Adaptive fractionation therapy: II. Biological effective dose.
Chen, Mingli; Lu, Weiguo; Chen, Quan; Ruchala, Kenneth; Olivera, Gustavo
2008-10-07
Radiation therapy is fractionized to differentiate the cell killing between the tumor and organ at risk (OAR). Conventionally, fractionation is done by dividing the total dose into equal fraction sizes. However, as the relative positions (configurations) between OAR and the tumor vary from fractions to fractions, intuitively, we want to use a larger fraction size when OAR and the tumor are far apart and a smaller fraction size when OAR and the tumor are close to each other. Adaptive fractionation accounts for variations of configurations between OAR and the tumor. In part I of this series, the adaptation minimizes the OAR (physical) dose and maintains the total tumor (physical) dose. In this work, instead, the adaptation is based on the biological effective dose (BED). Unlike the linear programming approach in part I, we build a fraction size lookup table using mathematical induction. The lookup table essentially describes the fraction size as a function of the remaining tumor BED, the OAR/tumor dose ratio and the remaining number of fractions. The lookup table is calculated by maximizing the expected survival of OAR and preserving the tumor cell kill. Immediately before the treatment of each fraction, the OAR-tumor configuration and thus the dose ratio can be obtained from the daily setup image, and then the fraction size can be determined by the lookup table. Extensive simulations demonstrate the effectiveness of our method compared with the conventional fractionation method.
Radiotherapy Dose Fractionation under Parameter Uncertainty
Davison, Matt; Kim, Daero; Keller, Harald
2011-11-30
In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.
Effects of Proton Radiation Dose, Dose Rate and Dose Fractionation on Hematopoietic Cells in Mice
Ware, J. H.; Sanzari, J.; Avery, S.; Sayers, C.; Krigsfeld, G.; Nuth, M.; Wan, X. S.; Rusek, A.; Kennedy, A. R.
2012-01-01
The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05–0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons. PMID:20726731
Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice.
Ware, J H; Sanzari, J; Avery, S; Sayers, C; Krigsfeld, G; Nuth, M; Wan, X S; Rusek, A; Kennedy, A R
2010-09-01
The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.
Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice
Ware, J.H.; Rusek, A.; Sanzari, J.; Avery, S.; Sayers, C.; Krigsfeld, G.; Nuth, M.; Wan, X.S.; Kennedy, A.R.
2010-09-01
The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.
Bentzen, Søren M
2005-01-01
Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.
[Diagnosis of uveitis with fractional doses of 32-P radionuclide].
Shambra, V V; Panfilova, G V
1989-01-01
For determination of the presence and activity of inflammation in the vascular coat of the eye as well as of the stopping of the disease, the authors propose to use radionuclide 32-P in a form of fractional doses in contradistinction to a single administration of a conventional dose. A common dose of the preparation is divided into four equal parts. At first, 1/4 of the dose is administered. One hour later, comparative external radiometry of the patient and the healthy eye is made. If there is seen no clear difference in intensity of accumulation, the second dose is administered. One hour later, repeated examination is made. After receiving clear data, further administration of the preparation is stopped. Administration of fractional doses suggests a decrease of ray load on the patient's organism, economy of the preparation without lowering the authenticity of examination.
Dose fractionation and biological optimization in carcinoma of the prostate.
Perez, Carlos A
2004-01-01
Three-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) have been increasingly used as an alternative to radical prostatectomy in patients with localized carcinoma of the prostate and in patients at high risk, in combination with hormonal therapy. To better understand the implications of dose-time and fractionation in prostate cancer, it is important to be familiar with some laboratory investigations dealing with the cell kinetics characteristics of this tumor. Biological and clinical considerations of dose fractionation, total dose of irradiation and local tumor control, elapsed overall treatment time and sequelae of irradiation are illustrated, based on an exhaustive review of the literature.
Normal tissue dose conformality measures to guide radiotherapy fractionation decisions
Myerson, Robert J.
2011-04-15
Purpose: To determine conditions under which hypofractionation could be favorable for a normal tissue--even if tumor [{alpha}/{beta}] exceeds the normal tissue's [{alpha}/{beta}]. Methods: The hypofractionation sufficiency condition (HSC) for an organ is defined as a dose conformality constraint such that, if satisfied, a family of tumor control probability isoeffective fractionation schemes will show decreasing normal tissue complication probability with decreasing number of fractions. Results: In the extended equivalent uniform dose (EUD) model [obtained by replacing dose with linear quadratic (LQ) 2 Gy equivalent dose], the HSC for a normal organ is proven to be satisfied if a suitably weighted average of the relative dose [hypofractionation sufficiency index (HSI)] is less than the ratio of normal tissue to tumor [{alpha}/{beta}]. The HSI is determined solely by dose distribution and the normal tissue volume factor, ''a.'' If the HSC is satisfied for every normal tissue of concern, then there is a therapeutic gain with hypofractionation. The corresponding multifractionation sufficiency condition (therapeutic gain with increasing number of fractions) and multifractionation sufficiency index (MSI) are also derived. A sample clinical case is presented. Conclusions: Within the context of the LQ/EUD models, conformality measures (HSI and MSI) can be used to inform fractionation decisions.
Radiation effect in mouse skin: Dose fractionation and wound healing
Gorodetsky, R.; Mou, X.D.; Fisher, D.R.; Taylor, J.M.; Withers, H.R. )
1990-05-01
Radiation induced dermal injury was measured by the gain in the physical strength of healing wounds in mouse skin. A sigmoid dose response for the inhibition of wound healing 14 days after surgery was found for single doses of X rays. The sparing of dermal damage from fractionation of the X-ray dose was quantified in terms of the alpha/beta ratio in the linear-quadratic (LQ) model, at a wide range of doses per fraction reaching as low as about 1 Gy. The fit and the appropriateness of the LQ model for the skin wound healing assay was examined with the use of the Fe-plot in which inverse total dose is plotted versus dose per fraction for wound strength isoeffects. The alpha/beta ratio of the skin was about 2.5 Gy (95% confidence of less than +/- 1 Gy) and was appropriate over a dose range of 1 Gy to about 8 Gy. The low alpha/beta value is typical for a late responding tissue. This assay, therefore, has the advantage of measuring and forecasting late radiation responses of the dermis within a short time after irradiation.
Dose fractionation and biological optimization in lung cancer.
Trodella, Lucio; D'Angelillo, Rolando M; Ramella, Sara; Ciresa, Marzia; Massaccesi, Mariangela
2004-01-01
The treatment of choice of patients with locally advanced non-small cell lung cancer is radiotherapy combined or not with chemotherapy. Only 30% of lung cancer patients are operable for cure at diagnosis. Consequently the knowledge of the radiobiological basis and of clinical outcomes achieved with radiation therapy is of the utmost importance. Total dose, fractionation, concomitant chemotherapy are the main factors to be examined. In order to improve local control several attempts are reported in the literature. They concern: changes in fractionation and total dose; the use of radiosensitizers and radioprotectors; combined chemoradiation and molecular therapies.
A molecular fraction method for measuring personnel radiation doses
NASA Astrophysics Data System (ADS)
Fadel, M. A.; Khalil, W. A.; Krodja, R. P.; Sheta, N.; Abd El-Baset, M. S.
1987-02-01
This work represents a development in fast and albedo neutron and gamma ray dosimetry, using cellulose nitrate, as a tissue equivalent material, in which radiation damage was registered. The changes in molecular fractions of the polymer were measured after irradiation with neutron fluences from a 252Cf source in the range 10 5-10 10 n/cm 2 and gamma doses in the range 10 -4-10 -1 Gy through the use of gel filtration chromatography. Effects of irradiation on phantom, phantom to dosimeter distance, phantom thickness and storage at extreme environmental conditions were studied on the detector response and readout. The results showed that main chain scission followed by formation of new molecular configurations is the predominant effect of radiation on the polymer. The method enables measurements of neutron fluences and gamma doses in mixed radiation fields. Empirical formulae for calculating the absorbed dose from the measured changes in molecular fraction intensities are given.
NASA Astrophysics Data System (ADS)
Tilly, David; Ahnesjö, Anders
2015-07-01
A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan. For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel. Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.
Tilly, David; Ahnesjö, Anders
2015-07-21
A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.
Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole
Kapp, D.S.; Wagner, F.C.; Lawrence, R.
1982-03-01
In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m/sup 2/. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.
Cauda equina tolerance to high-dose fractionated irradiation
Pieters, Richard S.; Niemierko, Andrzej; Fullerton, Barbara C.; Munzenrider, John E. . E-mail: jmunzenrider@partners.org
2006-01-01
Purpose: To report late neurologic toxicity rates and clinical outcomes for patients treated with high dose fractionated radiation therapy using three-dimensional treatment planning and combined proton and photon beams to portions of the cauda equina (L2-coccyx). Methods and Materials: Medical records of 53 patients treated to fields encompassing the cauda equina were reviewed for the onset of neurologic symptoms in the absence of local failure. All doses were normalized to equivalent dose delivered in 2-Gy fractions. Median cauda dose was 65.8 cobalt Gray equivalents (CGE) (range, 31.9-85.1). Median follow-up was 87 months (range, 14-217 months). Results: Nineteen patients experienced local recurrences, and 13 others had neurologic toxicity. A total of 54% (i.e., 7/13) of the toxicities occurred 5 years or more after treatment. Median caudal dose was 73.7 CGE in the group with neurologic toxicity, and 55.6 CGE in those without. On multivariate actuarial analysis, cauda dose and gender were statistically significant for neurotoxicity at p = 0.002 and p = 0.017, respectively. The estimated tolerance doses 5 years from treatment, TD 5/5 and TD 50/5, were 55 CGE and 72 CGE, respectively, for males and 67 CGE and 84 CGE for females. The tolerance doses were about 8 CGE lower when estimated at 10 years from treatment. Disease-free survival rates at 5 and 10 years were 66% and 53%, respectively. Conclusions: This study suggests that the probability of neurotoxicity is a relatively steep function of dose to cauda equina (slope {gamma}{sub 5} = approximately 3). The cauda equina tolerance is greater for females than males by about 11 CGE (at 2 CGE per fraction). Extended follow-up is necessary to accurately assess neurologic damage and then differentiate that phenomenon from local recurrence; the traditional 5-year assessment has limited meaning in this population. Local control remains an issue for these patients, even with the radical doses used.
Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy
Schlom, J.; Molinolo, A.; Simpson, J.F.; Siler, K.; Roselli, M.; Hinkle, G.; Houchens, D.P.; Colcher, D. )
1990-05-02
Monoclonal antibody (MAb) B72.3 IgG was radiolabeled with 131I and administered to female athymic NCr-nu mice bearing the LS-174T human colon adenocarcinoma xenograft to determine if fractionation of MAb dose had any advantage in tumor therapy. In the LS-174T xenograft, only approximately 30%-60% of tumor cells express the B72.3-reactive TAG-72 antigen. The LS-174T xenograft was used to reflect the heterogeneity of the TAG-72 antigen often seen in biopsy specimens from patients. In contrast to a single 600-muCi dose of 131I-B72.3 IgG where 60% of the animals died from toxic effects, two 300-muCi doses of 131I-B72.3 IgG reduced or eliminated tumor growth in 90% of mice, with only 10% of the animals dying from toxic effects. Dose fractionation even permitted escalation of the dose to three doses of 300 muCi of 131I-B72.3 IgG, resulting in even more extensive tumor reduction or elimination and minimal toxic effects. The use of an isotype-matched control MAb revealed a nonspecific component to tumor growth retardation, but the use of the specific B72.3 IgG demonstrated a much greater therapeutic effect. Tumors that had escaped MAb therapy were analyzed for expression of the B72.3-reactive TAG-72 antigen with the use of the immunoperoxidase method; they were shown to have the same antigenic phenotype as the untreated tumors. We verified tumor elimination by killing the test animals after a 7-week observation period and performing histologic examination of tumor sites. We also monitored toxic effects by histologic examination of numerous organs. These studies thus demonstrate the advantage of dose fractionation of a radiolabeled MAb for tumor therapy. We anticipate that the concept of dose fractionation can be practically applied in radioimmunotherapeutic clinical trials with the development and use of recombinant-chimeric MAbs and modified constructs.
Awakening the immune system with radiation: Optimal dose and fractionation.
Gandhi, Saumil J; Minn, Andy J; Vonderheide, Robert H; Wherry, E John; Hahn, Stephen M; Maity, Amit
2015-11-28
The importance of ionizing radiation has historically been limited to achieving local control of tumor cells. However, emerging evidence over the last decade suggests an increasingly important role for radiation in amplifying the antitumor immune response elicited by immunomodulatory agents. Combination of radiation with immunotherapy has been shown to elicit powerful systemic responses in several pre-clinical tumor models. Additionally, recent clinical observations support the use of radiation therapy for augmenting antitumor immunity in the metastatic setting. However, radiation dose and fractionation schedules for optimal synergy between radiotherapy and immunotherapy are not well defined. Here we review pre-clinical and clinical data relating to radiation dose and fractionation in the setting of immunotherapy and discuss optimal strategies for combining the two therapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
High dose bystander effects in spatially fractionated radiation therapy
Asur, Rajalakshmi; Butterworth, Karl T.; Penagaricano, Jose A.; Prise, Kevin M.; Griffin, Robert J.
2014-01-01
Traditional radiotherapy of bulky tumors has certain limitations. Spatially fractionated radiation therapy (GRID) and intensity modulated radiotherapy (IMRT) are examples of advanced modulated beam therapies that help in significant reductions in normal tissue damage. GRID refers to the delivery of a single high dose of radiation to a large treatment area that is divided into several smaller fields, while IMRT allows improved dose conformity to the tumor target compared to conventional three-dimensional conformal radiotherapy. In this review, we consider spatially fractionated radiotherapy approaches focusing on GRID and IMRT, and present complementary evidence from different studies which support the role of radiation induced signaling effects in the overall radiobiological rationale for these treatments. PMID:24246848
Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma
Zhang, Hualin E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.; Cao, Minsong; Das, Indra J.
2014-02-15
Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was at the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional
Single-Dose Versus Fractionated Stereotactic Radiotherapy for Brain Metastases
Kim, Yeon-Joo; Cho, Kwan Ho; Kim, Joo-Young; Lim, Young Kyung; Min, Hye Sook; Lee, Sang Hyun; Kim, Ho Jin; Gwak, Ho Shin; Yoo, Heon; Lee, Seung Hoon
2011-10-01
Purpose: To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group. Results: With a median follow-up period of 7 months, the median survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group (p = 0.89). Local progression-free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group (p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05). Conclusions: Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.
Fractional labelmaps for computing accurate dose volume histograms
NASA Astrophysics Data System (ADS)
Sunderland, Kyle; Pinter, Csaba; Lasso, Andras; Fichtinger, Gabor
2017-03-01
PURPOSE: In radiation therapy treatment planning systems, structures are represented as parallel 2D contours. For treatment planning algorithms, structures must be converted into labelmap (i.e. 3D image denoting structure inside/outside) representations. This is often done by triangulated a surface from contours, which is converted into a binary labelmap. This surface to binary labelmap conversion can cause large errors in small structures. Binary labelmaps are often represented using one byte per voxel, meaning a large amount of memory is unused. Our goal is to develop a fractional labelmap representation containing non-binary values, allowing more information to be stored in the same amount of memory. METHODS: We implemented an algorithm in 3D Slicer, which converts surfaces to fractional labelmaps by creating 216 binary labelmaps, changing the labelmap origin on each iteration. The binary labelmap values are summed to create the fractional labelmap. In addition, an algorithm is implemented in the SlicerRT toolkit that calculates dose volume histograms (DVH) using fractional labelmaps. RESULTS: We found that with manually segmented RANDO head and neck structures, fractional labelmaps represented structure volume up to 19.07% (average 6.81%) more accurately than binary labelmaps, while occupying the same amount of memory. When compared to baseline DVH from treatment planning software, DVH from fractional labelmaps had agreement acceptance percent (1% ΔD, 1% ΔV) up to 57.46% higher (average 4.33%) than DVH from binary labelmaps. CONCLUSION: Fractional labelmaps promise to be an effective method for structure representation, allowing considerably more information to be stored in the same amount of memory.
Complexity metric based on fraction of penumbra dose - initial study
NASA Astrophysics Data System (ADS)
Bäck, A.; Nordström, F.; Gustafsson, M.; Götstedt, J.; Karlsson Hauer, A.
2017-05-01
Volumetric modulated arc therapy improve radiotherapy outcome for many patients compared to conventional three dimensional conformal radiotherapy but require a more extensive, most often measurement based, quality assurance. Multi leaf collimator (MLC) aperture-based complexity metrics have been suggested to be used to distinguish complex treatment plans unsuitable for treatment without time consuming measurements. This study introduce a spatially resolved complexity score that correlate to the fraction of penumbra dose and will give information on the spatial distribution and the clinical relevance of the calculated complexity. The complexity metric is described and an initial study on the correlation between the complexity score and the difference between measured and calculated dose for 30 MLC openings is presented. The result of an analysis of the complexity scores were found to correlate to differences between measurements and calculations with a Pearson’s r-value of 0.97.
Shaw, William; Rae, William I D; Alber, Markus L
In image-guided adaptive brachytherapy (IGABT), dose distributions are optimized for each fraction. Optimum fractional dose can be constant or adapted to previous fractions and a conjecture about the future ones. We evaluate the efficacy of different fraction size schemes, derived from total IGABT dose constraints, against constant per-fraction constraints. This retrospective planning study included 20 IGABT patients where four different fractionation schedules were compared based on modern planning recommendations. A total high-risk-clinical target volume D90 (minimum dose in 90% of the volume) dose aim of 90.0 Gy with constant per-fraction organs at risk (OARs) dose constraint planning (CONST) was compared with conservative and aggressive fractionation compensation (COMP) techniques. COMP allows variations in the per-fraction dose constraints. Dose accumulation was performed through dose summation at a given volume and equivalent uniform dose (EUD) worst-case dose estimates. No significant differences were identifiable between dose metrics of CONST and COMP in the total patient population. However, a subgroup of patients with alternating dose-limiting OARs had significant benefit from COMP. Median high-risk-clinical target volume dose escalation ranged from 5% to 12%, whereas OAR dose increases were lower and ranged from 3% to 8%. EUD-based planning delivered similar tumor doses, although slightly lower OAR doses. By distributing the treatment aim over an increased number of treatment fractions, median tumor dose could be increased by a further 8% per additional treatment fraction at the same OAR dose levels for both CONST and COMP. COMP is effective in patients with alternating dose-limiting OARs and is enhanced using more treatment fractions and EUD constraints. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Andrews, David W. Werner-Wasik, Maria; Den, Robert B.; Paek, Sun Ha; Downes-Phillips, Beverly; Willcox, Thomas O.; Bednarz, Greg; Maltenfort, Mitchel; Evans, James J.; Curran, Walter J.
2009-06-01
Purpose: To describe our initial experience of fractionated stereotactic radiotherapy dose reduction comparing two dose cohorts with examination of tumor control rates and serviceable hearing preservation rates. Methods and Materials: After institutional review board approval, we initiated a retrospective chart review to study the hearing outcomes and tumor control rates. All data were entered into a JMP, version 7.01, statistical spreadsheet for analysis. Results: A total of 89 patients with serviceable hearing had complete serial audiometric data available for analysis. The higher dose cohort included 43 patients treated to 50.4 Gy with a median follow-up (latest audiogram) of 53 weeks and the lower dose cohort included 46 patients treated to 46.8 Gy with a median follow-up of 65 weeks. The tumor control rate was 100% in both cohorts, and the pure tone average was significantly improved in the low-dose cohort (33 dB vs. 40 dB, p = 0.023, chi-square). When the patient data were analyzed at comparable follow-up points, the actuarial hearing preservation rate was significantly longer for the low-dose cohort than for the high-dose cohort (165 weeks vs. 79 weeks, p = .0318, log-rank). Multivariate analysis revealed the dose cohort (p = 0.0282) and pretreatment Gardner-Robertson class (p = 0.0215) to be highly significant variables affecting the hearing outcome. Conclusion: A lower total dose at 46.8 Gy was associated with a 100% local control tumor rate and a greater hearing preservation rate. An additional dose reduction is justified to achieve the optimal dose that will yield the greatest hearing preservation rate without compromising tumor control for these patients.
Paul, Subhadip; Roy, Prasun Kumar
2016-02-01
Radiation therapy is one of the important treatment procedures of cancer. The day-to-day delivered dose to the tissue in radiation therapy often deviates from the planned fixed dose per fraction. This day-to-day variation of radiation dose is stochastic. Here, we have developed the mathematical formulation to represent the day-to-day stochastic dose variation effect in radiation therapy. Our analysis shows that that the fixed dose delivery approximation under-estimates the biological effective dose, even if the average delivered dose per fraction is equal to the planned dose per fraction. The magnitude of the under-estimation effect relies upon the day-to-day stochastic dose variation level, the dose fraction size and the values of the radiobiological parameters of the tissue. We have further explored the application of our mathematical formulation for adaptive dose calculation. Our analysis implies that, compared to the premise of the Linear Quadratic Linear (LQL) framework, the Linear Quadratic framework based analytical formulation under-estimates the required dose per fraction necessary to produce the same biological effective dose as originally planned. Our study provides analytical formulation to calculate iso-effect in adaptive radiation therapy considering day-to-day stochastic dose deviation from planned dose and also indicates the potential utility of LQL framework in this context.
Dose fractionation theorem in 3-D reconstruction (tomography)
Glaeser, R.M.
1997-02-01
It is commonly assumed that the large number of projections for single-axis tomography precludes its application to most beam-labile specimens. However, Hegerl and Hoppe have pointed out that the total dose required to achieve statistical significance for each voxel of a computed 3-D reconstruction is the same as that required to obtain a single 2-D image of that isolated voxel, at the same level of statistical significance. Thus a statistically significant 3-D image can be computed from statistically insignificant projections, as along as the total dosage that is distributed among these projections is high enough that it would have resulted in a statistically significant projection, if applied to only one image. We have tested this critical theorem by simulating the tomographic reconstruction of a realistic 3-D model created from an electron micrograph. The simulations verify the basic conclusions of high absorption, signal-dependent noise, varying specimen contrast and missing angular range. Furthermore, the simulations demonstrate that individual projections in the series of fractionated-dose images can be aligned by cross-correlation because they contain significant information derived from the summation of features from different depths in the structure. This latter information is generally not useful for structural interpretation prior to 3-D reconstruction, owing to the complexity of most specimens investigated by single-axis tomography. These results, in combination with dose estimates for imaging single voxels and measurements of radiation damage in the electron microscope, demonstrate that it is feasible to use single-axis tomography with soft X-ray microscopy of frozen-hydrated specimens.
Murphy, Martin J.; Lin, Peck-Sun; Ozhasoglu, Cihat
2007-02-15
The sequence of incremental dose delivery during a radiotherapy fraction can potentially influence the radiobiological effect. This would be most noticeable during the long fractions characteristic of hypo-fractionated stereotactic radiotherapy and radiosurgery. We demonstrate here the spatio-temporal variation of dose delivery by the CyberKnife to a lung tumor and propose strategies to reduce and/or correct for any resultant dose-time cytotoxic effects.
Accelerated heavy particles and the lens. III. Cataract enhancement by dose fractionation
Worgul, B.V.; Merriam, G.R. Jr.; Medvedovsky, C.; Brenner, D.J.
1989-04-01
For a number of biological end points it has been shown that, in contrast to low linear energy transfer (LET) radiation, dose fractionation of high-LET radiation does not result in a reduction in overall effectiveness. Studies were conducted to determine the effect of fractionating the exposures to heavy ion doses on the development of cataracts. Rat eyes were exposed to single doses of 1, 5, and 25 cGy of 570 MeV/amu40Ar ions and to 2, 4, and 10 Gy of 250 kVp X rays. These were compared to unirradiated controls and eyes which were exposed to the same total dose delivered in four fractions over 12 h. While in all cases fractionation of the exposure to X rays produced significant reduction in cataractogenic potential, fractionating doses of 40Ar ions caused a dose- and stage-dependent enhancement in the development of cataracts.
Effect of radiation protraction on BED in the case of large fraction dose
Kuperman, V. Y.
2013-08-15
Purpose: To investigate the effect of radiation protraction on biologically effective dose (BED) in the case when dose per fraction is significantly greater than the standard dose of 2 Gy.Methods: By using the modified linear-quadratic model with monoexponential repair, the authors investigate the effect of long treatment times combined with dose escalation.Results: The dependences of the protraction factor and the corresponding BED on fraction time were determined for different doses per fraction typical for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). In the calculations, the authors consider changes in the BED to the normal tissue under the condition of fixed BED to the target.Conclusion: The obtained results demonstrate that simultaneous increase in fraction time and dose per fraction can be beneficial for SRS and SBRT because of the related decrease in BED to normal structures while BED to the target is fixed.
Effects of single and fractionated low-dose irradiation on vascular endothelial cells.
Cervelli, Tiziana; Panetta, Daniele; Navarra, Teresa; Andreassi, Maria Grazia; Basta, Giuseppina; Galli, Alvaro; Salvadori, Piero A; Picano, Eugenio; Del Turco, Serena
2014-08-01
An increasing number of epidemiological studies suggest that chronic low-dose irradiation increases the risk of atherosclerosis. We evaluated and compared the in vitro biological effects of both single and fractionated low-doses of X-ray irradiation on endothelial cells. Human umbilical vein endothelial cells (HUVECs) were irradiated with X-rays, with single doses of 0.125, 0.25 and 0.5 Gy or fractionated doses of 2 × 0.125 Gy and 2 × 0.25 Gy, with 24 h interfraction interval. Survival, apoptosis, reactive oxygen species (ROS) production, nuclear factor-κB (NF-κB) activation, intercellular adhesion molecule-1 (ICAM-1) expression, HUVEC adhesiveness and DNA damage were investigated. We did not observe any effect on viability and apoptosis. Both single and fractionated doses induced ROS generation, NF-κB activation, ICAM-1 protein expression and HUVEC adhesiveness, but only fractionated doses increase significantly ICAM-1 mRNA. The effects measured after fractionated dose result always higher than those induced by the single dose. Moreover, we observed that DNA double strand break (DSB), visualized with γ-H2AX foci, is dose-dependent and that the kinetics of γ-H2AX foci is not affected by fractionated doses. We showed that single and fractionated low-dose irradiations with low energy X-rays do not affect cell viability and DNA repair. Interestingly, the greater increase of ICAM-1 surface exposure and endothelial adhesiveness observed after fractionated irradiation, suggests that fractionated low-doses may accelerate chronic vascular inflammation, from which the atherosclerotic process can arise. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery.
Kirkpatrick, John P; Meyer, Jeffrey J; Marks, Lawrence B
2008-10-01
The linear-quadratic (LQ) model is widely used to model the effect of total dose and dose per fraction in conventionally fractionated radiotherapy. Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery. Clinically, the LQ model often underestimates tumor control observed at radiosurgical doses. The underlying mechanisms implied by the LQ model do not reflect the vascular and stromal damage produced at the high doses per fraction encountered in radiosurgery and ignore the impact of radioresistant subpopulations of cells. The appropriate modeling of both tumor control and normal tissue toxicity in radiosurgery requires the application of emerging understanding of molecular-, cellular-, and tissue-level effects of high-dose/fraction-ionizing radiation and the role of cancer stem cells.
NASA Astrophysics Data System (ADS)
Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob
2009-01-01
Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.
Ma Lijun; Sahgal, Arjun; Descovich, Martina; Cho, Y.-B.; Chuang, Cynthia; Huang, Kim; Laperriere, Normand J.; Shrieve, Dennis C.; Larson, David A.
2010-03-01
Purpose: To investigate whether dose fall-off characteristics would be significantly different among intracranial radiosurgery modalities and the influence of these characteristics on fractionation schemes in terms of normal tissue sparing. Methods and Materials: An analytic model was developed to measure dose fall-off characteristics near the target independent of treatment modalities. Variations in the peripheral dose fall-off characteristics were then examined and compared for intracranial tumors treated with Gamma Knife, Cyberknife, or Novalis LINAC-based system. Equivalent uniform biologic effective dose (EUBED) for the normal brain tissue was calculated. Functional dependence of the normal brain EUBED on varying numbers of fractions (1 to 30) was studied for the three modalities. Results: The derived model fitted remarkably well for all the cases (R{sup 2} > 0.99). No statistically significant differences in the dose fall-off relationships were found between the three modalities. Based on the extent of variations in the dose fall-off curves, normal brain EUBED was found to decrease with increasing number of fractions for the targets, with alpha/beta ranging from 10 to 20. This decrease was most pronounced for hypofractionated treatments with fewer than 10 fractions. Additionally, EUBED was found to increase slightly with increasing number of fractions for targets with alpha/beta ranging from 2 to 5. Conclusion: Nearly identical dose fall-off characteristics were found for the Gamma Knife, Cyberknife, and Novalis systems. Based on EUBED calculations, normal brain sparing was found to favor hypofractionated treatments for fast-growing tumors with alpha/beta ranging from 10 to 20 and single fraction treatment for abnormal tissues with low alpha/beta values such as alpha/beta = 2.
High-dose, conventionally fractionated thoracic reirradiation for lung tumors.
Griffioen, Gwendolyn H M J; Dahele, Max; de Haan, Patricia F; van de Ven, Peter M; Slotman, Ben J; Senan, Suresh
2014-03-01
Loco-regional recurrences and second primary lung tumors are not uncommon after high-dose thoracic radiotherapy. The availability of improved radiotherapy techniques increases options for reirradiation. We describe a single-institutional experience with high-dose conventional thoracic reirradiation for both loco-regional recurrences and new primary tumors. Retrospective chart review of patients undergoing reirradiation between February 2004 and February 2013. Of 24 patients identified, 54% had a loco-regional recurrence, and 46% a new primary tumor. The majority (63%) had stage III NSCLC at both initial and second treatment; median interval between treatments was 51 months (5-189), median follow-up after reirradiation was 19.3 months (95% CI: 2.8-35.9). Median overall survival (OS) after reirradiation was 13.5 months, with 1-year survival 51%. Median event-free survival (EFS) was 8.4 months. Median time between reirradiation and local progression (n=8) or distant progression (n=8) was 6.7 and 11.8 months, respectively. Three patients died with possible grade 5 bleeding. Other toxicities were uncommon. Planning target volume (PTV) at reirradiation was the most important prognostic factor; PTV <300 versus ≥300cc was significantly associated with median OS (17.4 vs 8.2 months, p=0.03) and EFS (14.1 vs 5.5 months, p=0.03). Magnitude of overlap between the initial and subsequent PTVs, and between dose distributions, did not influence survival. Thoracic reirradiation with high dose conventional radiotherapy appears to deliver a meaningful survival benefit in low volume new primary or recurrent lung cancer. Further studies are needed to confirm these findings, and to establish reliable normal tissue tolerance doses for reirradiation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Low or High Fractionation Dose {beta}-Radiotherapy for Pterygium? A Randomized Clinical Trial
Viani, Gustavo Arruda; De Fendi, Ligia Issa; Fonseca, Ellen Carrara; Stefano, Eduardo Jose
2012-02-01
Purpose: Postoperative adjuvant treatment using {beta}-radiotherapy (RT) is a proven technique for reducing the recurrence of pterygium. A randomized trial was conducted to determine whether a low fractionation dose of 2 Gy within 10 fractions would provide local control similar to that after a high fractionation dose of 5 Gy within 7 fractions for surgically resected pterygium. Methods: A randomized trial was conducted in 200 patients (216 pterygia) between February 2006 and July 2007. Only patients with fresh pterygium resected using a bare sclera method and given RT within 3 days were included. Postoperative RT was delivered using a strontium-90 eye applicator. The pterygia were randomly treated using either 5 Gy within 7 fractions (Group 1) or 2 Gy within 10 fractions (Group 2). The local control rate was calculated from the date of surgery. Results: Of the 216 pterygia included, 112 were allocated to Group 1 and 104 to Group 2. The 3-year local control rate for Groups 1 and 2 was 93.8% and 92.3%, respectively (p = .616). A statistically significant difference for cosmetic effect (p = .034), photophobia (p = .02), irritation (p = .001), and scleromalacia (p = .017) was noted in favor of Group 2. Conclusions: No better local control rate for postoperative pterygium was obtained using high-dose fractionation vs. low-dose fractionation. However, a low-dose fractionation schedule produced better cosmetic effects and resulted in fewer symptoms than high-dose fractionation. Moreover, pterygia can be safely treated in terms of local recurrence using RT schedules with a biologic effective dose of 24-52.5 Gy{sub 10.}.
ANALYSIS OF RESPIRATORY DESPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS
ANALYSIS OF RESPIRATORY DEPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS. Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *S...
ANALYSIS OF RESPIRATORY DESPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS
ANALYSIS OF RESPIRATORY DEPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS. Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *S...
Simultaneous optimization of dose distributions and fractionation schemes in particle radiotherapy
Unkelbach, Jan; Zeng, Chuan; Engelsman, Martijn
2013-09-15
Purpose: The paper considers the fractionation problem in intensity modulated proton therapy (IMPT). Conventionally, IMPT fields are optimized independently of the fractionation scheme. In this work, we discuss the simultaneous optimization of fractionation scheme and pencil beam intensities.Methods: This is performed by allowing for distinct pencil beam intensities in each fraction, which are optimized using objective and constraint functions based on biologically equivalent dose (BED). The paper presents a model that mimics an IMPT treatment with a single incident beam direction for which the optimal fractionation scheme can be determined despite the nonconvexity of the BED-based treatment planning problem.Results: For this model, it is shown that a small α/β ratio in the tumor gives rise to a hypofractionated treatment, whereas a large α/β ratio gives rise to hyperfractionation. It is further demonstrated that, for intermediate α/β ratios in the tumor, a nonuniform fractionation scheme emerges, in which it is optimal to deliver different dose distributions in subsequent fractions. The intuitive explanation for this phenomenon is as follows: By varying the dose distribution in the tumor between fractions, the same total BED can be achieved with a lower physical dose. If it is possible to achieve this dose variation in the tumor without varying the dose in the normal tissue (which would have an adverse effect), the reduction in physical dose may lead to a net reduction of the normal tissue BED. For proton therapy, this is indeed possible to some degree because the entrance dose is mostly independent of the range of the proton pencil beam.Conclusions: The paper provides conceptual insight into the interdependence of optimal fractionation schemes and the spatial optimization of dose distributions. It demonstrates the emergence of nonuniform fractionation schemes that arise from the standard BED model when IMPT fields and fractionation scheme are optimized
Hill, R.P.
1982-03-01
The ability of five nitroimidazoles, metronidazole (MET), misonidazole (MISO), desmethymisonidazole (DMM), SR 2508 and SR 2555, to sensitize the KHT sarcoma to radiation treatment has been compared for drug doses in the range 0-1.5 g/Kg. Single radiation doses or two different daily fractionation schedules (4 fractions of 5 Gy each or 7 fraction of 3 Gy each) were used; the tumor cell survival was determined using either an in vivo or in vitro colony assay. Each radiation (100 kVp X rays at 11 Gy/min) treatment was given locally, 60-70 min (MET) or 30-40 min (other drugs) after either intraperitoneal (MET, MISO, DMM) or intraveous (SR 2508, SR 2555) injection of the drugs; these times have been shown to be optimum for this tumor. For the single doses and both fractionation schedules the tumor cell survival, following the irradiation treatment, declined as the drug dose increased in the range 0 to 0.75 g/Kg for all the drugs, but above this dose level a plateau was reached and the amount of sensitization remained essentially constant. In this plateau region the reduction in survival achieved was similar for single doses and 5 Gy fraction but was less for 3 Gy fractions, indicating that sensitization was smaller for the smaller dose fractions. For the 4 x 5 Gy fractionation schedule the plateau level of survival was lowest for MISO, DMM and SR 2508, slightly higher for SR 2555 and much higher for MET. For the 3 Gy fractions SR 2508 appeared slightly less effective than MISO and DMM.
High-dose fractionated radiation therapy for select patients with brain metastases
Pezner, R.D.; Lipsett, J.A.; Archambeau, J.O.; Fine, R.M.; Moss, W.T.
1981-08-01
Four patients with metastases to the brain were treated by high-dose fractionated radiation therapy. In all four cases, a complete response and prolonged disease-free survival could be documented. Unlike the standard therapy for such patients (i.e., craniotomy and postoperative irradiation), high-dose fractionated radiation therapy carries no operative risk and can encompass multiple brain metastases and metastases in deep or critical intracranial sites. The risk of radiotherapy side effects in the brain is discussed.
Definitive radiotherapy in locally advanced non-small cell lung cancer: dose and fractionation.
Dağoğlu, Nergiz; Karaman, Şule; Arifoğlu, Alptekin; Küçücük, Seden; Oral, Ethem N
2014-12-01
Definitive radiotherapy plays a major role in the treatment of locally advanced non-small cell lung cancer (LA NSCLC). After the impact of RT dose for lung cancer was established, a number of trials were structured with the aim of better local control and overall survival by either dose escalation or shortening the total treatment time through conventional/altered fractionation, even in combination with chemotherapy (CT) and other targeted agents. In spite of the increased number of these studies, the optimal dose or fractionation still remains to be determined. Another aspect questioned is the incorporation of these higher doses and shorter treatment times with chemotherapy or targeted agents. This review summarises the results of significant trials on dose and altered fractionation in the treatment of LA-NSCLC with an emphasis on possible future perspectives.
Storb, R.; Raff, R.F.; Graham, T.; Appelbaum, F.R.; Deeg, H.J.; Schuening, F.G.; Shulman, H.; Pepe, M. )
1993-03-20
The authors explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing [sup 60]Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. They found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionated total body irradiation. One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation. With granulocyte colony stimulating factor (GCSF) administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with GCSF after 400 cGy single dose total body irradiation, a study of GCSF after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with GCSF administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. 24 refs., 3 figs., 2 tabs.
Hardcastle, Nicholas; Bayliss, Adam; Wong, Jeannie Hsiu Ding; Rosenfeld, Anatoly B.; Tome, Wolfgang A.
2012-08-15
Purpose: A recent field safety notice from TomoTherapy detailed the underdosing of small, off-axis targets when receiving high doses per fraction. This is due to angular undersampling in the dose calculation gantry angles. This study evaluates a correction method to reduce the underdosing, to be implemented in the current version (v4.1) of the TomoTherapy treatment planning software. Methods: The correction method, termed 'Super Sampling' involved the tripling of the number of gantry angles from which the dose is calculated during optimization and dose calculation. Radiochromic film was used to measure the dose to small targets at various off-axis distances receiving a minimum of 21 Gy in one fraction. Measurements were also performed for single small targets at the center of the Lucy phantom, using radiochromic film and the dose magnifying glass (DMG). Results: Without super sampling, the peak dose deficit increased from 0% to 18% for a 10 mm target and 0% to 30% for a 5 mm target as off-axis target distances increased from 0 to 16.5 cm. When super sampling was turned on, the dose deficit trend was removed and all peak doses were within 5% of the planned dose. For measurements in the Lucy phantom at 9.7 cm off-axis, the positional and dose magnitude accuracy using super sampling was verified using radiochromic film and the DMG. Conclusions: A correction method implemented in the TomoTherapy treatment planning system which triples the angular sampling of the gantry angles used during optimization and dose calculation removes the underdosing for targets as small as 5 mm diameter, up to 16.5 cm off-axis receiving up to 21 Gy.
Biological dose representation for carbon-ion radiotherapy of unconventional fractionation.
Kanematsu, Nobuyuki; Inaniwa, Taku
2017-02-07
In carbon-ion radiotherapy, single-beam delivery each day in alternate directions has been common practice for efficient operation, taking advantage of the Bragg peak and the relative biological effectiveness (RBE) for uniform dose conformation to a tumor. Treatments are usually fractionated and treatment plans are evaluated with the total RBE-weighted dose; however, this is of limited relevance to the biological effect. In this study, we reformulate the biologically effective dose (BED) to normalize the dose-fractionation and cell-repopulation effects as well as the RBE of treating radiation, based on inactivation of a reference cell line by a reference carbon-ion radiation. The BED distribution virtually represents the biological effect of a treatment regardless of radiation modality or fractionation scheme. We applied the BED formulation to simplistic model treatments and to a preclinical survey for hypofractionation based on an actual prostate cancer treatment with carbon ions. The proposed formulation was demonstrated to be practical and to give theoretical implications. For a prostate cancer treatment in 12 fractions, the distributions of BED and of RBE-weighted dose were very similar. With hypofractionation, while the RBE-weighted dose distribution varied significantly, the BED distribution was nearly invariant, implying that carbon-ion radiotherapy would be effectively insensitive to fractionation. However, treatment evaluation with such a simplistic biological dose is intrinsically limited and must be complemented in practice by clinical experience and biological experiments.
Biological dose representation for carbon-ion radiotherapy of unconventional fractionation
NASA Astrophysics Data System (ADS)
Kanematsu, Nobuyuki; Inaniwa, Taku
2017-02-01
In carbon-ion radiotherapy, single-beam delivery each day in alternate directions has been common practice for efficient operation, taking advantage of the Bragg peak and the relative biological effectiveness (RBE) for uniform dose conformation to a tumor. Treatments are usually fractionated and treatment plans are evaluated with the total RBE-weighted dose; however, this is of limited relevance to the biological effect. In this study, we reformulate the biologically effective dose (BED) to normalize the dose-fractionation and cell-repopulation effects as well as the RBE of treating radiation, based on inactivation of a reference cell line by a reference carbon-ion radiation. The BED distribution virtually represents the biological effect of a treatment regardless of radiation modality or fractionation scheme. We applied the BED formulation to simplistic model treatments and to a preclinical survey for hypofractionation based on an actual prostate cancer treatment with carbon ions. The proposed formulation was demonstrated to be practical and to give theoretical implications. For a prostate cancer treatment in 12 fractions, the distributions of BED and of RBE-weighted dose were very similar. With hypofractionation, while the RBE-weighted dose distribution varied significantly, the BED distribution was nearly invariant, implying that carbon-ion radiotherapy would be effectively insensitive to fractionation. However, treatment evaluation with such a simplistic biological dose is intrinsically limited and must be complemented in practice by clinical experience and biological experiments.
Fractional dosing of yellow fever vaccine to extend supply: a modelling study.
Wu, Joseph T; Peak, Corey M; Leung, Gabriel M; Lipsitch, Marc
2016-12-10
The ongoing yellow fever epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa, Democratic Republic of the Congo, in July-August, 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidation of the conditions under which dose fractionation would reduce transmission. We estimate the effective reproductive number for yellow fever in Angola using disease natural history and case report data. With simple mathematical models of yellow fever transmission, we calculate the infection attack rate (the proportion of population infected over the course of an epidemic) with various levels of transmissibility and 5-fold fractional-dose vaccine efficacy for two vaccination scenarios, ie, random vaccination in a hypothetical population that is completely susceptible, and the Kinshasa vaccination campaign in July-August, 2016, with different age cutoff for fractional-dose vaccines. We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (ie, a proportion of vaccine recipients receive complete protection [VE] and the remainder receive no protection), n-fold fractionation can greatly reduce infection attack rate as long as VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (ie, the susceptibility of each vaccine recipient is reduced by a factor that is equal to the vaccine efficacy). The age cutoff for fractional-dose vaccines chosen by WHO for the Kinshasa vaccination campaign (2 years) provides the largest reduction in infection attack rate if the efficacy of 5-fold fractional-dose vaccines exceeds 20%. Dose fractionation is an effective strategy for reduction of the infection attack rate that would be robust with a
Sugano, Yasutaka; Mizuta, Masahiro; Takao, Seishin; Shirato, Hiroki; Sutherland, Kenneth L; Date, Hiroyuki
2015-11-01
Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose-volume histograms for tumor and normal tissues of organs around the tumor. Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of the tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose-volume histogram. It was found that the optimization of fractionation scheme incorporating the dose-volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8-32 fractions with a daily dose of 2.2-6.3 Gy. It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose-volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.
Analysis of dose fractionation in the palliation of metastases from malignant melanoma
Konefal, J.B.; Emami, B.; Pilepich, M.V.
1988-01-15
Sixty-five visceral metastases from malignant melanoma were treated with radiation therapy. A variety of total doses and dose fractions were used. Significant palliation was achieved in 40 of 65 (62%) symptomatic lesions. There was no correlation between total dose or dose fraction size and significant palliation. Brain and bone metastases were separately analyzed. Nineteen of 28 (68%) bone metastases were palliated. Appendicular bony metastases were more likely to be palliated than axial bony metastases (88% versus 60%). The palliation of bone metastases did not depend on total dose given or fraction size. Nine of 23 (39%) symptomatic brain metastases were palliated. There was no difference in the rate of palliation between solitary and multiple brain metastases. Palliation of brain lesions was not dependent on fraction size, although there was a trend to better palliation with higher total doses. These findings suggest that unlike treating cutaneous or nodal melanoma lesions for local control, there is no advantage in large fraction size when treating with palliative intent visceral melanoma lesions.
Target point correction optimized based on the dose distribution of each fraction in daily IGRT
NASA Astrophysics Data System (ADS)
Stoll, Markus; Giske, Kristina; Stoiber, Eva M.; Schwarz, Michael; Bendl, Rolf
2014-03-01
Purpose: To use daily re-calculated dose distributions for optimization of target point corrections (TPCs) in image guided radiation therapy (IGRT). This aims to adapt fractioned intensity modulated radiation therapy (IMRT) to changes in the dose distribution induced by anatomical changes. Methods: Daily control images from an in-room on-rail spiral CT-Scanner of three head-and-neck cancer patients were analyzed. The dose distribution was re-calculated on each control CT after an initial TPC, found by a rigid image registration method. The clinical target volumes (CTVs) were transformed from the planning CT to the rigidly aligned control CTs using a deformable image registration method. If at least 95% of each transformed CTV was covered by the initially planned D95 value, the TPC was considered acceptable. Otherwise the TPC was iteratively altered to maximize the dose coverage of the CTVs. Results: In 14 (out of 59) fractions the criterion was already fulfilled after the initial TPC. In 10 fractions the TPC can be optimized to fulfill the coverage criterion. In 31 fractions the coverage can be increased but the criterion is not fulfilled. In another 4 fractions the coverage cannot be increased by the TPC optimization. Conclusions: The dose coverage criterion allows selection of patients who would benefit from replanning. Using the criterion to include daily re-calculated dose distributions in the TPC reduces the replanning rate in the analysed three patients from 76% to 59% compared to the rigid image registration TPC.
SU-E-T-511: Do Presage 3D Dosimeters Show Dose Fractionation Sensitivity?
