M. A.

2008-08-11

Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScan(c) software, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

A Guide to the Gynoecium

ERIC Educational Resources Information Center

Burrows, G. E.

2010-01-01

Understanding flower structure is important from many perspectives such as keying out plants, understanding fruit structure, investigating pollinator biology and in plant breeding. Probably the most complicated parts of a flower are the female components (the gynoecium). Unfortunately, in many parts of the world, it is not possible for much of the…

Lighten the Load

ERIC Educational Resources Information Center

Kennedy, Mike

2008-01-01

The green movement in school design encompasses many techniques to improve the environmental friendliness and energy efficiency of a facility. Some are more complicated than others--probably not many people can explain the intricacies of a geothermal heating system, or the specifics of how solar or wind energy is harnessed. Most people, however,…

Current best management practices for harvesting and storing dry hay: a research review

USDA-ARS?s Scientific Manuscript database

The production of high-quality grass or legume hays in humid environments is complicated by slower drying rates, and increased probability of rainfall events compared to hay produced under arid climatic conditions. As a result, hay producers in humid environments often face the management dilemma of...

Application of thoracic endovascular aortic repair (TEVAR) in treating dwarfism with Stanford B aortic dissection

PubMed Central

Qiu, Jian; Cai, Wenwu; Shu, Chang; Li, Ming; Xiong, Qinggen; Li, Quanming; Li, Xin

2018-01-01

Abstract Rationale: To apply thoracic endovascular aortic repair (TEVAR) to treat dwarfism complicated with Stanford B aortic dissection. Patient concerns: In this report, we presented a 63-year-old male patient of dwarfism complicated with Stanford B aortic dissection successfully treated with TEVAR. Diagnoses: He was diagnosed with dwarfism complicated with Stanford B aortic dissection. Interventions: After conservative treatment, the male patient underwent TEVAR at 1 week after hospitalization. After operation, he presented with numbness and weakness of his bilateral lower extremities, and these symptoms were significantly mitigated after effective treatment. At 1- and 3-week after TEVAR, the aorta status was maintained stable and restored. Outcomes: The patient obtained favorable clinical prognosis and was smoothly discharged. During subsequent follow-up, he remained physically stable. Lessons: TEVAR is probably an option for treating dwarfism complicated with Stanford B aortic dissection, which remains to be validated by subsequent studies with larger sample size. PMID:29703033

Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeong, Eun Sook; Kim, Gabin; Shin, Ho Jung

A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30 mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague–Dawley (SD) rats for 28 days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence ofmore » compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity. - Highlights: • Endogenous metabolic profiles were assessed in rat after treatment of thioacetamide. • It significantly increased the levels of bile acids in serum but not in the liver. • Expression of the genes related to bile acid secretion and reuptake was decreased. • Increased serum bile acids result from block of enterohepatic circulation of bile acids.« less

Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

PubMed Central

Wang, Li; Collins, Carol; Kelly, Edward J.; Chu, Xiaoyan; Ray, Adrian S.; Salphati, Laurent; Xiao, Guangqing; Lee, Caroline; Lai, Yurong; Liao, Mingxiang; Mathias, Anita; Evers, Raymond; Humphreys, William; Hop, Cornelis E. C. A.; Kumer, Sean C.

2016-01-01

Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance–associated protein (MRP)2, MRP3, MRP4, sodium taurocholate–cotransporting polypeptide (NTCP), organic anion–transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers. Compared with control livers, the yield of membrane protein from alcoholic and hepatitis C cirrhosis livers was significantly reduced by 56 and 67%, respectively. The impact of liver cirrhosis on transporter protein expression was transporter-dependent. Generally, reduced protein expression (per gram of liver) was found in alcoholic cirrhosis livers versus control livers, with the exception that the expression of MRP3 was increased, whereas no change was observed for MATE1, MRP2, OATP2B1, and P-gp. In contrast, the impact of hepatitis C cirrhosis on protein expression of transporters (per gram of liver) was diverse, showing an increase (MATE1), decrease (BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp), or no change (BCRP, MRP3, OATP1B1, and 2B1). The expression of hepatobiliary transporter protein differed in different diseases (alcoholic versus hepatitis C cirrhosis). Finally, incorporation of protein expression of OATP1B1 in alcoholic cirrhosis into the Simcyp physiologically based pharmacokinetics cirrhosis module improved prediction of the disposition of repaglinide in liver cirrhosis patients. These transporter expression data will be useful in the future to predict transporter-mediated drug disposition in liver cirrhosis patients. PMID:27543206

Sensitization to autoimmune hepatitis in group VIA calcium-independent phospholipase A2-null mice led to duodenal villous atrophy with apoptosis, goblet cell hyperplasia and leaked bile acids.