Klawikowski, S; Alqathami, M; Ibbott, G; Adamovics, J; Benning, R
2014-06-01
Purpose: To determine whether Presage 3D polymer dosimeter dose response is sensitive to dose delivery fractionation. Bang gels have demonstrated a dose fractionation related dependence in which a single 400 cGy irradiation would produce a different detector response than four 100 cGy irradiations even if delivered closely in time to one another. Such a fractional dependent response in Presage would be detrimental for measuring multi-beam irradiations. Methods: Two separate batches of Presage were poured into cuvettes, and a third batch was molded into cuvette shaped blocks. A total of 37 cuvettes/blocks were irradiated in a Cobalt-60 irradiator to 400 cGy within solid water phantoms in either one, eight, or sixteen fractions. Another group of 15 cuvettes were also kept unirradiated and used for background subtraction between the pre-scan and post-scan results. The times between fractional deliveries were held constant at 30 seconds and the Cobalt irradiator dose rate was 49 cGy/min. Each Presage batch has a separate dose sensitivity and therefore fractionation response comparisons were only performed within the same batch. The cuvettes were first pre-scanned the day prior to irradiation and post-scanned the day after irradiation. Other than approximately 3 hours warming time prior to each irradiation and optical density measurement the cuvettes were stored in a refrigerator. All cuvettes were stored in a lightless environment throughout manufacturing and testing. The cuvettes’ optical densities were optically measured at 632 nm with a spectrophotometer. Results: No noticeable dose fractionation dependence was detected for any of the three independent batches of Presage for either the eight or sixteen fraction irradiation schemes. Conclusion: These results indicate using Presage 3D dosimeters to measure multi-beam photon irradiations common in IMRT, Gamma Knife, and Cyberknife treatment delivery schemes. Presage dosimeters are made by and trademarked by Heuris
The influence of dose heterogeneity on tumour control probability in fractionated radiation therapy
NASA Astrophysics Data System (ADS)
Wiklund, Kristin; Toma-Dasu, Iuliana; Lind, Bengt K.
2011-12-01
Theoretical modelling of tumour control probability (TCP) with respect to non-uniformity in the dose to the tumour, alternate fractionation schemes and tumour kinetics is a very useful tool for assessment of the influence of changes in dosimetric or radiobiological factors on the outcome of the treatment. Various attempts have been made to also include effects from non-uniform dose to the tumour volume, but the problem has not been fully solved and many factors were totally neglected or not accurately taken into account. This paper presents derivations of analytical expressions of TCP for macroscopic inter-cell dose variations and for random inter-fractional variations in average tumour dose, based on binomial statistics for the TCP and the well-known linear quadratic model for the cell survival. Numerical calculations have been performed to validate the analytical expressions. An analysis of the influence of the deterministic and stochastic heterogeneity in dose delivery on the TCP was performed. The precision requirements in dose delivery are discussed briefly with the support of the presented results. The main finding of this paper is that it is primarily the shape of the cell survival curve that governs how the response is affected by macroscopic dose variations. The analytical expressions for TCP accounting for heterogeneity in dose can quite well describe the TCP for varying dose from cell to cell and random dose in each fraction. An increased TCP is seen when a large number of fractions are used and the variations in dose to the cells are rather high for tissues with low α/β.
Fractionated doses of radioiodine for ablation of postsurgical thyroid tissue remnants
Arad, E.; Flannery, K.; Wilson, G.A.; O'Mara, R.E. )
1990-10-01
Patients who have differentiated thyroid carcinoma and have undergone total thyroidectomy are treated with radioiodine for ablation of functional thyroid remnants. Administration of a single therapeutic dose in excess of 30 mCi of l-131 requires hospitalization. In an attempt to obviate the necessity for hospitalization, the prospective ablative dose was divided into two or three fractions given at weekly intervals on an ambulatory basis. To assess the effectiveness of this approach, this group of patients was compared to a cohort of hospitalized patients treated with a single dose. Ablation was achieved in 9 out of 12 patients treated in a fractionated manner (a 75% success rate), whereas in 16 out of 20 patients given a single dose the thyroid remnants were completely eradicated (an 80% success rate). That the use of split, smaller doses administered at weekly intervals on an ambulatory basis presents a reasonable alternative for ablation of postsurgical, residual-functioning thyroid tissue.
Recalculation of dose for each fraction of treatment on TomoTherapy.
Thomas, Simon J; Romanchikova, Marina; Harrison, Karl; Parker, Michael A; Bates, Amy M; Scaife, Jessica E; Sutcliffe, Michael P F; Burnet, Neil G
2016-01-01
The VoxTox study, linking delivered dose to toxicity requires recalculation of typically 20-37 fractions per patient, for nearly 2000 patients. This requires a non-interactive interface permitting batch calculation with multiple computers. Data are extracted from the TomoTherapy(®) archive and processed using the computational task-management system GANGA. Doses are calculated for each fraction of radiotherapy using the daily megavoltage (MV) CT images. The calculated dose cube is saved as a digital imaging and communications in medicine RTDOSE object, which can then be read by utilities that calculate dose-volume histograms or dose surface maps. The rectum is delineated on daily MV images using an implementation of the Chan-Vese algorithm. On a cluster of up to 117 central processing units, dose cubes for all fractions of 151 patients took 12 days to calculate. Outlining the rectum on all slices and fractions on 151 patients took 7 h. We also present results of the Hounsfield unit (HU) calibration of TomoTherapy MV images, measured over an 8-year period, showing that the HU calibration has become less variable over time, with no large changes observed after 2011. We have developed a system for automatic dose recalculation of TomoTherapy dose distributions. This does not tie up the clinically needed planning system but can be run on a cluster of independent machines, enabling recalculation of delivered dose without user intervention. The use of a task management system for automation of dose calculation and outlining enables work to be scaled up to the level required for large studies.
Radiation as an immunological adjuvant: current evidence on dose and fractionation.
Demaria, Sandra; Formenti, Silvia C
2012-01-01
Ionizing radiation to a cancer site has the ability to convert the irradiated tumor in an immunogenic hub. However, radiation is a complex modifier of the tumor microenvironment and, by itself, is seldom sufficient to induce a therapeutically significant anti-tumor immune response, since it can also activate immune suppressive pathways. While several combinations of local radiation and immunotherapy have been shown in pre-clinical models to induce powerful anti-tumor immunity, the optimal strategy to achieve this effect remains to be defined. When used in vivo, radiation effects on tumors depend on the dose per fraction applied, the number of fractions used, and the total dose. Moreover, the interplay of these three variables is contingent upon the tumor setting studied, both in pre-clinical and clinical applications. To enable repair of the collateral damage to the normal tissue, radiation is usually given in multiple fractions, usually of 2 Gy. Generally, the use of larger fractions is limited to stereotactic applications, whereby optimal immobilization reduces inter- and intrafraction movement and permits a very conformal delivery of dose to the target, with optimal exclusion of normal tissue. Translation of the partnership of radiation and immunotherapy to the clinic requires a careful consideration of the radiation regimens used. To date, little is known on whether different dose/fractionation regimens have a specific impact on the anti-tumor immune response. Most experiments combining the two modalities were conducted with single fractions of radiotherapy. However, there is at least some evidencethat when combined with some specific immunotherapy approaches, the ability of radiation to promote anti-tumor immunity is dependent on the dose and fractionation employed. We critically review the available in vitro and in vivo data on this subject and discuss the potential impact of fractionation on the ability of radiation to synergize with immunotherapy.
Radiation as an immunological adjuvant: current evidence on dose and fractionation
Demaria, Sandra; Formenti, Silvia C.
2012-01-01
Ionizing radiation to a cancer site has the ability to convert the irradiated tumor in an immunogenic hub. However, radiation is a complex modifier of the tumor microenvironment and, by itself, is seldom sufficient to induce a therapeutically significant anti-tumor immune response, since it can also activate immune suppressive pathways. While several combinations of local radiation and immunotherapy have been shown in pre-clinical models to induce powerful anti-tumor immunity, the optimal strategy to achieve this effect remains to be defined. When used in vivo, radiation effects on tumors depend on the dose per fraction applied, the number of fractions used, and the total dose. Moreover, the interplay of these three variables is contingent upon the tumor setting studied, both in pre-clinical and clinical applications. To enable repair of the collateral damage to the normal tissue, radiation is usually given in multiple fractions, usually of 2 Gy. Generally, the use of larger fractions is limited to stereotactic applications, whereby optimal immobilization reduces inter- and intrafraction movement and permits a very conformal delivery of dose to the target, with optimal exclusion of normal tissue. Translation of the partnership of radiation and immunotherapy to the clinic requires a careful consideration of the radiation regimens used. To date, little is known on whether different dose/fractionation regimens have a specific impact on the anti-tumor immune response. Most experiments combining the two modalities were conducted with single fractions of radiotherapy. However, there is at least some evidencethat when combined with some specific immunotherapy approaches, the ability of radiation to promote anti-tumor immunity is dependent on the dose and fractionation employed. We critically review the available in vitro and in vivo data on this subject and discuss the potential impact of fractionation on the ability of radiation to synergize with immunotherapy. PMID
Dose fractionation effects in primary and metastatic human uveal melanoma cell lines.
van den Aardweg, Gerard J M J; Kiliç, Emine; de Klein, Annelies; Luyten, Gregorius P M
2003-11-01
To investigate the effects of split-dose irradiation on primary and metastatic uveal melanoma cell lines, with a clonogenic survival assay. Appropriate cell concentrations of four primary and four metastatic human uveal melanoma cell lines were cultured for irradiation with single doses and with two equal fractions separated by 5 hours. After irradiation, colony formation was allowed for 7 to 21 days. Two cutaneous melanomas were also tested for comparison. All survival curves were analyzed using the linear quadratic (LQ) model. Specific parameters for the intrinsic radiosensitivity (alpha-component, SF2), for the capacity of repair of DNA damage (beta-component), as well as the alpha/beta ratio were calculated. After single-dose irradiation a wide range in the values of the alpha- and beta-component was obtained for both primary and metastatic uveal melanomas, which resulted in a wide range of alpha/beta ratios. In contrast, calculations based on split-dose data, with which the beta-component could be estimated independent of the alpha-component, indicated that estimates for the capacity of sublethal DNA damage repair was very similar in all cell lines. This indicated that intrinsic factors dominated the radiosensitivity of these cell lines. Split-dose irradiation had little influence on the intrinsic radiosensitivity (alpha-component), but cell survival increased for all cell lines. For the two cutaneous melanomas comparable split-dose results were obtained. For both primary and metastatic uveal melanoma cell lines, data from single and fractionated doses indicate large variations in radiosensitivity, which are mainly dominated by the intrinsic radiosensitivities. Doses of approximately 8 Gy in five fractions would be sufficient to eradicate 10(9) cells (approximately 1 cm3) of the most radioresistant tumor cell lines, but this schedule is an overkill for the radiosensitive tumor cell lines. Based on specific morphologic and histologic tumor markers, more
The dependence of optimal fractionation schemes on the spatial dose distribution
NASA Astrophysics Data System (ADS)
Unkelbach, Jan; Craft, David; Salari, Ehsan; Ramakrishnan, Jagdish; Bortfeld, Thomas
2013-01-01
We consider the fractionation problem in radiation therapy. Tumor sites in which the dose-limiting organ at risk (OAR) receives a substantially lower dose than the tumor, bear potential for hypofractionation even if the α/β-ratio of the tumor is larger than the α/β-ratio of the OAR. In this work, we analyze the interdependence of the optimal fractionation scheme and the spatial dose distribution in the OAR. In particular, we derive a criterion under which a hypofractionation regimen is indicated for both a parallel and a serial OAR. The approach is based on the concept of the biologically effective dose (BED). For a hypothetical homogeneously irradiated OAR, it has been shown that hypofractionation is suggested by the BED model if the α/β-ratio of the OAR is larger than α/β-ratio of the tumor times the sparing factor, i.e. the ratio of the dose received by the tumor and the OAR. In this work, we generalize this result to inhomogeneous dose distributions in the OAR. For a parallel OAR, we determine the optimal fractionation scheme by minimizing the integral BED in the OAR for a fixed BED in the tumor. For a serial structure, we minimize the maximum BED in the OAR. This leads to analytical expressions for an effective sparing factor for the OAR, which provides a criterion for hypofractionation. The implications of the model are discussed for lung tumor treatments. It is shown that the model supports hypofractionation for small tumors treated with rotation therapy, i.e. highly conformal techniques where a large volume of lung tissue is exposed to low but nonzero dose. For larger tumors, the model suggests hyperfractionation. We further discuss several non-intuitive interdependencies between optimal fractionation and the spatial dose distribution. For instance, lowering the dose in the lung via proton therapy does not necessarily provide a biological rationale for hypofractionation.
Recalculation of dose for each fraction of treatment on TomoTherapy
Romanchikova, Marina; Harrison, Karl; Parker, Michael A; Bates, Amy M; Scaife, Jessica E; Sutcliffe, Michael PF; Burnet, Neil G
2016-01-01
Objective: The VoxTox study, linking delivered dose to toxicity requires recalculation of typically 20–37 fractions per patient, for nearly 2000 patients. This requires a non-interactive interface permitting batch calculation with multiple computers. Methods: Data are extracted from the TomoTherapy® archive and processed using the computational task-management system GANGA. Doses are calculated for each fraction of radiotherapy using the daily megavoltage (MV) CT images. The calculated dose cube is saved as a digital imaging and communications in medicine RTDOSE object, which can then be read by utilities that calculate dose–volume histograms or dose surface maps. The rectum is delineated on daily MV images using an implementation of the Chan–Vese algorithm. Results: On a cluster of up to 117 central processing units, dose cubes for all fractions of 151 patients took 12 days to calculate. Outlining the rectum on all slices and fractions on 151 patients took 7 h. We also present results of the Hounsfield unit (HU) calibration of TomoTherapy MV images, measured over an 8-year period, showing that the HU calibration has become less variable over time, with no large changes observed after 2011. Conclusion: We have developed a system for automatic dose recalculation of TomoTherapy dose distributions. This does not tie up the clinically needed planning system but can be run on a cluster of independent machines, enabling recalculation of delivered dose without user intervention. Advances in knowledge: The use of a task management system for automation of dose calculation and outlining enables work to be scaled up to the level required for large studies. PMID:26728661
Soonawala, Darius; Verdijk, Pauline; Wijmenga-Monsuur, Alienke J; Boog, Claire J; Koedam, Patrick; Visser, Leo G; Rots, Nynke Y
2013-08-12
For global eradication of poliomyelitis, inactivated poliovirus vaccine (IPV) needs to become available in all countries. Using fractional-doses (reduced-doses) may impact affordability and optimize the utilization of the production capacity. Intradermal administration has the potential to lower the dose without reducing immunogenicity. A needle-free jet injector may be a reliable way to administer vaccines intradermally. The primary objective of this randomized controlled trial was to compare the immunogenicity and tolerability of fractional-dose intradermal IPV (Netherlands Vaccine Institute, NVI) booster vaccination administered with a jet injector (PharmaJet) to full-dose and fractional-dose intramuscular vaccination with a needle and syringe. Immunogenicity was assessed by comparing the differences in the post-vaccination log2 geometric mean concentrations of neutralizing antibodies (GMC) between the study groups. A total of 125 Dutch adult volunteers with a well-documented vaccination history were randomized to one of four groups: full-dose intramuscular needle (IM-NS-0.5), full-dose intramuscular jet injector (IM-JI-0.5), 1/5th dose intramuscular needle (IM-NS-0.1), 1/5th dose intradermal jet injector (ID-JI-0.1). Vaccination with the JI was less painful (87% no pain) than vaccination with a NS (60% no pain), but caused more transient erythema (JI 85%, NS 24%) and swelling (JI 50%, NS 5%). Intradermal vaccination caused less vaccination site soreness (ID 16%, IM 52%). At baseline all subjects had seroprotective antibody concentrations. After 28 days, GMC were slightly lower in the ID-JI-0.1 group than in the reference group (IM-NS-0.5). The differences were not statistically significant, but the stringent non-inferiority criterion (i.e. a difference of 1 serum dilution in the microneutralization assay) was not met. After one year, differences in GMC were no longer apparent. In contrast, intramuscular vaccination with a fractional dose administered with a
Park, Shin-Hyung; Kim, Jae-Chul
2016-01-01
Purpose: The standard radiation dose for patients with locally rectal cancer treated with preoperative chemoradiotherapy is 45–50 Gy in 25–28 fractions. We aimed to assess whether a difference exists within this dose fractionation range. Materials and Methods: A retrospective analysis was performed to compare three dose fractionation schedules. Patients received 50 Gy in 25 fractions (group A), 50.4 Gy in 28 fractions (group B), or 45 Gy in 25 fractions (group C) to the whole pelvis, as well as concurrent 5-fluorouracil. Radical resection was scheduled for 8 weeks after concurrent chemoradiotherapy. Results: Between September 2010 and August 2013, 175 patients were treated with preoperative chemoradiotherapy at our institution. Among those patients, 154 were eligible for analysis (55, 50, and 49 patients in groups A, B, and C, respectively). After the median follow-up period of 29 months (range, 5 to 48 months), no differences were found between the 3 groups regarding pathologic complete remission rate, tumor regression grade, treatment-related toxicity, 2-year locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, or overall survival. The circumferential resection margin width was a prognostic factor for 2-year locoregional recurrence-free survival, whereas ypN category was associated with distant metastasis-free survival, disease-free survival, and overall survival. High tumor regression grading score was correlated with 2-year distant metastasis-free survival and disease-free survival in univariate analysis. Conclusion: Three different radiation dose fractionation schedules, within the dose range recommended by the National Comprehensive Cancer Network, had no impact on pathologic tumor regression and early clinical outcome for locally advanced rectal cancer. PMID:27306773
Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression
Rades, Dirk . E-mail: Rades.Dirk@gmx.net; Karstens, Johann H.; Hoskin, Peter J.; Rudat, Volker; Veninga, Theo; Schild, Steven E.; Dunst, Juergen
2007-02-01
Purpose: In many centers worldwide, radiotherapy for metastatic spinal cord compression (MSCC) is performed with 30 Gy in 10 fractions. This study investigated the potential benefit of dose escalation. Methods and Materials: Data from 922 patients with carcinomas causing MSCC were retrospectively evaluated. The outcome of 345 patients treated with 10 fractions of 3 Gy in 2 weeks was compared with the outcomes of 577 patients treated with 37.5 Gy in 15 fractions within 3 weeks or 40 Gy in 20 fractions within 4 weeks. Additionally, 10 potential prognostic factors were investigated: age, gender, performance status, tumor type, interval between cancer diagnosis and MSCC, number of involved vertebrae, other bone and visceral metastases, ambulatory status, and the interval to the development of motor deficits before radiotherapy. Results: Motor function improved in 19% of patients after 30 Gy in 10 fractions and in 22% after greater doses (p = 0.31). The local control (p = 0.28) and survival (p = 0.85) rates were not significantly different with doses >30 Gy. Better functional outcome was associated with the absence of visceral metastases, an interval between tumor diagnosis and MSCC of >12 months, ambulatory status, and an interval to the development of motor deficits of >7 days. Improved local control was significantly associated with no visceral metastases, improved survival with favorable histologic features (breast or prostate cancer), no visceral metastases, ambulatory status, an interval between cancer diagnosis and MSCC of >12 months, and an interval to the development of motor deficits of >7days. Conclusion: Escalation of the radiation dose to >30 Gy in 10 fractions did not improve the outcomes in terms of motor function, local control, or survival but did increase the treatment time for these frequently debilitated patients. Therefore, doses >30 Gy in 10 fractions are not recommended.
Huo, Michael; Sahgal, Arjun; Pryor, David; Redmond, Kristin; Lo, Simon; Foote, Matthew
2017-01-01
Background: Stereotactic body radiotherapy (SBRT) is an emerging treatment option for spinal metastases with demonstrated efficacy in the upfront, postoperative, and re-treatment settings, as well as for tumor histologies considered radioresistant. Uncertainty exists regarding the optimal dose and fractionation schedule, with single and multifraction regimens commonly utilized. Methods: A literature search of the PubMed and Medline databases was conducted to identify papers specific to spine SBRT and the effect of varying dose/fractionation regimens on outcomes. Bibliographies of relevant papers were searched for further references, and international spine SBRT experts were consulted. Results: Local control rates generally exceed 80% at 1 year, while high rates of pain control have been attained. There is insufficient evidence to suggest superiority of either single or multiple fraction regimens with respect to local control and pain control. Low rates of toxicity have been reported, assuming strict dose constraints are respected. Radiation myelopathy may be the most morbid toxicity, although the rates are low. The risk of vertebral compression fracture appears to be associated with higher doses per fraction such as those used in single-fraction regimens. The Spinal Instability Neoplastic Score should be considered when evaluating patients for spine SBRT, and prophylactic stabilisation may be warranted. Pain flare is a relatively common toxicity which may be mediated with prophylactic dexamethasone. Because of the treatment complexity and potentially serious toxicities, strict quality assurance should occur at the organizational, planning, dosimetric, and treatment delivery levels. Conclusion: Both single and multifraction regimens are safe and efficacious in spine SBRT for spinal metastases. There may be advantages to hypofractionated treatment over single-fraction regimens with respect to toxicity. Ongoing investigation is underway to define optimal dose and
Comparative assessment of single-dose and fractionated boron neutron capture therapy
Coderre, J.A.; Micca, P.L.; Fisher, C.D.
1995-12-01
The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.2 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 50 and 60% long-term (>1 year) survivors, respectively. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED{sub 50} for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 {+-} 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED{sub 50} to 14.7 {+-} 0.2 Gy and 15.5 {+-} 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED{sub 50} for myelopathy of 13.8 {+-} 0.6 Gy after a single fraction and 14.9 {+-} 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED{sub 50} of 14.3 {+-} 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation. It was observed that fractionation was of minor significance in the amelioration of damage to the normal central nervous system in the rat after boron neutron capture irradiation. 30 refs., 5 figs., 3 tabs.
Somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation
Littman, P.; Rosenstock, J.; Gale, G.; Krisch, R.E.; Meadows, A.; Sather, H.; Coccia, P.; DeCamagro, B.
1984-10-01
A group of children with acute lymphocytic leukemia was studied to investigate if a reduction in daily dose fraction of cranial radiation would reduce the incidence of somnolence syndrome. Thirty-one evaluable patients received 100 rad x 18 cranial radiation therapy. Sixty-six similar evaluable patients were given 180 rad x 10. Both groups received the same chemotherapy including intrathecal methotrexate. Clinically detectable somnolence appeared in 58% of each group without significant differences in the overall frequency or severity of somnolence. This study failed to substantiate a radiation dose fraction size dependence for somnolence syndrome in children with acute lymphocytic leukemia.
Uzan, J; Nahum, A E
2012-09-01
Radiobiological models provide a means of evaluating treatment plans. Keeping in mind their inherent limitations, they can also be used prospectively to design new treatment strategies which maximise therapeutic ratio. We propose here a new method to customise fractionation and prescription dose. To illustrate our new approach, two non-small cell lung cancer treatment plans and one prostate plan from our archive are analysed using the in-house software tool BioSuite. BioSuite computes normal tissue complication probability and tumour control probability using various radiobiological models and can suggest radiobiologically optimal prescription doses and fractionation schemes with limited toxicity. Dose-response curves present varied aspects depending on the nature of each case. The optimisation process suggests doses and fractionation schemes differing from the original ones. Patterns of optimisation depend on the degree of conformality, the behaviour of the normal tissue (i.e. "serial" or "parallel"), the volume of the tumour and the parameters of clonogen proliferation. Individualising the prescription dose and number of fractions with the help of BioSuite results in improved therapeutic ratios as evaluated by radiobiological models.
Comparative assessment of single-dose and fractionated boron neutron capture therapy.
Coderre, J A; Morris, G M; Micca, P L; Fisher, C D; Ross, G A
1995-12-01
The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)
Zois, Christos E; Giatromanolaki, Alexandra; Sivridis, Efthimios; Tokmakidis, Savvas P; Botaitis, Sotirios; Simopoulos, Constantinos; Kortsaris, Alexandros; Koukourakis, Michael I
2011-01-01
Amifostine is an important broad spectrum cytoprotective agent approved for protection during fractionated radiotherapy. The daily dose of amifostine used, however, is arbitrarily chosen and low compared to the actual tolerable dose. Cohorts of mice (n=6) were treated with one up to 4 consecutive fractions of 6 Gy of whole-body γ-irradiation ((60)Co), supported with increasing daily subcutaneous (s.c.) doses of amifostine (10 mg/g-300 mg/g). Survival and weight loss were monitored. Histopathological analysis was performed in mice receiving 3 × 6 Gy. By increasing the amifostine dose from 13 to 50 mg and to 160 mg/g, the 50% lethal dose of radiotherapy increased from 2 × 6 Gy to 3 × 6 Gy and to 4 × 6 Gy, respectively. To keep the median weight loss to less than 25% of the initial weight, the dose of amifostine demanded was 23 mg/g, 68 mg/g and 121 mg/g, for 2 × 6 Gy, 3 × 6 Gy and 4 × 6 Gy, respectively. Histopathological analysis revealed a net protection of the liver and intestine of the mice receiving amifostine. Extensive and multiple vacuolar degeneration of the cytoplasm with focal necrosis of hepatocytes and loss of the intestinal villi was the most striking finding in the dying mice treated without amifostine. Taking into account the strong association of daily amifostine dose with cytoprotective efficacy and that a slight reduction of the daily amifostine dose can substantially reduce the clinical protective effect during fractionated radiotherapy, it is suggested that randomized trials should be re-appraised adopting amifostine schedules close to the maximum tolerable dose.
Park, Clint; Papiez, Lech; Zhang Shichuan; Story, Michael; Timmerman, Robert D.
2008-03-01
Purpose: Overprediction of the potency and toxicity of high-dose ablative radiotherapy such as stereotactic body radiotherapy (SBRT) by the linear quadratic (LQ) model led to many clinicians' hesitating to adopt this efficacious and well-tolerated therapeutic option. The aim of this study was to offer an alternative method of analyzing the effect of SBRT by constructing a universal survival curve (USC) that provides superior approximation of the experimentally measured survival curves in the ablative, high-dose range without losing the strengths of the LQ model around the shoulder. Methods and Materials: The USC was constructed by hybridizing two classic radiobiologic models: the LQ model and the multitarget model. We have assumed that the LQ model gives a good description for conventionally fractionated radiotherapy (CFRT) for the dose to the shoulder. For ablative doses beyond the shoulder, the survival curve is better described as a straight line as predicted by the multitarget model. The USC smoothly interpolates from a parabola predicted by the LQ model to the terminal asymptote of the multitarget model in the high-dose region. From the USC, we derived two equivalence functions, the biologically effective dose and the single fraction equivalent dose for both CFRT and SBRT. Results: The validity of the USC was tested by using previously published parameters of the LQ and multitarget models for non-small-cell lung cancer cell lines. A comparison of the goodness-of-fit of the LQ and USC models was made to a high-dose survival curve of the H460 non-small-cell lung cancer cell line. Conclusion: The USC can be used to compare the dose fractionation schemes of both CFRT and SBRT. The USC provides an empirically and a clinically well-justified rationale for SBRT while preserving the strengths of the LQ model for CFRT.
Improved tumor targeting of radiolabeled RGD peptides using rapid dose fractionation.
Janssen, Marcel; Frielink, Cathelijne; Dijkgraaf, Ingrid; Oyen, Wim; Edwards, D Scott; Liu, Shuang; Rajopadhye, Milind; Massuger, Leon; Corstens, Frans; Boerman, Otto
2004-08-01
Arginine-glycine-aspartic acid (RGD) peptides preferentially bind to alphavbeta3 integrin, an integrin expressed on newly formed endothelial cells and on various tumor cells. When labeled with beta-emitting radionuclides, these peptides can be used for peptide-receptor radionuclide therapy of malignant tumors. These studies aimed to investigate whether tumor targeting and tumor therapy could be optimized by dose fractionation. The RGD-peptide DOTA-E-[c(RGDfK)]2 was labeled with 111In for biodistribution experiments and with 90Y for therapy experiments. In mice with NIH:OVCAR-3 ovarian carcinoma xenografts, optimal tumor uptake was obtained at peptide doses up to 1.0 microg (4.8 %ID/g). A peptide dose of 5 microg, required to administer the maximum tolerable dose (MTD) 90Y-DOTA-E-[c(RGDfK)]2, was administered as 5 portions of 1.0 microg. Tumor uptake of the fifth portion was significantly higher than that of the single 5.0 microg portion (3.3 %ID/g versus 2.1 %ID/g). The therapeutic efficacy of 37 MBq 90Y-DOTA-E-[c(RGDfK)]2 (1 x 5.0 microg) was compared with that of 37 MBq administered in five equal portions (5 x 1.0 microg). No difference in tumor growth between the fractionated and the nonfractionated therapy was observed. In conclusion, dose fractionation resulted in higher radiation doses. However, therapeutic efficacy of the radiolabeled peptide was not significantly improved by dose fractionation. Copyright Mary Ann Liebert, Inc.
Deeg, H.J.; Flournoy, N.; Sullivan, K.M.; Sheehan, K.; Buckner, C.D.; Sanders, J.E.; Storb, R.; Witherspoon, R.P.; Thomas, E.D.
1984-07-01
Two hundred seventy-seven patients, who have been followed for 1 to 12 years after marrow transplantation, have been examined for cataract development. In preparation for transplantation, 96 patients with aplastic anemia were conditioned with chemotherapy only, while 181 patients (two with aplastic anemia and 179 with a hematologic malignancy) were conditioned with a regimen of total body irradiation (TBI) and chemotherapy. TBI was delivered from two opposing /sup 60/Co sources at an exposure rate of 4 to 8 cGy/min, either as a single dose of 10 Gy (105 patients) or in fractions (76 patients). To date, 86 patients have developed cataracts. Kaplan-Meier product limit estimates of the incidence of cataracts for patients given chemotherapy only and no TBI, single-dose TBI, and fractionated TBI are 19, 80, 18%, respectively. On the basis of proportional hazards regression analyses, patients given single-dose TBI had a relative risk of developing cataracts that was 4.7-fold higher than in patients given fractionated TBI or chemotherapy only, suggesting a significant sparing effect with use of TBI dose fractionation.
Edmondson, Elijah F.; Hunter, Nancy R.; Weil, Michael M.; Mason, Kathryn A.
2015-07-15
Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. An overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor
Fractional poisson--a simple dose-response model for human norovirus.
Messner, Michael J; Berger, Philip; Nappier, Sharon P
2014-10-01
This study utilizes old and new Norovirus (NoV) human challenge data to model the dose-response relationship for human NoV infection. The combined data set is used to update estimates from a previously published beta-Poisson dose-response model that includes parameters for virus aggregation and for a beta-distribution that describes variable susceptibility among hosts. The quality of the beta-Poisson model is examined and a simpler model is proposed. The new model (fractional Poisson) characterizes hosts as either perfectly susceptible or perfectly immune, requiring a single parameter (the fraction of perfectly susceptible hosts) in place of the two-parameter beta-distribution. A second parameter is included to account for virus aggregation in the same fashion as it is added to the beta-Poisson model. Infection probability is simply the product of the probability of nonzero exposure (at least one virus or aggregate is ingested) and the fraction of susceptible hosts. The model is computationally simple and appears to be well suited to the data from the NoV human challenge studies. The model's deviance is similar to that of the beta-Poisson, but with one parameter, rather than two. As a result, the Akaike information criterion favors the fractional Poisson over the beta-Poisson model. At low, environmentally relevant exposure levels (<100), estimation error is small for the fractional Poisson model; however, caution is advised because no subjects were challenged at such a low dose. New low-dose data would be of great value to further clarify the NoV dose-response relationship and to support improved risk assessment for environmentally relevant exposures.
Dose-Escalation Study of Single-Fraction Stereotactic Body Radiotherapy for Liver Malignancies
Goodman, Karyn A.; Wiegner, Ellen A.; Maturen, Katherine E.; Zhang Zhigang; Mo Qianxing; Yang, George; Gibbs, Iris C.; Fisher, George A.; Koong, Albert C.
2010-10-01
Purpose: We performed a Phase I dose-escalation study to explore the feasibility and safety of treating primary and metastatic liver tumors with single-fraction stereotactic body radiotherapy (SBRT). Methods and Materials: Between February 2004 and February 2008, 26 patients were treated for 40 identifiable lesions. Nineteen patients had hepatic metastases, 5 had intrahepatic cholangiocarcinomas, and 2 had recurrent hepatocellular carcinomas. The prescribed radiation dose was escalated from 18 to 30 Gy at 4-Gy increments with a planned maximum dose of 30 Gy. Cumulative incidence functions accounted for competing risks to estimate local failure (LF) incidence over time under the competing risk of death. Results: All patients tolerated the single-fraction SBRT well without developing a dose-limiting toxicity. Nine acute Grade 1 toxicities, one acute Grade 2 toxicity, and two late Grade 2 gastrointestinal toxicities were observed. After a median of 17 months follow-up (range, 2-55 months), the cumulative risk of LF at 12 months was 23%. Fifteen patients have died: 11 treated for liver metastases and 4 with primary liver tumors died. The median survival was 28.6 months, and the 2-year actuarial overall survival was 50.4%. Conclusions: It is feasible and safe to deliver single-fraction, high-dose SBRT to primary or metastatic liver malignancies measuring {<=}5 cm. Moreover, single-fraction SBRT for liver lesions demonstrated promising local tumor control with minimal acute and long-term toxicity. Single-fraction SBRT appears to be a viable nonsurgical option, but further studies are warranted to evaluate both control rates and impact on quality of life.
Wölfelschneider, Jens; Friedrich, Thomas; Lüchtenborg, Robert; Zink, Klemens; Scholz, Michael; Dong, Lei; Durante, Marco; Bert, Christoph
2016-03-01
Scanned particle beam therapy may result in over and under dosages within the target volume. This study quantifies how CTV dose coverage improves with number of fractions and fields. Based on 4DCTs of nine lung tumor patients, treatment plans were optimized separately for four different fields using an ITV approach. 4D RBE-weighted dose distributions were calculated for varying motion parameters and fraction numbers. The total RBE-weighted dose was determined for one and four-field application per fraction. DVHs were analyzed for the tumor and interpreted based on statistical modeling. Dose homogeneity within the CTV increased with the fraction number, but depends significantly on the tumor motion amplitude. For single-field schedules and amplitudes >6mm, the dose coverage indices (V95min=90.7% and V107max=0.4%) differed to the stationary case even after 40 fractions. Target coverage for a four-field approach followed a proposed model and homogeneous dose distributions could be achieved 6-times faster than single-field treatments. Fractionated delivery improves dose homogeneity in scanned ion beam therapy of moving targets. The achievable homogeneity depends mainly on tumor volume and motion amplitude. The outcome of multiple-field irradiations can be predicted based on single-field results and accelerates the achievement of homogeneous dose distributions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Brenner, David J.
2008-01-01
The tool most commonly used for quantitative predictions of dose / fractionation dependencies in radiotherapy is the mechanistically-based linear-quadratic (LQ) model. The LQ formalism is now almost universally used for calculating radiotherapeutic isoeffect doses for different fractionation/protraction schemes. In summary, LQ has the following useful properties for predicting isoeffect doses: First, it is a mechanistic, biologically-based model; second, it has sufficiently few parameters to be practical; third, most other mechanistic models of cell killing predict the same fractionation dependencies as does LQ; fourth, it has well documented predictive properties for fractionation/dose-rate effects in the laboratory; fifth, it is reasonably well validated, experimentally and theoretically, up to about 10 Gy / fraction, and would be reasonable for use up to about 18 Gy per fraction. To date, there is no evidence of problems when LQ has been applied in the clinic. PMID:18725109
NASA Astrophysics Data System (ADS)
Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.
2015-05-01
The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.
Kim, M; Ghate, A; Phillips, M H
2009-07-21
The current state of the art in cancer treatment by radiation optimizes beam intensity spatially such that tumors receive high dose radiation whereas damage to nearby healthy tissues is minimized. It is common practice to deliver the radiation over several weeks, where the daily dose is a small constant fraction of the total planned. Such a 'fractionation schedule' is based on traditional models of radiobiological response where normal tissue cells possess the ability to repair sublethal damage done by radiation. This capability is significantly less prominent in tumors. Recent advances in quantitative functional imaging and biological markers are providing new opportunities to measure patient response to radiation over the treatment course. This opens the door for designing fractionation schedules that take into account the patient's cumulative response to radiation up to a particular treatment day in determining the fraction on that day. We propose a novel approach that, for the first time, mathematically explores the benefits of such fractionation schemes. This is achieved by building a stylistic Markov decision process (MDP) model, which incorporates some key features of the problem through intuitive choices of state and action spaces, as well as transition probability and reward functions. The structure of optimal policies for this MDP model is explored through several simple numerical examples.
Tilly, David; Tilly, Nina; Ahnesjö, Anders
2013-06-14
Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths. The planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk. The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.
Electron absorbed fractions and dose conversion factors for marrow and bone by skeletal regions
Eckerman, K.F.; Stabin, M.G.
2000-02-01
The possible inductions of bone cancer and leukemia are the two health effects of primary concern in the irradiation of the skeleton. The relevant target tissues to consider in the dosimetric evaluation have been the cells on or near endosteal surfaces of bone, from which osteosarcomas are thought to arise, and hematopoietic bone marrow, which is associated with leukemia. The complex geometry of the soft tissue-bone intermixture makes calculations of absorbed doses to these target regions a difficult problem. In the case of photon or neutron radiations, charged particle equilibrium may not exist in the vicinity of a soft tissue-bone mineral interface. In this paper, absorbed fraction data are developed for calculations of the dose in the target tissues from electron emitters deposited within the volume or on the surfaces of trabecular bone. The skeletal average absorbed fractions presented are consistent with usage of this quantity in the contemporary dosimetric formulations of the International Commission on Radiological Protection (ICRP). Implementation of the new bone and marrow model is then developed within the context of the calculational schema of the Medical Internal Radiation Dose (MIRD) Committee. Model parameters relevant to the calculation of dose conversion factors (S values) for different regions of the skeleton of individuals of various age are described, and an example calculation is performed for a monoclonal antibody which localizes in the marrow. The utility of these calculations for radiation dose calculations in nuclear medicine is discussed.
Melamed, J.S.; Chen, M.G.; Brown, J.W.; Katagiri, C.A.
1980-02-01
Using a dose fractionation scheme patterned after the current regimen for treatment of disseminated non-Hodgkin lymphoma, the authors studied the effects of irradation on progenitor and effector cells for hematopoiesis in five-month-old BC3F/sub 1/ mice. Fractions of 20 or 50 rad (0.2 or 0.5 Gy) total body irradation were given twice weekly to a final total dose of 200 or 500 rad (2 or 5 Gy), respectively. Weekly assays revealed a marked, sustained depression of stem cell activity, measured as numbers of spleen colony-forming units (CFU-S) and in vitro colony-forming cells (CFU-C), without corresponding depression of effector cells (red and white cells, and platelets). The lack of correlation between numbers of stem cells and peripheral elements is relevant to clinical assessment of marrow reserve.
Lee, Sang-wook; Suh, Chang Ok; Chung, Eun Ji; Kim, Gwi Eon
2002-04-01
To determine the optimal dose combination scheme of external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary radiation (ICR) for maximizing tumor control while conferring an acceptable late complication rate in the treatment of Stage IB uterine cervical cancer. We retrospectively analyzed 162 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB squamous cell carcinoma of the uterine cervix who received definitive RT between May 1979 and December 1990. Before HDR-ICR, all patients received EBRT to a total dose of 40-46 Gy (median 45), administered during 4-5 weeks to the whole pelvis. HDR-ICR was given 3 times weeks to a total dose of 24-51 Gy (median 39) at point A, using a dose of 3 Gy/fraction. Central shielding from EBRT was begun after the delivery using 20-45 Gy (median 40) of the external dose. The total dose to point A, calculated by adding the EBRT biologically effective dose (BED) and the ICR BED to point A, was 74.1-118.1 Gy (mean 95.2). The rectal point dose was calculated at the anterior rectal wall at the level of the cervical os. The local control rate, survival rate, and late complication rate were analyzed according to the irradiation dose and BED. The initial complete response rate was 99.4%. The overall 5-year survival rate and 5-year disease-free survival rate was 91.1% and 90.9%, respectively. The local failure rate was 4.9%, and the distant failure rate was 4.3%. Late complications were mild and occurred in 23.5% of patients, with 18.5% presenting with rectal complications and 4.9% with bladder complications. The mean rectal BED (the sum of the external midline BED and the ICR rectal point BED) was lower in the patients without rectal complications than in those with rectal complications (125.6 Gy vs. 142.7 Gy, p = 0.3210). The late rectal complication rate increased when the sum of the external midline BED and the rectal BED by ICR was >or=131 Gy (p = 0.1962). However, 5-year survival rates did
Greene-Schloesser, Dana M; Kooshki, Mitra; Payne, Valerie; D'Agostino, Ralph B; Wheeler, Kenneth T; Metheny-Barlow, Linda J; Robbins, Mike E
2014-09-01
To determine if the brain's response to single doses predicts its response to 'biologically equivalent' fractionated doses. Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of (137)Cs γ rays or their 'biologically equivalent' 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 μm sections of the dentate gyrus (DG). Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). These data demonstrate that the rat brain's cellular response to single doses often does not predict its cellular response to 'biologically equivalent' fWBI doses.
Kamen, B.A.; Moulder, J.E.; Kun, L.E.; Ring, B.J.; Adams, S.M.; Fish, B.L.; Holcenberg, J.S.
1984-11-01
The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same whether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.
Bedi, Meena; Firat, Selim; Semenenko, Vladimir A.; Schultz, Christopher; Tripp, Patrick; Byhardt, Roger; Wang, Dian
2012-05-01
Purpose: Intensity-modulated radiation therapy (IMRT) is the standard of care for head-and-neck cancer (HNC). We treated patients with HNC by delivering either a moderate hypofractionation (MHF) schedule (66 Gy at 2.2 Gy per fraction to the gross tumor [primary and nodal]) with standard dose fractionation (54-60 Gy at 1.8-2.0 Gy per fraction) to the elective neck lymphatics or a conventional dose and fractionation (CDF) schedule (70 Gy at 2.0 Gy per fraction) to the gross tumor (primary and nodal) with reduced dose to the elective neck lymphatics. We analyzed these two cohorts for treatment outcomes. Methods and Materials: Between November 2001 and February 2009, 89 patients with primary carcinomas of the oral cavity, larynx, oropharynx, hypopharynx, and nasopharynx received definitive IMRT with or without concurrent chemotherapy. Twenty patients were treated using the MHF schedule, while 69 patients were treated with the CDF schedule. Patient characteristics and dosimetry plans were reviewed. Patterns of failure including local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), overall survival (OS), and toxicities, including rate of feeding tube placement and percentage of weight loss, were reviewed and analyzed. Results: Median follow-up was 31.2 months. Thirty-five percent of patients in the MHF cohort and 77% of patients in the CDF cohort received chemotherapy. No RR was observed in either cohort. OS, DFS, LR, and DM rates for the entire group at 2 years were 89.3%, 81.4%, 7.1%, and 9.4%, respectively. Subgroup analysis showed no significant differences in OS (p = 0.595), DFS (p = 0.863), LR (p = 0.833), or DM (p = 0.917) between these two cohorts. Similarly, no significant differences were observed in rates of feeding tube placement and percentages of weight loss. Conclusions: Similar treatment outcomes were observed for MHF and CDF cohorts. A dose of 50 Gy at 1.43 Gy per fraction may be sufficient to electively
Lee, Seung Heon; Lee, Kyu Chan; Choi, Jinho; Ahn, So Hyun; Lee, Seok Ho; Sung, Ki Hoon; Kil, Se Hee
2015-06-01
The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy2/2. BED was calculated using maximum point dose of spinal cord. Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy2/2, equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy2/2 (12.1-67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45-50 Gy2/2 to the spinal cord is tolerable in 4 or more fractionation regimen.
Lee, Seung Heon; Lee, Kyu Chan; Choi, Jinho; Ahn, So Hyun; Lee, Seok Ho; Sung, Ki Hoon; Kil, Se Hee
2015-01-01
Background. The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. Patients and methods. Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy2/2. BED was calculated using maximum point dose of spinal cord. Results. Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy2/2, equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy2/2 (12.1–67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. Conclusions. In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45–50 Gy2/2 to the spinal cord is tolerable in 4 or more fractionation regimen. PMID:26029031
2013-01-01
Background Hypofractionated Radiosurgery (HR) is a therapeutic option for delivering partial brain radiotherapy (RT) to large brain metastases or resection cavities otherwise not amenable to single fraction radiosurgery (SRS). The use, safety and efficacy of HR for brain metastases is not well characterized and the optimal RT dose-fractionation schedule is undefined. Methods Forty-two patients treated with HR in 3-5 fractions for 20 (48%) intact and 22 (52%) resected brain metastases with a median maximum dimension of 3.9 cm (0.8-6.4 cm) between May 2008 and August 2011 were reviewed. Twenty-two patients (52%) had received prior radiation therapy. Local (LC), intracranial progression free survival (PFS) and overall survival (OS) are reported and analyzed for relationship to multiple RT variables through Cox-regression analysis. Results The most common dose-fractionation schedules were 21 Gy in 3 fractions (67%), 24 Gy in 4 fractions (14%) and 30 Gy in 5 fractions (12%). After a median follow-up time of 15 months (range 2-41), local failure occurred in 13 patients (29%) and was a first site of failure in 6 patients (14%). Kaplan-Meier estimates of 1 year LC, intracranial PFS, and OS are: 61% (95% CI 0.53 – 0.70), 55% (95% CI 0.47 – 0.63), and 73% (95% CI 0.65 – 0.79), respectively. Local tumor control was negatively associated with PTV volume (p = 0.007) and was a significant predictor of OS (HR 0.57, 95% CI 0.33 - 0.98, p = 0.04). Symptomatic radiation necrosis occurred in 3 patients (7%). Conclusions HR is well tolerated in both new and recurrent, previously irradiated intact or resected brain metastases. Local control is negatively associated with PTV volume and a significant predictor of overall survival, suggesting a need for dose escalation when using HR for large intracranial lesions. PMID:23759065
Keller, Harald; Hope, Andrew; Meier, Gabriel; Davison, Matt
2013-08-01
To explore the potential of a novel dose-volume based metric to assist in the selection of optimal fractionation schedules for lung cancer patients. Selecting the dose per fraction that maximizes the therapeutic ratio via a linear-quadratic effect on normal tissue complication probability and tumor cell survival is an optimization problem. The mathematical solution reveals that the optimal fractionation schedule is determined by a generalized dose ratio between the normal tissue and the tumor, here termed the bifurcation number B, that can be derived from the dose-volume histogram of the normal tissue. The bifurcation number characterizes the volume effect of a normal tissue and its dependency on the fractionation schedule. The clinical relevance of the bifurcation number was evaluated in 46 patients previously treated for nonsmall cell lung cancer (NSCLC) according to various fractionation protocols. Bifurcation numbers were computed for both lung and esophagus as the normal tissues. The value of the bifurcation number determines whether the volume effect reverses the traditional radiobiological advantage of small dose per fraction for the normal tissue. If B is smaller than the ratio of alpha/beta ratios between normal tissue and tumor, then a single fraction is optimal; otherwise the optimal treatment is an infinite number of doses (hence the name "bifurcation" number). These fractionation schedules correspond clinically to hypo- and standard/hyperfractionation, respectively. Compared with traditional dose-volume metrics, the bifurcation number is a unitless ratio and independent of dose fractionation. The B-numbers derived from the clinical treatment plans are also strongly consistent with historically prescribed clinical fractionation protocols for NSCLC treatments. The B-numbers for esophagus and lung for all patients receiving a high dose per fraction protocol (>7.5 Gy/fraction) were all smaller than the B-numbers for the patients receiving standard 2 Gy/fraction
Fractionated low doses of abdominal irradiation alters jejunal uptake of nutrients
Thomson, A.B.; Keelan, M.; Cheeseman, C.I.; Walker, K.
1986-06-01
Abdominal radiation is associated with changes in intestinal uptake of nutrients that begins within three days and persist for over 33 weeks. Clinically, fractionated doses of radiation (FDR) are used in an attempt to minimize the complications of this therapy, but the effects of fractionated doses of radiation on intestinal transport have not been defined. An in vitro technique was used to assess the jejunal and ileal uptake of varying concentrations of glucose and leucine, as well as the uptake of single concentrations of fatty acids and decanol in rats exposed 3, 7, and 14 days previously to a course of 200 cGy given on each of five consecutive days. FDR was associated with an increase in the uptake of decanol, and therefore a decrease in the effective resistance of the unstirred water layer. FDR had a variable effect on the uptake of glucose and leucine, with a decline in the value of the Michaelis constant (Km) and the passive permeability coefficient for glucose (Pd), whereas the Km for leucine was unchanged and the Pd for leucine was variably affected by FDR. The maximal transport rate (Jdm) for leucine progressively rose following FDR, whereas the Jdm for glucose initially rose, then fell. The uptake of galactose and medium chain-length fatty acids was unchanged by FDR, whereas the jejunal uptake of myristic acid rose, and the uptake of cholic acid declined, then returned to normal. FDR was associated with greater body weight gain and jejunal and ileal weight. The changes in nutrient uptake following FDR differed from the absorption changes occurring after a single dose of radiation. Thus, fractionated doses of abdominal radiation produce complex changes in the intestinal uptake of actively and passively transported nutrients, and these variable changes are influenced by the time following radiation exposure and by the solute studied.
Effects of fractionated doses of ionizing radiation on small intestinal motor activity
Otterson, M.F.; Sarna, S.K.; Moulder, J.E.
1988-11-01
The small intestinal motor effects of fractionated doses of ionizing radiation were studied in 6 conscious dogs. Eight strain-gauge transducers were implanted on the small intestine and a single gauge on the ascending colon, of each dog. After control recordings, an abdominal dose of 250 cGy was administered three times a week on alternate days for 3 successive weeks (total dose, 2250 cGy). Recordings were then made for 4 wk of follow-up. Giant migrating contractions occurred 11 times in 520 h of control recordings in the fasted and fed state, with a mean distance of origin of 55 +/- 16 cm from the ileocolonic junction. Abdominal field irradiation significantly increased the incidence and distance of origin of these giant contractions to 438 in 745 recording hours and 158 +/- 7 cm from the ileocolonic junction, respectively. The incidence of giant migrating contractions peaked after the second dose of radiation. The amplitude ratio of radiation-induced giant migrating contractions to phase III contractions, and their duration and velocity of migration, were similar to the control state. The dogs developed diarrhea and vomiting as early as the first fraction of radiation. Irradiation also increased the incidence of retrograde giant contractions from 8 in 520 h of control recording to 42 in 745 h of recording during the radiation schedule. The radiation-induced retrograde giant contractions peaked in incidence on the day of the first fraction of radiation and were more likely to be associated with a vomiting episode than those occurring in the control period. Migrating motor complex cycling persisted during radiation and its cycle length was not different from the control or postradiation values.
A framework to measure myocardial extracellular volume fraction using dual-phase low dose CT images
Liu, Yixun; Liu, Songtao; Nacif, Marcelo S.; Sibley, Christopher T.; Bluemke, David A.; Summers, Ronald M.; Yao, Jianhua
2013-01-01
Purpose: Myocardial extracellular volume fraction (ECVF) is a surrogate imaging biomarker of diffuse myocardial fibrosis, a hallmark of pathologic ventricular remodeling. Low dose cardiac CT is emerging as a promising modality to detect diffuse interstitial myocardial fibrosis due to its fast acquisition and low radiation; however, the insufficient contrast in the low dose CT images poses great challenge to measure ECVF from the image. Methods: To deal with this difficulty, the authors present a complete ECVF measurement framework including a point-guided myocardial modeling, a deformable model-based myocardium segmentation, nonrigid registration of pre- and post-CT, and ECVF calculation. Results: The proposed method was evaluated on 20 patients by two observers. Compared to the manually delineated reference segmentations, the accuracy of our segmentation in terms of true positive volume fraction (TPVF), false positive volume fraction (FPVF), and average surface distance (ASD), were 92.18% ± 3.52%, 0.31% ± 0.10%, 0.69 ± 0.14 mm, respectively. The interobserver variability measured by concordance correlation coefficient regarding TPVF, FPVF, and ASD were 0.95, 0.90, 0.94, respectively, demonstrating excellent agreement. Bland-Altman method showed 95% limits of agreement between ECVF at CT and ECVF at MR. Conclusions: The proposed framework demonstrates its efficiency, accuracy, and noninvasiveness in ECVF measurement and dramatically advances the ECVF at cardiac CT toward its clinical use. PMID:24089934
Guo, Changning; Ngo, Diem; Ahadi, Shafiq; Doub, William H
2013-09-01
Abbreviated impactors have been developed recently to allow more rapid evaluation of inhalation products as alternates to the eight-stage Andersen Cascade Impactor (ACI) which has been widely used in the pharmaceutical industry for assessing aerodynamic particle size distribution. In this paper, a two-stage abbreviated impactor, Westech Fine Particle Dose Impactor (WFPD), was used to characterize the aerodynamic particle size of metered dose inhaler (MDI) products, and the results were compared with those obtained using the standard eight-stage ACI. Seven commercial MDI products, with different propellants (chlorofluorocarbon/hydrofluoroalkane) and formulation types (suspension/solution, dry/normal/wet), were tested in this study by both WFPD and ACI. Substantially equivalent measures of fine particle fraction were obtained for most of the tested MDI products, but larger coarse particle fraction and extra-fine particle fraction values were measured from WFPD relative to those measured using the ACI. Use of the WFPD also produced more wall loss than the ACI. Therefore, it is recommended that the system suitability be evaluated on a product-by-product basis to establish substantial equivalency before implementing an abbreviated impactor measurement methodology for routine use in inhaler product characterization.
A framework to measure myocardial extracellular volume fraction using dual-phase low dose CT images
Liu, Yixun; Summers, Ronald M.; Yao, Jianhua; Liu, Songtao; Sibley, Christopher T.; Bluemke, David A.; Nacif, Marcelo S.
2013-10-15
Purpose: Myocardial extracellular volume fraction (ECVF) is a surrogate imaging biomarker of diffuse myocardial fibrosis, a hallmark of pathologic ventricular remodeling. Low dose cardiac CT is emerging as a promising modality to detect diffuse interstitial myocardial fibrosis due to its fast acquisition and low radiation; however, the insufficient contrast in the low dose CT images poses great challenge to measure ECVF from the image. Methods: To deal with this difficulty, the authors present a complete ECVF measurement framework including a point-guided myocardial modeling, a deformable model-based myocardium segmentation, nonrigid registration of pre- and post-CT, and ECVF calculation. Results: The proposed method was evaluated on 20 patients by two observers. Compared to the manually delineated reference segmentations, the accuracy of our segmentation in terms of true positive volume fraction (TPVF), false positive volume fraction (FPVF), and average surface distance (ASD), were 92.18% ± 3.52%, 0.31% ± 0.10%, 0.69 ± 0.14 mm, respectively. The interobserver variability measured by concordance correlation coefficient regarding TPVF, FPVF, and ASD were 0.95, 0.90, 0.94, respectively, demonstrating excellent agreement. Bland-Altman method showed 95% limits of agreement between ECVF at CT and ECVF at MR. Conclusions: The proposed framework demonstrates its efficiency, accuracy, and noninvasiveness in ECVF measurement and dramatically advances the ECVF at cardiac CT toward its clinical use.
Otsuka, Shinya; Shibamoto, Yuta; Iwata, Hiromitsu; Murata, Rumi; Sugie, Chikao; Ito, Masato; Ogino, Hiroyuki
2011-12-01
Purpose: To evaluate the compliance of linear-quadratic (LQ) model calculations in the high-dose range as used in stereotactic irradiation in a murine tumor model. Methods and Materials: Female 10-week-old Balb/c mice bearing 1-cm-diameter EMT6 tumors in the hind legs were used. Single doses of 10-25 Gy were compared with 2-5 fractions of 4-13 Gy given at 4-hour intervals. Cell survival after irradiation was determined by an in vivo-in vitro assay. Using an {alpha}/{beta} ratio determined for in vitro EMT6 cells and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually measured equivalent single doses for the hypofractionated doses. These fractionation schedules were also compared simultaneously to investigate the concordance/divergence of dose-survival curves plotted against actual radiation doses and biologically effective doses (BED). Results: Equivalent single doses for hypofractionated doses calculated from LQ formalism were lower than actually measured doses by 21%-31% in the 2- or 3-fraction experiments and by 27%-42% in the 4- or 5-fraction experiments. The differences were all significant. When a higher {alpha}/{beta} ratio was assumed, the discrepancy became smaller. In direct comparison of the 2- to 5-fraction schedules, respective dose-response curves almost overlapped when cell survival was plotted against actual radiation doses. However, the curves tended to shift downward by increasing the fraction number when cell survival was plotted against BED calculated using an {alpha}/{beta} ratio of 3.5 Gy for in vitro EMT6 cells. Conclusion: Conversion of hypofractionated radiation doses to single doses using the LQ formalism underestimated the in vivo effect of hypofractionated radiation by approximately 20%-40%. The discrepancy appeared to be larger than that seen in the previous in vitro study and tended to increase with the fraction number. BED appeared to be an unreliable measure
Deeg, H.J.; Storb, R.; Shulman, H.M.; Weiden, P.L.; Graham, T.C.; Thomas, E.D.
1982-04-01
Marrow transplants were carried out between unrelated DLA-nonidentical dogs. Recipients were conditioned for transplantation by total body irradiation (TBI) given eigher as a single dose of 9 Gy (900 rad) or fractionated in three increments of 6 Gy (600 rad) each at intervals of 48 hr. All recipients received marrow, less than or equal to 4 x 10(8) cells/kg, and no buffy coat cells. No immunosuppression was given after grafting. All 10 dogs given single dose total body irradiation failed to show engraftment and died with marrow aplasia and infectious complications (median survival 12 days). In contrast, all 10 dogs given fractionated TBI had sustained engraftment and died with graft-versus-host disease (GVHD) and infectious complications (median survival 12.5 days). None of the dogs died from radiation-induced gastroenteritis. In conclusion, resistance to DLA-nonidentical unrelated marrow grafts can be abrogated by high-dose TBI. This technique may allow hemopoietic engraftment even after i vitro manipulation of the marrow such as lymphocyte depletion by cell separation or treatment with anti-T cell antisera.
Deeg, H.J.; Storb, R.; Shulman, H.M.; Weiden, P.L.; Graham, T.C.; Thomas, E.D.
1982-04-01
Marrow transplants were carried out between unrelated DLA-nonidentical dogs. Recipients were conditioned for transplantation by total body irradiation (TBI) given either as a single dose of 9 Gy (900 rad) or fractionated in three increments of 6 Gy (600 rad) each at intervals of 48 hr. All recipients received marrow, less than or equal to to 4 X 10/sup 8/ cells/kg, and no buffy coat cells. No immunosuppression was given after grafting. All 10 dogs given single-dose total body irradiation failed to show engraftment and died with marrow aplasia and infectious complications (median survival 12 days). In contrast, all 10 dogs given fractionated TBI had sustained engraftment and died with graft-versus-host disease (GVHD) and infectious complications (median survival 12.5 days). None of the dogs died from radiation-induced gastroenteritis.In conclusion, resistance to DLA-nonidentical unrelated marrow grafts can be abrogated by high-dose TBI. This technique may allow hemopoietic engraftment even after in vitro manipulation of the marrow such as lymphocyte depletion by cell separation or treatment with anti-T cell antisera.
Esophageal Toxicity From High-Dose, Single-Fraction Paraspinal Stereotactic Radiosurgery
Cox, Brett W.; Jackson, Andrew; Hunt, Margie; Bilsky, Mark; Yamada, Yoshiya
2012-08-01
Purpose: To report the esophageal toxicity from single-fraction paraspinal stereotactic radiosurgery (SRS) and identify dosimetric and clinical risk factors for toxicity. Methods and Materials: A total of 204 spinal metastases abutting the esophagus (182 patients) were treated with high-dose single-fraction SRS during 2003-2010. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Dose-volume histograms were combined to generate a comprehensive atlas of complication incidence that identifies risk factors for toxicity. Correlation of dose-volume factors with esophageal toxicity was assessed using Fisher's exact test and logistic regression. Clinical factors were correlated with toxicity. Results: The median dose to the planning treatment volume was 24 Gy. Median follow-up was 12 months (range, 3-81). There were 31 (15%) acute and 24 (12%) late esophageal toxicities. The rate of grade {>=}3 acute or late toxicity was 6.8% (14 patients). Fisher's exact test resulted in significant median splits for grade {>=}3 toxicity at V12 = 3.78 cm{sup 3} (relative risk [RR] 3.7, P=.05), V15 = 1.87 cm{sup 3} (RR 13, P=.0013), V20 = 0.11 cm{sup 3} (RR 6, P=0.01), and V22 = 0.0 cm{sup 3} (RR 13, P=.0013). The median split for D2.5 cm{sup 3} (14.02 Gy) was also a significant predictor of toxicity (RR 6; P=.01). A highly significant logistic regression model was generated on the basis of D2.5 cm{sup 3}. One hundred percent (n = 7) of grade {>=}4 toxicities were associated with radiation recall reactions after doxorubicin or gemcitabine chemotherapy or iatrogenic manipulation of the irradiated esophagus. Conclusions: High-dose, single-fraction paraspinal SRS has a low rate of grade {>=}3 esophageal toxicity. Severe esophageal toxicity is minimized with careful attention to esophageal doses during treatment planning. Iatrogenic manipulation of the irradiated esophagus and systemic agents classically associated with radiation
Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.
Yang, Ying-Chieh; Chiang, Chi-Shiun
2016-01-01
Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer.
Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy
Yang, Ying-Chieh; Chiang, Chi-Shiun
2016-01-01
Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer. PMID:27446811
Townamchai, Kanokpis; Lee, Larissa; Viswanathan, Akila N.
2012-01-01
Purpose To evaluate local control, survival and toxicity in patients with early-stage endometrioid adenocarcinoma of the uterus treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) alone using a novel low dose regimen Methods We reviewed records of 414 patients with stage IA to stage II endometrial adenocarcinoma treated with VB alone from 2005 to 2011. Of these, 157 patients with endometrioid histology received 24 Gy in 6 fractions of HDR vaginal cylinder brachytherapy and constitute the study population. Dose was prescribed at the cylinder surface and delivered twice weekly in the post-operative setting. Local control and survival rates were calculated by the Kaplan-Meier method. Results All 157 patients completed the prescribed course of VB. Median follow-up time was 22.8 months (range, 1.5–76.5). Two patients developed vaginal recurrence, one in the periurethral region below the field and one in the fornix after treatment with a 2.5-cm cylinder. Three patients developed regional recurrence in the para-aortic region. Two patients developed distant metastasis (lung and carcinomatosis). The 2-year rate of vaginal control was 98.6%, locoregional control was 97.9% and disease-free survival was 96.8%. The 2-year overall survival rate was 98.7%. No Grade 2 or higher vaginal, gastrointestinal, genitourinary or skin long-term toxicity was reported for any patient. Conclusion Vaginal brachytherapy alone in early-stage endometrial cancer provides excellent results in terms of locoregional control and disease-free survival. The fractionation scheme of 24 Gy in 6 fractions prescribed to the cylinder surface was well-tolerated with minimal late toxicity. PMID:22850411
Badheka, Jigisha Prahaladray; Oza, Vrinda Pravinbhai; Vyas, Ashutosh; Baria, Deepika; Nehra, Poonam; Babu, Thomas
2017-01-01
Background and Aims: Spinal anaesthesia (SA) with bolus dose has rapid onset but may precipitate hypotension. When we inject local anaesthetic in fractions with a time gap, it provides a dense block with haemodynamic stability and also prolongs the duration of analgesia. We aimed to compare fractionated dose with bolus dose in SA for haemodynamic stability and duration of analgesia in patients undergoing elective lower segment caesarean section (LSCS). Methods: After clearance from the Institutional Ethics Committee, the study was carried out in sixty patients undergoing elective LSCS. Patients were divided into two groups. Group B patients received single bolus SA with injection bupivacaine heavy (0.5%) and Group F patients fractionated dose with two-third of the total dose of injection bupivacaine heavy (0.5%) given initially followed by one-third dose after 90 s. Time of onset and regression of sensory and motor blockage, intraoperative haemodynamics and duration of analgesia were recorded and analysed with Student's unpaired t-test. Result: All the patients were haemodynamically stable in Group F as compared to Group B. Five patients in Group F and fourteen patients in Group B required vasopressor. Duration of sensory and motor block and duration of analgesia were longer in Group F (273.83 ± 20.62 min) compared to Group B (231.5 ± 31.87 min) P < 0.05. Conclusion: Fractionated dose of SA provides greater haemodynamic stability and longer duration of analgesia compared to bolus dose. PMID:28216705
Pedicini, Piernicola; Strigari, Lidia; Benassi, Marcello; Caivano, Rocchina; Fiorentino, Alba; Nappi, Antonio; Salvatore, Marco; Storto, Giovanni
2014-04-01
To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volume histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.
Pedicini, Piernicola; Strigari, Lidia; Benassi, Marcello; Caivano, Rocchina; Fiorentino, Alba; Nappi, Antonio; Salvatore, Marco; Storto, Giovanni
2014-01-01
To increase the efficacy of radiotherapy for non-small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new "toxicity index" (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volume histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V20 in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC. Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study.
Peucelle, C; Martínez-Rovira, I; Prezado, Y
2015-10-01
This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 μm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 μm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys. The
Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study
Peucelle, C.; Martínez-Rovira, I.; Prezado, Y.
2015-10-15
Purpose: This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. Methods: The GATE/GEANT4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 μm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 μm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. Results: Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary
Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery
Moussazadeh, Nelson; Lis, Eric; Katsoulakis, Evangelia; Kahn, Sweena; Svoboda, Marek; DiStefano, Natalie M.; McLaughlin, Lily; Bilsky, Mark H.; Yamada, Yoshiya; Laufer, Ilya
2015-10-01
Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included disease progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen
A plausible radiobiological model of cardiovascular disease at low or fractionated doses
NASA Astrophysics Data System (ADS)
Little, Mark; Vandoolaeghe, Wendy; Gola, Anna; Tzoulaki, Ioanna
Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally-exposed groups receiving small daily radia-tion doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis, and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and can-cer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapo-lation would be appropriate for this endpoint.
Grewenig, Angelika; Schuler, Nadine; Rübe, Claudia E.
2015-08-01
Purpose: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation-induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure. Methods and Materials: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations. Results: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage. Conclusions: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm.
Zablotska, Lydia B.; Little, Mark P.; Cornett, R. Jack
2014-01-01
Risks of noncancer causes of death, particularly cardiovascular disease, associated with exposures to high-dose ionizing radiation, are well known. Recent studies have reported excess risk in workers who are occupationally exposed to low doses at a low dose rate, but the risks of moderately fractionated exposures, such as occur during diagnostic radiation procedures, remain unclear. The Canadian Fluoroscopy Cohort Study includes 63,707 tuberculosis patients exposed to multiple fluoroscopic procedures in 1930–1952 and followed-up for death from noncancer causes in 1950–1987. We used a Poisson regression to estimate excess relative risk (ERR) per Gy of cumulative radiation dose to the lung (mean dose = 0.79 Gy; range, 0–11.60). The risk of death from noncancer causes was significantly lower in these subjects compared with the Canadian general population (P < 0.001). We estimated small, nonsignificant increases in the risk of death from noncancer causes with dose. We estimated an ERR/Gy of 0.176 (95% confidence interval: 0.011, 0.393) (n = 5,818 deaths) for ischemic heart disease (IHD) after adjustment for dose fractionation. A significant (P = 0.022) inverse dose fractionation effect in dose trends of IHD was observed, with the highest estimate of ERR/Gy for those with the fewest fluoroscopic procedures per year. Radiation-related risks of IHD decreased significantly with increasing time since first exposure and age at first exposure (both P < 0.05). This is the largest study of patients exposed to moderately fractionated low-to-moderate doses of radiation, and it provides additional evidence of increased radiation-associated risks of death from IHD, in particular, significantly increased radiation risks from doses similar to those from diagnostic radiation procedures. The novel finding of a significant inverse dose-fractionation association in IHD mortality requires further investigation. PMID:24145888
Greene-Schloesser, Dana M.; Kooshki, Mitra; Payne, Valerie; D’Agostino, Ralph B.; Wheeler, Kenneth T.; Metheny-Barlow, Linda J.; Robbins, Mike E.
2014-01-01
Purpose To determine if the brain’s response to single doses predicts its response to ‘biologically equivalent’ fractionated doses. Methods Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of 137Cs γ rays or their ‘biologically equivalent’ 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 µm sections of the dentate gyrus (DG). Results Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). Conclusions These data demonstrate that the rat brain’s cellular response to single doses often does not predict its cellular response to ‘biologically equivalent’ fWBI doses. PMID:24937374
Leeman, Jonathan E; Clump, David A; Wegner, Rodney E; Heron, Dwight E; Burton, Steven A; Mintz, Arlan H
2012-07-11
Brainstem metastases represent an uncommon clinical presentation that is associated with a poor prognosis. Treatment options are limited given the unacceptable risks associated with surgical resection in this location. However, without local control, symptoms including progressive cranial nerve dysfunction are frequently observed. The objective of this study was to determine the outcomes associated with linear accelerator-based stereotactic radiotherapy or radiosurgery (SRT/SRS) of brainstem metastases. We retrospectively reviewed 38 tumors in 36 patients treated with SRT/SRS between February 2003 and December 2011. Treatment was delivered with the Cyberknife™ or Trilogy™ radiosurgical systems. The median age of patients was 62 (range: 28-89). Primary pathologies included 14 lung, 7 breast, 4 colon and 11 others. Sixteen patients (44%) had received whole brain radiation therapy (WBRT) prior to SRT/SRS; ten had received prior SRT/SRS at a different site (28%). The median tumor volume was 0.94 cm3 (range: 0.01-4.2) with a median prescription dose of 17 Gy (range: 12-24) delivered in 1-5 fractions. Median follow-up for the cohort was 3.2 months (range: 0.4-20.6). Nineteen patients (52%) had an MRI follow-up available for review. Of these, one patient experienced local failure corresponding to an actuarial 6-month local control of 93%. Fifteen of the patients with available follow-up imaging (79%) experienced intracranial failure outside of the treatment volume. The median time to distant intracranial failure was 2.1 months. Six of the 15 patients with distant intracranial failure (40%) had received previous WBRT. The actuarial overall survival rates at 6- and 12-months were 27% and 8%, respectively. Predictors of survival included Graded Prognostic Assessment (GPA) score, greater number of treatment fractions, and higher prescription dose. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that
Deeg, H.J.; Storb, R.; Weiden, P.L.; Schumacher, D.; Shulman, H.; Graham, T.; Thomas, E.D.
1981-11-01
Beagle dogs treated by total-body irradiation (TBI) were given autologous marrow grafts in order to avoid death from marrow toxicity. Acute and delayed non-marrow toxicities of high single-dose (27 dogs) and fractionated TBI (20 dogs) delivered at 0.05 or 0.1 Gy/min were compared. Fractionated TBI was given in increments of 2 Gy every 6 hr for three increments per day. Acute toxicity and early mortality (<1 month) at identical total irradiation doses were comparable for dogs given fractionated or single-dose TBI. With single-dose TBI, 14, 16, and 18 Gy, respectively, given at 0.05 Gy/min, 0/5, 5/5, and 2/2 dogs died from acute toxicity; with 10, 12, and 14 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 5/5 dogs died acutely. With fractionated TBI, 14 and 16 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 2/2 dogs died auctely. Early deaths were due to radiation enteritis with or without associated septicemia (29 dogs; less than or equal to Day 10). Three dogs given 10 Gy of TBI at 0.1 Gy/min died from bacterial pneumonia; one (Day 18) had been given fractionated and two (Days 14, 22) single-dose TBI. Fifteen dogs survived beyond 1 month; eight of these had single-dose TBI (10-14 Gy) and all died within 7 months of irradiation from a syndrome consisting of hepatic damage, pancreatic fibrosis, malnutrition, wasting, and anemia. Seven of the 15 had fractionated TBI, and only one (14 Gy) died on Day 33 from hepatic failure, whereas 6 (10-14 Gy) are alive and well 250 to 500 days after irradiation. In conclusion, fractionated TBI did not offer advantages over single-dose TBI with regard to acute toxicity and early mortality; rather, these were dependent upon the total dose of TBI. The total acutely tolerated dose was dependent upon the exposure rate; however, only dogs given fractionated TBI became healthy long-term survivors.
Saran, A; Pazzaglia, S; Pariset, L; Rebessi, S; Broerse, J J; Zoetelief, J; Di Majo, V; Coppola, M; Covelli, V
1994-05-01
As most occupational and environmental exposures to ionizing radiation are at low dose rates or in small dose fractions, risk estimation requires that the effects of the temporal distribution of dose are taken into account. Previous in vitro studies of oncogenic transformation, as well as in vivo studies of carcinogenesis induced by high-LET radiation, yielded controversial results concerning the presence of an inverse dose-rate effect. The present study tested the influence of one scheme of dose fractionation of monoenergetic neutrons on neoplastic transformation of C3H 10T1/2 cells. Neutrons of 0.5, 1.0 and 6.0 MeV were used. Cells were exposed to doses of 0.25 and 0.5 Gy, given acutely or in five fractions at 2-h intervals. The acute and fractionated irradiations with each energy were done on the same day. No significant difference between the two irradiation modes was found for both cell inactivation and neoplastic transformation at all energies. These results are in agreement with our data for fractionated fission-spectrum neutrons from the RSV-TAPIRO reactor.
Aoki, Masahiko; Sato, Mariko; Hirose, Katsumi; Akimoto, Hiroyoshi; Kawaguchi, Hideo; Hatayama, Yoshiomi; Ono, Shuichi; Takai, Yoshihiro
2015-04-22
Radiation-induced rib fracture after stereotactic body radiotherapy (SBRT) for lung cancer has been recently reported. However, incidence of radiation-induced rib fracture after SBRT using moderate fraction sizes with a long-term follow-up time are not clarified. We examined incidence and risk factors of radiation-induced rib fracture after SBRT using moderate fraction sizes for the patients with peripherally located lung tumor. During 2003-2008, 41 patients with 42 lung tumors were treated with SBRT to 54-56 Gy in 9-7 fractions. The endpoint in the study was radiation-induced rib fracture detected by CT scan after the treatment. All ribs where the irradiated doses were more than 80% of prescribed dose were selected and contoured to build the dose-volume histograms (DVHs). Comparisons of the several factors obtained from the DVHs and the probabilities of rib fracture calculated by Kaplan-Meier method were performed in the study. Median follow-up time was 68 months. Among 75 contoured ribs, 23 rib fractures were observed in 34% of the patients during 16-48 months after SBRT, however, no patients complained of chest wall pain. The 4-year probabilities of rib fracture for maximum dose of ribs (Dmax) more than and less than 54 Gy were 47.7% and 12.9% (p = 0.0184), and for fraction size of 6, 7 and 8 Gy were 19.5%, 31.2% and 55.7% (p = 0.0458), respectively. Other factors, such as D2cc, mean dose of ribs, V10-55, age, sex, and planning target volume were not significantly different. The doses and fractionations used in this study resulted in no clinically significant rib fractures for this population, but that higher Dmax and dose per fraction treatments resulted in an increase in asymptomatic grade 1 rib fractures.
Ju, Dehao; Shrimpton, John; Hearn, Alex
2010-05-31
In order to provide an improved understanding of the flow in pressurized-metered dose inhalers (pMDIs), especially monitoring the output temperature and mass flow rate to obtain maximum atomization efficiency from the available energy, a numerical model for a two phases, multi-component compressible flow in a pressurized-metered dose inhaler is presented and validated. It is suitable for testing with various formulations and different geometries for a range of pMDI devices. We validated the model against available data in the literature for a single component HFA 134a propellant, and then investigated the response of the model to other formulations containing non-volatile components. Further validation is obtained by an experiment using the dual beam method which acquired the actuation flow properties such as spray velocity and duration. The deviation of the numerical predictions for the peak exit velocity against the experimental results is 5.3% and that for effective spray duration 5.0%. From the numerical and experimental results, it is found that for the formulations with the mass fraction of HFA 134a>80%, the effective spray duration of the pMDI is around 0.1s. Furthermore the droplet peak exit velocity at the axial station x=25 mm from the actuation nozzle decreases from 20 to 15m/s with the reduction of the propellant (HFA 134a) from 95%. Formulations with the mass fraction of HFA 134a below 80% produce poor quality spray which is indicated from the unsteady peak exit velocity, changeable spray number density in each experimental test, and numerical simulations also confirmed the non-viability of this condition. Copyright (c) 2010 Elsevier B.V. All rights reserved.
The Effects of Radiation and Dose-Fractionation on Cancer and Non-Tumor Disease Development
Liu, William; Haley, Benjamin M.; Kwasny, Mary J.; Li, Jian-Jian; Grdina, David J.; Paunesku, Tatjana; Woloschak, Gayle E.
2012-01-01
The Janus series of radiation experiments, conducted from 1970 to 1992, explored the effects of gamma and neutron radiation on animal lifespan and disease development. Data from these experiments presents an opportunity to conduct a large scale analysis of both tumor and non-tumor disease development. This work was focused on a subset of animals from the Janus series of experiments, comparing acute or fractionated exposures of gamma or neutron radiation on the hazards associated with the development of tumor and non-tumor diseases of the liver, lung, kidney or vascular system. This study also examines how the co-occurrence of non-tumor diseases may affect tumor-associated hazards. While exposure to radiation increases the hazard of dying with tumor and non-tumor diseases, dose fractionation modulates these hazards, which varies across different organ systems. Finally, the effect that concurrent non-cancer diseases have on the hazard of dying with a tumor also differs by organ system. These results highlight the complexity in the effects of radiation on the liver, lung, kidney and vascular system. PMID:23249856
Tiwari, M; Sahu, S K; Bhangare, R C; Pandit, G G
2016-10-01
In this study, size fractionated mass and (210)Po activity concentrations in mainstream cigarette smoke (MCS) were monitored for three popular cigarette brands. Size segregated collection of MCS was carried out using a cascade type impactor, while mass and (210)Po activity concentration were analyzed gravimetrically and alpha spectrometry (following the radiochemical separation) respectively. Multiple-Path Particle Dosimetry (MPPD V2.11) model is used for prediction of deposition fraction calculations for the MCS deposition in different compartment of human respiratory tract. The activity concentration of (210)Po is founds 10.56 ± 2.46 mBq per cigarette for the tested cigarette brands. (210)Po size distribution indicates most of this associates with fine fraction (Dp < 2.23 μm) of cigarette smoke. The committed annual effective dose to smokers (smoking on an average 20 cigarette a day), considering the (210)Po and (210)Pb concentrations (assuming it is in secular equilibrium with (210)Po) in MCS, was estimated between 0.22 and 0.40 mSv, with mean value of 0.30 mSv for tested cigarette brands. Considering the risk factor of fatal cancer due to radiation exposure of lung (exposure time of 30 years); the average collective estimated fatal cancer risk is estimated as 1.5 × 10(-4) due to (210)Po and (210)Pb exposure to smokers. Copyright Â© 2016. Published by Elsevier Ltd.
Katsoulakis, Evangelia; Laufer, Ilya; Bilsky, Mark; Agaram, Narasimhan P; Lovelock, Michael; Yamada, Yoshiya
2017-01-01
OBJECTIVE Spine radiosurgery is increasingly being used to treat spinal metastases. As patients are living longer because of the increasing efficacy of systemic agents, appropriate follow-up and posttreatment management for these patients is critical. Tumor progression after spine radiosurgery is rare; however, vertebral compression fractures are recognized as a more common posttreatment effect. The use of radiographic imaging alone posttreatment may makeit difficult to distinguish tumor progression from postradiation changes such as fibrosis. This is the largest series from a prospective database in which the authors examine histopathology of samples obtained from patients who underwent surgical intervention for presumed tumor progression or mechanical pain secondary to compression fracture. The majority of patients had tumor ablation and resulting fibrosis rather than tumor progression. The aim of this study was to evaluate tumor histopathology and characteristics of patients who underwent pathological sampling because of radiographic tumor progression, fibrosis, or collapsed vertebrae after receiving high-dose single-fraction stereotactic radiosurgery. METHODS Between January 2005 and January 2014, a total of 582 patients were treated with linear accelerator-based single-fraction (18-24 Gy) stereotactic radiosurgery. The authors retrospectively identified 30 patients (5.1%) who underwent surgical intervention for 32 lesions with vertebral cement augmentation for either mechanical pain or instability secondary to vertebral compression fracture (n = 17) or instrumentation (n = 15) for radiographic tumor progression. Radiation and surgical treatment, histopathology, and long-term outcomes were reviewed. Survival and time to recurrence were calculated using the Kaplan-Meier method. RESULTS The mean age at the time of radiosurgery was 59 years (range 36-80 years). The initial pathological diagnoses were obtained for all patients and primarily included radioresistant
Impact of Fractionation and Dose in a Multivariate Model for Radiation-Induced Chest Wall Pain
Din, Shaun U.; Williams, Eric L.; Jackson, Andrew; Rosenzweig, Kenneth E.; Wu, Abraham J.; Foster, Amanda; Yorke, Ellen D.; Rimner, Andreas
2015-10-01
Purpose: To determine the role of patient/tumor characteristics, radiation dose, and fractionation using the linear-quadratic (LQ) model to predict stereotactic body radiation therapy–induced grade ≥2 chest wall pain (CWP2) in a larger series and develop clinically useful constraints for patients treated with different fraction numbers. Methods and Materials: A total of 316 lung tumors in 295 patients were treated with stereotactic body radiation therapy in 3 to 5 fractions to 39 to 60 Gy. Absolute dose–absolute volume chest wall (CW) histograms were acquired. The raw dose-volume histograms (α/β = ∞ Gy) were converted via the LQ model to equivalent doses in 2-Gy fractions (normalized total dose, NTD) with α/β from 0 to 25 Gy in 0.1-Gy steps. The Cox proportional hazards (CPH) model was used in univariate and multivariate models to identify and assess CWP2 exposed to a given physical and NTD. Results: The median follow-up was 15.4 months, and the median time to development of CWP2 was 7.4 months. On a univariate CPH model, prescription dose, prescription dose per fraction, number of fractions, D83cc, distance of tumor to CW, and body mass index were all statistically significant for the development of CWP2. Linear-quadratic correction improved the CPH model significance over the physical dose. The best-fit α/β was 2.1 Gy, and the physical dose (α/β = ∞ Gy) was outside the upper 95% confidence limit. With α/β = 2.1 Gy, V{sub NTD99Gy} was most significant, with median V{sub NTD99Gy} = 31.5 cm{sup 3} (hazard ratio 3.87, P<.001). Conclusion: There were several predictive factors for the development of CWP2. The LQ-adjusted doses using the best-fit α/β = 2.1 Gy is a better predictor of CWP2 than the physical dose. To aid dosimetrists, we have calculated the physical dose equivalent corresponding to V{sub NTD99Gy} = 31.5 cm{sup 3} for the 3- to 5-fraction groups.
Zheng, Xiao-Kang; Chen, Long-Hua; Yan, Xiao; Wang, Hong-Mei
2005-01-01
AIM: To explore the impact of prolonged fraction dose-delivery time modeling intensity-modulated radiation therapy (IMRT) on cell killing of human hepatocellular carcinoma (HCC) HepG2 and Hep3B cell lines. METHODS: The radiobiological characteristics of human HCC HepG2 and Hep3b cell lines were studied with standard clonogenic assays, using standard linear-quadratic model and incomplete repair model to fit the dose-survival curves. The identical methods were also employed to investigate the biological effectiveness of irradiation protocols modeling clinical conventional fractionated external beam radiotherapy (EBRT, fraction delivery time 3 min) and IMRT with different prolonged fraction delivery time (15, 30, and 45 min). The differences of cell surviving fraction irradiated with different fraction delivery time were tested with paired t-test. Factors determining the impact of prolonged fraction delivery time on cell killing were analyzed. RESULTS: The α/β and repair half-time (T1/2) of HepG2 and Hep3b were 3.1 and 7.4 Gy, and 22 and 19 min respectively. The surviving fraction of HepG2 irradiated modeling IMRT with different fraction delivery time was significantly higher than irradiated modeling EBRT and the cell survival increased more pronouncedly with the fraction delivery time prolonged from 15 to 45 min, while no significant differences of cell survival in Hep3b were found between different fraction delivery time protocols. CONCLUSION: The prolonged fraction delivery time modeling IMRT significantly decreased the cell killing in HepG2 but not in Hep3b. The capability of sub-lethal damage repair was the predominant factor determining the cell killing decrease. These effects, if confirmed by clinical studies, should be considered in designing IMRT treatments for HCC. PMID:15770720
Lin, P.-S. . E-mail: plin@vcu.edu; Wu, Andrew
2005-10-01
Purpose: To test whether or not the commonly prescribed daily dose of 2 Gy (whole fraction), when delivered as various partial fraction (PF) dose sequences simulating clinical treatment fields, produces equal biologic effects. Methods and Materials: Eleven actively proliferating cell lines derived from human and animal tissues were used in this study. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and clonogenic assays were used to determine the radiation effects on cell proliferation and survival, respectively. The 2 Gy dose was divided into 2 or more PFs for delivery to simulate the delivery of clinical treatment fields. Most irradiation sequences contained two parts consisting of at least 1 small PF, denoted by S which was 0.5 Gy or less, and a large PF, denoted by L which was 1 Gy or more. Irradiation schemes were designed to include the following conditions: (a) the 2 Gy dose divided into combinations of an L-dose and one or more S-doses; (b) the L-dose given either before or after the S-doses; and (c) delivery of all partial fractions within a fixed total time. Results: Significant differences in biologic effect were observed between sequences in which the L-dose was given before or after the S-doses in both the MTT and clonogenic assays. Nearly all the latter schemes, that is S-L, produced greater cytotoxic effects than the L-S schemes. Conclusions: These data demonstrate that the biologic effects of 2 Gy may differ in different clinical settings depending on the size and sequence of the partial fractions. The variation between cytotoxic effects is likely a result of the combination of low-dose hyper-radiosensitivity (HRS) and higher-dose increased radioresistance (IRR) effects established recently. We suggest that to ensure the optimal biologic effect of a prescribed dose of 2 Gy clinically, it is critical to consider the sequence in which the treatment fields are delivered when partial fractions of different sizes are used.
Rynasiewicz, J.J.; Sutherland, D.E.R.; Kawahara, K.; Kim, T.; Najarian, J.S.
1981-03-01
The survival or organ allografts is prolonged in mice and rats treated with fractionated, high-dose total lymphoid irradiation (TLI). We have studied the effect of TLI, alone or in combination with donor bone marrow or pharmacologic immunosuppression (cyclosporin-A: CY-A), on the survival of heterotopic rat heart allografts. Specifically, we evaluated the generalized immunosuppressive effect of TLI as a function of accumulated dose and fractionation schedule. In addition, TLI and CY-A were used individually in schedules that by themselves gave only moderate graft prolongation and then subsequently in sequential combination.
Demizu, Yusuke; Fujii, Osamu; Nagano, Fumiko; Terashima, Kazuki; Jin, Dongcun; Mima, Masayuki; Oda, Naoharu; Takeuchi, Kaoru; Takeda, Makiko; Ito, Kazuyuki; Fuwa, Nobukazu; Okimoto, Tomoaki
2015-11-01
Carbon ion therapy is a type of radiotherapy that can deliver high-dose radiation to a tumor while minimizing the dose delivered to organs at risk. Moreover, carbon ions are classified as high linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. A 73-year-old man with glottic squamous cell carcinoma, T3N0M0, refused laryngectomy and received carbon ion therapy of 70 Gy (relative biological effectiveness) in 35 fractions. Three months after the therapy, the patient had an upper airway inflammation, and then laryngeal edema and pain occurred. Five months after the therapy, the airway stenosis was severe and computed tomography showed lack of the left arytenoid cartilage and exacerbation of laryngeal necrosis. Despite the treatment, 5 and a half months after the therapy, the laryngeal edema and necrosis had become even worse and the surrounding mucosa was edematous and pale. Six months after the therapy, pharyngolaryngoesophagectomy and reconstruction with free jejunal autograft were performed. The surgical specimen pathologically showed massive necrosis and no residual tumor. Three years after the carbon ion therapy, he is alive without recurrence. The first reported laryngeal squamous cell carcinoma case treated with carbon ion therapy resulted in an unexpected radiation laryngeal necrosis. Tissue damage caused by carbon ion therapy may be difficult to repair even for radioresistant cartilage; therefore, hollow organs reinforced by cartilage, such as the larynx, may be vulnerable to carbon ion therapy. Caution should be exercised when treating tumors in or adjacent to such organs with carbon ion therapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Pan, Jianmin; Yusuf, Mehran B; Dragun, Anthony; Dunlap, Neal; Guan, Timothy; Boling, Warren; Rai, Shesh; Woo, Shiao
2016-01-01
Background: Our aim was to identify a dose-volume response relationship for brain metastases treated with frameless stereotactic radiosurgery (SRS). Methods: We reviewed patients who underwent frameless single-fraction linear accelerator SRS for brain metastases between 2007 and 2013 from an institutional database. Proportional hazards modeling was used to identify predictors of outcome. A ratio of maximum lesion dose per mm-diameter (Gy/mm) was constructed to establish a dose-volume relationship. Results: There were 316 metastases evaluated in 121 patients (2 - 33 mm in the largest diameter). The median peripheral dose was 18.0 Gy (range: 10.0 – 24.0 Gy). Local control was 84.8% for all lesions and was affected by location, peripheral dose, maximum dose, and lesion size (p values < 0.050). A dose-volume response relationship was constructed using the maximum dose and lesion size. A unit increase in Gy/mm was associated with decreased local failure (p = 0.005). Local control of 80%, 85%, and 90% corresponded to maximum doses per millimeter of 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively. Toxicity was uncommon and only 1.0% of lesions developed radionecrosis requiring surgery. Conclusions: For brain metastases less than 3 cm, a dose-volume response relationship exists between maximum radiosurgical dose and lesion size, which is predictive of local control. PMID:27284495
NASA Astrophysics Data System (ADS)
Bewes, J. M.; Suchowerska, N.; Jackson, M.; Zhang, M.; McKenzie, D. R.
2008-07-01
Intensity-modulated radiation therapy (IMRT) achieves optimal dose conformity to the tumor through the use of spatially and temporally modulated radiation fields. In particular, average dose rate and instantaneous dose rate (pulse amplitude) are highly variable within a single IMRT fraction. In this study we isolate these variables and determine their impact on cell survival. Survival was assessed using a clonogenic assay. Two cell lines of differing radiosensitivity were examined: melanoma (MM576) and non-small cell lung cancer (NCI-H460). The survival fraction was observed to be independent of instantaneous dose rate. A statistically significant trend to increased survival was observed as the average dose rate was decreased, for a constant total dose. The results are relevant to IMRT practice, where average treatment times can be significantly extended to allow for movement of the multi-leaf collimator (MLC). Our in vitro study adds to the pool of theoretical evidence for the consequences of protracted treatments. We find that extended delivery times can substantially increase the cell survival. This also suggests that regional variation in the dose-rate history across a tumor, which is inherent to IMRT, will affect radiation dose efficacy.
Sorbe, Bengt . E-mail: bengt.sorbe@orebroll.se; Straumits, Andris; Karlsson, Leif
2005-08-01
Purpose To compare two different fractionation schedules for postoperative vaginal high-dose-rate (HDR) irradiation in endometrial carcinomas. Methods and Materials In a complete geographic series of 290 low-risk endometrial carcinomas, the efficacy and side effects of two different fractionation schedules for postoperative vaginal irradiation were evaluated. The patients were treated during the years 1989-2003. The tumors were in International Federation of Gynecology and Obstetrics Stages IA-IB and Grades 1-2. The HDR MicroSelectron afterloading equipment (iridium-192) was used. Perspex vaginal applicators with diameters of 20-30 mm were used, and the dose was specified at 5 mm from the surface of the applicator. Six fractions were given, and the overall treatment time was 8 days. The size of the dose per fraction was randomly set to 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy). One hundred forty-four patients were treated with the 2.5-Gy fraction and 146 patients with the 5.0-Gy fraction. Results The overall locoregional recurrence rate of the complete series was 1.4% and the rate of vaginal recurrences 0.7%. There was no difference between the two randomized groups. The vaginal shortening measured by colpometry was not significant (p = 0.159) in the 2.5-Gy group (mean, 0.3 cm) but was highly significant (p < 0.000001) in the 5.0-Gy group (mean 2.1 cm) after 5 years. Mucosal atrophy and bleedings were significantly more frequent in the 5.0-Gy group. Symptoms noted in the 2.5-Gy group were not different from what could be expected in a normal group of postmenopausal women. Conclusion The fractionation schedule recommended for postoperative vaginal irradiation in low-risk endometrial carcinoma is six fractions of 2.5 Gy when the HDR technique is used.
Hiniker, Susan M; Modlin, Leslie A; Choi, Clara Y; Atalar, Banu; Seiger, Kira; Binkley, Michael S; Harris, Jeremy P; Liao, Yaping Joyce; Fischbein, Nancy; Wang, Lei; Ho, Anthony; Lo, Anthony; Chang, Steven D; Harsh, Griffith R; Gibbs, Iris C; Hancock, Steven L; Li, Gordon; Adler, John R; Soltys, Scott G
2016-04-01
Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures
Maruyama, Y.; Wierzbicki, J. )
1990-12-01
Time-dose fractionation factors (TDF) were calculated for 252Cf (Cf) neutron therapy versus 137Cs for intracavitary use in the preoperative treatment of bulky/barrel-shaped Stage IB cervix cancers. The endpoint assessed was gross and microscopic tumor eradication from the hysterectomy specimen. We reviewed the data obtained in clinical trials between 1976-1987 at the University of Kentucky Medical Center. Preoperative photon therapy was approximately 45 Gy of whole pelvis irradiation in 5 weeks for both 137Cs and Cf treated patients. 137Cs implant was done after pelvic irradiation x1 to a mean dose of 2104 +/- 36 cGy at point A at a dose rate of 50.5 cGy/h. There were 37.5% positive specimens. Using Cf intracavitary implants, dose varied from 109 to 459 neutron cGy in 1-2 sessions. Specimens were more frequently cleared of tumor (up to 100% at appropriate dose) and showed a dose-response relationship, both by nominal dose and by TDF adjusted analysis of dose, dose-rate, number of sessions, and overall time. Limited understanding of relative biological effectiveness, schedule, effect of implants, and dose rate all made it difficult to use TDF to study neutron effects. Relative biological effectiveness (RBE) was estimated and showed that for Cf, RBE was a complex function of treatment variables. In the pilot clinical studies, a value of 6.0 had been assumed. The present findings of RBE for tumor destruction are larger than those assumed. Cf was effective for cervix tumor therapy and produced control without significant side effects due to the brachytherapy method used. The TDF model was of limited value in the present analysis and more information is still needed for RBE, dose-rate, and fractionation effects for Cf neutrons to develop a more sophisticated and relevant model.