PubMed

Jiao, Li; Gan-Schreier, Hongying; Tuma-Kellner, Sabine; Stremmel, Wolfgang; Chamulitrat, Walee

2015-08-01

Chronic bowel disease can co-exist with severe autoimmune hepatitis (AIH) in an absence of primary sclerosing cholangitis. Genetic background may contribute to this overlap syndrome. We previously have shown that the deficiency of iPLA2β causes an accumulation of hepatocyte apoptosis, and renders susceptibility for acute liver injury. We here tested whether AIH induction in iPLA2β-null mice could result in intestinal injury, and whether bile acid metabolism was altered. Control wild-type (WT) and female iPLA2β-null (iPLA2β(-/-)) mice were intravenously injected with 10mg/kg concanavalinA (ConA) or saline for 24h. ConA treatment of iPLA2β(-/-) mice caused massive liver injury with increased liver enzymes, fibrosis, and necrosis. While not affecting WT mice, ConA treatment of iPLA2β(-/-) mice caused severe duodenal villous atrophy concomitant with increased apoptosis, cell proliferation, globlet cell hyperplasia, and endotoxin leakage into portal vein indicating a disruption of intestinal barrier. With the greater extent than in WT mice, ConA treatment of iPLA2β(-/-) mice increased jejunal expression of innate response cytokines CD14, TNF-α, IL-6, and SOCS3 as well as chemokines CCL2 and the CCL3 receptor CCR5. iPLA2β deficiency in response to ConA-induced AIH caused a significant decrease in hepatic and biliary bile acids, and this was associated with suppression of hepatic Cyp7A1, Ntcp and ABCB11/Bsep and upregulation of intestinal FXR/FGF15 mRNA expression. The suppression of hepatic Ntcp expression together with the loss of intestinal barrier could account for the observed bile acid leakage into peripheral blood. Thus, enteropathy may result from acute AIH in a susceptible host such as iPLA2β deficiency. Copyright © 2015 Elsevier B.V. All rights reserved.

SU-E-T-275: Radiobiological Evaluation of Intensity Modulated Radiotherapy Treatment for Locally Advanced Head and Neck Squamous Cell Carcinomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rekha Reddy, B.; Ravikumar, M.; Tanvir Pasha, C.R

2014-06-01

Purpose: To evaluate the radiobiological outcome of Intensity Modulated Radiotherapy Treatment (IMRT) for locally advanced head and neck squamous cell carcinomas using HART (Histogram Analysis in Radiation Therapy; J Appl Clin Med Phys 11(1): 137–157, 2010) program and compare with the clinical outcomes. Methods: We have treated 20 patients of stage III and IV HNSCC Oropharynx and hypopharynx with accelerated IMRT technique and concurrent chemotherapy. Delineation of tumor and normal tissues were done using Danish Head and Neck Cancer Group (DAHANCA) contouring guidelines and radiotherapy was delivered to a dose of 70Gy in 35 fractions to the primary and involvedmore » lymph nodes, 63Gy to intermediate risk areas and 56 Gy to lower risk areas, Monday to Saturday, 6 Days/week using 6 MV Photons with an expected overall treatment time of 6 weeks. The TCP and NTCP's were calculated from the dose-volume histogram (DVH) statistics using the Poisson Statistics (PS) and JT Lyman models respectively and the Resultwas correlated with clinical outcomes of the patients with mean follow up of 24 months. Results: Using HART program, the TCP (0.89± 0.01) of primary tumor and the NTCP for parotids (0.20±0.12), spinal cord (0.05±0.01), esophagus (0.30±0.2), mandible (0.35±0.21), Oral cavity (0.37±0.18), Larynx (0.30±0.15) were estimated and correlated with clinical outcome of the patients. Conclusion: Accelerated IMRT with Chemotherapy is a clinical feasible option in the treatment of locally advanced HNSCC with encouraging initial tumour response and acceptable acute toxicities. The correlation between the clinical outcomes and radiobiological model estimated parameters using HART programs are found to be satisfactory.« less

Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats.