SU-E-T-94: Daily Fraction Dose Recalculation Based On Rigid Registration Using Cone Beam CT
Bosse, C; Tuohy, R; Mavroidis, P; Shi, Z; Crownover, R; Papanikolaou, N; Stathakis, S
2014-06-01
Purpose: To calculate the daily fraction dose for a CBCT recalculation based on rigid registration and compare it to the planned CT dose. Methods: For this study, 30 patients that were previously treated (10 SBRT lung, 10 prostate and 10 abdomen) were considered. The daily CBCT images were imported into the Pinnacle treatment planning system from Mosaic. The prescribing physician contoured the regions of interest (ROI) on each CBCT and then dose was computed on each CBCT. Each CBCT dose distribution was then compared against the plan. The evaluation was based on isodose line comparison and Dose Volume Histogram comparison. Results: In the case of lung patients the dose differences between daily dose and plan dose were considered small. The PTV coverage was not compromised and the dose to the organs at risk had negligible differences. Larger differences were observed for prostate and abdomen patients. In these cases, although the PTV doses did not change on a daily basis, the doses to the organs at risk had significant differences. For a prostate patient, the bladder dose at 35% volume was 2714.444 cGy for the CT plan and 2844.747, 2801.556, 3552.37, and 2970.968 cGy for subsequent CBCTs. For the PTV on a SBRT patient, however, the CT plan had a dose at 35% volume of 6917.71 cGy and 6815.385, 6892.5, 6896.25, and 6922.9 cGy for the CBCTs. Conclusion: Daily dose validation is feasible using CBCT and treatment planning system. It provides means to evaluate the course of treatment for the patient undergoing radiation therapy and can assist in the decision of the need of adaptation of the treatment plan.
Jin Jinyue; Kong Fengming; Chetty, Indrin J.; Ajlouni, Munther; Ryu, Samuel; Ten Haken, Randall; Movsas, Benjamin
2010-03-01
Purpose: To assess how fraction size impacts lung radiation toxicity and therapeutic ratio in treatment of lung cancers. Methods and Materials: The relative damaged volume (RDV) of lung was used as the endpoint in the comparison of various fractionation schemes with the same normalized total dose (NTD) to the tumor. The RDV was computed from the biologically corrected lung dose-volume histogram (DVH), with an alpha/beta ratio of 3 and 10 for lung and tumor, respectively. Two different (linear and S-shaped) local dose-effect models that incorporated the concept of a threshold dose effect with a single parameter D{sub L50} (dose at 50% local dose effect) were used to convert the DVH into the RDV. The comparison was conducted using four representative DVHs at different NTD and D{sub L50} values. Results: The RDV decreased with increasing dose/fraction when the NTD was larger than a critical dose (D{sub CR}) and increased when the NTD was less than D{sub CR}. The D{sub CR} was 32-50 Gy and 58-87 Gy for a small tumor (11 cm{sup 3}) for the linear and S-shaped local dose-effect models, respectively, when D{sub L50} was 20-30 Gy. The D{sub CR} was 66-97 Gy and 66-99 Gy, respectively, for a large tumor (266 cm{sup 3}). Hypofractionation was preferred for small tumors and higher NTDs, and conventional fractionation was better for large tumors and lower NTDs. Hypofractionation might be beneficial for intermediate-sized tumors when NTD = 80-90 Gy, especially if the D{sub L50} is small (20 Gy). Conclusion: This computational study demonstrated that hypofractionated stereotactic body radiotherapy is a better regimen than conventional fractionation in lung cancer patients with small tumors and high doses, because it generates lower RDV when the tumor NTD is kept unchanged.
Li, Xueming; Zheng, Shawn; Agard, David A; Cheng, Yifan
2015-11-01
Newly developed direct electron detection cameras have a high image output frame rate that enables recording dose fractionated image stacks of frozen hydrated biological samples by electron cryomicroscopy (cryoEM). Such novel image acquisition schemes provide opportunities to analyze cryoEM data in ways that were previously impossible. The file size of a dose fractionated image stack is 20-60 times larger than that of a single image. Thus, efficient data acquisition and on-the-fly analysis of a large number of dose-fractionated image stacks become a serious challenge to any cryoEM data acquisition system. We have developed a computer-assisted system, named UCSFImage4, for semi-automated cryo-EM image acquisition that implements an asynchronous data acquisition scheme. This facilitates efficient acquisition, on-the-fly motion correction, and CTF analysis of dose fractionated image stacks with a total time of ∼60s/exposure. Here we report the technical details and configuration of this system.
Sugano, Yasutaka; Mizuta, Masahiro; Takao, Seishin; Shirato, Hiroki; Sutherland, Kenneth L.; Date, Hiroyuki
2015-11-15
Purpose: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose–volume histograms for tumor and normal tissues of organs around the tumor. Methods: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of the tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose–volume histogram. Results: It was found that the optimization of fractionation scheme incorporating the dose–volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8–32 fractions with a daily dose of 2.2–6.3 Gy. Conclusions: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose–volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.
Song, C.W.; Kim, T.H.; Khan, F.M.; Kersey, J.H.; Levitt, S.H.
1981-12-01
Total body irradiation (TBI) followed by bone marrow transplantation is being used in the treatment of malignant or non-malignant hemopoietic disorders. It has been believed that the ability of hemopoietic cells to repair sublethal radiation damage is negligible. Therefore, several schools of investigators suggested that TBI in a single exposure at extremely low dose rate (5 rad/min) over several hours, or in several fractions in 2-3 days, should yield a higher therapeutic gain, as compared with a single exposure at a high dose rate (25 rad/min). We reviewed the existing data in the literature, in particular, the response of hemopoietic cells to fractionated doses of irradiation and found that the repair capacity of both malignant and non-malignant hemopoietic cells might be greater than has been thought. It is concluded that we should not underestimate the ability of hemopoietic cells to repair sublethal radiation damage in using TBI.
Song, C.W.; Kim, T.H.; Khan, F.M.; Kersey, J.H.; Levitt, S.H.
1981-12-01
Total body irradiation (TBI) followed by bone marrow transplantation is being used in the treatment of malignant or non-malignant hemopoietic disorders. It has been believed that the ability of hemopoietic cells to repair sublethal radiation damage is negligible. Therefore, several schools of investigators suggested that TBI in a single exposure at extremely low dose rate (5 rad/min) over several hours, or in several fractions in 2-3 days, should yield a higher therapeutic gain, as compared with a single exposure at a high dose rate (26 rad/min). We reviewed the existing data in the literature, in particular, the response of hemopoietic cells to fractionated doses of irradiation and found that the repair capacity of both malignant and non-malignant hemopoietic cells might be greater than has been thought. It is concluded that we should not underestimate the ability of hemopoietic cells to repair sublethal radiation damage in using TBI.
Littbrand, B; Edsmyr, F; Révész, L
1975-01-01
Experimental observations are described which form the basis of a low dose-fractionation scheme designed in an attempt to circumvent the problem presented for radiotherapy by the particular radioresistance of poorly oxygenated cells. In a preliminary investigation the scheme was tested in the treatment of carcinoma of the bladder. A total of 45 patients were included in the trial, randomized to be treated according to either of two fractionation schemes. Scheme I : 100 rad 3 times a day, 5 days a week, a total tumor dose of 8 400 rad, 2 weeks of rest in middle of the treatment period. Scheme II : 200 rad once a day, 5 days a week, a total tumor dose of 6 400 rad, 2 weeks of rest in the middle of the treatment period. The results suggest an improved therapeutic ratio with Scheme I in comparison to Scheme II.
Salivary secretion in children after fractionated or single-dose TBI.
Garming Legert, K; Remberger, M; Ringdèn, O; Heimdahl, A; Dahllöf, G
2012-03-01
The incidence of long-term oral complications after hematopoietic SCT (HSCT) varies between 60 and 100%. The aim of this study was to compare the salivary secretion rate and the contribution of known risk factors for a low salivary secretion rate 1 year after HSCT in children conditioned with fractionated TBI (fTBI) and in children conditioned with single-dose TBI (sTBI). The study involved 44 patients, 27 conditioned with sTBI and 17 conditioned with fTBI. The unstimulated and stimulated salivary secretion rates (USSRs and SSSRs) were estimated before HSCT and at 1-year follow-up. Risk factors that may have influenced the salivary secretion rate were recorded. An SSSR of ≤0.5 mL/min and a USSR of ≤0.1 mL/min were chosen as cut-off points for salivary dysfunction. The median reduction in stimulated salivary flow 1 year after HSCT was 56% in the sTBI group and 12% in the fTBI group (P=0.003). The median reduction in unstimulated salivary flow 1 year after HSCT was 74% in the sTBI group and 33% in the fTBI group (P=0.003). In the multivariate model, a significant correlation between both sTBI (odds ratio (OR)=6.49, 95% confidence interval (CI)=1.40-30, P=0.014) and seropositivity of the recipient for 3-4 herpesviruses (OR=6.57, 95% CI=1.26-34, P=0.021) and a low stimulated salivary secretion rate (<0.5 mL/min) was found 1 year after HSCT.
Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.
2014-01-01
BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at
Sood, Brij M; Gorla, Giridhar; Gupta, Sajel; Garg, Madhur; Deore, Shivaji; Runowicz, Carolyn D; Fields, Abbie L; Goldberg, Gary L; Anderson, Patrick S; Vikram, Bhadrasain
2002-07-01
In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as
Streitparth, Florian; Pech, Maciej; Boehmig, Michael; Ruehl, Ricarda; Peters, Nils; Wieners, Gero; Steinberg, Johannes; Lopez-Haenninen, Enrique; Felix, Roland; Wust, Peter; Ricke, Jens . E-mail: jens.ricke@medizin.uni-magdeburg.de
2006-08-01
Purpose: The aim of this study was to assess the tolerance dose of gastric mucosa for single-fraction computed tomography (CT)-guided, high-dose-rate (HDR) brachytherapy of liver malignancies. Methods and Materials: A total of 33 patients treated by CT-guided HDR brachytherapy of liver malignancies in segments II and/or III were included. Dose planning was performed upon a three-dimensional CT data set acquired after percutaneous applicator positioning. All patients received gastric protection post-treatment. For further analysis, the contours of the gastric wall were defined in every CT slice using Brachyvision Software. Dose-volume histograms were calculated for each treatment and correlated with clinical data derived from questionnaires assessing Common Toxicity Criteria (CTC). All patients presenting symptoms of upper GI toxicity were examined endoscopically. Results: Summarizing all patients the minimum dose applied to 1 ml of the gastric wall (D{sub 1ml}) ranged from 6.3 to 34.2 Gy; median, 14.3 Gy. Toxicity was present in 18 patients (55%). We found nausea in 16 (69%), emesis in 9 (27%), cramping in 13 (39%), weight loss in 12 (36%), gastritis in 4 (12%), and ulceration in 5 patients (15%). We found a threshold dose D{sub 1ml} of 11 Gy for general gastric toxicity and 15.5 Gy for gastric ulceration verified by an univariate analysis (p = 0.01). Conclusions: For a single fraction, small volume irradiation we found in the upper abdomen a threshold dose D{sub 1ml} of 15.5 Gy for the clinical endpoint ulceration of the gastric mucosa. This in vivo assessment is in accordance with previously published tolerance data.
Sasi, Sharath P; Yan, Xinhua; Zuriaga-Herrero, Marian; Gee, Hannah; Lee, Juyong; Mehrzad, Raman; Song, Jin; Onufrak, Jillian; Morgan, James; Enderling, Heiko; Walsh, Kenneth; Kishore, Raj; Goukassian, David A
2017-08-01
Deep-space travel presents risks of exposure to ionizing radiation composed of a spectrum of low-fluence protons ((1)H) and high-charge and energy (HZE) iron nuclei (e.g., (56)Fe). When exposed to galactic cosmic rays, each cell in the body may be traversed by (1)H every 3-4 days and HZE nuclei every 3-4 months. The effects of low-dose sequential fractionated (1)H or HZE on the heart are unknown. In this animal model of simulated ionizing radiation, middle-aged (8-9 months old) male C57BL/6NT mice were exposed to radiation as follows: group 1, nonirradiated controls; group 2, three fractionated doses of 17 cGy (1)H every other day ((1)H × 3); group 3, three fractionated doses of 17 cGy (1)H every other day followed by a single low dose of 15 cGy (56)Fe two days after the final (1)H dose ((1)H × 3 + (56)Fe); and group 4, a single low dose of 15 cGy (56)Fe followed (after 2 days) by three fractionated doses of 17 cGy (1)H every other day ((56)Fe + (1)H × 3). A subgroup of mice from each group underwent myocardial infarction (MI) surgery at 28 days postirradiation. Cardiac structure and function were assessed in all animals at days 7, 14 and 28 after MI surgery was performed. Compared to the control animals, the treatments that groups 2 and 3 received did not induce negative effects on cardiac function or structure. However, compared to all other groups, the animals in group 4, showed depressed left ventricular (LV) functions at 1 month with concomitant enhancement in cardiac fibrosis and induction of cardiac hypertrophy signaling at 3 months. In the irradiated and MI surgery groups compared to the control group, the treatments received by groups 2 and 4 did not induce negative effects at 1 month postirradiation and MI surgery. However, in group 3 after MI surgery, there was a 24% increase in mortality, significant decreases in LV function and a 35% increase in post-infarction size. These changes were associated with significant decreases in the angiogenic and cell
Zhang, Xiao-Jun; Chinkes, David L; Herndon, David N; Wolfe, Robert R
2009-09-01
The flooding dose method continues to be useful in measuring protein fractional synthetic rate (FSR) in a tissue. However, flooding of free amino acid pools eliminates enrichment difference between plasma and tissue free amino acid pools, which makes it impossible to concomitantly measure protein fractional breakdown rate (FBR). We hypothesized that a subflooding dose of an amino acid reduces the enrichment difference between plasma and tissue free amino acid pool to a minimal measurable level, thus allowing concomitant measurement of protein FSR and FBR. Phenylalanine (40% enriched) at 50 mg/kg was intravenously injected as a bolus in 6 anesthetized rabbits. Arterial blood and chest skin samples were taken before the injection and for 120 minutes after the injection. Fractional breakdown rate of skin protein calculated from 15-60-120-minute sampling times was 11.3%/d +/- 2.0%/d, which was close (P = .66) to the corresponding FSR of 10.0%/d +/- 2.3%/d. The subflooding dose injection did not disturb the FBR approach because modifications on the FBR equation to account for the changes of plasma phenylalanine concentration resulted in the same value (11.5%/d +/- 1.4%/d). The FBR was positively correlated with the FSR (r = 0.80, P < .05). These findings indicate maintenance of protein mass in the skin, which is a metabolic characteristic of the skin. This subflooding dose method provides a methodological choice to concomitantly measure both FSR and FBR in a tissue.
2011-01-01
Background To assess brachytherapy catheter positioning accuracy and to evaluate the effects of prolonged irradiation time on the tolerance dose of normal liver parenchyma following single-fraction irradiation with 192 Ir. Materials and methods Fifty patients with 76 malignant liver tumors treated by computed tomography (CT)-guided high-dose-rate brachytherapy (HDR-BT) were included in the study. The prescribed radiation dose was delivered by 1 - 11 catheters with exposure times in the range of 844 - 4432 seconds. Magnetic resonance imaging (MRI) datasets for assessing irradiation effects on normal liver tissue, edema, and hepatocyte dysfunction, obtained 6 and 12 weeks after HDR-BT, were merged with 3D dosimetry data. The isodose of the treatment plan covering the same volume as the irradiation effect was taken as a surrogate for the liver tissue tolerance dose. Catheter positioning accuracy was assessed by calculating the shift between the 3D center coordinates of the irradiation effect volume and the tolerance dose volume for 38 irradiation effects in 30 patients induced by catheters implanted in nearly parallel arrangement. Effects of prolonged irradiation were assessed in areas where the irradiation effect volume and tolerance dose volume did not overlap (mismatch areas) by using a catheter contribution index. This index was calculated for 48 irradiation effects induced by at least two catheters in 44 patients. Results Positioning accuracy of the brachytherapy catheters was 5-6 mm. The orthogonal and axial shifts between the center coordinates of the irradiation effect volume and the tolerance dose volume in relation to the direction vector of catheter implantation were highly correlated and in first approximation identically in the T1-w and T2-w MRI sequences (p = 0.003 and p < 0.001, respectively), as were the shifts between 6 and 12 weeks examinations (p = 0.001 and p = 0.004, respectively). There was a significant shift of the irradiation effect towards
Lovelock, D. Michael; Zhang, Zhigang; Jackson, Andrew; Keam, Jennifer; Bekelman, Justin; Bilsky, Mark; Lis, Eric; Yamada, Yoshiya
2011-01-01
Purpose In the setting of high-dose single-fraction image-guided radiotherapy of spine metastases, the delivered dose is hypothesized to be a significant factor in local control. We investigated the dependence of local control on measures of dose insufficiency. Methods and Materials The minimum doses received by the hottest 100%, 98%, and 95% (Dmin, D98, and D95) of the gross target volume (GTV) were computed for 91 consecutively treated lesions observed in 79 patients. Prescribed doses of 18–24 Gy were delivered in a single fraction. The spinal cord and cauda equina were constrained to a maximum dose of 12–14 Gy and 16 Gy, respectively. A rank-sum test was used to assess the differences between radiographic local failure and local control. Results With a median follow-up of 18 months, seven local failures have occurred. The distributions of GTV Dmin, D98, and D95 for treatments resulting in local failure were found to be statistically different from the corresponding distributions of the patient group as a whole. Taking no account of histology, p values calculated for Dmin, D98, and D95 were 0.004, 0.012, and 0.031, respectively. No correlations between local failure and target volume or between local failure and anatomic location were found. Conclusions The results indicate that Dmin, D98, and D95 may be important risk factors for local failure. No local failures in any histology were observed when Dmin was >15 Gy, suggesting that this metric may be an important predictor of local control. PMID:20350795
Hauck, Carlin R; Ye, Hong; Chen, Peter Y; Gustafson, Gary S; Limbacher, Amy; Krauss, Daniel J
2017-05-01
Prostate-specific antigen (PSA) bounce is a temporary elevation of the PSA level above a prior nadir. The purpose of this study was to determine whether the frequency of a PSA bounce following high-dose-rate (HDR) interstitial brachytherapy for the treatment of prostate cancer is associated with individual treatment fraction size. Between 1999 and 2014, 554 patients underwent treatment of low- or intermediate-risk prostate cancer with definitive HDR brachytherapy as monotherapy and had ≥3 subsequent PSA measurements. Four different fraction sizes were used: 950 cGy × 4 fractions, 1200 cGy × 2 fractions, 1350 cGy × 2 fractions, 1900 cGy × 1 fraction. Four definitions of PSA bounce were applied: ≥0.2, ≥0.5, ≥1.0, and ≥2.0 ng/mL above the prior nadir with a subsequent return to the nadir. The median follow-up period was 3.7 years. The actuarial 3-year rate of PSA bounce for the entire cohort was 41.3%, 28.4%, 17.4%, and 6.8% for nadir +0.2, +0.5, +1.0, and +2.0 ng/mL, respectively. The 3-year rate of PSA bounce >0.2 ng/mL was 42.2%, 32.1%, 41.0%, and 59.1% for the 950-, 1200-, 1350-, and 1900-cGy/fraction levels, respectively (P=.002). The hazard ratio for bounce >0.2 ng/mL for patients receiving a single fraction of 1900 cGy compared with those receiving treatment in multiple fractions was 1.786 (P=.024). For patients treated with a single 1900-cGy fraction, the 1-, 2-, and 3-year rates of PSA bounce exceeding the Phoenix biochemical failure definition (nadir +2 ng/mL) were 4.5%, 18.7%, and 18.7%, respectively, higher than the rates for all other administered dose levels (P=.025). The incidence of PSA bounce increases with single-fraction HDR treatment. Knowledge of posttreatment PSA kinetics may aid in decision making regarding management of potential biochemical failures. Copyright © 2017 Elsevier Inc. All rights reserved.
Yamada, Yoshiya Bilsky, Mark H.; Lovelock, D. Michael; Venkatraman, Ennapadam S.; Toner, Sean; Johnson, Jared; Zatcky, Joan N.P.; Zelefsky, Michael J.; Fuks, Zvi
2008-06-01
Purpose: To report tumor control and toxicity for patients treated with image-guided intensity-modulated radiotherapy (RT) for spinal metastases with high-dose single-fraction RT. Methods and Materials: A total of 103 consecutive spinal metastases in 93 patients without high-grade epidural spinal cord compression were treated with image-guided intensity-modulated RT to doses of 18-24 Gy (median, 24 Gy) in a single fraction between 2003 and 2006. The spinal cord dose was limited to a 14-Gy maximal dose. The patients were prospectively examined every 3-4 months with clinical assessment and cross-sectional imaging. Results: The overall actuarial local control rate was 90% (local failure developed in 7 patients) at a median follow-up of 15 months (range, 2-45 months). The median time to local failure was 9 months (range, 2-15 months) from the time of treatment. Of the 93 patients, 37 died. The median overall survival was 15 months. In all cases, death was from progression of systemic disease and not local failure. The histologic type was not a statistically significant predictor of survival or local control. The radiation dose was a significant predictor of local control (p = 0.03). All patients without local failure also reported durable symptom palliation. Acute toxicity was mild (Grade 1-2). No case of radiculopathy or myelopathy has developed. Conclusion: High-dose, single-fraction image-guided intensity-modulated RT is a noninvasive intervention that appears to be safe and very effective palliation for patients with spinal metastases, with minimal negative effects on quality of life and a high probability of tumor control.
Jagetia, Ganesh Chandra; Rajanikant, Golgod Krishnamurthy
2012-02-01
Fractionated irradiation (IR) before or after surgery of malignant tumours causes a high frequency of wound healing complications. Our aim was to investigate the effect of curcumin (CUM) on the healing of deep excision wound of mice exposed to fractionated IR by mimicking clinical conditions. A full-thickness dermal excision wound was created on the shaved dorsum of mice that were orally administered or not with 100 mg of CUM per kilogram body weight before partial body exposure to 10, 20 or 40 Gy given as 2 Gy/day for 5, 10 or 20 days. The wound contraction was determined periodically by capturing video images of the wound from day 1 until complete healing of wounds. Fractionated IR caused a dose-dependent delay in the wound contraction and prolonged wound healing time, whereas CUM administration before fractionated IR caused a significant elevation in the wound contraction and reduced mean wound healing time. Fractionated IR reduced the synthesis of collagen, deoxyribonucleic acid (DNA) and nitric oxide (NO) at different post-IR times and treatment of mice with CUM before IR elevated the synthesis of collagen, DNA and NO significantly. Histological examination showed a reduction in the collagen deposition, fibroblast and vascular densities after fractionated IR, whereas CUM pre-treatment inhibited this decline significantly. Our study shows that CUM pre-treatment accelerated healing of irradiated wound and could be a substantial therapeutic strategy in the management of irradiated wounds.
Sudhoff, M; Lamba, M; Kumar, N; Ward, A; Elson, H
2015-06-15
Purpose: To systematically characterize inter-fraction breast variability and determine implications on delivered dose. Methods: Weekly port films were used to characterize breast setup variability. Five evenly spaced representative positions across the contour of each breast were chosen on the electronic port film in reference to graticule, and window and level was set such that the skin surface of the breast was visible. Measurements from the skin surface to treatment field edge were taken on each port film at each position and compared to the planning DRR, quantifying the variability. The systematic measurement technique was repeated for all port films for 20 recently treated breast cancer patients. Measured setup variability for each patient was modeled as a normal distribution. The distribution was randomly sampled from the model and applied as isocentric shifts in the treatment planning computer, representing setup variability for each fraction. Dose was calculated for each shifted fraction and summed to obtain DVHs and BEDs that modeled the dose with daily setup variability. Patients were categorized in to relevant groupings that were chosen to investigate the rigorousness of immobilization types, treatment techniques, and inherent anatomical difficulties. Mean position differences and dosimetric differences were evaluated between planned and delivered doses. Results: The setup variability was found to follow a normal distribution with mean position differences between the DRR and port film between − 8.6–3.5 mm with sigma range of 5.3–9.8 mm. Setup position was not found to be significantly different than zero. The mean seroma or whole breast PTV dosimetric difference, calculated as BED, ranged from a −0.23 to +1.13Gy. Conclusion: A systematic technique to quantify and model setup variability was used to calculate the dose in 20 breast cancer patients including variable setup. No statistically significant PTV or OAR BED differences were found between
Marshall, Thomas I; Chaudhary, Pankaj; Michaelidesová, Anna; Vachelová, Jana; Davídková, Marie; Vondráček, Vladimir; Schettino, Giuseppe; Prise, Kevin M
2016-05-01
To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited. Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfraction period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism. Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens. The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of
Marshall, Thomas I.; Chaudhary, Pankaj; Michaelidesová, Anna; Vachelová, Jana; Davídková, Marie; Vondráček, Vladimir; Schettino, Giuseppe; Prise, Kevin M.
2016-01-01
Purpose To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited. Methods and Materials Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfraction period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism. Results Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens. Conclusions The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used
Nakamura, Jean L; Phong, Connie; Pinarbasi, Emile; Kogan, Scott C; Vandenberg, Scott; Horvai, Andrew E; Faddegon, Bruce A; Fiedler, Dorothea; Shokat, Kevan; Houseman, Benjamin T; Chao, Richard; Pieper, Russell O; Shannon, Kevin
2010-01-01
Secondary malignant neoplasms (SMNs) are increasingly common complications of cancer therapy that have proven difficult to model in mice. Clinical observations suggest that the development of SMN correlates with radiation dose; however, this relationship has not been investigated systematically. We developed a novel procedure for administering fractionated cranial irradiation (CI) and investigated the incidence and spectrum of cancer in control and heterozygous Nf1 mutant mice irradiated to a moderate (15 Gy) or high dose (30 Gy). Heterozygous Nf1 inactivation cooperated with CI to induce solid tumors and myeloid malignancies, with mice developing many of the most common SMNs found in human patients. CI-induced malignancies segregated according to radiation dose as Nf1+/− mice developed predominately hematologic abnormalities after 15 Gy, while solid tumors predominated at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and non-hematologic cancers. Genetic and biochemical studies revealed discrete patterns of somatic Nf1 and Trp53 inactivation and we observed hyperactive Ras signaling in many radiation-induced solid tumors. This technique for administering focal fractionated irradiation will facilitate mechanistic and translational studies of SMNs. PMID:21199799
Kim, Yongbok; Hsu, I-Chow J; Pouliot, Jean
2007-09-17
The objective of this work is to measure the cranio-caudal displacement of catheters occurring between consecutive fractions of transrectal ultrasound (TRUS) guided high dose rate (HDR) prostate brachytherapy. Ten consecutive patients were treated with 2 fractions of 9.5 Gy TRUS guided HDR brachytherapy using dental putty for the fixation of catheters. For each patient, a CT scan with 3 mm slice thickness was acquired before each of the two fractions. Two different references were employed to measure the catheter displacement between fractions: the ischial bone as a bony marker (BM) and the center of two gold markers (COGM) implanted in the prostate. The catheter displacement was calculated by multiplying the thickness of CT slice with the difference in number of CT slices between the reference slice and the slice containing the tip of a catheter. The average (range) magnitude of caudal catheter displacement was 2.7 mm (-6.0 to 13.5 mm) for BM method and 5.4 mm (-3.75 to 18.0 mm) for COGM method, respectively. The measurement data obtained from BM and COGM methods verified that both prostate movement and catheter displacement occurred independently between fractions. The most anterior and medial two catheters (catheter position 8 and 12) had the greatest tendency to be displaced in the caudal direction because they were located at the most distant position from the fulcrum, susceptible to the rotation of the dental putty in lateral plane due to the movement of patient legs between fractions. In conclusion, the use of both BM and COGM methods can demonstrate the prostate and catheter movement relative to the BM between fractions. We found a pattern of catheter displacement using our technique. Based on our finding further improvement of our results may be possible by modification of our current technique.
Hijazi, Hussam; Chevallier, Daniel; Gal, Jocelyn; Chand, Marie-Eve; Gautier, Mathieu; Hannoun-Levi, Jean-Michel
2013-01-01
Purpose To analyse early toxicity of high-dose-rate brachytherapy (HDRB) boost for prostate cancer using 3 fractionation schemes. Material and methods From February 2009 to May 2012, after the first course of external beam radiation therapy (EBRT 46 Gy/23 f), 124 patients underwent HDRB boost for low (7%), intermediate (19%), and high-risk (73%) prostate cancers. From February to December 2009, Group 1 (G1) = 18 Gy/3 f/2 d (24%); from January 2010 to April 2011, Group 2 (G2) = 18 Gy/2 f/2 d (42%), and from May to September 2011, Group 3 (G3) = 14 Gy/1 f/1 d (34%). Planning and CT-scan was performed before each fraction. Dose constraints for G1/G2 were V100 rectum = 0 and V125 urethra = 0, while for G3 V90 rectum = 0 and V115 urethra = 0. Genito-urinary (GU) and Gastro-intestinal (GI) acute toxicities were assessed at 1 month (for the 3 fractionation schemes) and 6 months (for 18 Gy/3 f and 18 Gy/2 f) after the boost (CTCv3.0). Results Median follow-up was 25 months (8-46.9), median age was 71 years (50-82), and median CTV was 31 cc (16-71). The grades of acute GI and GU toxicities at 1 and 6 months after HDRB were mainly Grade 1 with few Grade 2 (GU: 5% at 1 month; GI: 1% at 6 months). One patient developed G4 sepsis toxicity 2 days after HDRB and recovered without after-effects. No significant differences were observed at 1 and 6 months after the HDRB between treatment groups. Conclusions The right fractionation remains under discussion, but prostate cancer HDRB boost using a single fraction (providing similar results in terms of acute toxicity) is more comfortable for the patient, and less time consuming for the medical staff. PMID:24474968
Heidari, Pedram; Wehrenberg-Klee, Eric; Habibollahi, Peiman; Yokell, Daniel; Kulke, Matthew; Mahmood, Umar
2013-12-01
Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are currently lacking to optimize dosing of octreotide therapy on an individual basis. Multiple factors such as total tumor burden, receptor expression levels, and nontarget organ metabolism/excretion may contribute to a variation in SSTR octreotide occupancy with a given dose among different patients. In this study, we report the development of an imaging method to measure surface SSTR expression and occupancy level using the PET radiotracer (68)Ga-DOTATOC. In an animal model, SSTR occupancy by octreotide was assessed quantitatively with (68)Ga-DOTATOC PET, with the finding that increased occupancy resulted in decreased tumor proliferation rate. The results suggested that quantitative SSTR imaging during octreotide therapy has the potential to determine the fractional receptor occupancy in NETs, thereby allowing octreotide dosing to be optimized readily in individual patients. Clinical trials validating this approach are warranted.
Landuyt, W.; Ang, K. K.; van der Schueren, E.
1986-01-01
Tolerance of the lip mucosa of NMRI mice to single and fractionated irradiation combined with cis-diamminedichloroplatinum (II) (cis-DDP) was investigated. For the various combination schedules total drug doses varying from 6 mg kg-1 to 13 mg kg-1 were injected i.p. It was found that cis-DDP did not alter the radiation sensitivity of this tissue at any of the time intervals tested (ranging from 24 h before to 72 h after single dose irradiations). When 5 daily drug injections were given concomitantly with 5 daily radiation treatments, a slight reduction of the lip mucosal reactions occurred, possibly due to partial synchronisation during treatment. No effect was seen when a single injection of cis-DDP preceded two irradiations given with increasing intervals up to 4 h. Both these combined fractionated treatment data suggest no inhibitory effect on repair of sublethal radiation damage. When repeated daily injections of cis-DDP were given in between 2 radiation doses separated by 10 days, no interference with repopulation could be detected. The present study also demonstrated an increase in systemic drug toxicity when cis-DDP was combined with irradiation, compared with that seen with either agent alone. PMID:3778802
Shin, Eunhyuk; Han, Youngyih; Park, Hee-Chul; Sung Kim, Jin; Hwan Ahn, Sung; Suk Shin, Jung; Gyu Ju, Sang; Ho Choi, Doo; Lee, Jaiki
2013-01-01
This study was conducted to evaluate the cumulative dosimetric error that occurs in both target and surrounding normal tissues when treating a moving target in multifractional treatment with tomotherapy. An experiment was devised to measure cumulative error in multifractional treatments delivered to a horseshoe-shaped clinical target volume (CTV) surrounding a cylinder shape of organ at risk (OAR). Treatments differed in jaw size (1.05 vs 2.5 cm), pitch (0.287 vs 0.660), and modulation factor (1.5 vs 2.5), and tumor motion characteristics differing in amplitude (1 to 3 cm), period (3 to 5 second), and regularity (sinusoidal vs irregular) were tested. Treatment plans were delivered to a moving phantom up to 5-times exposure. Dose distribution on central coronal plane from 1 to 5 times exposure was measured with GAFCHROMIC EBT film. Dose differences occurring across 1 to 5 times exposure of treatment and between treatment plans were evaluated by analyzing measurements of gamma index, gamma index histogram, histogram changes, and dose at the center of the OAR. The experiment showed dose distortion due to organ motion increased between multiexposure 1 to 3 times but plateaued and remained constant after 3-times exposure. In addition, although larger motion amplitude and a longer period of motion both increased dosimetric error, the dose at the OAR was more significantly affected by motion amplitude rather than motion period. Irregularity of motion did not contribute significantly to dosimetric error when compared with other motion parameters. Restriction of organ motion to have small amplitude and short motion period together with larger jaw size and small modulation factor (with small pitch) is effective in reducing dosimetric error. Pretreatment measurements for 3-times exposure of treatment to a moving phantom with patient-specific tumor motion would provide a good estimation of the delivered dose distribution.
Zakariaee, R; Brown, C J; Hamarneh, G; Parsons, C A; Spadinger, I
2014-08-15
Dosimetric parameters based on dose-volume histograms (DVH) of contoured structures are routinely used to evaluate dose delivered to target structures and organs at risk. However, the DVH provides no information on the spatial distribution of the dose in situations of repeated fractions with changes in organ shape or size. The aim of this research was to develop methods to more accurately determine geometrically localized, cumulative dose to the bladder wall in intracavitary brachytherapy for cervical cancer. The CT scans and treatment plans of 20 cervical cancer patients were used. Each patient was treated with five high-dose-rate (HDR) brachytherapy fractions of 600cGy prescribed dose. The bladder inner and outer surfaces were delineated using MIM Maestro software (MIM Software Inc.) and were imported into MATLAB (MathWorks) as 3-dimensional point clouds constituting the “bladder wall”. A point-set registration toolbox for MATLAB, Coherent Point Drift (CPD), was used to non-rigidly transform the bladder-wall points from four of the fractions to the coordinate system of the remaining (reference) fraction, which was chosen to be the emptiest bladder for each patient. The doses were accumulated on the reference fraction and new cumulative dosimetric parameters were calculated. The LENT-SOMA toxicity scores of these patients were studied against the cumulative dose parameters. Based on this study, there was no significant correlation between the toxicity scores and the determined cumulative dose parameters.
Ding, C; Hrycushko, B; Jiang, S; Meyer, J; Timmerman, R
2014-06-01
Purpose: To compare the radiobiological effect on large tumors and surrounding normal tissues from single fraction SRS, multi-fractionated SRT, and multi-staged SRS treatment. Methods: An anthropomorphic head phantom with a centrally located large volume target (18.2 cm{sup 3}) was scanned using a 16 slice large bore CT simulator. Scans were imported to the Multiplan treatment planning system where a total prescription dose of 20Gy was used for a single, three staged and three fractionated treatment. Cyber Knife treatment plans were inversely optimized for the target volume to achieve at least 95% coverage of the prescription dose. For the multistage plan, the target was segmented into three subtargets having similar volume and shape. Staged plans for individual subtargets were generated based on a planning technique where the beam MUs of the original plan on the total target volume are changed by weighting the MUs based on projected beam lengths within each subtarget. Dose matrices for each plan were export in DICOM format and used to calculate equivalent dose distributions in 2Gy fractions using an alpha beta ratio of 10 for the target and 3 for normal tissue. Results: Singe fraction SRS, multi-stage plan and multi-fractionated SRT plans had an average 2Gy dose equivalent to the target of 62.89Gy, 37.91Gy and 33.68Gy, respectively. The normal tissue within 12Gy physical dose region had an average 2Gy dose equivalent of 29.55Gy, 16.08Gy and 13.93Gy, respectively. Conclusion: The single fraction SRS plan had the largest predicted biological effect for the target and the surrounding normal tissue. The multi-stage treatment provided for a more potent biologically effect on target compared to the multi-fraction SRT treatments with less biological normal tissue than single-fraction SRS treatment.
Selvaraj, Jothybasu; Uzan, Julien; Baker, Colin; Nahum, Alan
2013-04-01
Geometric uncertainties are inevitable in radiotherapy. To account for these uncertainties, a margin is added to the clinical target volume (CTV) to create the planning target volume (PTV), and its size is critical for obtaining an optimal treatment plan. Dose-based (i.e., physical) margin recipes have been published and widely used, but it is important to consider fractionation and the radiobiological characteristics of the tumor when deriving margins. Hence a tumor control probability (TCP)-based margin is arguably more appropriate. Margins required for ≤ 1% loss in mean population TCP (relative to a static tumor) for varying numbers of fractions, varying slope of the dose-response curve (γ50) and varying degrees of dose distribution conformity are investigated for spherical and four-field (4F)-brick dose distributions. To simulate geometric uncertainties, systematic (Σ) and random (σ) tumor displacements were sampled from Gaussian distributions and applied to each fraction for a spherical CTV. Interfraction tumor motion was simulated and the dose accumulated from fraction to fraction on a voxel-by-voxel basis to calculate TCP. PTV margins derived from this work for various fraction numbers and dose-response slopes (γ50) for different degrees of geometric uncertainties are compared with margins calculated using published physical-dose- and TCP-based recipes. Larger margins are required for a decrease in the number of fractions and for an increase in γ50 for both spherical and 4F-brick dose distributions. However, the margins can be close to zero for the 4F-brick distribution for small geometric uncertainties (Σ = 1, σ = 1 mm) irrespective of the number of fractions and the magnitude of γ50 due to the higher "incidental" dose outside the tumor. For Σ = 1 mm and σ = 3 mm, physical-dose-based recipes underestimate the margin only for the combination of hypofractionated treatments and tumors with a high γ50. For all other situations TCP-based margins are
Liu, J.C.; Bacza, E.T.; Findley, D.O.; Forell, B.W.
1983-09-01
Eighty-five patients with acute myelogenous or acute lymphoblastic leukemia were treated at the Cit of Hope National Medicine Center with chemotherapy, total body irradiation, and bone marrow transplant. The average mid-line dose to these patients was 1002 rad with a uniformity of 8%.
Simon, Raphael; Wang, Jin Y.; Boyd, Mary A.; Tulapurkar, Mohan E.; Ramachandran, Girish; Tennant, Sharon M.; Pasetti, Marcela; Galen, James E.; Levine, Myron M.
2013-01-01
Non-typhoidal Salmonella (NTS) serovars S. Enteritidis and S. Typhimurium are a major cause of invasive bacterial disease (e.g., bacteremia, meningitis) in infants and young children in sub-Saharan Africa and also occasionally cause invasive disease in highly susceptible hosts (young infants, the elderly, and immunocompromised subjects) in industrialized countries. No licensed vaccines exist against human NTS infections. NTS core and O polysaccharide (COPS) and FliC (Phase 1 flagellin subunits) each constitute protective antigens in murine models. S. Enteritidis COPS conjugated to FliC represents a promising vaccine approach that elicits binding and opsonophagocytic antibodies and protects mice against lethal challenge with virulent S. Enteritidis. We examined the protective efficacy of fractional dosages of S. Enteritidis COPS:FliC conjugate vaccines in mice, and also established that protection can be passively transferred to naïve mice by administering sera from mice immunized with conjugate. Mice were immunized with three doses of either 10 µg, 2.5 µg (full dose), 0.25 µg, or 0.025 µg S. Enteritidis COPS:FliC conjugate at 28 day intervals. Antibody titers to COPS and FliC measured by ELISA fell consonant with progressively smaller vaccine dosage levels; anti-FliC IgG responses remained robust at fractional dosages for which anti-COPS serum IgG titers were decreased. Nevertheless, >90% protection against intraperitoneal challenge was observed in mice immunized with fractional dosages of conjugate that elicited diminished titers to both FliC and COPS. Passive transfer of immune sera from mice immunized with the highest dose of COPS:FliC to naïve mice was also protective, demonstrating the role of antibodies in mediating protection. These results provide important insights regarding the potency of Salmonella glycoconjugate vaccines that use flagellin as a carrier protein. PMID:23741368
Singh, Parminder; Saini, Komal; Mishra, Rosaline; Sahoo, Bijay Kumar; Bajwa, Bikramjit Singh
2016-08-01
In this study, measurements of indoor radon ((222)Rn), thoron ((220)Rn) and their equilibrium equivalent concentration (EEC) were carried out in 96 dwellings from 22 different villages situated in Hamirpur district, Himachal Pradesh, India, by using LR-115 type II-based pinhole twin cup dosimeters and deposition-based progeny sensors (DRPS/DTPS). The annual average indoor (222)Rn and (220)Rn concentrations observed in these dwellings were 63.82 and 89.59 Bq/m(3), respectively, while the average EEC (attached + unattached) for (222)Rn and (220)Rn was 29.28 and 2.74 Bq/m(3). For (222)Rn (f Rn) and (220)Rn (f Tn), the average values of unattached fraction were 0.11 and 0.09, respectively. The equilibrium factors for radon (F Rn) and thoron (F Tn) varied from 0.12 to 0.77 with an average of 0.50, and from 0.01 to 0.34 with an average of 0.05, respectively. The annual inhalation dose due to mouth and nasal breathing was calculated using dose conversion factors and unattached fractions. The indoor annual effective doses for (222)Rn (AEDR) and (220)Rn (AEDT) were found to be 1.92 and 0.83 mSv a(-1), respectively. The values of (222)Rn/(220)Rn concentrations and annual effective doses obtained in the present study are within the safe limits as recommended by the International Commission on Radiological Protection for indoor dwelling exposure conditions.
Little, Mark P; Gola, Anna; Tzoulaki, Ioanna
2009-10-01
Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.
Provisional Reference Dose for the Aromatic Fraction of Jet Fuel: Insight into Complex Mixtures
2005-04-01
Petroleum Hydrocarbon Criteria Working Group UF uncertainty factor UV ultraviolet light wt% weight percent vi PROVISIONAL REFERENCE DOSE FOR THE AROMATIC...week) included. RBC = red blood cell. UF = total uncertainty factor , including modifying factors when applied. aU.S. EPA (2004). bThis unpublished...approach applied uncertainty factors to NOAELs or LOAELs from the critical 11 studies. The TPHCWG primarily accepted default values of 10 for
McCarthy, Ian D; Brown, James
2016-07-01
The flooding dose technique of Garlick et al. (1980) has become the main method for measuring tissue and whole-animal rates of protein synthesis in ectotherms. However, single tissue samples are used to determine rates of protein synthesis and no studies have examined the pattern of flooding in large tissues such as the white muscle in fishes, which can comprise up to 55% of the wet body mass of a fish and which is poorly perfused. The present study has examined, for the first time, the patterns of flooding and measured rates of protein synthesis in five different regions of the white muscle in the Arctic charr Salvelinus alpinus ranging in size from 25g to 1.6kg following a flooding dose injection of L-[(3)H]-phenylalanine. The results indicate that the degree of flooding (i.e. free pool specific radioactivity relative to that of the injection solution) and elevation in free phenylalanine concentrations can vary between regions but the calculated fractional rates of protein synthesis were similar in four of the five regions studied. The variability in rates of protein synthesis increased with body size with greater variability observed between regions for fish >1kg in body mass. For consistency between studies, it is recommended that samples are taken from the epaxial muscle in the region below the dorsal fin when measuring fractional rates of white muscle synthesis in fishes. Copyright © 2016 Elsevier Inc. All rights reserved.
Potter, Charles A
2002-11-01
ICRP Publication 68 presents dose coefficients developed using systems of new models for the respiratory tract and metabolism of certain elements. The utility of these dose coefficients and associated models is limited without a method for calculating intake from bioassay results using the same models as in that publication. The calculation of a radionuclide intake requires values of expected fractions of the intake in bioassay samples collected at specific times after intake. The general system of models has been solved using a commercial software package and a method for solution of systems of first-order linear differential equations that uses eigenvectors and eigenvalues derived from the system of equations. The result of this work is a series of tables of fractions of acute inhalation intakes for different bioassay methods, times, and compound classes for intakes for those elements listed in ICRP Publication 68. The values in these tables can be used for intake calculations, development of bioassay frequencies, and development of action levels.
Tucker, Susan L.; Michalski, Jeff M.; Bosch, Walter R.; Mohan, Radhe; Dong, Lei; Winter, Kathryn; Purdy, James A.; Cox, James D.
2012-01-01
Background and Purpose For toxicities occurring during the course of radiotherapy, it is conceptually inaccurate to perform normal-tissue complication probability analyses using the complete dose-volume histogram. The goal of this study was to analyze acute rectal toxicity using a novel approach in which the fit of the Lyman-Kutcher-Burman (LKB) model is based on the fractional rectal dose-volume histogram (DVH). Materials and Methods Grade ≥2 acute rectal toxicity was analyzed in 509 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06. These patients had no field reductions or treatment-plan revisions during therapy, allowing the fractional rectal DVH to be estimated from the complete rectal DVH based on the total number of dose fractions delivered. Results The majority of patients experiencing Grade ≥2 acute rectal toxicity did so before completion of radiotherapy (70/80=88%). Acute rectal toxicity depends on fractional mean rectal dose, with no significant improvement in the LKB model fit when the volume parameter differs from n=1. The incidence of toxicity was significantly lower for patients who received hormone therapy (P=0.024). Conclusions Variations in fractional mean dose explain the differences in incidence of acute rectal toxicity, with no detectable effect seen here for differences in numbers of dose fractions delivered. PMID:22673726
High-dose-rate brachytherapy delivered in two fractions as monotherapy for low-risk prostate cancer
Alwers, Elizabeth; Cifuentes, Javier; Bobadilla, Ivan; Torres, Felipe; Arbelaez, Juan; Gaitan, Armando; Cortes, Helber; Acevedo, Yenny; Quintero, Paulo; Vasquez, Jaider
2015-01-01
Purpose High-dose-rate (HDR) brachytherapy has been accepted as an effective and safe method to treat prostate cancer. The aim of this study was to describe acute toxicity following HDR brachytherapy to the prostate, and to examine the association between dosimetric parameters and urinary toxicity in low-risk prostate cancer patients. Material and methods Patients with low-risk prostate cancer were given HDR brachytherapy as monotherapy in two 12.5 Gy fractions. Planning objectives for the planning target volume (PTV) were V100% ≥ 90% and V150% ≤ 35%. Planning objectives for organs at risk were V75% ≤ 1 cc for the bladder, rectum and perineum, and V125% ≤ 1 cc for the urethra. Toxicity was assessed three months after treatment using the Common Terminology Criteria for Adverse Events. Results Seventy-three patients were included in the analysis. Thirty-three patients (45%) reported having any type of toxicity in the three months following HDR brachytherapy. Most toxicity cases (26%) were grade 1 urinary toxicity. Mean coverage index was 0.89 and mean V100 was 88.85. Doses administered to the urethra were associated with urinary toxicity. Patients who received more than 111.3% of the prescribed dose in 1 cc of the urethra were four times more likely to have urinary toxicity compared to patients receiving less than 111.3% (OR = 4.71, 95% CI: 1.43-15.6; p = 0.011). Conclusions High-dose-rate brachytherapy administered as monotherapy for prostate cancer proved to be a safe alternative treatment for patients with low-risk prostate cancer. Urinary toxicity was associated with the dose administered to 1 cc and 0.1 cc of the urethra and was remarkably inferior to the reported toxicity in similar studies. PMID:25829931
Stubblefield, Michael D; Ibanez, Katarzyna; Riedel, Elyn R; Barzilai, Ori; Laufer, Ilya; Lis, Eric; Yamada, Yoshiya; Bilsky, Mark H
2017-03-01
OBJECTIVE The object of this study was to determine the percentage of high-dose (1800-2600 cGy) single-fraction stereotactic radiosurgery (SF-SRS) treatments to the spine that result in peripheral nervous system (PNS) injury. METHODS All patients treated with SF-SRS for primary or metastatic spine tumors between January 2004 and May 2013 and referred to the Rehabilitation Medicine Service for evaluation and treatment of neuromuscular, musculoskeletal, or functional impairments or pain were retrospectively identified. RESULTS Five hundred fifty-seven SF-SRS treatments in 447 patients resulted in 14 PNS injuries in 13 patients. All injures resulted from SF-SRS delivered to the cervical or lumbosacral spine at 2400 cGy. The overall percentage of SF-SRS treatments resulting in PNS injury was 2.5%, increasing to 4.5% when the thoracic spine was excluded from analysis. The median time to symptom onset following SF-SRS was 10 months (range 4-32 months). The plexus (cervical, brachial, and/or lumbosacral) was affected clinically and/or electrophysiologically in 12 (86%) of 14 cases, the nerve root in 2 (14%) of 14, and both in 6 (43%) of 14 cases. All patients experienced pain and most (93%) developed weakness. Peripheral nervous system injuries were CTCAE Grade 1 in 14% of cases, 2 in 64%, and 3 in 21%. No dose relationship between SF-SRS dose and PNS injury was detected. CONCLUSIONS Single-fraction SRS to the spine can result in PNS injury with major implications for function and quality of life.
Semenov, A V; Vorobtsova, I E; Zharinov, G M
2010-01-01
The dose-response of unstable chromosome exchanges (UCE) in lymphocytes of 4 cancer patients undergone whole-body fractionated gamma-rays exposure (at the daily dose of 0.115 Gy up to the total dose 1.15 Gy) was compared with corresponding dose-response for lymphocytes of the same patients, irradiated in vitro at the same dose range. In vivo irradiation yielded lower frequency of UCE on the dose unit than in vitro irradiation. It was shown that the in vivo dose-response curve gives more adequate dose estimation than in vitro one. This curve could be used for reconstruction of absorbed dose in the cases of analogous character of in-controlled irradiation of people.
Mukherjee, Kanchan Kumar; Kumar, Narendra; Tripathi, Manjul; Oinam, Arun S; Ahuja, Chirag K; Dhandapani, Sivashanmugam; Kapoor, Rakesh; Ghoshal, Sushmita; Kaur, Rupinder; Bhatt, Sandeep
2017-01-01
To evaluate the feasibility, safety and efficacy of dose fractionated gamma knife radiosurgery (DFGKRS) on a daily schedule beyond the linear quadratic (LQ) model, for large volume arteriovenous malformations (AVMs). Between 2012-16, 14 patients of large AVMs (median volume 26.5 cc) unsuitable for surgery or embolization were treated in 2-3 of DFGKRS sessions. The Leksell G frame was kept in situ during the whole procedure. 86% (n = 12) patients had radiologic evidence of bleed, and 43% (n = 6) had presented with a history of seizures. 57% (n = 8) patients received a daily treatment for 3 days and 43% (n = 6) were on an alternate day (2 fractions) regimen. The marginal dose was split into 2 or 3 fractions of the ideal prescription dose of a single fraction of 23-25 Gy. The median follow up period was 35.6 months (8-57 months). In the three-fraction scheme, the marginal dose ranged from 8.9-11.5 Gy, while in the two-fraction scheme, the marginal dose ranged from 11.3-15 Gy at 50% per fraction. Headache (43%, n = 6) was the most common early postoperative complication, which was controlled with short course steroids. Follow up evaluation of at least three years was achieved in seven patients, who have shown complete nidus obliteration in 43% patients while the obliteration has been in the range of 50-99% in rest of the patients. Overall, there was a 67.8% reduction in the AVM volume at 3 years. Nidus obliteration at 3 years showed a significant rank order correlation with the cumulative prescription dose (p 0.95, P value 0.01), with attainment of near-total (more than 95%) obliteration rates beyond 29 Gy of the cumulative prescription dose. No patient receiving a cumulative prescription dose of less than 31 Gy had any severe adverse reaction. In co-variate adjusted ordinal regression, only the cumulative prescription dose had a significant correlation with common terminology criteria for adverse events (CTCAE) severity (P value 0.04), independent of age, AVM volume
Lee, Eun-Jung; Kim, Jun Won; Yoo, Hyun; Kwak, Woori; Choi, Won Hoon; Cho, Seoae; Choi, Yu Jeong; Lee, Yoon-Jin; Cho, Jaeho
2015-08-14
We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm{sup 2} fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C–C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin. - Highlights: • Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33. • Vascular endothelial cells damaged by high-dose radiation secrete IL-33. • Blocking IL-33 suppressed migration of inflammatory cells and cytokine secretion. • IL
NASA Astrophysics Data System (ADS)
Stemkens, Bjorn; Glitzner, Markus; Kontaxis, Charis; de Senneville, Baudouin Denis; Prins, Fieke M.; Crijns, Sjoerd P. M.; Kerkmeijer, Linda G. W.; Lagendijk, Jan J. W.; van den Berg, Cornelis A. T.; Tijssen, Rob H. N.
2017-09-01
Stereotactic body radiation therapy (SBRT) has shown great promise in increasing local control rates for renal-cell carcinoma (RCC). Characterized by steep dose gradients and high fraction doses, these hypo-fractionated treatments are, however, prone to dosimetric errors as a result of variations in intra-fraction respiratory-induced motion, such as drifts and amplitude alterations. This may lead to significant variations in the deposited dose. This study aims to develop a method for calculating the accumulated dose for MRI-guided SBRT of RCC in the presence of intra-fraction respiratory variations and determine the effect of such variations on the deposited dose. For this, RCC SBRT treatments were simulated while the underlying anatomy was moving, based on motion information from three motion models with increasing complexity: (1) STATIC, in which static anatomy was assumed, (2) AVG-RESP, in which 4D-MRI phase-volumes were time-weighted, and (3) PCA, a method that generates 3D volumes with sufficient spatio-temporal resolution to capture respiration and intra-fraction variations. Five RCC patients and two volunteers were included and treatments delivery was simulated, using motion derived from subject-specific MR imaging. Motion was most accurately estimated using the PCA method with root-mean-squared errors of 2.7, 2.4, 1.0 mm for STATIC, AVG-RESP and PCA, respectively. The heterogeneous patient group demonstrated relatively large dosimetric differences between the STATIC and AVG-RESP, and the PCA reconstructed dose maps, with hotspots up to 40% of the D99 and an underdosed GTV in three out of the five patients. This shows the potential importance of including intra-fraction motion variations in dose calculations.
Schwer, Amanda L.; Damek, Denise M.; Kavanagh, Brian D.; Gaspar, Laurie E.; Lillehei, Kevin; Stuhr, Kelly; Chen Changhu
2008-03-15
Purpose: To determine the maximum tolerated dose (MTD) of fractionated stereotactic radiosurgery (SRS) with gefitinib in patients with recurrent malignant gliomas. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had pathologically proved recurrent anaplastic astrocytoma or glioblastoma. Patients started gefitinib (250 mg/day) 7 days before SRS and continued for 1 year or until disease progression. SRS was delivered in three fractions over 3 days. The planning target volume (PTV) was the T1-weighted MRI postcontrast enhancing lesion + 2 mm. The first cohort received an SRS dose of 18 Gy, and subsequent cohorts received higher doses up to the maximum dose of 36 Gy. Dose-limiting toxicity (DLT) was any Grade 3 toxicity. The MTD was exceeded if 2 of 6 patients in a cohort experienced DLT. Results: Characteristics of the 15 patients enrolled were: 9 men, 6 women; median age, 47 years (range, 23-65 years); 11 glioblastoma, 4 AA; median prior RT dose, 60 Gy (range, 54-61.2 Gy); median interval since RT, 12 months (range, 3-57 months); median PTV, 41 cc (range, 12-151 cc). Median follow-up time was 7 months (range, 2-28 months). Median time on gefitinib was 5 months (range, 2-12 months). No patient experienced a DLT, and the SRS dose was escalated from 18 to 36 Gy. Grade 1-2 gefitinib-related dermatitis and diarrhea were common (10 and 7 patients, respectively). Conclusion: Fractionated SRS to a dose of 36 Gy in three fractions is well tolerated with gefitinib at daily dose of 250 mg. Further studies of SRS and novel molecular targeted agents are warranted in this challenging clinical setting.
Resik, Sonia; Tejeda, Alina; Mach, Ondrej; Sein, Carolyn; Molodecky, Natalie; Jarrahian, Courtney; Saganic, Laura; Zehrung, Darin; Fonseca, Magile; Diaz, Manuel; Alemany, Nilda; Garcia, Gloria; Hung, Lai Heng; Martinez, Yenisleydis; Sutter, Roland W
2015-10-26
The World Health Organization recommends that as part of the polio end-game strategy a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries currently using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5 of full dose) IPV (fIPV) by intradermal (ID) injection may reduce costs, but its conventional administration is with Bacillus Calmette-Guerin (BCG) needle and syringe (NS), which is time consuming and technically challenging. We compared injection quality achieved with BCG NS and three needle-free jet injectors and assessed ergonomic features of the injectors. Children between 12 and 20 months of age who had previously received OPV were enrolled in the Camaguey, Cuba study. Subjects received a single fIPV dose administered intradermally with BCG NS or one of three needle-free injector devices: Bioject Biojector 2000® (B2000), Bioject ID Pen® (ID Pen), or PharmaJet Tropis® (Tropis). We measured bleb diameter and vaccine loss as indicators of ID injection quality, with desirable injection quality defined as bleb diameter ≥5mm and vaccine loss <10%. We surveyed vaccinators to evaluate ergonomic features of the injectors. We further assessed the injection quality indicators as predictors of immune response, measured by increase in poliovirus neutralizing antibodies in blood between day 0 (pre-IPV) and 21 (post-vaccination). Delivery by BCG NS and Tropis resulted in the highest proportion of subjects with desirable injection quality; health workers ranked Biojector2000 and Tropis highest for ergonomic features. We observed that vaccine loss and desirable injection quality were associated with an immune response for poliovirus type 2 (P=0.02, P=0.01, respectively). Our study demonstrated the feasibility of fIPV delivery using needle-free injector devices with high acceptability among health workers. We did not observe the indicators of injection quality to be uniformly associated with immune
Neuner, Geoffrey; Mohiuddin, Majid M.; Vander Walde, Noam; Goloubeva, Olga; Ha, Jonathan; Yu, Cedric X.; Regine, William F.
2012-04-01
Purpose: Spatially fractionated GRID radiotherapy (SFGRT) using a customized Cerrobend block has been used to improve response rates in patients with bulky tumors. The clinical efficacy of our own multileaf collimator (MLC) technique is unknown. We undertook a retrospective analysis to compare clinical response rates attained using these two techniques. Methods and Materials: Seventy-nine patients with bulky tumors (median diameter, 7.6 cm; range, 4-30 cm) treated with SFGRT were reviewed. Between 2003 and late 2005, the Cerrobend block technique (n = 39) was used. Between late 2005 and 2008, SFGRT was delivered using MLC-shaped fields (n = 40). Dose was prescribed to dmax (depth of maximum dose) and was typically 15 Gy. Eighty percent of patients in both groups received external beam radiotherapy in addition to SFGRT. The two-sided Fisher-Freeman-Halton test was used to compare pain and mass effect response rates between the two groups. Results: Sixty-one patients (77%) were treated for palliative intent and 18 (23%) for curative intent. The majority of patients had either lung or head-and-neck primaries in both groups; the most frequent site of SFGRT application was the neck. The majority of patients complained of either pain (65%) or mass effect (58%) at intake. Overall response rates for pain and mass response were no different between the Cerrobend and MLC groups: pain, 75% and 74%, respectively (p = 0.50), and mass effect, 67% and 73%, respectively (p = 0.85). The majority of toxicities were Grade 1 or 2, and only 3 patients had late Grade 3-4 toxicities. Conclusions: MLC-based and Cerrobend-based SFGRT have comparable and encouraging response rates when used either in the palliative or curative setting. MLC-based SGFRT should allow clinics to more easily adopt this novel treatment approach for the treatment of bulky tumors.
polysaccharide fraction as far as the precipitin or skin reaction was concerned. Not a single non- cryptococcosis patient demonstrated a positive reaction when...examined with the antigen, of 500 mcg./ml. or less in concentration. So far, the investigation was not extended to clinical cryptococcosis . However, should a...clinical cryptococcosis patient reveal positive skin or precipitin reaction in which the polysaccharide fraction is used as its antigen at an
NASA Astrophysics Data System (ADS)
Mínguez, Pablo; Gustafsson, Johan; Flux, Glenn; Sjögreen Gleisner, Katarina
2016-03-01
In this work, the biologically effective dose (BED) is investigated for fractionated molecular radiotherapy (MRT). A formula for the Lea-Catcheside G-factor is derived which takes the possibility of combinations of sub-lethal damage due to radiation from different administrations of activity into account. In contrast to the previous formula, the new G-factor has an explicit dependence on the time interval between administrations. The BED of tumour and liver is analysed in MRT of neuroblastoma with 131I-mIBG, following a common two-administration protocol with a mass-based activity prescription. A BED analysis is also made for modified schedules, when due to local regulations there is a maximum permitted activity for each administration. Modifications include both the simplistic approach of delivering this maximum permitted activity in each of the two administrations, and also the introduction of additional administrations while maintaining the protocol-prescribed total activity. For the cases studied with additional (i.e. more than two) administrations, BED of tumour and liver decreases at most 12% and 29%, respectively. The decrease in BED of the tumour is however modest compared to the two-administration schedule using the maximum permitted activity, where the decrease compared to the original schedule is 47%.
Regules, Jason A; Cicatelli, Susan B; Bennett, Jason W; Paolino, Kristopher M; Twomey, Patrick S; Moon, James E; Kathcart, April K; Hauns, Kevin D; Komisar, Jack L; Qabar, Aziz N; Davidson, Silas A; Dutta, Sheetij; Griffith, Matthew E; Magee, Charles D; Wojnarski, Mariusz; Livezey, Jeffrey R; Kress, Adrian T; Waterman, Paige E; Jongert, Erik; Wille-Reece, Ulrike; Volkmuth, Wayne; Emerling, Daniel; Robinson, William H; Lievens, Marc; Morelle, Danielle; Lee, Cynthia K; Yassin-Rajkumar, Bebi; Weltzin, Richard; Cohen, Joe; Paris, Robert M; Waters, Norman C; Birkett, Ashley J; Kaslow, David C; Ballou, W Ripley; Ockenhouse, Christian F; Vekemans, Johan
2016-09-01
Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. NCT01857869. Published by Oxford University Press on behalf of the Infectious Diseases Society of America, 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Favor, J; Neuhäuser-Klaus, A; Ehling, U H; Wulff, A; van Zeeland, A A
1997-03-21
Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102 x C3H)F1 mice were exposed to 4 x 10, 2 x 40. 4 x 20 or 4 x 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 x 40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2 x 40, 4 x 20 and 4 x 40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.
Tran, Kathy Ngoc; Zanjani, Salman; Smith, Wayne; Karpelowsky, Jonathan; Summerhayes, Katie; Estoesta, Edgar; Chard, Jennifer
2016-01-01
Purpose To report peri-operative fractionated high-dose-rate (HDR) brachytherapy with a 3D customized Freiburg flap applicator to treat locally recurrent Wilms’ tumor, followed by immediate hyperthermic intraperitoneal chemotherapy for a 16-year-old with a second recurrence of nephroblastoma (Wilms’ tumor). Material and methods The tumor was excised and surgical bed was treated with fractionated HDR brachytherapy using a Freiburg flap applicator. Hyperthermic intraperitoneal chemotherapy was performed immediately after the removal of brachytherapy applicator. Results The Freiburg flap was successfully reconstructed to enable delivery of conformable peri-operative HDR brachytherapy. The clinical target volume (CTV) D90 was 26 Gy in 5 fractions. Conclusions Peri-operative fractionated HDR brachytherapy with a customized Freiburg flap applicator was delivered successfully across a large multi-disciplinary team. PMID:27895685
Kiratli, Pinar Ozgen; Salanci, Bilge Volkan
2003-06-01
Since its release for routine clinical use, (99m)Tc-mercaptoacetyltriglycine (MAG3) has become an important alternative to (131)I-labeled orthoiodohippuran. The cold kit for MAG3 is expensive, especially in developing countries. Therefore, unique storage conditions should be provided for cost reduction. Cold fractioning is a well-known procedure but has special requirements, such as a nitrogen tank and a laminar flow hood. The aim of this study was to prolong the shelf life of (99m)Tc-labeled MAG3 by a hot fractioning method, which separates the patient doses after (99m)Tc labeling. The radiochemical purity of the (99m)Tc-labeled MAG3 kit was tested under different storage conditions. Hot fractioning of the (99m)Tc-labeled MAG3 kit was found to be a possible alternative to cold fractioning for routine clinical studies.
Yu, V; Nguyen, D; Pajonk, F; Kaprealian, T; Kupelian, P; Steinberg, M; Low, D; Sheng, K
2015-06-15
Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to explore the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work
Rahimi, Asal; Thomas, Kimberly; Spangler, Ann; Rao, Roshni; Leitch, Marilyn; Wooldridge, Rachel; Rivers, Aeisha; Seiler, Stephen; Albuquerque, Kevin; Stevenson, Stella; Goudreau, Sally; Garwood, Dan; Haley, Barbara; Euhus, David; Heinzerling, John; Ding, Chuxiong; Gao, Ang; Ahn, Chul; Timmerman, Robert
2017-05-01
To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting
World Health Organization
2017-10-13
This article presents the World Health Organization's (WHO) recommendations on the use of fractional doses of yellow fever vaccines excerpted from the "Yellow fever vaccine: WHO position on the use of fractional doses - June 2017, Addendum to Vaccines and vaccination against yellow fever WHO: Position Paper - June 2013″, published in the Weekly Epidemiological Record [1,2]. This addendum to the 2013 position paper pertains specifically to use of fractional dose YF (fYF) vaccination (fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as usual per manufacturer recommendations) in the context of YF vaccine supply shortages beyond the capacity of the global stockpile. The current WHO position on the use of yellow fever (YF) vaccine is set out in the 2013 WHO position paper on vaccines and vaccination against YF and those recommendations are unchanged. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of Yellow Fever vaccines were discussed by SAGE in October 2016; evidence presented at these meetings can be accessed at: www.who.int/immunization/sage/meetings/2016/October/presentations_background_docs/en/. Copyright © 2017. Published by Elsevier Ltd.
Fan, Shuang Min; Chen, Wei; Xiong, Li; Xia, Yong; Xie, Yue Bin; Chen, Jing
2016-06-01
Radiation-induced optic neuropathy (RION) is a devastating late complication of radiotherapy. However, research on the imaging performance of RION is not sufficient. The aim of this study was to investigate the performance of magnetic resonance diffusion tensor imaging (DTI) early after injury of the optic nerve of rhesus monkeys by a single-dose/fractionation-scheme of stereotactic radiosurgery (SRS). The intraorbital optic nerve contour of 5 rhesus monkeys was acquired by magnetic resonance imaging (MRI). Then, the unilateral intraorbital optic nerves of 5 rhesus monkeys were injured by gamma knife surgery (GKS) with a single-dose/fractionation scheme (marginal dose of 15Gy, 50% isodose curve). DTI was performed before the irradiation and 1week, 2weeks, 4weeks, and 24weeks after injury to obtain the cross-sectional area, and the fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD) and radial diffusivity (RD) values. The cross-sectional area of the injured optic nerve exhibited significant atrophy 24weeks after SRS. FA declined 1week after injury; this value then increased slightly but remained lower than before injury (P<0.05). AD began to decline in the 2weeks after injury and gradually disappeared (P<0.05). SRS with a single-dose/fractionation scheme (marginal dose of 15Gy, 50% isodose curve) on the unilateral intraorbital optic nerve can induce RION. DTI can detect RION at an early stage. FA and AD are useful indicators for RION diagnosis. In the early stage, the primary site of RION may be the vascular endothelium. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
NASA Astrophysics Data System (ADS)
Pervez, Nadeem
Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.
Gérard, M; Jumeau, R; Pichon, B; Biau, J; Blais, E; Horion, J; Noël, G
2017-10-01
Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of α/β ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.
Liu, Dijie; Balkin, Ethan R; Jia, Fang; Ruthengael, Varyanna C; Smith, C Jeffrey; Lewis, Michael R
2015-09-01
The overall goal of these studies was to test the hypothesis that simultaneous down-regulation of a tumor survival gene and delivery of internally emitted cytotoxic radiation will be more effective than either treatment modality alone. The objectives were to evaluate the therapeutic efficacy of a (177)Lu-labeled anti-bcl-2-PNA-Tyr(3)-octreotate antisense conjugate in a mouse model bearing human non-Hodgkin's lymphoma (NHL) tumor xenografts and to optimize targeted antisense radiotherapy by dose fractionation. In the initial therapy studies, tumor-bearing mice were given saline, nonradioactive DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate, (177)Lu-DOTA-Tyr(3)-octreotate, (177)Lu-DOTA-PNA-peptide alone, or (177)Lu-DOTA-PNA-peptide followed by a chase dose of nonradioactive PNA-peptide. The MTD of (177)Lu-DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate was then determined. Subsequently single dose MTD and four weekly fractionated doses were directly compared, followed by histopathologic evaluation. Antisense radiotherapy using 4.44 MBq of the (177)Lu-DOTA-PNA-peptide followed by nonradioactive PNA-peptide was significantly more effective than other low dose treatment regimens. A dose of 18.5 MBq of (177)Lu-DOTA-PNA-peptide was determined to be the approximate maximum tolerated dose (MTD). The median times to progression to a 1cm(3) tumor volume were 32 and 49 days for single dose MTD and fractionated dose (4 × 4.63 MBq) groups, respectively. Histopathology revealed metastases in the single dose groups, but not in the dose fractionation group. Targeted antisense radiotherapy using (177)Lu-DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate and DOTA-PNA-peptide conjugate effectively inhibited tumor progression in a mouse model of NHL. Furthermore, a dose fractionation regimen had a significant advantage over a single high dose, in terms of tumor growth inhibition and prevention of metastasis. Down-regulating bcl-2, an anti-apoptotic proto-oncogene, is a mechanism to reverse chemotherapy resistance or
Effet de la dose d'irradiation sur la fraction tocophérolique d'huiles végétales
NASA Astrophysics Data System (ADS)
Chaouch, A.; El Fartah, S.; Pouliquen-Sonaglia, I.; Lesgards, G.; Raffi, J.; Trihi, M.
1999-01-01
Tocopherols, minor components of vegetable oils, are very important due to their high antioxydant power; we studied separation and quantification of tocopherol fraction with regard to the irradiation dose, using liquid chromatography combined with electrochemical detection. Dans les huiles végétales, les tocophérols sont des constituants mineurs très importants grâce à leur pouvoir antioxydant très élevé. Notre travail s'est porté sur la séparation et la quantification de la fraction tocophérolique et son évolution en fonction des différentes doses d'ionisation par la technique C.L.H.P. / détection électrochimique.
K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose
K-Ras mutant fraction (MF) was measured to examine the default assumption of low dose linearity in the benzo[a]pyrene (B[a]P) mutational response. Groups of ten male A/J mice (7-9 weeks-old) received a single i.p. injection of 0, 0.05, 0.5, 5, or 50 mg/kg B[a]P, and were sacrifi...
K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose
K-Ras mutant fraction (MF) was measured to examine the default assumption of low dose linearity in the benzo[a]pyrene (B[a]P) mutational response. Groups of ten male A/J mice (7-9 weeks-old) received a single i.p. injection of 0, 0.05, 0.5, 5, or 50 mg/kg B[a]P, and were sacrifi...
Favor, J; Neuhäuser-Klaus, A; Ehling, U H
1988-04-01
A combined dominant cataract-recessive specific locus mutation experiment for fractionated exposure to ethylnitrosourea (2 X 80 mg/kg, 24-h fractionation interval) was designed to determine if lower doses of ethylnitrosourea are more effective in inducing dominant cataract mutations as suggested by previous results. This observation was not confirmed by the present experiment. The extensive, statistically more reliable specific locus results indicate an additive effect of fractionated ethylnitrosourea treatment. A saturable repair system for ethylnitrosourea-induced DNA damage has been previously documented (Karran et al., 1979; Sega et al., 1986; Van Zeeland et al., 1985). Two parameters inherent to a saturable system, the minimal time required for the saturated system to recover and the minimal dose to saturate the system are important, and results of experiments employing a fractionation exposure protocol must be interpreted relative to these two parameters. Longer fractionation intervals or smaller doses result in a reduced mutagenic effect. Due to the inherently lower experimental variability of the specific locus mutation assay as compared to the dominant cataract assay, the specific locus assay is the test of choice to determine factors affecting the mammalian germ cell mutation rate. The dominant cataract test requires a larger investment of experimental resources to achieve a comparable degree of accuracy. The dominant cataract mutation test is important in assessing the mutation rate to dominant alleles in germ cells of mammals. Due to the immediate expression of the mutant phenotype in newly occurring dominant mutations, a dominant mutation assay screens a genetically relevant endpoint in an assessment of the mutagenic hazard for man in mouse experiments. A multi-endpoint design screening specific locus, dominant cataract, and biochemical mutational endpoints (Ehling et al., 1985) allows a systematic comparison of mutagenic results for different classes
Shimura, Tsutomu; Hamada, Nobuyuki; Sasatani, Megumi; Kamiya, Kenji; Kunugita, Naoki
2014-01-01
Cyclin D1 is a mitogenic sensor that responds to growth signals from the extracellular environment and regulates the G 1-to-S cell cycle transition. When cells are acutely irradiated with a single dose of 10 Gy, cyclin D1 is degraded, causing cell cycle arrest at the G 1/S checkpoint. In contrast, cyclin D1 accumulates in human tumor cells that are exposed to long-term fractionated radiation (0.5 Gy/fraction of X-rays). In this study we investigated the effect of fractionated low-dose radiation exposure on cyclin D1 localization in 3 strains of normal human fibroblasts. To specifically examine the nuclear accumulation of cyclin D1, cells were treated with a hypotonic buffer containing detergent to remove cytoplasmic cyclin D1. Proliferating cell nuclear antigen (PCNA) immunofluorescence was used to identify cells in S phase. With this approach, we observed S-phase nuclear retention of cyclin D1 following low-dose fractionated exposures, and found that cyclin D1 nuclear retention increased with exposure time. Cells that retained nuclear cyclin D1 were more likely to have micronuclei than non-retaining cells, indicating that the accumulation of nuclear cyclin D1 was associated with genomic instability. Moreover, inhibition of the v-akt murine thymoma viral oncogene homolog (AKT) pathway facilitated cyclin D1 degradation and eliminated cyclin D1 nuclear retention in cells exposed to fractionated radiation. Thus, cyclin D1 may represent a useful marker for monitoring long-term effects associated with exposure to low levels of radiation.
Yoon, Sang Min; Huh, Seung Jae . E-mail: sjhuh@smc.samsung.co.kr; Park, Won; Lee, Jeung Eun; Park, Young Je; Nam, Hee Rim; Lim, Do Hoon; Ahn, Yong Chan
2006-08-01
Purpose: This study evaluated the treatment results of external beam radiotherapy administered in six fractions per week and high-dose-rate (HDR) brachytherapy for the treatment of cervical cancer. Methods and Materials: From July 2000 to July 2003, 43 patients were enrolled in this study. The patients received 45 Gy from a 10-MV photon beam using four-field box or anterior-posterior beams. Parametrial regions and the pelvic side walls were boosted with up to 50.4 Gy using a midline block. The daily fraction dose was 1.8 Gy administered in six-weekly fractions, from Monday to Saturday. HDR brachytherapy was also delivered at doses of 24 Gy to point A in six fractions twice a week. The median follow-up time was 37 months (range, 9-60 months). Results: The median overall treatment time was 51 days for all patients (range, 44-62 days). Thirty-four patients (79.1%) achieved complete remission and 8 (18.6%) achieved partial remission after radiotherapy. Locoregional recurrence occurred in 5 patients (11.6%), and a distant metastasis was encountered in 6 patients (13.9%). The 3-year overall survival, locoregional, and distant metastasis-free survival rates were 74.7%, 87.8%, and 84.7%, respectively. Grade 2 and 3 late rectal complications were encountered in 3 (6.5%) and 1 (2.2%), respectively. There were no Grade 3 late bladder complications. Conclusions: Six fractions per week of external beam radiotherapy and HDR brachytherapy is an effective treatment for patients with a carcinoma of the uterine cervix and can be used as a possible alternative to concomitant chemoradiotherapy in elderly patients or in patients with co-morbidity.
Jebsen, Nina L.; Engellau, Jacob; Engström, Katarina; Bauer, Henrik C.; Monge, Odd R.; Muren, Ludvig P.; Eide, Geir E.; Trovik, Clement S.; Bruland, Øyvind S.
2013-08-01
Purpose: To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. Methods and Materials: LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. Results: Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence interval [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03-1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. Conclusions: No significant dose–response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma.
Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.; Poele, Johannes A.M. te; Russell, Nicola S.; Daemen, Mat J.A.P.; Stewart, Fiona A.
2008-07-01
Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaque size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.
Szluha, Kornelia; Lazanyi, Kornelia; Furka, Andrea; Kiss, Ferenc; Szabo, Imre; Pintye, Eva; Miko, Iren; Nemeth, Norbert
2014-01-01
Despite of the studies on widespread biological effects of irradiation, surprisingly only little number of papers can be found dealing with its in vivo hemorheological impact. Furthermore, other studies suggested that low-dose irradiation might differ from high-dose in more than linear ways. On Balb/c Jackson female adult mice hematological and hemorheological impacts of total body irradiation were investigated 1 hour following 0.002, 0.005, 0.01, 0.02, 0.05 and 0.1 Gy dose irradiation. In case of 0.01 Gy further groups were analyzed 30 minutes, 2, 4, 6, 24 and 48 h after irradiation. According to the results, it seems that the dose-dependent changes of blood micro-rheological parameters are not linear. The irradiation dose of 0.01 Gy acted as a point of 'inflexion', because by this dose we found the most expressed changes in hematological parameters, as well as in red blood cell aggregation, deformability and osmoscan data. The time-dependent changes showed progressive decrease in pH, rise in lactate concentration, further decrease in erythrocyte aggregation index and deformability, with moderate shifting of the optimal osmolarity point and modulation in membrane stability. As conclusion, low-dose total body irradiation may cause micro-rheological changes, being non-linearly correlated with the irradiation dose.
Shalaby, S M; Bosseila, M; Fawzy, M M; Abdel Halim, D M; Sayed, S S; Allam, R S H M
2016-11-01
Morphea is a rare fibrosing skin disorder that occurs as a result of abnormal homogenized collagen synthesis. Fractional ablative laser resurfacing has been used effectively in scar treatment via abnormal collagen degradation and induction of healthy collagen synthesis. Therefore, fractional ablative laser can provide an effective modality in treatment of morphea. The study aimed at evaluating the efficacy of fractional carbon dioxide laser as a new modality for the treatment of localized scleroderma and to compare its results with the well-established method of UVA-1 phototherapy. Seventeen patients with plaque and linear morphea were included in this parallel intra-individual comparative randomized controlled clinical trial. Each with two comparable morphea lesions that were randomly assigned to either 30 sessions of low-dose (30 J/cm(2)) UVA-1 phototherapy (340-400 nm) or 3 sessions of fractional CO2 laser (10,600 nm-power 25 W). The response to therapy was then evaluated clinically and histopathologically via validated scoring systems. Immunohistochemical analysis of TGF-ß1 and MMP1 was done. Patient satisfaction was also assessed. Wilcoxon signed rank test for paired (matched) samples and Spearman rank correlation equation were used as indicated. Comparing the two groups, there was an obvious improvement with fractional CO2 laser that was superior to that of low-dose UVA-1 phototherapy. Statistically, there was a significant difference in the clinical scores (p = 0.001), collagen homogenization scores (p = 0.012), and patient satisfaction scores (p = 0.001). In conclusion, fractional carbon dioxide laser is a promising treatment modality for cases of localized morphea, with proved efficacy of this treatment on clinical and histopathological levels.
Chen, Wei-Yu; Fang, Chia-Lang; Al-Suwayeh, Saleh A; Yang, Hung-Hsu; Li, Yi-Ching; Fang, Jia-You
2013-09-01
The ablative fractional laser is a new modality used for surgical resurfacing. It is expected that laser treatment can generally deliver drugs into and across the skin, which is toxicologically relevant. The aim of this study was to establish skin absorption characteristics of antibiotics, sunscreens, and macromolecules via laser-treated skin and during postoperative periods. Nude mice were employed as the animal model. The skin received a single irradiation of a fractional CO2 laser, using fluences of 4-10 mJ with spot densities of 100-400 spots/cm(2). In vitro skin permeation using Franz cells was performed. Levels of skin water loss and erythema were evaluated, and histological examinations with staining by hematoxylin and eosin, cyclooxygenase-2, and claudin-1 were carried out. Significant signs of erythema, edema, and scaling of the skin treated with the fractional laser were evident. Inflammatory infiltration and a reduction in tight junctions were also observed. Laser treatment at 6 mJ increased tetracycline and tretinoin fluxes by 70- and 9-fold, respectively. A higher fluence resulted in a greater tetracycline flux, but lower skin deposition. On the other hand, tretinoin skin deposition increased following an increase in the laser fluence. The fractional laser exhibited a negligible effect on modulating oxybenzone absorption. Dextrans with molecular weights of 4 and 10 kDa showed increased fluxes from 0.05 to 11.05 and 38.54 μg/cm(2)/h, respectively. The optimized drug dose for skin treated with the fractional laser was 1/70-1/60 of the regular dose. The skin histology and drug absorption had recovered to a normal status within 2-3 days. Our findings provide the first report on risk assessment of excessive skin absorption after fractional laser resurfacing.
Eggebeen, Joel; Kim-Shapiro, Daniel B.; Haykowsky, Mark; Morgan, Timothy M.; Basu, Swati; Brukaker, Peter; Rejeski, Jack; Kitzman, Dalane W.
2015-01-01
Objective To test whether a relatively low single dose or week-long dosing of dietary inorganic nitrate can improve exercise tolerance in patients with Heart Failure with preserved ejection fraction (HFPEF). Background Exercise intolerance is the primary manifestation of HFPEF and is largely due to non-cardiac factors that reduce oxygen delivery to active skeletal muscles. A recent study showed improved exercise capacity in patients with HFPEF after a single, acute dose of beetroot juice (BRJ, 12.9 mmol inorganic nitrate) while another recent study showed neutral and negative effects of an organic nitrate. Methods Twenty HFPEF patients (age: 69 ± 7 years) were enrolled in an initial cross-over design comparing a single, acute dose of BRJ (6.1 mmol nitrate) to a nitrate-depleted, placebo BRJ. A second, one week of daily dosing, phase employed an all-treated design in which patients consumed BRJ for an average of 7 days. The primary outcome of the study was submaximal aerobic endurance, measured as cycling time to exhaustion at 75% of measured maximal power output. Results No adverse events were associated with the intervention. Submaximal aerobic endurance improved 24% after one week of daily BRJ dosing (p =0.02), but was not affected by the single, acute dose of the BRJ compared to placebo. Consumption of BRJ significantly reduced resting systolic blood pressure and increased plasma nitrate and nitrite in both dosing schemes. Conclusions One week of daily dosing with BRJ (6.1 mmol inorganic nitrate) significantly improves submaximal aerobic endurance and blood pressure in elderly HFPEF patients. PMID:26874390
Destée, Alain; Rérat, Karin; Bourdeix, Isabelle
2009-01-01
Two strategies to manage symptom re-emergence due to wearing-off with conventional levodopa/dopa-decarboxylase inhibitor (DDCI) therapy were compared in patients with Parkinson's disease (PD) in this randomized, open-label trial. PD patients receiving 3 daily doses of levodopa/DDCI were randomized to either levodopa/DDCI and entacapone or an increased dose frequency of levodopa/DDCI with or without an increased total daily dose (dose fractionation). After 1 month of treatment, patients were followed up for 1 year. A greater proportion of levodopa/DDCI and entacapone-treated patients had treatment success compared with dose-fractionated patients, according to investigator Clinical Global Impression of Change scores at 1 month (68 vs. 59%, respectively) and 1 year (60 vs. 51%, respectively). Mean 'off' time (time with symptoms) was improved in both groups at 1 month and 1 year, despite a reduction in the mean daily levodopa dose in the levodopa/DDCI and entacapone group at 1 month. The mean daily levodopa dose was increased in the dose fractionation group. At 1 month, there was a 4% reduction in patients experiencing dyskinesia with levodopa/DDCI and entacapone and a 3% increase with dose fractionation. These data suggest that levodopa/DDCI and entacapone reduces time with symptoms, the rate of motor complications and the daily levodopa dose compared with dose fractionation. However, as the observed differences were not statistically significant, further studies are required to confirm these results.
Crane, Christopher H.; Koay, Eugene J.
2016-01-01
The emergence and success of stereotactic body radiation therapy (SBRT) in lung cancer has led to its rapid adoption for liver cancers. SBRT can achieve excellent results for small liver tumors. However, the vast majority of physicians interpret SBRT as meaning doses of radiation (4 to 20 Gy) that may not be ablative, but are delivered within about 1 week (i.e., in 3 to 6 fractions). Adherence to this approach has limited the effectiveness of SBRT for large liver tumors (> 7 cm) owing to the need to reduce doses to meet organ constraints. The prognosis for patients who present with large liver tumors is poor with median survival times of 12 months or less, and most such patients die from tumor-related liver failure. Herein, we present a comprehensive solution to achieve stereotactic ablative body radiation (SABR) doses for patients with large liver tumors by using a combination of classical, modern, and novel concepts of radiotherapy: fractionation, dose painting, motion management, image guidance, and simultaneous integrated protection. We discuss these concepts in the context of large inoperable liver tumors and review how this approach can substantially prolong survival for patients, most of whom otherwise have a very poor prognosis and few effective treatment options. PMID:26950735
Combs, Stephanie E.; Welzel, Thomas; Schulz-Ertner, Daniela; Huber, Peter E.; Debus, Juergen
2010-01-15
Purpose: To evaluate the outcomes of patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT) vs. those treated with stereotactic radiosurgery (SRS). Methods and Materials: This study is based on an analysis of 200 patients with 202 VSs treated with FSRT (n = 172) or SRS (n = 30). Patients with tumor progression and/or progression of clinical symptoms were selected for treatment. In 165 out of 202 VSs (82%), RT was performed as the primary treatment for VS, and for 37 VSs (18%), RT was conducted for tumor progression after neurosurgical intervention. For patients receiving FSRT, a median total dose of 57.6 Gy was prescribed, with a median fractionation of 5 x 1.8 Gy per week. For patients who underwent SRS, a median single dose of 13 Gy was prescribed to the 80% isodose. Results: FSRT and SRS were well tolerated. Median follow-up time was 75 months. Local control was not statistically different for both groups. The probability of maintaining the pretreatment hearing level after SRS with doses of <=13 Gy was comparable to that of FSRT. The radiation dose for the SRS group (<=13 Gy vs. >13 Gy) significantly influenced hearing preservation rates (p = 0.03). In the group of patients treated with SRS doses of <=13 Gy, cranial nerve toxicity was comparable to that of the FSRT group. Conclusions: FSRT and SRS are both safe and effective alternatives for the treatment of VS. Local control rates are comparable in both groups. SRS with doses of <=13 Gy is a safe alternative to FSRT. While FSRT can be applied safely for the treatment of VSs of all sizes, SRS should be reserved for smaller lesions.
Yoshioka, Yasuo; Konishi, Koji; Sumida, Iori; Takahashi, Yutaka; Isohashi, Fumiaki; Ogata, Toshiyuki; Koizumi, Masahiko; Yamazaki, Hideya; Nonomura, Norio; Okuyama, Akihiko; Inoue, Takehiro
2011-06-01
Purpose: To evaluate an extreme hypofractionation regimen with 54 Gy in nine fractions provided by high-dose-rate (HDR) brachytherapy as monotherapy for prostate cancer by reporting 5-year clinical results. Methods and Materials: Between 1996 and 2005, 112 patients with localized prostate cancer were treated with HDR brachytherapy without external beam radiotherapy. Of the 112 patients, 15 were considered low risk, 29 intermediate risk, and 68 as high risk. The prescribed dose was uniformly 54 Gy in nine fractions within 5 days. Of the 112 patients, 94 also received hormonal therapy. The median follow-up time was 5.4 years. Results: All the patients safely completed the treatment regimen. The 5-year prostate-specific antigen (PSA) failure-free, local control, disease-free survival, and overall survival rate was 83%, 97%, 87%, and 96%, respectively. The 5-year PSA failure-free rate for low-, intermediate-, and high-risk patients was 85% (95% confidence interval, 66-100%), 93% (95% confidence interval, 83-100%), and 79% (95% confidence interval, 69-89%), respectively. The significant prognostic factors for PSA failure were the initial PSA level (p = .029) and younger age (p = .019). The maximal toxicities observed were Grade 3 using the Common Terminology Criteria for Adverse Events, version 3.0, for both acute and late toxicity (6 and 3 patients had acute and late Grade 3 toxicity, respectively). Late Grade 2 toxicity was observed in 13 patients. Conclusion: Monotherapeutic HDR brachytherapy with an extreme hypofractionation regimen of 54 Gy in nine fractions associated with hormonal therapy was feasible, and its toxicity was acceptable. The interim tumor control rate at a median 5.4 years was promising, even for patients with locally advanced disease. This dose-fractionation scheme might be referred to by other terms, such as stereotactic body radiotherapy. Studies with longer follow-up periods and from multiple institutions are needed to confirm the efficacy of
López-Palop, Ramón; Carrillo, Pilar; Frutos, Araceli; Cordero, Alberto; Agudo, Pilar; Mashlab, Samer; Bertomeu-Martínez, Vicente
2013-05-01
Intravenous adenosine is considered the drug of choice to obtain maximum hyperemia in the measurement of the fractional flow reserve (FFR). However, comparative studies performed between intravenous and intracoronary administration have not used high doses of intracoronary adenosine. The present study compared the efficacy and safety of high doses of intracoronary adenosine to intravenous administration when calculating the FFR. Intracoronary bolus doses of 60, 180, 300, and 600 μg adenosine were compared to an intravenous administration of 140 μg/kg/min, 200 μg/kg/min, and 140 μg/kg/min plus an intracoronary bolus of 120 μg. All the cases were performed using the radial approach. FFR was assessed in 102 patients with 108 intermediate lesions by an intracoronary pressure wire. The intracoronary dose of 60 μg was associated with a significantly greater FFR compared to the intravenous infusion (0.02 ± 0.03, p = 0.001). The intracoronary doses of 300 (-0.01 ± 0.00; p = 0.006) and 600 μg (-0.02 ± 0.00; p <0.0005) were significantly associated with a smaller FFR compared to the intravenous infusion. An intracoronary dose of 600 μg revealed a significantly greater percentage of lesions with an FFR <0.80 compared to intravenous infusion at 140 μg/kg/min (37.6 vs 31.5%; p <0.05) and 200 μg/kg/min (37.6 vs 32.4%; p <0.05) and compared to intracoronary doses of 60 (26.9%) and 180 μg (31.5%). In conclusion, an intracoronary bolus dose >300 μg can be equal to or more effective than an intravenous infusion of adenosine in achieving maximum hyperemia when calculating the FFR. Its use could simplify these procedures without having an effect on safety.
Ramroth, Johanna; Cutter, David J; Darby, Sarah C; Higgins, Geoff S; McGale, Paul; Partridge, Mike; Taylor, Carolyn W
2016-11-15
The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no
Dewan, M Zahidunnabi; Galloway, Ashley E; Kawashima, Noriko; Dewyngaert, J Keith; Babb, James S; Formenti, Silvia C; Demaria, Sandra
2009-09-01
This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody. TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the inhibition of the secondary tumor. Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
Dewan, M. Zahidunnabi; Galloway, Ashley E.; Kawashima, Noriko; Dewyngaert, J. Keith; Babb, James S.; Formenti, Silvia C.; Demaria, Sandra
2009-01-01
Purpose This study tested the hypothesis that the type of dose-fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody. Experimental design TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated, and a “secondary” site outside the radiotherapy field. When both tumors were palpable mice were randomly assigned to 8 groups receiving no radiotherapy or 3 distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3 or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 mAb against CTLA-4. Mice were followed for tumors growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. Results In either of the 2 models tested treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors, but had no effect on the secondary tumors, outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (p<0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (p<0.01). Frequency of CD8+ T cells showing tumor-specific IFNγ production was proportional to the inhibition of the secondary tumor. Conclusions Fractionated, but not single dose radiotherapy, induces an abscopal effect when in combination with anti-CTLA-4 antibody, in two preclinical carcinoma models. PMID:19706802
Thomas, Tarita O.; Agrawal, Priya; Guitart, Joan; Rosen, Steven T.; Querfeld, Christiane; Kuzel, Timothy M.
2013-03-01
Purpose: Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. Methods and Materials: This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fisher's exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. Results: Two hundred seventy individual lesions were treated, with the majority (97%) treated with ≥700 cGy; mean follow-up was 41.3 months (range, 3-180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sézary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. Conclusions: A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient.