PubMed

Zhao, Wen; Zitzow, Jeremiah D; Weaver, Yi; Ehresman, David J; Chang, Shu-Ching; Butenhoff, John L; Hagenbuch, Bruno

2017-03-01

Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na+/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter. Furthermore, we demonstrated that the human apical sodium-dependent bile salt transporter (ASBT) contributes to the intestinal reabsorption of PFOS. However, so far no sodium-independent uptake transporters for PFSAs have been identified in human hepatocytes or enterocytes. In addition, perfluoroalkyl carboxylates (PFCAs) with 8 and 9 carbons were shown to preferentially distribute to the liver of rodents; however, no rat or human liver uptake transporters are known to transport these PFCAs. Therefore, we tested whether PFBS, PFHxS, PFOS, and PFCAs with 7-10 carbons are substrates of organic anion transporting polypeptides (OATPs). We used CHO and HEK293 cells to demonstrate that human OATP1B1, OATP1B3, and OATP2B1 can transport PFBS, PFHxS, PFOS, and the 2 PFCAs (C8 and C9). In addition, we show that rat OATP1A1, OATP1A5, OATP1B2, and OATP2B1 transport all 3 PFSAs. In conclusion, our results suggest that besides NTCP and ASBT, OATPs also are capable of contributing to the enterohepatic circulation and extended human serum elimination half-lives of the tested perfluoroalkyl acids. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Complications of subthalamic nucleus stimulation in Parkinson's disease.

PubMed

Umemura, Atsushi; Oka, Yuichi; Yamamoto, Kenichi; Okita, Kenji; Matsukawa, Noriyuki; Yamada, Kazuo

2011-01-01

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective for medically refractory Parkinson's disease. We retrospectively analyzed complications in 180 consecutive patients who underwent bilateral STN-DBS. Surgery-related complications were symptomatic intracerebral hemorrhage in 2, chronic subdural hematoma in 1, and transient deterioration of medication-induced psychosis in 2 patients. Device-related complications involved device infection in 5, skin erosion in 5, and implantable pulse generator malfunction in 2 patients. All of these patients required surgical repair. Surgery and device-related complications could be reduced with increased surgical experience and the introduction of new surgical equipment and technology. Treatment or stimulation-related complications were intractable dyskinesia/dystonia in 11, problematic dysarthria in 7, apraxia of eyelid opening (ALO) in 11, back pain in 10, and restless leg syndrome in 6 patients. Neuropsychiatric complications were transient mood changes in some, impulse control disorder in 2, severe depression related to excessive reduction of dopaminergic medications in 2, rapid progression of dementia in 1, and suicide attempts in 2 patients. Most complications were mild and transient. Dysarthria and ALO were the most frequent permanent sequelae after STN-DBS. Treatment-related adverse events may be caused not only by the effect of stimulation effect but also excessive reduction of dopaminergic medication, or progression of the disease. In conclusion, STN-DBS seems to be a relatively safe procedure. Although serious complications with permanent sequelae are rare, significant incidences of adverse effects occur. Physicians engaged in this treatment should have a comprehensive understanding of the probable complications and how to avoid them.

NAFLD fibrosis score: a prognostic predictor for mortality and liver complications among NAFLD patients.

PubMed

Treeprasertsuk, Sombat; Björnsson, Einar; Enders, Felicity; Suwanwalaikorn, Sompongse; Lindor, Keith D