Matsuyama, Tomohiko; Kogo, Kasei; Oya, Natsuo
2013-03-15
Purpose: To evaluate the efficacy and toxicity of fractionated stereotactic radiation therapy (FSRT) based on biological effective dose (BED), a novel approach to deliver a fixed BED irrespective of dose fractionation, for brain metastases from non-small cell lung cancer (NSCLC). Methods and Materials: Between March 2005 and March 2009 we treated 299 patients with 1 to 5 lesions from NSCLC (573 total brain metastases) with FSRT using Novalis. The dose fractionation schedules were individually determined to deliver a peripheral BED10 (α/β ratio = 10) of approximately 80 Gy{sub 10}. The median number of fractions was 3 (range, 2-10), the median peripheral BED10 was 83.2 Gy (range, 19.1-89.6 Gy). Patients were followed up with magnetic resonance imaging (MRI) studies performed at 1- to 2-month intervals. The local tumor control rate and overall local progression-free and intracranial relapse-free survival were calculated by the Kaplan-Meier method. Results: Local control rates for all 573 lesions at 6 and 12 months were 96.3% and 94.5%, respectively. By multivariate analysis the tumor diameter was the only factor predictive of the local control rate (P=.001). The median overall survival, local progression-free survival, and intracranial relapse-free survival were 17.1, 14.9, and 4.4 months, respectively. The overall survival, local progression-free survival, and intracranial relapse-free survival rates at 6 and 12 months were 78.5% and 63.3%, 74.3% and 57.8%, and 41.0% and 21.8%, respectively. Six patients (2%) manifested progressive radiation injury to the brain even during therapy with corticosteroids; they underwent hyperbaric oxygen therapy, and follow-up MRI showed improvement. Conclusions: This study showed that BED-based FSRT for brain metastases from NSCLC is a promising strategy that may yield excellent outcomes with acceptable toxicity. Criteria must be established to determine the optimal dose fractionation for individual patients.
Chua, Daniel TT; Wu, Shao-Xiong; Lee, Victor; Tsang, Janice
2009-01-01
Background wLocal failure is an important cause of morbidity and mortality in nasopharyngeal carcinoma (NPC). Although surgery or brachytherapy may be feasible in selected cases, most patients with local failure require external beam re-irradiation. Stereotactic radiation using single or multiple fractions have been employed in re-irradiation of NPC, but the optimal fractionation scheme and dose are not clear. Methods Records of 125 NPC patients who received salvage stereotactic radiation were reviewed. A matched-pair design was used to select patients with similar prognostic factors who received stereotactic re-irradiation using single fraction (SRS) or multiple fractions (SRM). Eighty-six patients were selected with equal number in SRS and SRM groups. All patients were individually matched for failure type (persistent or recurrent), rT stage (rT1-2 or rT3-4), and tumor volume (≤ 5 cc, >5–10 cc, or >10 cc). Median dose was 12.5 Gy in single fraction by SRS, and 34 Gy in 2–6 fractions by SRM. Results Local control rate was better in SRM group although overall survival rates were similar. One- and 3-year local failure-free rates were 70% and 51% in SRS group compared with 91% and 83% in SRM group (p = 0.003). One- and 3-year overall survival rates were 98% and 66% in SRS group compared with 78% and 61% in SRM group (p = 0.31). The differences in local control were mainly observed in recurrent or rT2-4 disease. Incidence of severe late complications was 33% in SRS group vs. 21% in SRM group, including brain necrosis (16% vs. 12%) and hemorrhage (5% vs. 2%). Conclusion Our study showed that SRM was superior to SRS in salvaging local failures of NPC, especially in the treatment of recurrent and rT2-4 disease. In patient with local failure of NPC suitable for stereotactic re-iradiation, use of fractionated treatment is preferred. PMID:19463191
Hirabayashi, Yoko; Tsuboi, Isao; Nakachi, Kei; Kusunoki, Yoichiro; Inoue, Tohru
2015-03-01
The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity. To investigate why the recovery in the number of cells in the LKS fraction was delayed, expression levels of genes related to cellular proliferation and apoptosis of cells in the bone marrow and LKS fraction were analyzed by real-time polymerase chain reaction (RT-PCR). In the case of 21-month-old mice after radiation exposure, Ccnd1, PiK3r1 and Fyn were overexpressed solely in cells in the LKS fraction. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by radiation, single-dose radiation seemed to induce the acceleration of aging, which is related to the essential biological responses during aging based on a lifetime-dependent relationship between a living creature and xenobiotic materials.
Buratovic, Sonja; Stenerlöw, Bo; Fredriksson, Anders; Sundell-Bergman, Synnöve; Eriksson, Per
2016-07-01
To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 μg/kg b.w.) twice daily on postnatal day (PND) 10, 10-11, 10-12 or 10-13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.
Lanini, Juliana; Galduróz, José Carlos Fernandes; Pompéia, Sabine
2016-01-01
Caffeine is widely used, often consumed with food, and improves simple and complex/executive attention under fasting conditions. We investigated whether these cognitive effects are observed when personalized habitual doses of caffeine are ingested by caffeine consumers, whether they are influenced by nutriments and if various executive domains are susceptible to improvement. This was a double-blind, placebo-controlled study including 60 young, healthy, rested males randomly assigned to one of four treatments: placebo fasting, caffeine fasting, placebo meal and caffeine meal. Caffeine doses were individualized for each participant based on their self-reported caffeine consumption at the time of testing (morning). The test battery included measures of simple and sustained attention, executive domains (inhibiting, updating, shifting, dual tasking, planning and accessing long-term memory), control measures of subjective alterations, glucose and insulin levels, skin conductance, heart rate and pupil dilation. Regardless of meal intake, acute habitual doses of caffeine decreased fatigue, and improved simple and sustained attention and executive updating. This executive effect was not secondary to the habitual weekly dose consumed, changes in simple and sustained attention, mood, meal ingestion and increases in cognitive effort. We conclude that the morning caffeine "fix" has positive attentional effects and selectively improved executive updating whether or not caffeine is consumed with food.
Liu, Junyang; Kaidu, Motoki; Sasamoto, Ryuta; Ayukawa, Fumio; Yamana, Nobuko; Sato, Hiraku; Tanaka, Kensuke; Kawaguchi, Gen; Ohta, Atsushi; Maruyama, Katsuya; Abe, Eisuke; Kasahara, Takashi; Nishiyama, Tsutomu; Tomita, Yoshihiko; Aoyama, Hidefumi
2016-01-01
We investigated the outcomes of treatment for patients with localized prostate cancer (PCa) treated with 3D conformal radiation therapy (3D-CRT) followed by two-fraction high-dose-rate brachytherapy within a single day (2-fr.-HDR-BT/day) at a single institution. A total of 156 consecutive Asian males (median age, 67 years) were enrolled. To compare our findings with those of other studies, we analyzed our results using the D'Amico classification, assigning the patients to low- (n =5; 3.2%), intermediate- (n =36; 23.1%) and high-risk (n =115; 73.7%) groups (Stage T3 PCa patients were classified as high-risk). One patient in the D'Amico low-risk group (20%), 13 intermediate-risk patients (36.1%) and 99 high-risk patients (86.1%) underwent androgen deprivation therapy. We administered a prescription dose of 39 Gy in 13 fractions of 3D-CRT combined with 18 Gy of HDR-BT in two 9-Gy fractions delivered within a single day. We did not distinguish between risk groups in determining the prescription dose. The median follow-up period was 38 months. Of the 156 patients, one died from primary disease and five died from other diseases. The 3-year overall survival (OS) rates were 100%, 100% and 93.7%, and the 3-year ‘biochemical no evidence of disease (bNED)’ rates were 100%, 100% and 96.9% for the D'Amico low-, intermediate- and high-risk groups, respectively. No patient developed ≥ Grade 3 early toxicity. The Grade 3 late genitourinary toxicity rate was 2.6%, and no ≥ Grade 3 late gastrointestinal toxicity occurred. The efficacy and safety of this study were satisfactory, and longer-term follow-up is necessary. PMID:26983988
Nam, Taek Keun
2004-01-01
To evaluate the toxicities and efficacies of two fractionation regimens of high-dose-rate brachytherapy in uterine cervical cancer, patients were stratified by stage Ib-IIa versus IIb-IVa, and randomly assigned to receive 3 Gy fractions (group A) or 5 Gy fractions (group B). External radiotherapy was performed using a 10 MV radiography with a daily 1.8 Gy up to 30.6 Gy to the whole pelvis, and then with a midline shield up to 45.0 Gy. Brachytherapy was performed with 3 Gy × 10 times or 5 Gy × 5 times, and this was followed by booster brachytherapy of a smaller fraction to the residual tumor. Between August 1999 to July 2000, 46 patients were eligible. Median follow-up period was 42 months (5-49). The range of age was 37-83 yr (median, 58). The three-year disease-specific survival rates of group A (n=23) and B (n=23) were 90.5%, 84.9%, respectively (p=0.64). The three-year pelvic control rates of group A and B were 90.0% and 90.9%, respectively (p=0.92). The incidences of late complications of the rectum or bladder of grade 2 or greater in groups A and B were 23.8% and 9.1%, respectively (p=0.24). Our study showed that the results of two regimens were comparable. Fractionation regimen using 5 Gy fractions seems to be safe and effective, and offers shorter treatment duration. PMID:14966348
Horton, Janet K.; Blitzblau, Rachel C.; Yoo, Sua; Geradts, Joseph; Chang, Zheng; Baker, Jay A.; Georgiade, Gregory S.; Chen, Wei; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Broadwater, Gloria; Groth, Jeff; Palta, Manisha; Dewhirst, Mark; Barry, William T.; Duffy, Eileen A.; Chi, Jen-Tsan A.; Hwang, E. Shelley
2015-01-01
Summary This phase I dose-escalation trial evaluates the feasibility of single-dose preoperative partial breast irradiation delivered with external beam techniques in early stage breast cancer patients. No acute dose-limiting toxicity was observed at 15, 18, or 21Gy. Paired pre- and post-radiation imaging and tumor biopsies offer unique insight into the biology of breast cancer radiation response. Purpose Women with biologically favorable early stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large post-operative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase I trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods Women 55 or older with clinically node negative, ER+ and/or PR+, HER2-, T1 invasive carcinomas or low-intermediate grade in situ disease ≤2cm were enrolled (n=32). Intensity-modulated radiotherapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21Gy (n=16) to the tumor with a 1.5cm margin. Lumpectomy was performed within 10 days. Paired pre- and post-radiation MRI images and patient tumor samples were analyzed. Results No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent and chronic toxicities were grade 1-2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions Preoperative single-dose
Desai, Sejal; Kumar, Amit; Laskar, S; Pandey, B N
2013-01-01
Cytokines are known to play pivotal roles in cancer initiation, progression and pathogenesis. Accumulating evidences suggest differences in basal and stress-induced cytokine profiles of cancers with diverse origin. However, a comprehensive investigation characterising the cytokine profile of various tumor types after acute and fractionated doses of gamma-irradiation, and its effect on survival of bystander cells is not well known in literature. In the present study, we have evaluated the cytokine secretion profile of human tumor cell lines (HT1080, U373MG, HT29, A549 and MCF-7) either before (basal) or after acute (2, 6 Gy) and fractionated doses (3×2 Gy) of gamma-irradiation in culture medium obtained from these cells by multiplex bead array/ELISA. Moreover, clonogenic assays were performed to evaluate the effect of conditioned medium (CM) on the survival and growth of respective cells. Based on the screening of 28 analytes, our results showed that the basal profiles of these cell lines varied considerably in terms of the number and magnitude of secreted factors, which was minimum in MCF-7. Interestingly, TNF-α, IL-1β, PDGF-AA, TGF-β1, fractalkine, IL-8, VEGF and GCSF were found in CM of all the cell lines. However, secretion of certain cytokines was cell line-specific. Moreover, CM caused increase in clonogenic survival of respective tumor cells (in the order HT1080>U373MG>HT29>A549>MCF-7), which was correlated with the levels of IL-1β, IL-6, IL-8, GMCSF and VEGF in their CM. After irradiation, the levels of most of the cytokines increased markedly in a dose dependent manner. The fold change in cytokine levels was lower in irradiated conditioned medium (ICM) of tumor cells collected after fractionated than respective acute dose, except in MCF-7. Interestingly, amongst these cell lines, the radiation-induced fold increase in cytokine levels was maximum in ICM of A549 cells. Moreover, bystander A549 cells treated with respective ICM showed dose dependent
Arruda Viani, Gustavo; Stefano, Eduardo Jose; Vendito Soares, Francisco; Afonso, Sergio Luis
2011-07-15
Purpose: To evaluate whether the risk of local recurrence depends on the biologic effective dose (BED) or fractionation dose in patients with resectable rectal cancer undergoing preoperative radiotherapy (RT) compared with surgery alone. Methods and Materials: A meta-analysis of randomized controlled trials (RCTs) was performed. The MEDLINE, Embase, CancerLit, and Cochrane Library databases were systematically searched for evidence. To evaluate the dose-response relationship, we conducted a meta-regression analysis. Four subgroups were created: Group 1, RCTs with a BED >30 Gy{sub 10} and a short RT schedule; Group 2, RCTs with BED >30 Gy{sub 10} and a long RT schedule; Group 3, RCTs with BED {<=}30 Gy{sub 10} and a short RT schedule; and Group 4, RCTs with BED {<=}30 Gy{sub 10} and a long RT schedule. Results: Our review identified 21 RCTs, yielding 9,097 patients. The pooled results from these 21 randomized trials of preoperative RT showed a significant reduction in mortality for groups 1 (p = .004) and 2 (p = .03). For local recurrence, the results were also significant in groups 1 (p = .00001) and 2 (p = .00001).The only subgroup that showed a greater sphincter preservation (SP) rate than surgery was group 2 (p = .03). The dose-response curve was linear (p = .006), and RT decreased the risk of local recurrence by about 1.7% for each Gy{sub 10} of BED. Conclusion: Our data have shown that RT with a BED of >30 Gy{sub 10} is more efficient in reducing local recurrence and mortality rates than a BED of {<=}30 Gy{sub 10}, independent of the schedule of fractionation used. A long RT schedule with a BED of >30 Gy{sub 10} should be recommended for sphincter preservation.
Paubelle, Etienne; Ducastelle-Leprêtre, Sophie; Labussière-Wallet, Hélène; Nicolini, Franck Emmanuel; Barraco, Fiorenza; Plesa, Adriana; Salles, Gilles; Wattel, Eric; Thomas, Xavier
2017-03-01
Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.
Niemoeller, Olivier M; Pöllinger, Barbara; Niyazi, Maximilian; Corradini, Stefanie; Manapov, Farkhad; Belka, Claus; Huber, Rudolf M
2013-01-07
To determine the efficacy of high dose rate endobronchial brachytherapy (HDR-BT) for the treatment of centrally located lung tumors, two different fractionation schedules were compared regarding local tumor response, side effects and survival. Mature retrospective results with longer follow-up and more patients were analyzed. Initial results were published by Huber et al. in 1995. 142 patients with advanced, centrally located malignant tumors with preferential endoluminal growth were randomized to receive 4 fractions of 3.8 Gy (time interval: 1 week, n = 60, group I) or 2 fractions of 7.2 Gy (time interval: 3 weeks, n = 82, group II) endobronchial HDR-BT.Age, gender, tumor stage, Karnofsky Performance Score and histology were equally distributed between both groups. Local tumor response with 2 fractions of 7.2 Gy was significantly higher as compared to 4 fractions of 3.8 Gy (median 12 vs. 6 weeks; p ≤ 0.015). Median survival was similar in both groups (19 weeks in the 4 fractions group vs. 18 weeks in the 2 fractions group). Fatal hemoptysis was less frequent following irradiation with 2 × 7.2 Gy than with 4 × 3.8 Gy, although the difference did not achieve statistical significance (12.2% vs. 18.3%, respectively. p = 0,345). Patients presenting with squamous cell carcinoma were at higher risk of bleeding compared to other histology (21.9% vs. 9%, p = 0,035).Multivariate analysis with regard to overall survival, revealed histology (p = 0.02), Karnofsky Performance Score (p < 0.0001) and response to therapy (p < 0.0001) as significant prognostic factors. For patients showing complete response the median survival was 57 weeks, while for patients with progressive disease median survival time was 8 weeks, p < 0.0001.The KPS at the start of the treatment was significantly correlated with survival. Patients presenting with a KPS ≤ 60 at the start had a significantly (p = 0,032) shorter survival time (10 weeks) than
Morton, Gerard C.; Loblaw, D. Andrew; Chung, Hans; Tsang, Gail; Sankreacha, Raxa; Deabreu, Andrea; Zhang Liying; Mamedov, Alexandre; Cheung, Patrick; Batchelar, Deidre; Danjoux, Cyril; Szumacher, Ewa
2011-08-01
Purpose: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. Methods and Materials: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. Results: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose
Dale, E; Hellebust, T P; Skjønsberg, A; Høgberg, T; Olsen, D R
2000-07-01
To calculate the normal tissue complication probability (NTCP) of late radiation effects on the rectum and bladder from repetitive CT scans during fractionated high-dose-rate brachytherapy (HDRB) and external beam radiotherapy (EBRT) of the uterine cervix and compare the NTCP with the clinical frequency of late effects. Fourteen patients with cancer of the uterine cervix (Stage IIb-IVa) underwent 3-6 (mean, 4.9) CT scans in treatment position during their course of HDRB using a ring applicator with an Iridium stepping source. The rectal and bladder walls were delineated on the treatment-planning system, such that a constant wall volume independent of organ filling was achieved. Dose-volume histograms (DVH) of the rectal and bladder walls were acquired. A method of summing multiple DVHs accounting for variable dose per fraction were applied to the DVHs of HDRB and EBRT together with the Lyman-Kutcher NTCP model fitted to clinical dose-volume tolerance data from recent studies. The D(mean) of the DVH from EBRT was close to the D(max) for both the rectum and bladder, confirming that the DVH from EBRT corresponded with homogeneous whole-organ irradiation. The NTCP of the rectum was 19.7% (13.5%, 25. 9%) (mean and 95% confidence interval), whereas the clinical frequency of late rectal sequelae (Grade 3-4, RTOG/EORTC) was 13% based on material from 200 patients. For the bladder the NTCP was 61. 9% (46.8%, 76.9%) as compared to the clinical frequency of Grade 3-4 late effects of 14%. If only 1 CT scan from HDRB was assumed available, the relative uncertainty (standard deviation or SD) of the NTCP value for an arbitrary patient was 20-30%, whereas 4 CT scans provided an uncertainty of 12-13%. The NTCP for the rectum was almost consistent with the clinical frequency of late effects, whereas the NTCP for bladder was too high. To obtain reliable (SD of 12-13%) NTCP values, 3-4 CT scans are needed during 5-7 fractions of HDRB treatments.
Rovirosa, Angeles; Ascaso, Carlos; Sanchez-Reyes, Alberto; Herreros, Antonio; Abellana, Rosa; Pahisa, Jaume; Lejarcegui, Jose Antonio; Biete, Albert
2011-10-01
Purpose: To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated. Patients and Methods: Federation Internationale de Gynecologie Obstetrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1-67 of 89 patients received external beam irradiation (EBI; 44-50 Gy) plus HDRBT (3 fractions of 4-6 Gy); Group 2-22 of 89 patients received HDRBT alone (6 fractions of 4-5 Gy). OTT: Group 1-HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2-HDRBT was completed in <15 days in 11 patients and in {>=}16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves. Results: With a mean follow-up of 31 months (range, 6-70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2. Conclusions: Three fractions of 4-5 Gy in 3-5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity.
Abouaf, Lucie; Girard, Nicolas; Lefort, Thibaud; D'hombres, Anne; Tilikete, Caroline; Vighetto, Alain; Mornex, Francoise
2012-03-01
Purpose: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM. Methods and Materials: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test. Results: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision. Conclusions: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.
Sato, Morio Mori, Takashi; Shirai, Shintaro; Kishi, Kazushi; Inagaki, Takeshi; Hara, Isao
2008-11-15
Purpose: To evaluate the preliminary outcomes of high-dose-rate (HDR) brachytherapy of a single implant with two fractions and external beam radiotherapy (EBRT) for hormone-naive prostate cancer. Methods and Materials: Between March 2000 and Sept 2003, a total of 53 patients with tumor Stage T1c-T3b N0 M0 prostate cancer were treated with HDR brachytherapy boost doses (7.5 Gy/fraction) and 50-Gy EBRT during a 5.5-week period. Median follow-up was 61 months. Patients were divided into groups with localized (T1c-T2b) and advanced disease (T3a-T3b). We used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure. According to recommendations of the Radiation Therapy Oncology Group-ASTRO Phoenix Consensus Conference, biochemical failure-free control rates (BF-FCRs) at 3 years were investigated as 2 years short of the median follow-up. Results: Between April 2000 and Sept 2007, Common Terminology Criteria for Adverse Events Version 2.0 late Grade 2 genitourinary and gastrointestinal toxicity rates were 0% and 3.8%, respectively. Erectile preservation was 25% at 5 years. Overall survival was 88.1% and cause-specific survival was 100%. At 3 years, ASTRO BF-FCRs of the localized and advanced groups were 100% and 42%, respectively (p = 0.001). Conclusions: The HDR brachytherapy of a single implant with two fractions plus EBRT is effective in treating patients with localized hormone-naive prostate cancer, with the least genitourinary and gastrointestinal toxicities; however, longer median BF-FCR follow-up is required to assess these findings.
Horton, Janet K; Blitzblau, Rachel C; Yoo, Sua; Geradts, Joseph; Chang, Zheng; Baker, Jay A; Georgiade, Gregory S; Chen, Wei; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Broadwater, Gloria; Groth, Jeff; Palta, Manisha; Dewhirst, Mark; Barry, William T; Duffy, Eileen A; Chi, Jen-Tsan A; Hwang, E Shelley
2015-07-15
Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to
Horton, Janet K.; Blitzblau, Rachel C.; Yoo, Sua; Geradts, Joseph; Chang, Zheng; Baker, Jay A.; Georgiade, Gregory S.; Chen, Wei; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Broadwater, Gloria; Groth, Jeff; Palta, Manisha; Dewhirst, Mark; Barry, William T.; Duffy, Eileen A.; and others
2015-07-15
Purpose: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods and Materials: Women aged ≥55 years with clinically node-negative, estrogen receptor–positive, and/or progesterone receptor–positive HER2−, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. Results: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should
Ghilezan, Michel; Martinez, Alvaro; Gustason, Gary; Krauss, Daniel; Antonucci, J. Vito; Chen, Peter; Fontanesi, James; Wallace, Michelle; Ye Hong; Casey, Alyse; Sebastian, Evelyn; Kim, Leonard; Limbacher, Amy
2012-07-01
Purpose: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy Multiplication-Sign 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy Multiplication-Sign 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. Methods and Materials: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of {<=}12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. Results: The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Conclusions: Favorable
van de Glind, Gerline; Rebel, Heggert; van Kempen, Marika; Tensen, Kees; de Gruijl, Frank
2016-02-16
Sunburns and especially sub-sunburn chronic UV exposure are associated with increased risk of squamous cell carcinomas (SCCs). Here we focus on a possible difference in tumor initiation from a single severe-sunburn dose (on day 1, 21 hairless mice) and from an equal dose fractionated into very low sub-sunburn doses not causing any (growth-promoting) epidermal hyperplasia (40 days daily exposure, n=20). From day 47 all mice received 12-O-Tetradecanoylphorbol-13-acetate (TPA) applications (2x/wk) for 20 weeks to promote tumor development within the lifetime of the animals. After the sub-sunburn regimen sparse DNA damage-retaining basal cells (quiescent stem cells, QSCs) remained in the non-hyperplastic epidermis. These cells were forced to divide by TPA. After discontinuation of TPA tumors regressed and disappeared in the 'sunburn group' but persisted and grew in the 'sub-sunburn group' (0.06 vs 2.50 SCCs and precursors ≥4 mm/mouse after 280 days, p=0.03). As the tumors carried no mutations in p53, H/K/N-Ras and Notch1/2, these 'usual suspects' were not involved in the UV-driven tumor initiation. Although we could not selectively eliminate QSCs (unknown phenotype) to establish causality, our data suggest that forcing specifically DNA damage-retaining QSCs to divide--with high mutagenic risk--gives rise to persisting (mainly 'in situ') skin carcinomas.
van de Glind, Gerline; Rebel, Heggert; van Kempen, Marika; Tensen, Kees; de Gruijl, Frank
2016-01-01
Sunburns and especially sub-sunburn chronic UV exposure are associated with increased risk of squamous cell carcinomas (SCCs). Here we focus on a possible difference in tumor initiation from a single severe-sunburn dose (on day 1, 21 hairless mice) and from an equal dose fractionated into very low sub-sunburn doses not causing any (growth-promoting) epidermal hyperplasia (40 days daily exposure, n=20). From day 47 all mice received 12-O-Tetradecanoylphorbol-13-acetate (TPA) applications (2x/wk) for 20 weeks to promote tumor development within the lifetime of the animals. After the sub-sunburn regimen sparse DNA damage-retaining basal cells (quiescent stem cells, QSCs) remained in the non-hyperplastic epidermis. These cells were forced to divide by TPA. After discontinuation of TPA tumors regressed and disappeared in the ‘sunburn group’ but persisted and grew in the ‘sub-sunburn group’ (0.06 vs 2.50 SCCs and precursors ≥4mm/mouse after 280 days, p=0.03). As the tumors carried no mutations in p53, H/K/N-Ras and Notch1/2, these ‘usual suspects' were not involved in the UV-driven tumor initiation. Although we could not selectively eliminate QSCs (unknown phenotype) to establish causality, our data suggest that forcing specifically DNA damage-retaining QSCs to divide – with high mutagenic risk - gives rise to persisting (mainly ‘in situ’) skin carcinomas. PMID:26797757
Stanojlović, Miloš; Zlatković, Jelena; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zarić, Marina; Horvat, Anica; Drakulić, Dunja
2015-01-01
Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.
Kirchheiner, Kathrin; Czajka-Pepl, Agnieszka; Scharbert, Gisela; Wetzel, Léonore; Sturdza, Alina; Dörr, Wolfgang; Pötter, Richard
2014-06-01
Purpose: To investigate the psychological consequences of high-dose-rate brachytherapy with 2 fractions in 1 application under spinal/epidural anesthesia in the treatment of locally advanced cervical cancer. Methods and Materials: In 50 patients with locally advanced cervical cancer, validated questionnaires were used for prospective assessment of acute and posttraumatic stress disorder (ASD/PTSD) (Impact of Event Scale–Revision), anxiety/depression (Hospital Anxiety and Depression Scale), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/Cervical Cancer 24), physical functioning (World Health Organization performance status), and pain (visual analogue scale), before and during treatment and 1 week and 3 months after treatment. Qualitative interviews were recorded in open format for content analysis. Results: Symptoms of ASD occurred in 30% of patients 1 week after treatment; and of PTSD in 41% 3 months after treatment in association with this specific brachytherapy procedure. Pretreatment predictive variables explain 82% of the variance of PTSD symptoms. Helpful experiences were the support of the treatment team, psychological support, and a positive attitude. Stressful factors were pain, organizational problems during treatment, and immobility between brachytherapy fractions. Conclusions: The specific brachytherapy procedure, as performed in the investigated mono-institutional setting with 2 fractions in 1 application under spinal/epidural anesthesia, bears a considerable risk of traumatization. The source of stress seems to be not the brachytherapy application itself but the maintenance of the applicator under epidural anesthesia in the time between fractions. Patients at risk may be identified before treatment, to offer targeted psycho-social support. The patients' open reports regarding helpful experiences are an encouraging feedback for the treatment team; the reported stressful factors
Videtic, Gregory M.M. Stephans, Kevin L.; Woody, Neil M.; Reddy, Chandana A.; Zhuang, Tingliang; Magnelli, Anthony; Djemil, Toufik
2014-09-01
Purpose: To review outcomes of 2 single-fraction lung stereotactic body radiation therapy (SBRT) schedules used for medically inoperable early stage lung cancer. Methods and Materials: Patients in our institution have been treated on and off protocols using single-fraction SBRT (30 Gy and 34 Gy, respectively). All patients had node-negative lung cancer measuring ≤5 cm and lying ≥2 cm beyond the trachea-bronchial tree and were treated on a Novalis/BrainLAB system with the ExactTrac positioning system for daily image guidance. Results: For the interval from 2009 to 2012, 80 patients with 82 lesions were treated with single-fraction lung SBRT. Fifty-five patients (69%) and 25 patients (31%) received 30 Gy and 34 Gy, respectively. In a comparison of 30 Gy and 34 Gy cohorts, patient and tumor characteristics were balanced and median follow-up in months was 18.7 and 17.8, respectively. The average heterogeneity-corrected mean doses to the target were 33.75 Gy and 37.94 Gy for the 30-Gy and 34-Gy prescriptions, respectively. Comparing 30-Gy and 34-Gy cohorts, 92.7% and 84.0% of patients, respectively, experienced no toxicity (P was not significant), and had neither grade 3 nor higher toxicities. For the 30-Gy and 34-Gy patients, rates of 1-year local failure, overall survival, and lung cancer-specific mortality were 2.0% versus 13.8%, 75.0% versus 64.0%, and 2. 1% versus 16.0%, respectively (P values for differences were not significant). Conclusions: This is the largest single-fraction lung SBRT series yet reported. and it confirms the safety, efficacy, and minimal toxicity of this schedule for inoperable early stage lung cancer.
NASA Astrophysics Data System (ADS)
Burigo, Lucas; Pshenichnov, Igor; Mishustin, Igor; Bleicher, Marcus
2015-04-01
Depth and radial dose profiles for therapeutic 1H, 4He, 12C and 16O beams are calculated using the Geant4-based Monte Carlo model for Heavy-Ion Therapy (MCHIT). 4He and 16O ions are presented as alternative options to 1H and 12C broadly used for ion-beam cancer therapy. Biological dose profiles and survival fractions of cells are estimated using the modified Microdosimetric Kinetic model. Depth distributions of cell survival of healthy tissues, assuming 10% and 50% survival of tumor cells, are calculated for 6 cm SOBPs at two tumor depths and for different tissues radiosensitivities. It is found that the optimal ion choice depends on (i) depth of the tumor, (ii) dose levels and (iii) the contrast of radiosensitivities of tumor and surrounding healthy tissues. Our results indicate that 12C and 16O ions are more appropriate to spare healthy tissues in the case of a more radioresistant tumor at moderate depths. On the other hand, a sensitive tumor surrounded by more resistant tissues can be better treated with 1H and 4He ions. In general, 4He beam is found to be a good candidate for therapy. It better spares healthy tissues in all considered cases compared to 1H. Besides, the dose conformation is improved for deep-seated tumors compared to 1H, and the damage to surrounding healthy tissues is reduced compared to heavier ions due to the lower impact of nuclear fragmentation. No definite advantages of 16O with respect to 12C ions are found in this study.
James, S.J.; Enger, S.M.; Peterson, W.J.; Makinodan, T. )
1990-06-01
Very low doses of ionizing radiation can enhance immune responsiveness and extend life span in normal mice. Total lymphoid irradiation at relatively high doses of radiation can retard autoimmune disease in genetically susceptible mice, but may impair immune function. In order to determine whether fractionated low dose exposure would enhance immune response and retard lymphadenopathy in autoimmune-prone mice, groups of C57B1/6 lpr/lpr mice were sham irradiated, exposed 5 days/week for 4 weeks to 0.04 Gy/day, or to 0.1 Gy/day. After the radiation protocol, the mice were evaluated for splenic T cell proliferative capacity, T cell subset distribution, and total spleen cell numbers. The independent and additive effect of caloric restriction was additionally assessed since this intervention has been shown to increase immune responsiveness and retard disease progression in autoimmune-prone mice. The congenic C57B1/6 +/+ immunologically normal strain was evaluated in parallel as congenic control. The results indicated that mitogen-stimulated proliferation was up-regulated in both strains of mice after exposure to 0.04 Gy/day. The proliferative capacity was additively enhanced when radiation at this dose level was combined with caloric restriction. Exposure to 0.1 Gy/day resulted in further augmentation of proliferative response in the lpr/lpr mice, but was depressive in the +/+ mice. Although the proportions of the various T cell subpopulations were altered in both strains after exposure to LDR, the specific subset alterations were different within each strain. Additional experiments were subsequently performed to assess whether the thymus is required for LDR-induced immune potentiation. Thymectomy completely abrogated the LDR effect in the +/+ mice, suggesting that thymic processing and/or trafficking is adaptively altered with LDR in this strain.
Sakaguchi, N.; Sakaguchi, S. Scripps Research Institute, La Jolla, CA PRESTO, JRDC, Institute of Phical and Chemical Research, Tsukuba, Ibaraki ); Miyai, K. )
1992-11-01
Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.
Huang, Eng-Yen; Sun, Li-Min; Lin, Hao; Lan, Jen-Hong; Chanchien, Chan-Chao; Huang, Yu-Jie; Wang, Chang-Yu; Wang, Chong-Jong
2013-01-01
To compare the treatment results of 2 fractionation schedules for high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. From June 2001 through January 2008, 267 patients with stage IB-IVA cervical cancer were enrolled in the study. All patients underwent 4-field pelvic irradiation and HDR-ICBT. The median central and parametrial doses were 39.6 Gy and 45 Gy, respectively. Patient underwent either 6 Gy×4 (HDR-4) (n=144) or 4.5 Gy×6 (HDR-6) (n=123) to point A of ICBT using 192Ir isotope twice weekly. The rates of overall survival, locoregional failure, distant metastasis, proctitis, cystitis, and enterocolitis were compared between HDR-4 and HDR-6. There were no significant differences in the demographic data between HDR-4 and HDR-6 except for total treatment time. The 5-year proctitis rates were 23.0% and 21.5% in HDR-4 and HDR-6 (P=.399), respectively. The corresponding rates of grade 2-4 proctitis were 18.7% and 9.6% (P=.060). The corresponding rates of grades 3-4 proctitis were 5.2% and 1.3% (P=.231). Subgroup analysis revealed that HDR-4 significantly increased grade 2-4 proctitis in patients aged≥62 years old (P=.012) but not in patients aged<62 years (P=.976). The rates of overall survival, locoregional failure, distant metastasis, cystitis, and enterocolitis were not significantly different between HDR-4 and HDR-6 schedules. The small fraction size of HDR-ICBT is associated with grade 2 proctitis without compromise of prognosis in elderly patients. This schedule is suggested for patients who tolerate an additional 2 applications of HDR-ICBT. Copyright © 2013 Elsevier Inc. All rights reserved.
Huang, Eng-Yen; Sun, Li-Min; Lin, Hao; Lan, Jen-Hong; Chanchien, Chan-Chao; Huang, Yu-Jie; Wang, Chang-Yu; Wang, Chong-Jong
2013-01-01
Purpose: To compare the treatment results of 2 fractionation schedules for high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. Methods and Materials: From June 2001 through January 2008, 267 patients with stage IB-IVA cervical cancer were enrolled in the study. All patients underwent 4-field pelvic irradiation and HDR-ICBT. The median central and parametrial doses were 39.6 Gy and 45 Gy, respectively. Patient underwent either 6 Gy Multiplication-Sign 4 (HDR-4) (n=144) or 4.5 Gy Multiplication-Sign 6 (HDR-6) (n=123) to point A of ICBT using {sup 192}Ir isotope twice weekly. The rates of overall survival, locoregional failure, distant metastasis, proctitis, cystitis, and enterocolitis were compared between HDR-4 and HDR-6. Results: There were no significant differences in the demographic data between HDR-4 and HDR-6 except for total treatment time. The 5-year proctitis rates were 23.0% and 21.5% in HDR-4 and HDR-6 (P=.399), respectively. The corresponding rates of grade 2-4 proctitis were 18.7% and 9.6% (P=.060). The corresponding rates of grades 3-4 proctitis were 5.2% and 1.3% (P=.231). Subgroup analysis revealed that HDR-4 significantly increased grade 2-4 proctitis in patients aged {>=}62 years old (P=.012) but not in patients aged <62 years (P=.976). The rates of overall survival, locoregional failure, distant metastasis, cystitis, and enterocolitis were not significantly different between HDR-4 and HDR-6 schedules. Conclusion: The small fraction size of HDR-ICBT is associated with grade 2 proctitis without compromise of prognosis in elderly patients. This schedule is suggested for patients who tolerate an additional 2 applications of HDR-ICBT.
Pumford, N R; Roberts, D W; Benson, R W; Hinson, J A
1990-08-01
The hepatotoxicity of acetaminophen correlates with the formation of 3-(cystein-S-yl)acetaminophen protein adducts. Using a sensitive and specific immunochemical assay, we quantitated the formation of these protein adducts in liver fractions and serum after administration of a hepatotoxic dose of acetaminophen (400 mg/kg) to B6C3F1 mice. Adducts in the cytosolic fraction increased to 3.6 nmol/mg protein at 2 hr and then decreased to 1.1 nmol/mg protein by 8 hr. Concomitant with the decrease in adducts in the cytosol, 3-(cystein-S-yl)acetaminophen protein adducts appeared in serum and their levels paralleled increases in serum alanine aminotransferase. Microsomal protein adducts peaked at 1 hr (0.7 nmol/mg protein) and subsequently decreased to 0.2 nmol/mg at 8 hr. The 4000 g pellet (nuclei, plasma membranes, and cell debris) had the highest level of adducts (3.5 nmol/mg protein), which remained constant from 1 to 8 hr. Evaluation of fractions purified from a 960 g pellet indicated that the highest concentration of 3-(cystein-S-yl)acetaminophen protein adducts was located in plasma membranes and mitochondria; peak levels were 10.3 and 5.1 nmol/mg respectively. 3-(Cystein-S-yl)acetaminophen protein adducts were detected in nuclei only after enzymatic hydrolysis of the proteins. The localization of high levels of 3-(cystein-S-yl)acetaminophen protein adducts in plasma membranes and mitochondria may play a critical role in acetaminophen toxicity.
Stankevicius, Vaidotas; Kuodyte, Karolina; Schveigert, Diana; Bulotiene, Danute; Paulauskas, Tomas; Daniunaite, Kristina; Suziedelis, Kestutis
2017-06-01
In clinical practice ionizing radiation (IR) is primarily applied to cancer treatment in the form of fractionated dose (FD) irradiation. Despite this fact, a substantially higher amount of current knowledge in the field of radiobiology comes from in vitro studies based on the cellular response to single dose (SD) irradiation. In addition, intrinsic and acquired resistance to IR remains an issue in clinical practice, leading to radiotherapy treatment failure. Numerous previous studies suggest that an improved understanding of the molecular processes involved in the radiation-induced DNA damage response to FD irradiation could improve the effectiveness of radiotherapy. Therefore, the present study examined the differential expression of genes and microRNA (miRNA) in murine Lewis lung cancer (LLC)1 cells exposed to SD or FD irradiation. The results of the present study indicated that the gene and miRNA expression profiles of LLC1 cells exposed to irradiation were dose delivery type-dependent. Data analysis also revealed that mRNAs may be regulated by miRNAs in a radiation-dependent manner, suggesting that these mRNAs and miRNAs are the potential targets in the cellular response to SD or FD irradiation. However, LLC1 tumors after FD irradiation exhibited no significant changes in the expression of selected genes and miRNAs observed in the irradiated cells in vitro, suggesting that experimental in vitro conditions, particularly the tumor microenvironment, should be considered in detail to promote the development of efficient radiotherapy approaches. Nevertheless, the present study highlights the primary signaling pathways involved in the response of murine cancer cells to irradiation. Data presented in the present study can be applied to improve the outcome and development of radiotherapy in preclinical animal model settings.
Jamal, Syed M; Bouma, Annemarie; van den Broek, Jan; Stegeman, Arjan; Chénard, Gilles; Dekker, Aldo
2008-11-25
The aim of this study was to determine a relationship between vaccine potency (amount of PD50 per dose) and fraction of clinically protected cattle following homologous challenge with infectious foot-and-mouth disease (FMD) virus, and to determine the effect of method of fractionation, serotype, type of adjuvant, valency and type of virus culture on the dose-response curve. Data from 297 potency tests of FMD vaccines, comprising 4004 vaccinated cattle, performed at the FMD vaccine production facility in the Netherlands, were used for the present study. A generalised linear mixed effect model was used to analyse the results. Our study showed that the relation between FMD vaccine potency and fraction protected was also affected by the serotype and type of adjuvant. No common level of protection could be assigned to all FMD vaccines with the same amount of PD50 per dose, this information is essential when designing a new standard FMD vaccines control.
NASA Astrophysics Data System (ADS)
Xie, Yiting; Salvatore, Mary; Liu, Shuang; Jirapatnakul, Artit; Yankelevitz, David F.; Henschke, Claudia I.; Reeves, Anthony P.
2017-03-01
A fully-automated computer algorithm has been developed to identify early-stage Usual Interstitial Pneumonia (UIP) using features computed from low-dose CT scans. In each scan, the pre-segmented lung region is divided into N subsections (N = 1, 8, 27, 64) by separating the lung from anterior/posterior, left/right and superior/inferior in 3D space. Each subsection has approximately the same volume. In each subsection, a classic density measurement (fractional high-density volume h) is evaluated to characterize the disease severity in that subsection, resulting in a feature vector of length N for each lung. Features are then combined in two different ways: concatenation (2*N features) and taking the maximum in each of the two corresponding subsections in the two lungs (N features). The algorithm was evaluated on a dataset consisting of 51 UIP and 56 normal cases, a combined feature vector was computed for each case and an SVM classifier (RBF kernel) was used to classify them into UIP or normal using ten-fold cross validation. A receiver operating characteristic (ROC) area under the curve (AUC) was used for evaluation. The highest AUC of 0.95 was achieved by using concatenated features and an N of 27. Using lung partition (N = 27, 64) with concatenated features had significantly better result over not using partitions (N = 1) (p-value < 0.05). Therefore this equal-volume partition fractional high-density volume method is useful in distinguishing early-stage UIP from normal cases.
Singh, Anurag K; Guion, Peter; Susil, Robert C; Citrin, Deborah E; Ning, Holly; Miller, Robert W; Ullman, Karen; Smith, Sharon; Crouse, Nancy Sears; Godette, Denise J; Stall, Bronwyn R; Coleman, C Norman; Camphausen, Kevin; Ménard, Cynthia
2006-01-01
Purpose To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost. Materials and methods Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml. Results Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6. Conclusion We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive. PMID:16914054
Perez, C.A.; Stanley, K.; Rubin, P.; Kramer, S.; Brady, L.; Perez-Tamayo, R.; Brown, G.S.; Concannon, J.; Rotman, M.; Seydel, H.G.
1980-06-01
Analysis is presented of a prospective randomized study involving 365 patients with histologically proven unresectable non-oat-cell carcinoma of the lung treated with deffinitive radiotherapy. The patients were radomized to one of four treatment regimens: 4000 rad split course, or 4000, 5000, or 6000-rad continuous courses in five fractions per week. Ninety to 100 patients were accessioned to each group. The one-year survival rate is 50% and the two-year survival rate, 25%. The patients treated with the split course have the lowest survival rate in comparison with the other groups. The complete and partial local regression of tumor was 49% in patients treated with 4000 rad and 55% in the groups treated with 5000 and 6000 rad. For patients who achieved complete regression of the tumor following irradiation, the two-year survival rate is 40%, in contrast to 20% for those with partial regression, and no survivors among the patients with stable or progressive disease. The incidence of intrathoracic recurrence was 33% for patients treated with 6000 rad, 39% for those receiving 5000 rad, and 44 to 49% for those treated with a 4000-rad split or continuous course. At present, the data stongly suggest that patients treated with 5000 or 6000 rad have a better response, tumor control, and survival rate than those receiving lower doses. Patients with high performance status or with tumors in earlier stages have a two-year survival rate of approx. 40%, in comparison with 20% for other patients. The various irradiation regimens have been well tolerated, with complications being slightly higher in the 4000-rad split course group and in the 6000-rad continuous course group. The most frequent complications have been pneumonitis, pulmonary fibrosis, and dyspagia due to transient esophagitis. Further investigation will be necessary before the optimal management of patients with bronchogenic carcinoma by irradiation is established.
McCarthy, Ian D; Nicholls, Ruth; Malham, Shelagh K; Whiteley, Nia M
2016-01-01
For the first time, use of the flooding dose technique using (3)H-Phenylalanine is validated for measuring whole-animal and tissue-specific rates of protein synthesis in the blue mussel Mytilus edulis (61mm shell length; 4.0g fresh body mass). Following injection, the phenylalanine-specific radioactivities in the gill, mantle and whole-animal free pools were elevated within one hour and remained elevated and stable for up to 6h following injection of (3)H-phenylalanine into the posterior adductor muscle. Incorporation of (3)H-phenylalanine into body protein was linear over time following injection and the non-significant intercepts for the regressions suggested incorporation into body protein occurred rapidly after injection. These results validate the technique for measuring rates of protein synthesis in mussels. There were no differences in the calculated rates following 1-6h incubation in gill, mantle or whole-animal and fractional rates of protein synthesis from the combined time course data were 9.5±0.8%d(-1) for the gill, 2.5±0.3%d(-1) for the mantle and 2.6±0.3%d(-1) for the whole-animal, respectively (mean values±SEM). The whole-animal absolute rate of protein synthesis was calculated as 18.9±0.6mg protein day(-1). The use of this technique in measuring one of the major components of maintenance metabolism and growth will provide a valuable and convenient tool in furthering our understanding of the protein metabolism and energetics of this keystone marine invertebrate and its ability to adjust and respond to fluctuations, such as that expected as a result of climate change. Copyright © 2015 Elsevier Inc. All rights reserved.
Chiou, W L; Jeong, H Y; Chung, S M; Wu, T C
2000-02-01
To conduct a retrospective evaluation of using dog as an animal model to study the fraction of oral dose absorbed (F) of 43 drugs in humans and to briefly discuss potential factors that might have contributed to the observed differences in absorption. Mean human and dog absorption data obtained under fasted state of 43 drugs with markedly different physicochemical and pharmacological properties and with mean F values ranging from 0.015 to 1.0 were obtained from the literature. Correlation of F values between humans and dogs was studied. Based on the same references, additional F data for humans and rats were also obtained for 18 drugs. Among the 43 drugs studied, 22 drugs were virtually completely absorbed in both dogs and humans. However, the overall correlation was relatively poor (r2 = 0.5123) as compared to the earlier rat vs. human study on 64 drugs (r2 = 0.975). Several drugs showed much better absorption in dogs than in humans. Marked differences in the nonliner absorption profiles between the two species were found for some drugs. Also, some drugs had much longer Tmax values and prolonged absorption in humans than in dogs that might be theoretically predicted. Data on 18 drugs further support great similarity in F between humans and rats reported earlier from our laboratory. Although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, the present study suggests that one may need to exercise caution in the interpretation of data obtained. Exact reasons for the observed interspecies differences in oral absorption remain to be explored.