2013-02-28

To study whether the severity of liver fibrosis estimated by the nonalcoholic fatty liver disease (NAFLD) fibrosis score can predict all-cause mortality, cardiac complications, and/or liver complications of patients with NAFLD over long-term follow-up. A cohort of well-characterized patients with NAFLD diagnosed during the period of 1980-2000 was identified through the Rochester Epidemiology Project. The NAFLD fibrosis score (NFS) was used to separate NAFLD patients with and without advanced liver fibrosis. We used the NFS score to classify the probability of fibrosis as < -1.5 for low probability, > -1.5 to < 0.67 for intermediate probability, and > 0.67 for high probability. Primary endpoints included all-cause death and cardiovascular- and/or liver-related mortality. From the 479 patients with NAFLD assessed, 302 patients (63%) greater than 18 years old were included. All patients were followed, and medical charts were reviewed until August 31, 2009 or the date when the first primary endpoint occurred. By using a standardized case record form, we recorded a detailed history and physical examination and the use of statins and metformin during the follow-up period. A total of 302/479 (63%) NAFLD patients (mean age: 47 ± 13 year) were included with a follow-up period of 12.0 ± 3.9 year. A low probability of advanced fibrosis (NFS < -1.5 at baseline) was found in 181 patients (60%), while an intermediate or high probability of advanced fibrosis (NSF > -1.5) was found in 121 patients (40%). At the end of the follow-up period, 55 patients (18%) developed primary endpoints. A total of 39 patients (13%) died during the follow-up. The leading causes of death were non-hepatic malignancy (n = 13/39; 33.3%), coronary heart disease (CHD) (n = 8/39; 20.5%), and liver-related mortality (n = 5/39; 12.8%). Thirty patients had new-onset CHD, whereas 8 of 30 patients (27%) died from CHD-related causes during the follow-up. In a multivariate analysis, a higher NFS at baseline and the presence of new-onset CHD were significantly predictive of death (OR = 2.6 and 9.2, respectively; P < 0.0001). Our study showed a significant, graded relationship between the NFS, as classified into 3 subgroups (low, intermediate and high probability of liver fibrosis), and the occurrence of primary endpoints. The use of metformin or simvastatin for at least 3 mo during the follow-up was associated with fewer deaths in patients with NAFLD (OR = 0.2 and 0.03, respectively; P < 0.05). Additionally, the rate of annual NFS change in patients with an intermediate or high probability of advanced liver fibrosis was significantly lower than those patients with a low probability of advanced liver fibrosis (0.06 vs 0.09, P = 0.004). The annual NFS change in patients who died was significantly higher than those in patients who survived (0.14 vs 0.07, P = 0.03). At the end of the follow-up, we classified the patients into 3 subgroups according to the progression pattern of liver fibrosis by comparing the NFS at baseline to the NFS at the end of the follow-up period. Most patients were in the stable-fibrosis (60%) and progressive-fibrosis (37%) groups, whereas only 3% were in the regressive fibrosis. A higher NAFLD fibrosis score at baseline and a new onset of CHD were significantly predictive of death in patients with NAFLD.

Treatment of benign esophageal stricture by Eder-Puestow or balloon dilators: a comparison between randomized and prospective nonrandomized trials.

PubMed

Yamamoto, H; Hughes, R W; Schroeder, K W; Viggiano, T R; DiMagno, E P

1992-03-01

To determine whether the natural history of strictures is affected by the type of dilator used to treat newly diagnosed peptic strictures, we designed a prospective randomized trial to compare the results after Eder-Puestow or Medi-Tech balloon dilation. We entered 31 patients into the trial. We also prospectively followed up all 92 nonrandomized patients who underwent their first dilation for a benign stricture during the same period as the prospective randomized trial. The nonrandomized patients also underwent dilation with either the Eder-Puestow or the balloon technique at the discretion of the gastroenterologist performing the endoscopy. We found no statistically significant differences in the immediate or long-term results of the two methods among the randomized, nonrandomized, and overall combined groups. All but 1 of the 123 patients had immediate relief of dysphagia. Within each group of patients, the probability of remaining free of dysphagia 1 year after the initial dilation was approximately 20%, and the probability of not requiring a second dilation was approximately 65% with either technique. Major (esophageal rupture) and minor (bleeding or chest pain) complications occurred in 1% and 5% of the patients and 0.4% and 3% of the total dilation procedures, respectively. The esophageal rupture and four of six minor complications occurred after repeated dilations. Five of the six minor complications occurred with use of the Eder-Puestow dilators. We conclude that Eder-Puestow and balloon dilations of benign esophageal strictures are associated with similar outcomes, but repeated dilations and the Eder-Puestow technique may be associated with an increased risk of complications.