Wan, Siu-Hin; Stevens, Susanna R; Borlaug, Barry A; Anstrom, Kevin J; Deswal, Anita; Felker, G Michael; Givertz, Michael M; Bart, Bradley A; Tang, W H Wilson; Redfield, Margaret M; Chen, Horng H
2016-08-01
The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 μg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points. ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P=0.001) and nesiritide (interaction P=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P<0.05 for all). There was no interaction between vasoactive treatment's effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF. In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF. URL: http
Vardeny, Orly; Claggett, Brian; Packer, Milton; Zile, Michael R; Rouleau, Jean; Swedberg, Karl; Teerlink, John R; Desai, Akshay S; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D
2016-10-01
In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001). In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Niewald, Marcus; Holtmann, Henrik; Prokein, Benjamin; Hautmann, Matthias G; Rösler, Hans-Peter; Graeber, Stefan; Dzierma, Yvonne; Ruebe, Christian; Fleckenstein, Jochen
2015-08-19
Our first trial on radiotherapy for painful heel spur published in 2012 comparing the analgesic effect of a standard dose (6 × 1.0 Gy within three weeks) to that of a very low one (6 × 0.1 Gy within three weeks) resulted in a highly significant superiority of the standard dose arm. In the meantime, experimental data have shown that lower single doses in the range of 0.5 - 0.7 Gy might be even more effective than the current standard dose of 1.0 Gy. Therefore, we conducted a second trial comparing the analgesic effect of standard single doses of 1.0 Gy to that of low single doses of 0.5 Gy using uniform total doses of 6 Gy. One hundred twenty-seven patients were randomized to receive radiation therapy either with a total dose of 6.0 Gy applied in 6 fractions of 1.0 Gy twice weekly (standard dose) or with the same total dose applied in 12 fractions of 0.5 Gy three times weekly (experimental dose). In all patients lateral opposing 6MV photon beams were used. The results were measured using Visual analogue scale (VAS), Calcaneodynia score (CS) and SF-12 health survey. The first phase of this trial ended after a three months' follow-up; it will be continued up to 48 weeks. Nine patients had to be excluded after randomization either due to the withdrawal of informed consent to radiotherapy by the patients or radiotherapy with an incorrect dosage. The groups were comparable concerning biographical and disease data. The mean calcaneodynia score (CS) was higher in the experimental group (p = 0.002). After three months' follow-up, we saw a very favorable pain relief in both arms (decline of VAS score: standard arm 42 points, experimental arm 44 points (n.s.), but we did not notice any statistically significant difference between the arms neither concerning the pain parameters nor the quality of life parameters. No relevant acute side effects were recorded. Favorable laboratory results could not be translated into an enhanced pain relief in our patients. This
Miralbell, Raymond; Roberts, Stephen A; Zubizarreta, Eduardo; Hendry, Jolyon H
2012-01-01
There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), α (dose-response slope using very low doses per fraction), and the ratio α/β that characterizes dose-fractionation sensitivity. There was no significant difference between the α/β value for the three risk groups, and the value of α/β for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the α/β value. The overall α/β value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings. Copyright © 2012
Miralbell, Raymond; Roberts, Stephen A.; Zubizarreta, Eduardo; Hendry, Jolyon H.
2012-01-01
Purpose: There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. Methods and Materials: Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), {alpha} (dose-response slope using very low doses per fraction), and the ratio {alpha}/{beta} that characterizes dose-fractionation sensitivity. Results: There was no significant difference between the {alpha}/{beta} value for the three risk groups, and the value of {alpha}/{beta} for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the {alpha}/{beta} value. Conclusions: The overall {alpha}/{beta} value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk
Turco, Laura; Catone, Tiziana; Caloni, Francesca; Di Consiglio, Emma; Testai, Emanuela; Stammati, Annalaura
2011-02-01
Caco-2 cell line is one of the most used in vitro model to study intestinal absorption of compounds at screening level. Several clones have been isolated from Caco-2 cell line and characterized for their activities. Among them, TC7 clone was isolated from a late passage of the parental Caco-2 line and has shown to consist of a more homogeneous population with respect to the most representative functions of the small intestinal enterocytes, with more developed intercellular junctions. On the basis of these characteristics, it was selected within the framework of the EU A-Cute-Tox project to check its suitability to predict intestinal transport. In the present study, drugs, synthetic or natural chemicals have been characterized for their absorption profile in TC7 cells cultivated on semi-permeable filters for 21 days. The absorption experiments have been performed with the highest nontoxic concentration as determined in a preliminary set of cytotoxicity tests. The apparent permeability coefficient (P(app)) has been extrapolated by calculating the passage of the test compound from the donor to the receiver compartment as a time function. The samples have been collected at different time intervals and the concentration of the test compounds analyzed by analytical methods (HPLC, GC, GC/MS). The P(app) obtained with the TC7 clone are comparable to those obtained with the parental cell line. However, some drawbacks related to the experimental system have been highlighted (i.e. low mass balance, adsorption to the plastics), on the basis of which some compounds were excluded from the analysis. In order to check the predictability of the model, a regression analysis has been performed by plotting P(app) values vs. the fraction absorbed in humans (FA, expressed as % of the administered dose). Additional elaborations have highlighted that the specific absorption pathway (passive, active and carrier-mediated) and other factors (i.e. efflux proteins and/or metabolic activity
2014-01-01
; Aspartate aminotransferase, ↓2.2×] origin. Surprisingly, the immunoblot analysis of the same PM resolved by 2D-ELFO indicated that the “active”, morphine-induced pool of Gβ subunits represented just a minor fraction of the total signal of Gβ which was decreased 1.2x only. The dominant signal of Gβ was unchanged. Conclusion Brain cortex of rats exposed to increasing doses of morphine is far from being adapted. Significant up-regulation of proteins functionally related to oxidative stress and apoptosis suggests a major change of energy metabolism resulting in the state of severe brain cell “discomfort” or even death. PMID:24528483
Khvostunov, I K; Kursova, L V; Shepel', N N; Ragulin, Iu A; Sevan'kaev, A V; Gulidov, I A; Glazyrin, D A; Ivanova, I N
2012-01-01
The objective of this study was to investigate in vivo the dose response of radiation induced chromosomal aberrations in human blood lymphocytes of lung cancer patients given non-uniform fractional exposures to high doses of therapeutic 60Co gamma-rays delivered synchronously with polychemotherapy. The chromosome aberration analysis was carried out in peripheral blood lymphocytes of 13 lung cancer patients who manifested II to IV developmental clinical stage. During the course of radiotherapy they received the accumulated tumor dose ranged 47.5 to 70 Gy. The yield ofdicentrics, centric rings and fragments was measured in the blood samples taken before treatment, after the first day and after the complete course of radiotherapy. Based on cytogenetic measurements of 3 patients, the average tumor dose after the first day was estimated to be 2.1 to 3.0 Gy given that the corresponding physical dose was (1.0 Gy + 1.5 Gy). The quotient of the individual dose estimated by the frequency of aberrations to the physical dose after the complete course of radiotherapy was calculated for all 13 patients. The mean quotient was shown to be equal to 93 +/- 9% ranged 50 to 154%.
Lauche, Olivier; Delouya, Guila; Taussky, Daniel; Menard, Cynthia; Béliveau-Nadeau, Dominic; Hervieux, Yannick; Larouche, Renée
2016-01-01
Purpose To validate the feasibility of a single-fraction high-dose-rate brachytherapy (HDRBT) boost for prostate cancer using real-time transrectal ultrasound (TRUS) based planning. Material and methods From August 2012 to September 2015, 126 patients underwent a single-fraction HDRBT boost of 15 Gy using real-time TRUS based planning. External beam radiation therapy (EBRT) (37.5 Gy/15 fractions, 44 Gy/22 fractions, or 45 Gy/25 fractions) was performed before (31%) or after (69%) HDRBT boost. Genito-urinary (GU) and gastro-intestinal (GI) toxicity were assessed 4 and 12 months after the end of combined treatment using the international prostate symptom score scale (IPSS) and the common terminology criteria for adverse events (CTCAE) v3.0. Results All dose-planning objectives were achieved in 90% of patients. Prostate D90 ≥ 105% and ≤ 115% was achieved in 99% of patients, prostate V150 ≤ 40% in 99%, prostate V200 < 11% in 96%, urethra D10 < 120% for 99%, urethra V125 = 0% in 100%, and rectal V75 < 1 cc in 93% of patients. Median IPSS score was 4 at baseline and did not change at 4 and 12 months after combined treatment. No patients developed ≥ grade 2 GI toxicity. With a median follow-up of 10 months, only two patients experienced biochemical failure. Among patients who didn't receive ADT, cumulative percentage of patients with PSA ≤ 1 ng/ml at 4 and 18 months was respectively 23% and 66%. Conclusions Single-fraction HDRBT boost of 15 Gy using real-time TRUS based planning achieves consistently high dosimetry quality. In combination with EBRT, toxicity outcomes appear promising. A longer follow-up is needed to assess long-term outcome and toxicities. PMID:27257413
2013-01-01
Background Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Methods Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. Results A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur
Liu, Yue-E; Lin, Qiang; Meng, Fan-Jie; Chen, Xue-Ji; Ren, Xiao-Cang; Cao, Bin; Wang, Na; Zong, Jie; Peng, Yu; Ku, Ya-Jun; Chen, Yan
2013-08-11
Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur. High-dose accelerated
Bäck, Tom; Chouin, Nicolas; Lindegren, Sture; Kahu, Helena; Jensen, Holger; Albertsson, Per; Palm, Stig
2017-04-01
The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm(3), NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with (211)At-MX35-F(ab')2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with (211)At-MX35-F(ab')2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for
Sau, Sourav; Sau, Saikat; Dutta, Premnath; Gayen, Ganesh Chandra; Banerjee, Sanatan; Basu, Avijit
2014-01-01
Introduction: To investigate the effect of different hypo fractionated thoracic radiotherapy schedules in relation to thoracic pain relief, overall survival and post radiotherapy HRQOL in metastatic NSCLC. Material and methods: Stage IV NSCLC and had intra-thoracic symptoms, included in the study. Patients were randomly assigned to three treatments arms. (i) 17 Gy in 2 fractions in one week (ii) 20 Gy in five fractions in one week. (iii) 30 Gy in 10 fractions in two weeks. BPI module was used to assess pain score before and after the thoracic radiotherapy. Functional assessment of cancer therapy-G (FACT-G) used to investigate changes in HRQOL. Clinicians’ assessment of symptom improvement were recorded at 2nd, 6th and 12th weeks after completion of TRT. Results: Pain relief, HRQOL and OS were equivalent in all the three arms. The median OS were 6 months, 5 months, 6 months in arm A, B and arm C, respectively. Conclusion: Protracted palliative thoracic radiotherapy renders no added advantage of relief of symptoms, HRQOL and overall survival compared to short course palliative TRT in metastatic NSCLC. PMID:25378842
2012-01-01
Background The OneDosePlusTM system, based on MOSFET solid-state radiation detectors and a handheld dosimetry reader, has been used to evaluate intra-fraction movements of patients with breast and prostate cancer. Methods An Action Threshold (AT), defined as the maximum acceptable discrepancy between measured dose and dose calculated with the Treatment Planning System (TPS) (for each field) has been determined from phantom data. To investigate the sensitivity of the system to direction of the patient movements, fixed displacements have been simulated in phantom. The AT has been used as an indicator to establish if patients move during a treatment session, after having verified the set-up with 2D and/or 3D images. Phantom tests have been performed matching different linear accelerators and two TPSs (TPS1 and TPS2). Results The ATs have been found to be very similar (5.0% for TPS1 and 4.5% for TPS2). From statistical data analysis, the system has been found not sensitive enough to reveal displacements smaller than 1 cm (within two standard deviations). The ATs applied to in vivo treatments showed that among the twenty five patients treated for breast cancer, only four of them moved during each measurement session. Splitting data into medial and lateral field, two patients have been found to move during all these sessions; the others, instead, moved only in the second part of the treatment. Patients with prostate cancer have behaved better than patients with breast cancer. Only two out of twenty five moved in each measurement session. Conclusions The method described in the paper, easily implemented in the clinical practice, combines all the advantages of in vivo procedures using the OneDosePlusTM system with the possibility of detecting intra-fraction patient movements. PMID:22716260
Moreno-Cantú, J J; Thompson, C J; Zatorre, R J
1998-12-01
We evaluated the performance of the ECAT EXACT HR+ 3-D whole-body positron emission tomography (PET) scanner when employed to measure brain function using H2(15)O bolus activation protocols that are completed in single same-day data acquisition sessions. Using vibrotactile and auditory stimuli as independent activation tasks, we studied the scanner performance under different imaging conditions in five healthy volunteers. Cerebral blood flow images were acquired from each volunteer using H2(15)O bolus injections of activity varying from 5-20 mCi. One-session dose-fractionation strategies were analyzed for rCBF, standard activity-concentration, switched, and cold-bolus/switched protocols. Performance characteristics. The scanner dead time grew linearly with injected dose from 10% to 25%. Random events varied from 30% to 50% of the detected events. Random and scattered events were corrected adequately at all doses. Estimated noise-effective-count curves plateau at about 10 mCi. One-session 12-injection bolus PET activation protocols. Using an acquisition protocol that accounts for the scanner performance and the practical aspects of imaging volunteers and neurological patients in a single same-day session, we assessed the correlation between the significance of activation foci and the dose/injection used. The one-session protocol employs 12 bolus injections/subject. We present evidence suggesting that when an rCBF protocol is used, image noise is reduced significantly when the activity injected increases from 5 to 10 mCi. Increasing the dose from 10 to 15 or 20 mCi yielded further but smaller reductions. Our observations also suggest that image noise will be strongly reduced if a 20-mCi dose/injection is used when data are collected using protocols that employ long acquisition times such as a switched or a cold-bolus/switched protocol.
Reiss, Kim A; Herman, Joseph M; Armstrong, Deborah; Zahurak, Marianna; Fyles, Anthony; Brade, Anthony; Milosevic, Michael; Dawson, Laura A; Scardina, Angela; Fischer, Patricia; Hacker-Prietz, Amy; Kinders, Robert J; Wang, Lihua; Chen, Alice; Temkin, Sarah; Horiba, Naomi; Stayner, Lee-Anne; Siu, Lillian L; Azad, Nilofer S
2017-03-01
The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient. Copyright Â© 2017 Elsevier Inc. All rights reserved.
Steffen, Ingo G.; Wust, Peter; Ruehl, Ricarda
2010-07-15
Purpose: To determine the additional value of fluorodeoxyglucose-positron emission tomography (PET) for clinical target volume definition in the planning of computed tomography (CT)-guided interstitial brachytherapy for liver metastases. Patients and Methods: A total of 19 patients with liver metastases from colorectal cancer treated in 25 sessions were included in the present study. All patients had undergone fluorodeoxyglucose-PET for patient evaluation before interstitial CT-guided brachytherapy. A contrast-enhanced CT scan of the upper abdomen was obtained for radiation planning. The clinical target volume (CTV) was defined by a radiation oncologist and radiologist. After registration of the CT scan with the PET data set, the target volume was defined again using the fusion images. Results: PET revealed one additional liver lesion that was not visible on CT. The median CT-CTV (defined using CT and magnetic resonance imaging) was 68 cm{sup 3} (range 4-260). The PET/CT-CTV (median, 78 cm{sup 3}; range, 4-273) was significantly larger, with a median gain of 24.5% (interquartile range, 2.1-71.5%; p = .022). An increased CTV was observed in 15 cases and a decrease in 6; in 4 cases, the CT-CTV and PET/CT-CTV were equal. Incomplete dose coverage of PET/CT-CTVs was indicative of early local progression (p = .004); however, CT-based radiation plans did not show significant differences in the local control rates when stratified by dose coverage. Conclusion: Retrospective implementation of fluorodeoxyglucose-PET for CTV specification for CT-guided brachytherapy for colorectal liver metastases revealed a significant change in the CTVs. Additional PET-positive tumor regions with incomplete dose coverage could explain unexpected early local progression.
Cho, Jaeho; Kodym, Reinhard; Seliounine, Serguei
2010-07-01
Purpose: To investigate the underlying biology associated with stereotactic body radiotherapy (SBRT), both in vivo models and image-guided, highly focal irradiation systems are necessary. Here, we describe such an irradiation system and use it to examine normal tissue toxicity in a small-animal model at lung volumes similar to those associated with human therapy. Methods and Materials: High-dose radiation was delivered to a small volume of the left lung of C3H/HeJCr mice using a small-animal stereotactic irradiator. The irradiator has a collimation mechanism to produce focal radiation beams, an imaging subsystem consisting of a fluorescent screen coupled to a charge-coupled device camera, and a manual positioning stage. Histopathologic examination and micro-CT were used to evaluate the radiation response. Results: Focal obliteration of the alveoli by fibrous connective tissue, hyperplasia of the bronchiolar epithelium, and presence of a small number of inflammatory cells are the main reactions to low-volume/high-dose irradiation of the mouse lung. The tissue response suggested a radiation dose threshold for early phase fibrosis lying between 40 and 100 Gy. The irradiation system satisfied our requirements of high-dose-rate, small beam diameter, and precise localization and verification. Conclusions: We have established an experimental model and image-guided animal irradiation system for the study of high dose per fraction irradiations such as those used with SBRT at volumes analogous to those used in human beings. It will also allow the targeting of specific anatomical structures of the thorax or ultimately, orthotopic tumors of the lung.
Cho, Jaeho; Kodym, Reinhard; Seliounine, Serguei; Richardson, James A; Solberg, Timothy D; Story, Michael D
2010-07-01
To investigate the underlying biology associated with stereotactic body radiotherapy (SBRT), both in vivo models and image-guided, highly focal irradiation systems are necessary. Here, we describe such an irradiation system and use it to examine normal tissue toxicity in a small-animal model at lung volumes similar to those associated with human therapy. High-dose radiation was delivered to a small volume of the left lung of C3H/HeJCr mice using a small-animal stereotactic irradiator. The irradiator has a collimation mechanism to produce focal radiation beams, an imaging subsystem consisting of a fluorescent screen coupled to a charge-coupled device camera, and a manual positioning stage. Histopathologic examination and micro-CT were used to evaluate the radiation response. Focal obliteration of the alveoli by fibrous connective tissue, hyperplasia of the bronchiolar epithelium, and presence of a small number of inflammatory cells are the main reactions to low-volume/high-dose irradiation of the mouse lung. The tissue response suggested a radiation dose threshold for early phase fibrosis lying between 40 and 100 Gy. The irradiation system satisfied our requirements of high-dose-rate, small beam diameter, and precise localization and verification. We have established an experimental model and image-guided animal irradiation system for the study of high dose per fraction irradiations such as those used with SBRT at volumes analogous to those used in human beings. It will also allow the targeting of specific anatomical structures of the thorax or ultimately, orthotopic tumors of the lung. (c) 2010 Elsevier Inc. All rights reserved.
NASA Astrophysics Data System (ADS)
Tapiero, Charles S.; Vallois, Pierre
2016-11-01
The premise of this paper is that a fractional probability distribution is based on fractional operators and the fractional (Hurst) index used that alters the classical setting of random variables. For example, a random variable defined by its density function might not have a fractional density function defined in its conventional sense. Practically, it implies that a distribution's granularity defined by a fractional kernel may have properties that differ due to the fractional index used and the fractional calculus applied to define it. The purpose of this paper is to consider an application of fractional calculus to define the fractional density function of a random variable. In addition, we provide and prove a number of results, defining the functional forms of these distributions as well as their existence. In particular, we define fractional probability distributions for increasing and decreasing functions that are right continuous. Examples are used to motivate the usefulness of a statistical approach to fractional calculus and its application to economic and financial problems. In conclusion, this paper is a preliminary attempt to construct statistical fractional models. Due to the breadth and the extent of such problems, this paper may be considered as an initial attempt to do so.
Stemkens, B; Glitzner, M; Kontaxis, C; Prins, F; Crijns, SPM; Kerkmeijer, L; Lagendijk, J; Berg, CAT van den; Tijssen, RHN; Denis de Senneville, B
2016-06-15
Purpose: To assess the dose deposition in simulated single-fraction MR-Linac treatments of renal cell carcinoma, when inter-cycle respiratory motion variation is taken into account using online MRI. Methods: Three motion characterization methods, with increasing complexity, were compared to evaluate the effect of inter-cycle motion variation and drifts on the accumulated dose for an SBRT kidney MR-Linac treatment: 1) STATIC, in which static anatomy was assumed, 2) AVG-RESP, in which 4D-MRI phase-volumes were time-weighted, based on the respiratory phase and 3) PCA, in which 3D volumes were generated using a PCA-model, enabling the detection of inter-cycle variations and drifts. An experimental ITV-based kidney treatment was simulated in a 1.5T magnetic field on three volunteer datasets. For each volunteer a retrospectively sorted 4D-MRI (ten respiratory phases) and fast 2D cine-MR images (temporal resolution = 476ms) were acquired to simulate MR-imaging during radiation. For each method, the high spatio-temporal resolution 3D volumes were non-rigidly registered to obtain deformation vector fields (DVFs). Using the DVFs, pseudo-CTs (generated from the 4D-MRI) were deformed and the dose was accumulated for the entire treatment. The accuracies of all methods were independently determined using an additional, orthogonal 2D-MRI slice. Results: Motion was most accurately estimated using the PCA method, which correctly estimated drifts and inter-cycle variations (RMSE=3.2, 2.2, 1.1mm on average for STATIC, AVG-RESP and PCA, compared to the 2DMRI slice). Dose-volume parameters on the ITV showed moderate changes (D99=35.2, 32.5, 33.8Gy for STATIC, AVG-RESP and PCA). AVG-RESP showed distinct hot/cold spots outside the ITV margin, which were more distributed for the PCA scenario, since inter-cycle variations were not modeled by the AVG-RESP method. Conclusion: Dose differences were observed when inter-cycle variations were taken into account. The increased inter
Morton, Gerard C.; Loblaw, D. Andrew; Sankreacha, Raxa
2010-07-01
Purpose: To determine the short- and medium-term effects of a single high-dose-rate brachytherapy fraction of 15Gy and hypofractionated external beam radiation therapy for prostate cancer. Methods and Materials: Eligible patients had localized prostate cancer with a Gleason score of 7 and a prostate-specific antigen (PSA) concentration of <20 ng/ml or a Gleason score of 6 with a PSA concentration of 10 to 20 ng/ml. Patients received high-dose-rate brachytherapy as a single 15-Gy dose, followed by external beam radiation therapy at 37.5Gy in 15 fractions, and were followed prospectively for toxicity (using Common Terminology Criteria for Adverse Events version 3.0), urinary symptoms (using the International Prostate Symptom Score [IPSS]), erectile function (with the International Index of Erectile Function [IIEF]), and health-related quality of life (with the Expanded Prostate Cancer Index Composite [EPIC]). Clinical examinations and PSA measurements were performed at every visit, and prostate biopsies were repeated at 2 years. The trial accrued 125 patients, with a median follow-up of 1.14 years. Results: Acute grade 2 and 3 genitourinary toxicity occurred in 62% and 1.6% of patients, respectively, and acute grade 2 gastrointestinal toxicity occurred in 6.5% of patients. No grade 3 late toxicity has occurred: 47% of patients had grade 2 genitourinary and 10% of patients had grade 2 gastrointestinal toxicity. Median IPSSs rose from 5 at baseline to 12 at 1 month and returned to 7 at 3 months. Of the total number of patients who were initially potent (IIEF, >21), 8% of patients developed mild to moderate dysfunction, and 27% of patients developed severe erectile dysfunction. Baseline EPIC bowel, urinary, and sexual bother scores decreased by 9, 7, and 19 points, respectively, at 1 year. No patient has experienced biochemical failure, and 16 of the first 17 biopsy results showed no malignancy. Conclusions: Treatment is well tolerated in the short and medium term, with
Takeda, Atsuya; Sanuki, Naoko; Kunieda, Etsuo Ohashi, Toshio; Oku, Yohei; Takeda, Toshiaki; Shigematsu, Naoyuki; Kubo, Atsushi
2009-02-01
Purpose: To retrospectively analyze the clinical outcomes of stereotactic body radiotherapy (SBRT) for patients with Stages 1A and 1B non-small-cell lung cancer. Methods and Materials: We reviewed the records of patients with non-small-cell lung cancer treated with curative intent between Dec 2001 and May 2007. All patients had histopathologically or cytologically confirmed disease, increased levels of tumor markers, and/or positive findings on fluorodeoxyglucose positron emission tomography. Staging studies identified their disease as Stage 1A or 1B. Performance status was 2 or less according to World Health Organization guidelines in all cases. The prescribed dose of 50 Gy total in five fractions, calculated by using a superposition algorithm, was defined for the periphery of the planning target volume. Results: One hundred twenty-one patients underwent SBRT during the study period, and 63 were eligible for this analysis. Thirty-eight patients had Stage 1A (T1N0M0) and 25 had Stage 1B (T2N0M0). Forty-nine patients were not appropriate candidates for surgery because of chronic pulmonary disease. Median follow-up of these 49 patients was 31 months (range, 10-72 months). The 3-year local control, disease-free, and overall survival rates in patients with Stages 1A and 1B were 93% and 96% (p = 0.86), 76% and 77% (p = 0.83), and 90% and 63% (p = 0.09), respectively. No acute toxicity was observed. Grade 2 or higher radiation pneumonitis was experienced by 3 patients, and 1 of them had fatal bacterial pneumonia. Conclusions: The SBRT at 50 Gy total in five fractions to the periphery of the planning target volume calculated by using a superposition algorithm is feasible. High local control rates were achieved for both T2 and T1 tumors.
Brand, M. J.; Callejas, R. J.
1985-10-08
Process and apparatus are provided for the recovery of low, medium and high boiling components from feed streams containing same wherein reboiler fouling, gumming and the like are minimized, via the control of fractionator reboiler temperatures.
Phillips, Philip
2010-12-01
Precisely what are the electrons in a high-temperature superconductor doing before they superconduct? Strong electronic correlations may give rise to composite rather than fractionalized excitations, as is typical in other strongly coupled systems such as quark matter.
Understanding Multiplication of Fractions.
ERIC Educational Resources Information Center
Sweetland, Robert D.
1984-01-01
Discussed the use of Cuisenaire rods in teaching the multiplication of fractions. Considers whole number times proper fraction, proper fraction multiplied by proper fraction, mixed number times proper fraction, and mixed fraction multiplied by mixed fractions. (JN)
ERIC Educational Resources Information Center
Bhattacharyya, Sonalee; Namakshi, Nama; Zunker, Christina; Warshauer, Hiroko K.; Warshauer, Max
2016-01-01
Making math more engaging for students is a challenge that every teacher faces on a daily basis. These authors write that they are constantly searching for rich problem-solving tasks that cover the necessary content, develop critical-thinking skills, and engage student interest. The Mystery Fraction activity provided here focuses on a key number…
ERIC Educational Resources Information Center
Bhattacharyya, Sonalee; Namakshi, Nama; Zunker, Christina; Warshauer, Hiroko K.; Warshauer, Max
2016-01-01
Making math more engaging for students is a challenge that every teacher faces on a daily basis. These authors write that they are constantly searching for rich problem-solving tasks that cover the necessary content, develop critical-thinking skills, and engage student interest. The Mystery Fraction activity provided here focuses on a key number…
1981-12-15
13 3. Solvent Fractionation Experiments .................................... 15 4. Fourier Transform Infrared Spectra for A240 Petrolem Pitch AG 12...34 and Mesophase Pitch AG 164B ............................... 21 5. Fourier Transform Infrared Spectra ................................... 23 6...compared by Fourier transform infrared (FTIR) analysis using a Digilab Model FTS 14 spectrophotometer (Rockwell International, Anaheim, California
Fraction Reduction through Continued Fractions
ERIC Educational Resources Information Center
Carley, Holly
2011-01-01
This article presents a method of reducing fractions without factoring. The ideas presented may be useful as a project for motivated students in an undergraduate number theory course. The discussion is related to the Euclidean Algorithm and its variations may lead to projects or early examples involving efficiency of an algorithm.
Fraction Reduction through Continued Fractions
ERIC Educational Resources Information Center
Carley, Holly
2011-01-01
This article presents a method of reducing fractions without factoring. The ideas presented may be useful as a project for motivated students in an undergraduate number theory course. The discussion is related to the Euclidean Algorithm and its variations may lead to projects or early examples involving efficiency of an algorithm.
NASA Astrophysics Data System (ADS)
Bell, Peter M.
A rash of new controversy has emerged around the subject of mass-independent isotope fractionation effects, particularly in the case of the oxygen isotopes. To be sure, the controversy has been around for awhile, but it has been given new impetus by the results of a recent study by Mark H. Thiemens and John E. Heidenreich III of the University of California, San Diego (Science, March 4, 1983).Gustav Arrhenius has been trying to convince the planetary science community that chemical effects in isotope fractionation processes could explain observations in meteorites that appear to be outside of the traditionally understood mass-dependent fractionations (G. Arrhenius, J . L. McCrumb, and N. F. Friedman, Astrophys. Space Sci, 65, 297, 1974). Robert Clayton had made the basic observations of oxygen in carbonaceous chondrites that the slope of the δ17 versus δ18 line was 1 instead of the slope of ½ characteristic of terrestrial rocks and lunar samples (Ann. Rev. Nucl. Part. Sci., 28, 501, 1978). The mass-independent effects were ascribed to the apparent contribution of an ancient presolar system component of O16.
Maximizing Tumor Immunity With Fractionated Radiation
Schaue, Doerthe; Ratikan, Josephine A.; Iwamoto, Keisuke S.; McBride, William H.
2012-07-15
Purpose: Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Methods and Materials: Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-{gamma} enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4{sup +}CD25{sup hi}Foxp3{sup +} T cells. Results: After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Conclusions: Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy.
Radiation Dose-Volume Effects of Optic Nerves and Chiasm
Mayo, Charles; Martel, Mary K.; Marks, Lawrence B.; Flickinger, John; Nam, Jiho; Kirkpatrick, John
2010-03-01
Publications relating radiation toxicity of the optic nerves and chiasm to quantitative dose and dose-volume measures were reviewed. Few studies have adequate data for dose-volume outcome modeling. The risk of toxicity increased markedly at doses >60 Gy at {approx}1.8 Gy/fraction and at >12 Gy for single-fraction radiosurgery. The evidence is strong that radiation tolerance is increased with a reduction in the dose per fraction. Models of threshold tolerance were examined.
A dynamic programming approach to adaptive fractionation
NASA Astrophysics Data System (ADS)
Ramakrishnan, Jagdish; Craft, David; Bortfeld, Thomas; Tsitsiklis, John N.
2012-03-01
We conduct a theoretical study of various solution methods for the adaptive fractionation problem. The two messages of this paper are as follows: (i) dynamic programming (DP) is a useful framework for adaptive radiation therapy, particularly adaptive fractionation, because it allows us to assess how close to optimal different methods are, and (ii) heuristic methods proposed in this paper are near-optimal, and therefore, can be used to evaluate the best possible benefit of using an adaptive fraction size. The essence of adaptive fractionation is to increase the fraction size when the tumor and organ-at-risk (OAR) are far apart (a ‘favorable’ anatomy) and to decrease the fraction size when they are close together. Given that a fixed prescribed dose must be delivered to the tumor over the course of the treatment, such an approach results in a lower cumulative dose to the OAR when compared to that resulting from standard fractionation. We first establish a benchmark by using the DP algorithm to solve the problem exactly. In this case, we characterize the structure of an optimal policy, which provides guidance for our choice of heuristics. We develop two intuitive, numerically near-optimal heuristic policies, which could be used for more complex, high-dimensional problems. Furthermore, one of the heuristics requires only a statistic of the motion probability distribution, making it a reasonable method for use in a realistic setting. Numerically, we find that the amount of decrease in dose to the OAR can vary significantly (5-85%) depending on the amount of motion in the anatomy, the number of fractions and the range of fraction sizes allowed. In general, the decrease in dose to the OAR is more pronounced when: (i) we have a high probability of large tumor-OAR distances, (ii) we use many fractions (as in a hyper-fractionated setting) and (iii) we allow large daily fraction size deviations.
Commercial SNF Accident Release Fractions
J. Schulz
2004-11-05
The purpose of this analysis is to specify and document the total and respirable fractions for radioactive materials that could be potentially released from an accident at the repository involving commercial spent nuclear fuel (SNF) in a dry environment. The total and respirable release fractions are used to support the preclosure licensing basis for the repository. The total release fraction is defined as the fraction of total commercial SNF assembly inventory, typically expressed as an activity inventory (e.g., curies), of a given radionuclide that is released to the environment from a waste form. Radionuclides are released from the inside of breached fuel rods (or pins) and from the detachment of radioactive material (crud) from the outside surfaces of fuel rods and other components of fuel assemblies. The total release fraction accounts for several mechanisms that tend to retain, retard, or diminish the amount of radionuclides that are available for transport to dose receptors or otherwise can be shown to reduce exposure of receptors to radiological releases. The total release fraction includes a fraction of airborne material that is respirable and could result in inhalation doses; this subset of the total release fraction is referred to as the respirable release fraction. Accidents may involve waste forms characterized as: (1) bare unconfined intact fuel assemblies, (2) confined intact fuel assemblies, or (3) canistered failed commercial SNF. Confined intact commercial SNF assemblies at the repository are contained in shipping casks, canisters, or waste packages. Four categories of failed commercial SNF are identified: (1) mechanically and cladding-penetration damaged commercial SNF, (2) consolidated/reconstituted assemblies, (3) fuel rods, pieces, and debris, and (4) nonfuel components. It is assumed that failed commercial SNF is placed into waste packages with a mesh screen at each end (CRWMS M&O 1999). In contrast to bare unconfined fuel assemblies, the
Calculation of effective dose.
McCollough, C H; Schueler, B A
2000-05-01
The concept of "effective dose" was introduced in 1975 to provide a mechanism for assessing the radiation detriment from partial body irradiations in terms of data derived from whole body irradiations. The effective dose is the mean absorbed dose from a uniform whole-body irradiation that results in the same total radiation detriment as from the nonuniform, partial-body irradiation in question. The effective dose is calculated as the weighted average of the mean absorbed dose to the various body organs and tissues, where the weighting factor is the radiation detriment for a given organ (from a whole-body irradiation) as a fraction of the total radiation detriment. In this review, effective dose equivalent and effective dose, as established by the International Commission on Radiological Protection in 1977 and 1990, respectively, are defined and various methods of calculating these quantities are presented for radionuclides, radiography, fluoroscopy, computed tomography and mammography. In order to calculate either quantity, it is first necessary to estimate the radiation dose to individual organs. One common method of determining organ doses is through Monte Carlo simulations of photon interactions within a simplified mathematical model of the human body. Several groups have performed these calculations and published their results in the form of data tables of organ dose per unit activity or exposure. These data tables are specified according to particular examination parameters, such as radiopharmaceutical, x-ray projection, x-ray beam energy spectra or patient size. Sources of these organ dose conversion coefficients are presented and differences between them are examined. The estimates of effective dose equivalent or effective dose calculated using these data, although not intended to describe the dose to an individual, can be used as a relative measure of stochastic radiation detriment. The calculated values, in units of sievert (or rem), indicate the amount of
Howe, G R; McLaughlin, J
1996-06-01
The relationship between exposure to low-linear energy transfer ionizing radiation and subsequent breast cancer mortality risk is reported based on a further 7 years of follow-up in the Canadian fluoroscopy study. Amongst 31,917 women first treated for tuberculosis in a Canadian institution between 1930 and 1952, a total of 688 breast cancer deaths were observed between 1950 and 1987. There is a strong linear trend of increasing risk with increasing dose (P < 0.0001), with the excess relative risk per sievert decreasing with age at exposure (P = 0.0003). The excess relative risk is approximately constant between 5 and 39 years after exposure, with a suggestion of a decrease between 40 and 57 years after exposure, though this could be a chance effect (P = 0.22). Combined analyses of the Canadian fluoroscopy data and the data for the atomic bomb survivors with respect to breast cancer mortality are also reported. In general the two studies are reasonably consistent, the only distinct difference being the much greater excess relative risk per sievert amongst women exposed to very high doses in the province of Nova Scotia (P, heterogeneity <0.0001). Based on the combined data sets a simple relative risk (RR) model for the effect of a dose of D sieverts at age A years is developed: RR(D) = 1.0 + 0.52D exp[-0.10(A-15)]. This model fits the combined data well, and is used to predict excess lifetime risks of breast cancer mortality after radiation exposure from routine annual mammography.
Fractional vector calculus and fractional Maxwell's equations
Tarasov, Vasily E.
2008-11-15
The theory of derivatives and integrals of non-integer order goes back to Leibniz, Liouville, Grunwald, Letnikov and Riemann. The history of fractional vector calculus (FVC) has only 10 years. The main approaches to formulate a FVC, which are used in the physics during the past few years, will be briefly described in this paper. We solve some problems of consistent formulations of FVC by using a fractional generalization of the Fundamental Theorem of Calculus. We define the differential and integral vector operations. The fractional Green's, Stokes' and Gauss's theorems are formulated. The proofs of these theorems are realized for simplest regions. A fractional generalization of exterior differential calculus of differential forms is discussed. Fractional nonlocal Maxwell's equations and the corresponding fractional wave equations are considered.
Functional fractionation of platelets.
Haver, V M; Gear, A R
1981-02-01
Studies of platelet populations suggest that they are heterogeneous in size, age, and metabolic parameters. In an attempt to correlate these parameters with efficiency of aggregation, a new technique, functional fractionation, was developed. Platelet populations are separated by their differential reactivity to aggregating agents. For example, low doses of ADP (0.1 to 0.7 microM) are added to stirred PRP, after which gentle centrifugation is used to remove aggregates from single unreacted platelets. The loose aggregates can be readily dispersed for comparison of the physical or biochemical properties of the reacted versus unreacted platelets. It was found that reactive platelets were larger (6.5 micrometer3) than unreacted platelets (5.51 micrometer3). No significant difference in density existed between the two populations, and no release of [14C]serotonin from prelabeled platelets occurred during functional fractionation. Scanning and transmission electron microscopy confirmed the size difference and revealed that in both populations platelets were structurally intact with a normal discoid shape and no significant difference in organelle content. Human platelets most reactive to ADP were also enriched in glycogen (3.6-fold), ATP (1.6-fold), and ADP (twofold), compared with less reactive cells. These "reactive" cells took up more 51[Cr] and contained 1.9 times more surface sialic acid. In an in vivo aging experiment, rats were injected with 75[Se]methionine. Shortly after labeling (1 day), the most reactive platelets possessed the highest amount of 75[Se]. These results reveal that functionally active platelets, which are also larger, are more active metabolically than less reactive platelets, possess a higher negative surface charge, and may be a younger population.
The radiosurgery fractionation quandary: single fraction or hypofractionation?
Kirkpatrick, John P; Soltys, Scott G; Lo, Simon S; Beal, Kathryn; Shrieve, Dennis C; Brown, Paul D
2017-04-01
Stereotactic radiosurgery (SRS), typically administered in a single session, is widely employed to safely, efficiently, and effectively treat small intracranial lesions. However, for large lesions or those in close proximity to critical structures, it can be difficult to obtain an acceptable balance of tumor control while avoiding damage to normal tissue when single-fraction SRS is utilized. Treating a lesion in 2 to 5 fractions of SRS (termed "hypofractionated SRS" [HF-SRS]) potentially provides the ability to treat a lesion with a total dose of radiation that provides both adequate tumor control and acceptable toxicity. Indeed, studies of HF-SRS in large brain metastases, vestibular schwannomas, meningiomas, and gliomas suggest that a superior balance of tumor control and toxicity is observed compared with single-fraction SRS. Nonetheless, a great deal of effort remains to understand radiobiologic mechanisms for HF-SRS driving the dose-volume response relationship for tumors and normal tissues and to utilize this fundamental knowledge and the results of clinic studies to optimize HF-SRS. In particular, the application of HF-SRS in the setting of immunomodulatory cancer therapies offers special challenges and opportunities.
Initialized Fractional Calculus
NASA Technical Reports Server (NTRS)
Lorenzo, Carl F.; Hartley, Tom T.
2000-01-01
This paper demonstrates the need for a nonconstant initialization for the fractional calculus and establishes a basic definition set for the initialized fractional differintegral. This definition set allows the formalization of an initialized fractional calculus. Two basis calculi are considered; the Riemann-Liouville and the Grunwald fractional calculi. Two forms of initialization, terminal and side are developed.
Fractional kinetics in multi-compartmental systems.
Dokoumetzidis, Aristides; Magin, Richard; Macheras, Panos
2010-10-01
Fractional calculus, the branch of calculus dealing with derivatives of non-integer order (e.g., the half-derivative) allows the formulation of fractional differential equations (FDEs), which have recently been applied to pharmacokinetics (PK) for one-compartment models. In this work we extend that theory to multi-compartmental models. Unlike systems defined by a single ordinary differential equation (ODE), considering fractional multi-compartmental models is not as simple as changing the order of the ordinary derivatives of the left-hand side of the ODEs to fractional orders. The latter may produce inconsistent systems which violate mass balance. We present a rationale for fractionalization of ODEs, which produces consistent systems and allows processes of different fractional orders in the same system. We also apply a method of solving such systems based on a numerical inverse Laplace transform algorithm, which we demonstrate that is consistent with analytical solutions when these are available. As examples of our approach, we consider two cases of a basic two-compartment PK model with a single IV dose and multiple oral dosing, where the transfer from the peripheral to the central compartment is of fractional order α < 1, accounting for anomalous kinetics and deep tissue trapping, while all other processes are of the usual order 1. Simulations with the studied systems are performed using the numerical inverse Laplace transform method. It is shown that the presence of a transfer rate of fractional order produces a non-exponential terminal phase, while multiple dose and constant infusion systems never reach steady state and drug accumulation carries on indefinitely. The IV fractional system is also fitted to PK data and parameter values are estimated. In conclusion, our approach allows the formulation of systems of FDEs, mixing different fractional orders, in a consistent manner and also provides a method for the numerical solution of these systems.
Sabzikar, Farzad; Meerschaert, Mark M.; Chen, Jinghua
2015-07-15
Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a tempered fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered fractional difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series.
MEERSCHAERT, MARK M.; SABZIKAR, FARZAD; CHEN, JINGHUA
2014-01-01
Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a tempered fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series. PMID:26085690
Fraction Sense: Foundational Understandings.
Fennell, Francis Skip; Karp, Karen
2016-08-09
The intent of this commentary is to identify elements of fraction sense and note how the research studies provided in this special issue, in related but somewhat different ways, validate the importance of such understandings. Proficiency with fractions serves as a prerequisite for student success in higher level mathematics, as well as serving as a gateway to many occupations and varied contexts beyond the mathematics classroom. Fraction sense is developed through instructional opportunities involving fraction equivalence and magnitude, comparing and ordering fractions, using fraction benchmarks, and computational estimation. Such foundations are then extended to operations involving fractions and decimals and applications involving proportional reasoning. These components of fraction sense are all addressed in the studies provided in this issue, with particular consideration devoted to the significant importance of the use of the number line as a central representational tool for conceptually understanding fraction magnitude. © Hammill Institute on Disabilities 2016.
Multiple anatomy optimization of accumulated dose
Watkins, W. Tyler Siebers, Jeffrey V.; Moore, Joseph A.; Gordon, James; Hugo, Geoffrey D.
2014-11-01
Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dose variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.
FRACTIONAL INTEGRATION TOOLBOX.
Marinov, Toma M; Ramirez, Nelson; Santamaria, Fidel
2013-09-01
The problems formulated in the fractional calculus framework often require numerical fractional integration/differentiation of large data sets. Several existing fractional control toolboxes are capable of performing fractional calculus operations, however, none of them can efficiently perform numerical integration on multiple large data sequences. We developed a Fractional Integration Toolbox (FIT), which efficiently performs fractional numerical integration/differentiation of the Riemann-Liouville type on large data sequences. The toolbox allows parallelization and is designed to be deployed on both CPU and GPU platforms.
NASA Astrophysics Data System (ADS)
Dewi, D. A. K.; Suryadi, D.; Suratno, T.; Mulyana, E.; Kurniawan, H.
2017-02-01
Introducing fractions is identical to divide an object. Suppose we divide the apple into two parts. One divided into two parts, the question arises whether one part can be called a half or not. Based on this activity, how can students give meaning to fractions. This study aims at designing a different fractions lesson by applying Didactical Design Research. In doing so, we undertook several research phases: 1) thinking what is fractions and why students should learn this concept; 2) designing didactical situation based on identified learning obstacles; and 3) reflecting retrospectively on the lesson design and its implementation as to redesign the fractions lesson. Our analysis revealed that most students held epistemological obstacles in giving meaning of fractions because they only know fractions as numbers that have numerator and denominator. By positioning ourselves as students, we discuss the ideal design to help students in constructing the meaning of fractions.
Impact of variable RBE on proton fractionation
Dasu, Alexandru; Toma-Dasu, Iuliana
2013-01-15
Purpose: To explore the impact of variable proton relative biological effectiveness (RBE) on dose fractionation for clinically relevant situations. A generic RBE = 1.1 is generally used for isoeffect calculations, while experimental studies showed that proton RBE varies with tissue type, dose, and linear energy transfer (LET). Methods: An analytical expression for the LET and {alpha}/{beta} dependence of the linear-quadratic (LQ) model has been used for proton simulations in parallel with the assumption of a generic RBE = 1.1. Calculations have been performed for ranges of LET values and fractionation sensitivities to describe clinically relevant cases, such as the treatment of head and neck and prostate tumors. Isoeffect calculations were compared with predictions from a generic RBE value and reported clinical results. Results: The generic RBE = 1.1 appears to be a reasonable estimate for the proton RBE of rapidly growing tissues irradiated with low LET radiation. However, the use of a variable RBE predicts larger differences for tissues with low {alpha}/{beta} (both tumor and normal) and at low doses per fraction. In some situations these differences may appear in contrast to the findings from photon studies highlighting the importance of accurate accounting for the radiobiological effectiveness of protons. Furthermore, the use of variable RBE leads to closer predictions to clinical results. Conclusions: The LET dependence of the RBE has a strong impact on the predicted effectiveness of fractionated proton radiotherapy. The magnitude of the effect is modulated by the fractionation sensitivity and the fractional dose indicating the need for accurate analyses both in the target and around it. Care should therefore be employed for changing clinical fractionation patterns or when analyzing results from clinical studies for this type of radiation.
ERIC Educational Resources Information Center
Graham, Alan; Graham, Louise
2003-01-01
Describes a very successful attempt to teach fractions to year 5 pupils based on pupils making their own fraction pack. Children decided for themselves how to make the fractional slices used in the activity using colored cardboard sheets and templates of a paper circle consisting of 24 equal slices. (Author/NB)
Unfolding Fraction Multiplication
ERIC Educational Resources Information Center
Wyberg, Terry; Whitney, Stephanie R.; Cramer, Kathleen A.; Monson, Debra S.; Leavitt, Seth
2011-01-01
Students often have difficulty understanding fractions, in general, and understanding how to multiply fractions, in particular. To move past this potential problem area, students need to develop a deeper understanding of multiplication and connect the ideas to fractions. In this article, the authors share their insights into teaching fraction…
ERIC Educational Resources Information Center
Graham, Alan; Graham, Louise
2003-01-01
Describes a very successful attempt to teach fractions to year 5 pupils based on pupils making their own fraction pack. Children decided for themselves how to make the fractional slices used in the activity using colored cardboard sheets and templates of a paper circle consisting of 24 equal slices. (Author/NB)
Radiation dose estimates for radiopharmaceuticals
Stabin, M.G.; Stubbs, J.B.; Toohey, R.E.
1996-04-01
Tables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms.
Pitch fractionation. Technical report
Weinberg, V.L.; White, J.L.
1981-12-15
Petroleum pitch (Ashland A240) has been subjected to thermal treatment and solvent fractionation to produce refined pitches to be evaluated as impregnants for carbon-carbon composites. The solvent fractions were obtained by sequential Soxhlet extraction with solvents such as hexane, cyclohexane, toluene, and pyridine. The most severe thermal treatment produced a mesophase pitch (approximately 50% mesophase); an appreciable portion of the mesophase was soluble in strong solvents. There were substantial differences in chemical composition and in pyrolysis behavior of the fractions. As the depth of fraction increased, the pyrolysis yield and bloating increased, and the microstructure of the coke became finer until glassy microconstituents were formed in the deepest fractions.
Cheng, Jonathan C.; Schultheiss, Timothy E. Wong, Jeffrey Y.C.
2008-08-01
Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age {>=}18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function.
Dividing Fractions: A Pedagogical Technique
ERIC Educational Resources Information Center
Lewis, Robert
2016-01-01
When dividing one fraction by a second fraction, invert, that is, flip the second fraction, then multiply it by the first fraction. To multiply fractions, simply multiply across the denominators, and multiply across the numerators to get the resultant fraction. So by inverting the division of fractions it is turned into an easy multiplication of…
Dividing Fractions: A Pedagogical Technique
ERIC Educational Resources Information Center
Lewis, Robert
2016-01-01
When dividing one fraction by a second fraction, invert, that is, flip the second fraction, then multiply it by the first fraction. To multiply fractions, simply multiply across the denominators, and multiply across the numerators to get the resultant fraction. So by inverting the division of fractions it is turned into an easy multiplication of…
Dose to medium versus dose to water as an estimator of dose to sensitive skeletal tissue
NASA Astrophysics Data System (ADS)
Walters, B. R. B.; Kramer, R.; Kawrakow, I.
2010-08-01
The purpose of this study is to determine whether dose to medium, Dm, or dose to water, Dw, provides a better estimate of the dose to the radiosensitive red bone marrow (RBM) and bone surface cells (BSC) in spongiosa, or cancellous bone. This is addressed in the larger context of the ongoing debate over whether Dm or Dw should be specified in Monte Carlo calculated radiotherapy treatment plans. The study uses voxelized, virtual human phantoms, FAX06/MAX06 (female/male), incorporated into an EGSnrc Monte Carlo code to perform Monte Carlo dose calculations during simulated irradiation by a 6 MV photon beam from an Elekta SL25 accelerator. Head and neck, chest and pelvis irradiations are studied. FAX06/MAX06 include precise modelling of spongiosa based on µCT images, allowing dose to RBM and BSC to be resolved from the dose to bone. Modifications to the FAX06/MAX06 user codes are required to score Dw and Dm in spongiosa. Dose uncertainties of ~1% (BSC, RBM) or ~0.5% (Dm, Dw) are obtained after up to 5 days of simulations on 88 CPUs. Clinically significant differences (>5%) between Dm and Dw are found only in cranial spongiosa, where the volume fraction of trabecular bone (TBVF) is high (55%). However, for spongiosa locations where there is any significant difference between Dm and Dw, comparisons of differential dose volume histograms (DVHs) and average doses show that Dw provides a better overall estimate of dose to RBM and BSC. For example, in cranial spongiosa the average Dm underestimates the average dose to sensitive tissue by at least 5%, while average Dw is within ~1% of the average dose to sensitive tissue. Thus, it is better to specify Dw than Dm in Monte Carlo treatment plans, since Dw provides a better estimate of dose to sensitive tissue in bone, the only location where the difference is likely to be clinically significant.
FRACTIONAL PEARSON DIFFUSIONS.
Leonenko, Nikolai N; Meerschaert, Mark M; Sikorskii, Alla
2013-07-15
Pearson diffusions are governed by diffusion equations with polynomial coefficients. Fractional Pearson diffusions are governed by the corresponding time-fractional diffusion equation. They are useful for modeling sub-diffusive phenomena, caused by particle sticking and trapping. This paper provides explicit strong solutions for fractional Pearson diffusions, using spectral methods. It also presents stochastic solutions, using a non-Markovian inverse stable time change.
Leonenko, Nikolai N.; Meerschaert, Mark M.
2013-01-01
Pearson diffusions are governed by diffusion equations with polynomial coefficients. Fractional Pearson diffusions are governed by the corresponding time-fractional diffusion equation. They are useful for modeling sub-diffusive phenomena, caused by particle sticking and trapping. This paper provides explicit strong solutions for fractional Pearson diffusions, using spectral methods. It also presents stochastic solutions, using a non-Markovian inverse stable time change. PMID:23626377
Dose Rate Effects in Linear Bipolar Transistors
NASA Technical Reports Server (NTRS)
Johnston, Allan; Swimm, Randall; Harris, R. D.; Thorbourn, Dennis
2011-01-01
Dose rate effects are examined in linear bipolar transistors at high and low dose rates. At high dose rates, approximately 50% of the damage anneals at room temperature, even though these devices exhibit enhanced damage at low dose rate. The unexpected recovery of a significant fraction of the damage after tests at high dose rate requires changes in existing test standards. Tests at low temperature with a one-second radiation pulse width show that damage continues to increase for more than 3000 seconds afterward, consistent with predictions of the CTRW model for oxides with a thickness of 700 nm.
Dose Rate Effects in Linear Bipolar Transistors
NASA Technical Reports Server (NTRS)
Johnston, Allan; Swimm, Randall; Harris, R. D.; Thorbourn, Dennis
2011-01-01
Dose rate effects are examined in linear bipolar transistors at high and low dose rates. At high dose rates, approximately 50% of the damage anneals at room temperature, even though these devices exhibit enhanced damage at low dose rate. The unexpected recovery of a significant fraction of the damage after tests at high dose rate requires changes in existing test standards. Tests at low temperature with a one-second radiation pulse width show that damage continues to increase for more than 3000 seconds afterward, consistent with predictions of the CTRW model for oxides with a thickness of 700 nm.
Robison, W.L.; Conrado, C.L.; Bogen, K.T
1999-10-06
radionuclides. However, we continually see {sup 137}Cs in the groundwater at all contaminated atolls; the turnover time of the groundwater is about 5 y. The {sup 137}Cs can only get to the groundwater by leaching through the soil column when a portion of the soluble fraction of {sup 137}Cs inventory in the soil is transported to the groundwater when rainfall is heavy enough to cause recharge of the aquifer. This process is causing a loss of {sup 137}Cs out of the root zone of the plants that provides an environmental loss constant ({lambda}{sub env}) in addition to radiological decay {lambda}{sub rad}. Consequently, there is an effective rate of loss, {lambda}{sub eff} = {lambda}{sub rad} + {lambda}{sub env} that is the sum of the radiological and environmental-loss decay constants. We have had, and continue to have, a vigorous program to determine the rate of the environmental loss process. What we do know at this time is that the loss of {sup 137}Cs over time is greater than the estimate based on radiological decay only, and that the actual dose received by the Utirik people over 30-, 50-, or 70-y will be less than those presented in this report.
ERIC Educational Resources Information Center
Wilkerson, Trena L.; Bryan, Tommy; Curry, Jane
2012-01-01
This article describes how using candy bars as models gives sixth-grade students a taste for learning to represent fractions whose denominators are factors of twelve. Using paper models of the candy bars, students explored and compared fractions. They noticed fewer different representations for one-third than for one-half. The authors conclude…
ERIC Educational Resources Information Center
Pagni, David
2007-01-01
In this article, the author presents a paper folding activity that can be used for teaching fractions. This activity can be used to describe areas of folded polygons in terms of a standard unit of measure. A paper folding fractions worksheet and its corresponding solutions are also presented in this article. (Contains 2 figures.)
ERIC Educational Resources Information Center
Usiskin, Zalman P.
2007-01-01
In the 1970s, the movement to the metric system (which has still not completely occurred in the United States) and the advent of hand-held calculators led some to speculate that decimal representation of numbers would render fractions obsolete. This provocative proposition stimulated Zalman Usiskin to write "The Future of Fractions" in 1979. He…
Bajona-Xandri, C.; Martinez-Legaz, J.E.
1994-12-31
This paper studies the minimax fractional programming problem, assuming quasiconvexity of the objective function, under the lower subdifferentiability viewpoint. Necessary and sufficient optimality conditions and dual properties are found. We present applications of this theory to find the Pareto efficient solutions of a multiobjective fractional problem and to solve several economic models.
ERIC Educational Resources Information Center
Wilkerson, Trena L.; Bryan, Tommy; Curry, Jane
2012-01-01
This article describes how using candy bars as models gives sixth-grade students a taste for learning to represent fractions whose denominators are factors of twelve. Using paper models of the candy bars, students explored and compared fractions. They noticed fewer different representations for one-third than for one-half. The authors conclude…
Can Kindergartners Do Fractions?
ERIC Educational Resources Information Center
Cwikla, Julie
2014-01-01
Mathematics professor Julie Cwikla decided that she needed to investigate young children's understandings and see what precurricular partitioning notions young minds bring to the fraction table. Cwikla realized that only a handful of studies have examined how preschool-age and early elementary school-age students solve fraction problems (Empson…
(Carbon isotope fractionation inplants)
O'Leary, M.H.
1990-01-01
The objectives of this research are: To develop a theoretical and experimental framework for understanding isotope fractionations in plants; and to develop methods for using this isotope fractionation for understanding the dynamics of CO{sub 2} fixation in plants. Progress is described.
Can Kindergartners Do Fractions?
ERIC Educational Resources Information Center
Cwikla, Julie
2014-01-01
Mathematics professor Julie Cwikla decided that she needed to investigate young children's understandings and see what precurricular partitioning notions young minds bring to the fraction table. Cwikla realized that only a handful of studies have examined how preschool-age and early elementary school-age students solve fraction problems (Empson…
Yao, Weirong; Xu, Shouping; Du Lei; Xie, Chuanbin; Ma, Lin
2012-09-01
To implement dose reconstruction and dose-guided intensity modulated radiotherapy for helical tomotherapy. Dose reconstruction was implemented on adaptive helical tomotherapy with the online megavoltage CT (MVCT) imaging from a patient with nasopharyngeal cancer. The differences of isodose line between actual and planned deposition were analysis in 3D distribution, on which the hot spot and cold spot were lined. The dose delivered to these areas was modulated in later fractions to keep the planned requirement. The differences between actual and planned isodose line were shown on the image visually. The modulation to the hot spot and cold spot in later fraction corrected the incorrectly delivered dose to achieve the requirement of primary plan. The dose reconstruction and dose-guided intensity modulated radiotherapy can be implemented in adaptive helical tomotherapy.
Fractional dissipative standard map.
Tarasov, Vasily E; Edelman, M
2010-06-01
Using kicked differential equations of motion with derivatives of noninteger orders, we obtain generalizations of the dissipative standard map. The main property of these generalized maps, which are called fractional maps, is long-term memory. The memory effect in the fractional maps means that their present state of evolution depends on all past states with special forms of weights. Already a small deviation of the order of derivative from the integer value corresponding to the regular dissipative standard map (small memory effects) leads to the qualitatively new behavior of the corresponding attractors. The fractional dissipative standard maps are used to demonstrate a new type of fractional attractors in the wide range of the fractional orders of derivatives.
Minimizing metastatic risk in radiotherapy fractionation schedules
NASA Astrophysics Data System (ADS)
Badri, Hamidreza; Ramakrishnan, Jagdish; Leder, Kevin
2015-11-01
Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor α /β values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger α /β values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the α /β values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.
Assessing dose rate distributions in VMAT plans
NASA Astrophysics Data System (ADS)
Mackeprang, P.-H.; Volken, W.; Terribilini, D.; Frauchiger, D.; Zaugg, K.; Aebersold, D. M.; Fix, M. K.; Manser, P.
2016-04-01
Dose rate is an essential factor in radiobiology. As modern radiotherapy delivery techniques such as volumetric modulated arc therapy (VMAT) introduce dynamic modulation of the dose rate, it is important to assess the changes in dose rate. Both the rate of monitor units per minute (MU rate) and collimation are varied over the course of a fraction, leading to different dose rates in every voxel of the calculation volume at any point in time during dose delivery. Given the radiotherapy plan and machine specific limitations, a VMAT treatment plan can be split into arc sectors between Digital Imaging and Communications in Medicine control points (CPs) of constant and known MU rate. By calculating dose distributions in each of these arc sectors independently and multiplying them with the MU rate, the dose rate in every single voxel at every time point during the fraction can be calculated. Independently calculated and then summed dose distributions per arc sector were compared to the whole arc dose calculation for validation. Dose measurements and video analysis were performed to validate the calculated datasets. A clinical head and neck, cranial and liver case were analyzed using the tool developed. Measurement validation of synthetic test cases showed linac agreement to precalculated arc sector times within ±0.4 s and doses ±0.1 MU (one standard deviation). Two methods for the visualization of dose rate datasets were developed: the first method plots a two-dimensional (2D) histogram of the number of voxels receiving a given dose rate over the course of the arc treatment delivery. In similarity to treatment planning system display of dose, the second method displays the dose rate as color wash on top of the corresponding computed tomography image, allowing the user to scroll through the variation over time. Examining clinical cases showed dose rates spread over a continuous spectrum, with mean dose rates hardly exceeding 100 cGy min-1 for conventional
Fractional calculus in bioengineering.
Magin, Richard L
2004-01-01
Fractional calculus (integral and differential operations of noninteger order) is not often used to model biological systems. Although the basic mathematical ideas were developed long ago by the mathematicians Leibniz (1695), Liouville (1834), Riemann (1892), and others and brought to the attention of the engineering world by Oliver Heaviside in the 1890s, it was not until 1974 that the first book on the topic was published by Oldham and Spanier. Recent monographs and symposia proceedings have highlighted the application of fractional calculus in physics, continuum mechanics, signal processing, and electromagnetics, but with few examples of applications in bioengineering. This is surprising because the methods of fractional calculus, when defined as a Laplace or Fourier convolution product, are suitable for solving many problems in biomedical research. For example, early studies by Cole (1933) and Hodgkin (1946) of the electrical properties of nerve cell membranes and the propagation of electrical signals are well characterized by differential equations of fractional order. The solution involves a generalization of the exponential function to the Mittag-Leffler function, which provides a better fit to the observed cell membrane data. A parallel application of fractional derivatives to viscoelastic materials establishes, in a natural way, hereditary integrals and the power law (Nutting/Scott Blair) stress-strain relationship for modeling biomaterials. In this review, I will introduce the idea of fractional operations by following the original approach of Heaviside, demonstrate the basic operations of fractional calculus on well-behaved functions (step, ramp, pulse, sinusoid) of engineering interest, and give specific examples from electrochemistry, physics, bioengineering, and biophysics. The fractional derivative accurately describes natural phenomena that occur in such common engineering problems as heat transfer, electrode/electrolyte behavior, and sub
Fractionation: past, present, future.
Saedi, Nazanin; Jalian, H Ray; Petelin, Anthony; Zachary, Christopher
2012-06-01
The development of fractional photothermolysis is a milestone in the history of laser technology and cutaneous resurfacing. Based on the concept that skin is treated in a fractional manner, where narrow cylinders of tissue are thermally heated and normal adjacent skin is left unaffected, the fractional devices have shown effectiveness in treating a variety of conditions. Since its development, we are becoming more adept at using optimal parameters to induce near carbon dioxide laser benefits with a much more comfortable postoperative period and fewer complications. The future remains bright for fractionated laser devices and with new devices and wavelengths, the applications of this technology continue to grow. Copyright © 2012 Elsevier Inc. All rights reserved.
NASA Astrophysics Data System (ADS)
Laskin, Nick
2000-12-01
A new extension of a fractality concept in financial mathematics has been developed. We have introduced a new fractional Langevin-type stochastic differential equation that differs from the standard Langevin equation: (i) by replacing the first-order derivative with respect to time by the fractional derivative of order μ; and (ii) by replacing “white noise” Gaussian stochastic force by the generalized “shot noise”, each pulse of which has a random amplitude with the α-stable Lévy distribution. As an application of the developed fractional non-Gaussian dynamical approach the expression for the probability distribution function (pdf) of the returns has been established. It is shown that the obtained fractional pdf fits well the central part and the tails of the empirical distribution of S&P 500 returns.
Catalytic reforming of naphtha fractions
Bishop, K.C.; Vorhis, F.H.
1980-09-16
Production of motor gasoline and a btx-enriched reformate by fractionating a naphtha feedstock into a mid-boiling btxprecursor fraction, a relatively high-boiling fraction and a relatively low-boiling fraction; catalytically reforming the btxprecursor fraction in a first reforming zone; combining the relatively high-boiling and low-boiling fractions and catalytically reforming the combined fractions in a second reforming zone.
Panprasitwech, Oranit; Laohakosol, Vichian; Chaichana, Tuangrat
2010-11-11
Explicit formulae for continued fractions with symmetric patterns in their partial quotients are constructed in the field of formal power series. Similar to the work of Cohn in 1996, which generalized the so-called folding lemma to {kappa}-fold symmetry, the notion of {kappa}-duplicating symmetric continued fractions is investigated using a modification of the 1995 technique due to Clemens, Merrill and Roeder.
Thermodynamics in Fractional Calculus
NASA Astrophysics Data System (ADS)
Meilanov, R. P.; Magomedov, R. A.
2014-11-01
A generalization of thermodynamics in the formalism of fractional-order derivatives is given. Results of the traditional thermodynamics of Carnot, Clausius, and Helmholtz are obtained in the particular case where the exponent of a fractional-order derivative is equal to unity. A one-parametric "fractal" equation of state is obtained with account of the second virial coefficient. The application of the resulting equation of state in the case of the gas argon is considered.
Intracellular Cadmium Isotope Fractionation
NASA Astrophysics Data System (ADS)
Horner, T. J.; Lee, R. B.; Henderson, G. M.; Rickaby, R. E.
2011-12-01
Recent stable isotope studies into the biological utilization of transition metals (e.g. Cu, Fe, Zn, Cd) suggest several stepwise cellular processes can fractionate isotopes in both culture and nature. However, the determination of fractionation factors is often unsatisfactory, as significant variability can exist - even between different organisms with the same cellular functions. Thus, it has not been possible to adequately understand the source and mechanisms of metal isotopic fractionation. In order to address this problem, we investigated the biological fractionation of Cd isotopes within genetically-modified bacteria (E. coli). There is currently only one known biological use or requirement of Cd, a Cd/Zn carbonic anhydrase (CdCA, from the marine diatom T. weissfloggii), which we introduce into the E. coli genome. We have also developed a cleaning procedure that allows for the treating of bacteria so as to study the isotopic composition of different cellular components. We find that whole cells always exhibit a preference for uptake of the lighter isotopes of Cd. Notably, whole cells appear to have a similar Cd isotopic composition regardless of the expression of CdCA within the E. coli. However, isotopic fractionation can occur within the genetically modified E. coli during Cd use, such that Cd bound in CdCA can display a distinct isotopic composition compared to the cell as a whole. Thus, the externally observed fractionation is independent of the internal uses of Cd, with the largest Cd isotope fractionation occurring during cross-membrane transport. A general implication of these experiments is that trace metal isotopic fractionation most likely reflects metal transport into biological cells (either actively or passively), rather than relating to expression of specific physiological function and genetic expression of different metalloenzymes.
Adaptive fractionation therapy: I. Basic concept and strategy
NASA Astrophysics Data System (ADS)
Lu, Weiguo; Chen, Mingli; Chen, Quan; Ruchala, Kenneth; Olivera, Gustavo
2008-10-01
Radiotherapy is fractionized to increase the therapeutic ratio. Fractionation in conventional treatment is determined as part of the prescription, and a fixed fraction size is used for the whole course of treatment. Due to patients' day-to-day variations on the relative distance between the tumor and the organs at risk (OAR), a better therapeutic ratio may be attained by using an adaptive fraction size. Intuitively, we want to use a larger fraction size when OAR and the tumor are far apart and a smaller fraction size when OAR and the tumor are close to each other. The concept and strategies of adaptive fractionation therapy (AFT) are introduced in this paper. AFT is an on-line adaptive technique that utilizes the variations of internal structures to get optimal OAR sparing. Changes of internal structures are classified as different configurations according to their feasibility to the radiation delivery. A priori knowledge is used to describe the probability distribution of these configurations. On-line processes include identifying the configuration via daily image guidance and optimizing the current fraction size. The optimization is modeled as a dynamic linear programming problem so that at the end of the treatment course, the tumor receives the same planned dose while OAR receives less dose than the regular fractionation delivery. Extensive simulations, which include thousands of treatment courses with each course consisting of 40 fractions, are used to test the efficiency and robustness of the presented technique. The gains of OAR sparing depend on the variations on configurations and the bounds of the fraction size. The larger the variations and the looser the bounds are, the larger the gains will be. Compared to the conventional fractionation technique with 2 Gy/fraction in 40 fractions, for a 20% variation on tumor-OAR configurations and [1 Gy, 3 Gy] fraction size bounds, the cumulative OAR dose with adaptive fractionation is 3-8 Gy, or 7-20% less than that
Chromatographic methods of fractionation.
Friesen, A D
1987-01-01
Chromatography's functional versatility, separation efficiency, gentle non-denaturing separating process and ease of automation and scale-up make it attractive for industrial scale protein purification. The Winnipeg Rh Institute's new Plasma Fractionation facility is an example of the use of chromatography for the large scale purification of plasma protein fractions. The fractionation facility has a capacity to process 800 litres of plasma per batch into blood clotting factor VIII and IX, albumin and intravenous immune serum globulin (i.v. ISG). Albumin and i.v. ISG are purified using ion exchange columns of DEAE-Sepharose (230 litre size), DEAE-Biogel (150 litre size) and CM-Sepharose (150 litre size). The chromatographic process is automated using a Modicon 584 Programmable Logic Controller to regulate valves, pumps and sensors which control plasma flow during fractionation. The stainless steel tanks and piping are automatically cleaned-in-place. The high degree of automation and cleaning provides efficient operation and sanitary processing. Chromatographic methods (DEAE-Sepharose and metal chelation) are also being used at the pilot scale to purify the human blood products superoxide dismutase and hemoglobin from outdated red blood cells. Characterization of the protein fractions produced by chromatography has shown them to be of equal or higher quality than fractions produced by other techniques.
Fractional laser skin resurfacing.
Alexiades-Armenakas, Macrene R; Dover, Jeffrey S; Arndt, Kenneth A
2012-11-01
Laser skin resurfacing (LSR) has evolved over the past 2 decades from traditional ablative to fractional nonablative and fractional ablative resurfacing. Traditional ablative LSR was highly effective in reducing rhytides, photoaging, and acne scarring but was associated with significant side effects and complications. In contrast, nonablative LSR was very safe but failed to deliver consistent clinical improvement. Fractional LSR has achieved the middle ground; it combined the efficacy of traditional LSR with the safety of nonablative modalities. The first fractional laser was a nonablative erbium-doped yttrium aluminum garnet (Er:YAG) laser that produced microscopic columns of thermal injury in the epidermis and upper dermis. Heralding an entirely new concept of laser energy delivery, it delivered the laser beam in microarrays. It resulted in microscopic columns of treated tissue and intervening areas of untreated skin, which yielded rapid reepithelialization. Fractional delivery was quickly applied to ablative wavelengths such as carbon dioxide, Er:YAG, and yttrium scandium gallium garnet (2,790 nm), providing more significant clinical outcomes. Adjustable laser parameters, including power, pitch, dwell time, and spot density, allowed for precise determination of percent surface area, affected penetration depth, and clinical recovery time and efficacy. Fractional LSR has been a significant advance to the laser field, striking the balance between safety and efficacy.
21 years of Biologically Effective Dose
Fowler, J F
2010-01-01
In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for “biologically equivalent dose”, from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be “triangulated” to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion “How Fractionation Really Works”. BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation. PMID:20603408
Dose rate mapping of VMAT treatments
NASA Astrophysics Data System (ADS)
Podesta, Mark; Antoniu Popescu, I.; Verhaegen, Frank
2016-06-01
Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min-1 and 12 Gy min-1 but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates <1 Gy min-1. Pelvic plans on average have a lower mean dose rate within the PTV than lung or head and neck plans but a comparable mean dose rate within the organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.
Dose rate mapping of VMAT treatments.
Podesta, Mark; Popescu, I Antoniu; Verhaegen, Frank
2016-06-07
Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min(-1) and 12 Gy min(-1) but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates <1 Gy min(-1). Pelvic plans on average have a lower mean dose rate within the PTV than lung or head and neck plans but a comparable mean dose rate within the organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.
Sudahar, H; Kurup, P G G; Murali, V; Mahadev, P; Velmurugan, J
2013-01-01
The present study is to analyze the CyberKnife hypofractionated dose distribution of localized prostate cancer in terms of high-dose rate (HDR) brachytherapy equivalent doses to assess the degree of HDR brachytherapy resemblance of CyberKnife dose distribution. Thirteen randomly selected localized prostate cancer cases treated using CyberKnife with a dose regimen of 36.25Gy in 5 fractions were considered. HDR equivalent doses were calculated for 30Gy in 3 fractions of HDR brachytherapy regimen. The D5% of the target in the CyberKnife hypofractionation was 41.57 ± 2.41Gy. The corresponding HDR fractionation (3 fractions) equivalent dose was 32.81 ± 1.86Gy. The mean HDR fractionation equivalent dose, D98%, was 27.93 ± 0.84Gy. The V100% of the prostate target was 95.57% ± 3.47%. The V100% of the bladder and the rectum were 717.16 and 79.6mm(3), respectively. Analysis of the HDR equivalent dose of CyberKnife dose distribution indicates a comparable resemblance to HDR dose distribution in the peripheral target doses (D98% to D80%) reported in the literature. However, there is a substantial difference observed in the core high-dose regions especially in D10% and D5%. The dose fall-off within the OAR is also superior in reported HDR dose distribution than the HDR equivalent doses of CyberKnife.
Burnouf, Thierry
2007-04-01
Protein products fractionated from human plasma are an essential class of therapeutics used, often as the only available option, in the prevention, management, and treatment of life-threatening conditions resulting from trauma, congenital deficiencies, immunologic disorders, or infections. Modern plasma product production technology remains largely based on the ethanol fractionation process, but much has evolved in the last few years to improve product purity, to enhance the recovery of immunoglobulin G, and to isolate new plasma proteins, such as alpha1-protease inhibitor, von Willebrand factor, and protein C. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risk associated to plasma products is the transmission of blood-borne infectious agents. A complete set of measures--and, most particularly, the use of dedicated viral inactivation and removal treatments--has been implemented throughout the production chain of fractionated plasma products over the last 20 years to ensure optimal safety, in particular, and not exclusively, against HIV, hepatitis B virus, and hepatitis C virus. In this review, we summarize the practices of the modern plasma fractionation industry from the collection of the raw plasma material to the industrial manufacture of fractionated products. We describe the quality requirements of plasma for fractionation and the various treatments applied for the inactivation and removal of blood-borne infectious agents and provide examples of methods used for the purification of the various classes of plasma protein therapies. We also highlight aspects of the good manufacturing practices and the regulatory environment that govern the whole chain of production. In a regulated and professional environment, fractionated plasma products manufactured by modern processes are certainly among the lowest-risk therapeutic biological products in use today.
Radiation Dose-Volume Effects in the Spinal Cord
Kirkpatrick, John P.; Kogel, Albert J. van der; Schultheiss, Timothy E.
2010-03-01
Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (alpha/beta = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.
Identifying Fractions on Number Lines.
ERIC Educational Resources Information Center
Bright, George W.; And Others
1988-01-01
This study investigated the ways students represented fractions on number lines and the effects of instruction on those representations. The instruction primarily concerned representing fractions and ordering fractions on number lines. (Author/PK)
Repair of skin damage during fractionated irradiation with gamma rays and low-LET carbon ions.
Ando, Koichi; Koike, Sachiko; Uzawa, Akiko; Takai, Nobuhiko; Fukawa, Takeshi; Furusawa, Yoshiya; Aoki, Mizuho; Hirayama, Ryoichi
2006-06-01
In clinical use of carbon-ion beams, a deep-seated tumor is irradiated with a Spread-Out Bragg peak (SOBP) with a high-LET feature, whereas surface skin is irradiated with an entrance plateau, the LET of which is lower than that of the peak. The repair kinetics of murine skin damage caused by an entrance plateau of carbon ions was compared with that caused by photons using a scheme of daily fractionated doses followed by a top-up dose. Right hind legs received local irradiations with either 20 keV/microm carbon ions or gamma rays. The skin reaction of the irradiated legs was scored every other day up to Day 35 using a scoring scale that consisted of 10 steps, ranging from 0.5 to 5.0. An isoeffect dose to produce a skin reaction score of 3.0 was used to obtain a total dose and a top-up dose for each fractionation. Dependence on a preceding dose and on the time interval of a top-up dose was examined using gamma rays. For fractionated gamma rays, the total dose linearly increased while the top-up dose linearly decreased with an increase in the number of fractions. The magnitude of damage repair depended on the size of dose per fraction, and was larger for 5.2 Gy than 12.5 Gy. The total dose of carbon ions with 5.2 Gy per fraction did not change till 2 fractions, but abruptly increased at the 3rd fraction. Factors such as rapid repopulation, induced repair and cell cycle synchronization are possible explanations for the abrupt increase. As an abrupt increase/decrease of normal tissue damage could be caused by changing the number of fractions in carbon-ion radiotherapy, we conclude that, unlike photon therapy, skin damage should be carefully studied when the number of fractions is changed in new clinical trials.
Sampath, V.R.; Bachmann, D.E.
1993-07-27
A fractionator feed section in a fractionator to which is fed a feed mixture comprising a vapor component and a liquid component and which fractionator comprises a tray above said feed section which passes liquid reflux to said feed section, said feed section comprising: (a) a downwardly extending, elongated first baffle; (b) a downwardly extending, elongated second baffle; (c) a seal pan below said first baffle and said second baffle, said seal pan comprising a seal pan mixture of liquids into which a portion of said first baffle and a portion of said second baffle extend to form a mixing zone; (d) a feed nozzle which introduces said liquid component and said vapor component downward into said mixing zone; and, (e) a trough which introduces said liquid reflux to said mixing zone, wherein said liquid component and said liquid reflux mix to form said seal pan mixture of liquids.
Iterated fractional Tikhonov regularization
NASA Astrophysics Data System (ADS)
Bianchi, Davide; Buccini, Alessandro; Donatelli, Marco; Serra-Capizzano, Stefano
2015-05-01
Fractional Tikhonov regularization methods have been recently proposed to reduce the oversmoothing property of the Tikhonov regularization in standard form, in order to preserve the details of the approximated solution. Their regularization and convergence properties have been previously investigated showing that they are of optimal order. This paper provides saturation and converse results on their convergence rates. Using the same iterative refinement strategy of iterated Tikhonov regularization, new iterated fractional Tikhonov regularization methods are introduced. We show that these iterated methods are of optimal order and overcome the previous saturation results. Furthermore, nonstationary iterated fractional Tikhonov regularization methods are investigated, establishing their convergence rate under general conditions on the iteration parameters. Numerical results confirm the effectiveness of the proposed regularization iterations.
Fractional generalization of Liouville equations.
Tarasov, Vasily E
2004-03-01
In this paper fractional generalization of Liouville equation is considered. We derive fractional analog of normalization condition for distribution function. Fractional generalization of the Liouville equation for dissipative and Hamiltonian systems was derived from the fractional normalization condition. This condition is considered as a normalization condition for systems in fractional phase space. The interpretation of the fractional space is discussed. Copyright 2004 American Institute of Physics.
Antimicrobial activity of the solvent fractions from Bulbine natalensis Tuber.
Yakubu, M T; Mostafa, M; Ashafa, A O T; Afolayan, A J
2012-01-01
Bulbine natalensis Baker has been acclaimed to be used as an antimicrobial agent in the folklore medicine of South Africa without scientific evidence to substantiate or refute this claim. In view of this, the in vitro antimicrobial activity of solvent fractions (ethanol, ethyl acetate, n-butanol and water) from Bulbine natalensis Tuber against 4 Gram positive and 12 Gram negative bacteria as well as 3 fungal species were investigated using agar dilution. The ethanolic extract, n-butanol and ethyl acetate fractions inhibited 75, 87.5 and 100% respectively of the bacterial species in this study. The ethanolic, n-butanol and ethyl acetate fractions produced growth inhibition at MIC range of 1-10, 3-10 as well as 1 and 5 mg/ml respectively whereas the water fraction did not inhibit the growth of any of the bacterial species. Again, it was only the ethyl acetate fraction that inhibited the growth of Shigelli flexneri, Staphyloccus aureus and Escherichia coli. The ethanolic, ethyl acetate and n-butanolic fractions dose dependently inhibited the growth of Aspergillus niger and A. flavus whereas the water fraction produced 100% growth inhibition of the Aspergillus species at all the doses investigated. In contrast, no growth inhibition was produced on Candida albicans. The growth inhibition produced by the solvent fractions of B. natalensis Tuber in this study thus justifies the acclaimed use of the plant as an antimicrobial agent. The ethyl acetate fraction was the most potent.
Bamberger, Judith A.; Glissmeyer, John A.
2004-01-01
This document presents results of experiments conducted to measure release fractions during certain tank retrieval processes. The tests were performed in a 1/4 scale model of a waste storage tank. The retrieval processes simulated were: (1) Discharging liquid or slurry from the mouth of a vertically oriented two-in. Schedule 40 pipe. The discharging material was in free-fall from the mouth of the pipe near the top of the tank into a liquid or slurry pool at the bottom of the tank. (2) The jet from a 9/16-in.-diameter nozzle transferring liquid or slurry waste from one side of the tank to the other. The discharging liquid was aimed at the opposite side of the tank from the nozzle and either impacted the tank wall or fell into a liquid or slurry pool in the bottom of the tank. (3) A high pressure fan jet of liquid striking a steel plate or simulated waste from a stand-off distance of a few inches. For each process, a water-soluble fluorescent dye was added to the liquid fraction as a tracer. Kaolin clay was used to represent the solids. The tank was covered and there was no forced ventilation in the tank during the tests. Six air samples were collected during each test. The air samples were collected at fixed positions in the tank. The air sample filters were dried and weighed to determine the solids collection. The fluorescent dye was then leached from each filter and quantified with a fluorometer to determine the collection of liquid. Samples of the slurry and liquid simulants were also collected to determine the quantities of simulant used in each test. To calculate the release fraction, the quantity collected on each air sample was adjusted for the fraction of the tank volume sampled and divided by the quantity of material exposed in the simulation. The method was not as sensitive for the solids content as it was for the liquid content, but in those instances where a solids release fraction was determined, it was in relatively good agreement with that of the
FRACTIONAL CRYSTALLIZATION FEED ENVELOPE
HERTING DL
2008-03-19
Laboratory work was completed on a set of evaporation tests designed to establish a feed envelope for the fractional crystallization process. The feed envelope defines chemical concentration limits within which the process can be operated successfully. All 38 runs in the half-factorial design matrix were completed successfully, based on the qualitative definition of success. There is no feed composition likely to be derived from saltcake dissolution that would cause the fractional crystallization process to not meet acceptable performance requirements. However, some compositions clearly would provide more successful operation than other compositions.
In vitro studies on the adjuvanticity of Brucella fractions.
Serre, A; Vendrell, J P; Huguet, M F; Cannat, A
1982-01-01
Two Brucella fractions, the murein-linked fraction PI and the murein-free fraction SF, behave as in vitro adjuvants for primary anti-sheep erythrocyte responses: added to Mishell and Dutton-type cultures of spleen cells from B6/DB F1 mice they significantly enhance the number of direct anti-sheep erythrocyte PFC observed on day 5. They exert both nonspecific, polyclonal activating effects and antigen-dependent specific adjuvanticity. These two functions, however, differ in their dose responses and in their cellular requirements and can therefore be dissociated. Thus, polyclonal activation requires high doses of the "adjuvant fraction," is enhanced by adherent-cell depletion, and is not impaired by T-cell depletion. Specific adjuvanticity, on the other hand, requires lower doses of the adjuvant fractions (very high doses are in fact suppressive) and is T-cell and adherent-cell dependent. Moreover, adjuvanticity can be transferred to unstimulated spleen cells (or restored in adherent-cell-depleted populations) by PI- or SF-stimulated adherent cells or by the filtered supernatants of such cultures; adjuvant-soluble factors are therefore involved in the phenomena of adherent, T- and B-cell cooperation required for the adjuvanticity of Brucella fractions. PMID:6982864
Videodisc Instruction in Fractions.
ERIC Educational Resources Information Center
Carnine, Douglas; And Others
1987-01-01
How laser videodisc technology can be used to improve mathematics instruction is described, with note of the development of a videodisc curriculum on mastering fractions. Relevant research is reviewed, as well as how teachers can use the technology. The instructional design is described, and field-testing and revision reported. (MNS)
ERIC Educational Resources Information Center
Vinogradova, Natalya; Blaine, Larry
2013-01-01
Almost everyone loves chocolate. However, the same cannot be said about fractions, which are loved by markedly fewer. Middle school students tend to view them with wary respect, but little affection. The authors attempt to sweeten the subject by describing a type of game involving division of chocolate bars. The activity they describe provides a…
Innes, W.; Klein, S.; Perl, M.; Price, J.C.
1982-06-01
A device to search for fractional charge in matter is described. The sample is coupled to a low-noise amplifier by a periodically varying capacitor and the resulting signal is synchronously detected. The varying capacitor is constructed as a rapidly spinning wheel. Samples of any material in volumes of up to 0.05 ml may be searched in less than an hour.
Fraction collector for electrophoresis
NASA Technical Reports Server (NTRS)
Bier, M.
1977-01-01
Rotating-tube electrophoresis apparatus employs rotating jet of eluting buffer to reduce effects of convection during separation. Designed for separation of microorganisms and biological species, system combines gravity/gradient compensating of lumen with buffer flush at fraction outlet to increase separation efficiency.
Fractions through Fruit Salad.
ERIC Educational Resources Information Center
Lincoln, Lisa
1987-01-01
The mathematics concept of fractions was taught to a group of learning disabled, dyslexic, and multiply handicapped students (15-20 years old) by preparing a fruit salad. Enthusiastic student participation and enhanced knowledge illustrated the effectiveness of employing several sensory modes in learning activities. (CB)
Momentum fractionation on superstrata
Bena, Iosif; Martinec, Emil; Turton, David; Warner, Nicholas P.
2016-05-11
Superstrata are bound states in string theory that carry D1, D5, and momentum charges, and whose supergravity descriptions are parameterized by arbitrary functions of (at least) two variables. In the D1-D5 CFT, typical three-charge states reside in highdegree twisted sectors, and their momentum charge is carried by modes that individually have fractional momentum. Understanding this momentum fractionation holographically is crucial for understanding typical black-hole microstates in this system. We use solution-generating techniques to add momentum to a multi-wound supertube and thereby construct the first examples of asymptotically-flat superstrata. The resulting supergravity solutions are horizonless and smooth up to well-understood orbifold singularities. Upon taking the AdS3 decoupling limit, our solutions are dual to CFT states with momentum fractionation. We give a precise proposal for these dual CFT states. Lastly, our construction establishes the very nontrivial fact that large classes of CFT states with momentum fractionation can be realized in the bulk as smooth horizonless supergravity solutions.
ERIC Educational Resources Information Center
Caldwell, Karin D.
1988-01-01
Describes a technique for separating samples that range over 15 orders of magnitude in molecular weight. Discusses theory, apparatus, and sample preparation techniques. Lists several types of field-flow fractionation (FFF) and their uses: sedimentation FFF, thermal FFF, flow FFF, electrical FFF, and steric FFF. (ML)
ERIC Educational Resources Information Center
Vinogradova, Natalya; Blaine, Larry
2013-01-01
Almost everyone loves chocolate. However, the same cannot be said about fractions, which are loved by markedly fewer. Middle school students tend to view them with wary respect, but little affection. The authors attempt to sweeten the subject by describing a type of game involving division of chocolate bars. The activity they describe provides a…
Momentum fractionation on superstrata
Bena, Iosif; Martinec, Emil; Turton, David; ...
2016-05-11
Superstrata are bound states in string theory that carry D1, D5, and momentum charges, and whose supergravity descriptions are parameterized by arbitrary functions of (at least) two variables. In the D1-D5 CFT, typical three-charge states reside in highdegree twisted sectors, and their momentum charge is carried by modes that individually have fractional momentum. Understanding this momentum fractionation holographically is crucial for understanding typical black-hole microstates in this system. We use solution-generating techniques to add momentum to a multi-wound supertube and thereby construct the first examples of asymptotically-flat superstrata. The resulting supergravity solutions are horizonless and smooth up to well-understood orbifoldmore » singularities. Upon taking the AdS3 decoupling limit, our solutions are dual to CFT states with momentum fractionation. We give a precise proposal for these dual CFT states. Lastly, our construction establishes the very nontrivial fact that large classes of CFT states with momentum fractionation can be realized in the bulk as smooth horizonless supergravity solutions.« less
Prognostic value of radiobiological hypoxia during fractionated irradiation for local tumor control.
Zips, Daniel; Böke, Simon; Kroeber, Theresa; Meinzer, Andreas; Brüchner, Kerstin; Thames, Howard D; Baumann, Michael; Yaromina, Ala
2011-05-01
Previous experiments showed that the fraction of radiobiologically hypoxic tumor cells (rHF) in un-treated tumors did not accurately predict local tumor control after fractionated irradiation. Thus, the prognostic value of rHF determined during fractionated irradiation was investigated. Six human squamous cell carcinoma lines were transplanted into nude mice and then irradiated with 15 fractions over 3 weeks. Thereafter, single dose irradiation under normal and clamped blood flow was given. Local tumor control rates were used to calculate the rHF and the TCD₅₀, i.e., the radiation dose necessary to control 50% of the tumors, after single dose irradiation. These values were compared with the in parallel determined TCD₅₀ after 30 fractions in 6 weeks. The rHF after 15 fractions varied between 28% and 100%. No correlation was found with the TCD₅₀ after 30 fractions in 6 weeks. Single dose top-up TCD₅₀ under ambient and clamp conditions after 15 fractions significantly correlated with TCD₅₀ after 30 fractions in 6 weeks. rHF after 15 fractions is not a prognostic parameter for the outcome after fractionated irradiation. In contrast, the radiobiological parameters number of tumor stem cells, intrinsic radiosensitivity, and number of radiobiologically hypoxic tumor cells appear promising to predict outcome after fractionated irradiation.
Optimal fractionation in radiotherapy with multiple normal tissues.
Saberian, Fatemeh; Ghate, Archis; Kim, Minsun
2016-06-01
The goal in radiotherapy is to maximize the biological effect (BE) of radiation on the tumour while limiting its toxic effects on healthy anatomies. Treatment is administered over several sessions to give the normal tissue time to recover as it has better damage-repair capabilities than tumour cells. This is termed fractionation. A key problem in radiotherapy involves finding an optimal number of treatment sessions (fractions) and the corresponding dosing schedule. A major limitation of existing mathematically rigorous work on this problem is that it includes only a single normal tissue. Since essentially no anatomical region of interest includes only one normal tissue, these models may incorrectly identify the optimal number of fractions and the corresponding dosing schedule. We present a formulation of the optimal fractionation problem that includes multiple normal tissues. Our model can tackle any combination of maximum dose, mean dose and dose-volume type constraints for serial and parallel normal tissues as this is characteristic of most treatment protocols. We also allow for a spatially heterogeneous dose distribution within each normal tissue. Furthermore, we do not a priori assume that the doses are invariant across fractions. Finally, our model uses a spatially optimized treatment plan as input and hence can be seamlessly combined with any treatment planning system. Our formulation is a mixed-integer, non-convex, quadratically constrained quadratic programming problem. In order to simplify this computationally challenging problem without loss of optimality, we establish sufficient conditions under which equal-dosage or single-dosage fractionation is optimal. Based on the prevalent estimates of tumour and normal tissue model parameters, these conditions are expected to hold in many types of commonly studied tumours, such as those similar to head-and-neck and prostate cancers. This motivates a simple reformulation of our problem that leads to a closed
A radiobiological model of reoxygenation and fractionation effects.
Guerrero, Mariana; Carlson, David J
2017-05-01
The purpose of this study was to develop a radiobiological model of reoxygenation that fulfills the following goals: (a) Quantify the reoxygenation effect for different fractionations (b) Model the hypoxic fraction in tumors as a function of the number of radiation treatments. (c) Develop a simple analytical expression for a reoxygenation term in biological effect calculations. The model considers tumor cells in two compartments: an aerobic (or normoxic) population of cells and a hypoxic population including cells under a range of reduced oxygen concentrations. The surviving fraction is predicted using the linear-quadratic (LQ) model. A hypoxia reduction factor (HRF) is used to quantify reductions in radiosensitivity parameters αA and βA as cellular oxygen concentration decreases. The HRF is defined as the ratio of the dose at a specific level of hypoxia to the dose under fully aerobic conditions to achieve equal cell killing. The model assumes that a fraction of the hypoxic cells (Δ) moves from the hypoxic to the aerobic compartment after each daily fraction. As an example, we compare the effect of reoxygenation on biological response for a standard dose fractionation for nonsmall cell lung cancer (NSCLC) (d = 2 Gy, n = 33) to typical fractionations for stereotactic body radiotherapy (SBRT) and other nonstandard fractionations. The reoxygenation effect is parameterized for biological effect calculations and an analytic expression for the surviving fraction after n daily treatments is derived. The hypoxic fraction either increases or decreases with n depending on the reoxygenation parameter Δ. For certain combinations of parameters, the biological effect of reoxygenation goes as -(n-1) · ln(1-Δ) providing a simple expression that can be introduced in biologically effective dose (BED) calculations. The model is used to compare fractionation schedules and quantitatively interpret results from molecular imaging studies of hypoxia. Based on the comparison of
Stewart, F.A.; Oussoren, Y.; Luts, A.; Begg, A.C.; Dewit, L.; Lebesque, J.; Bartelink, H.
1987-05-01
Functional kidney damage in mice was measured after a series of fractionated X-irradiations. Doses per fraction of 0.75-12.5 Gy were given as 2, 5, 10, 30, 40, 60, or 80 equal doses in a total treatment time of 4 weeks. Renal function (measured by clearance of /sup 51/CrEDTA or hematocrit levels) deteriorated progressively, in a dose related manner, from 20 to 46 weeks after the start of treatment. The changes in renal function versus time were fitted by a polynomial regression through all data and interpolated values for /sup 51/CrEDTA clearance were then calculated at 30 and 40 weeks after treatment. Steep dose response curves were obtained and these were used to calculate isoeffective doses for the different fractionation schedules. There was a marked increase in total isoeffective doses from 2-30 fractions and these data were well described by a linear quadratic (L.Q.) expression for damage with an alpha/beta ratio of 2.3 +/- 0.2 Gy. There was only a slight increase in the total isoeffect dose as the size of the dose per fraction was decreased below 2 Gy and the measured isoeffect doses after 40 to 80 fractions were lower than predicted on the basis of an L.Q. model assuming complete repair between successive irradiations. The flexure dose for mouse kidneys irradiated 3 times per day was, effectively, 1 to 2 Gy and hyperfractionation using lower doses per fraction did not lead to significant, additional repair.
Goal Sketches in Fraction Learning
ERIC Educational Resources Information Center
Sophian, Catherine; Madrid, Samara
2003-01-01
To examine how conceptual knowledge about fraction magnitudes changes as students' learning progresses, 5th and 7th-grade students were asked to solve fraction magnitude problems that entailed finding a fraction between two given fractions and then to evaluate solutions for similar problems that were modeled for them. When the given fractions…
Creating, Naming, and Justifying Fractions
ERIC Educational Resources Information Center
Siebert, Daniel; Gaskin, Nicole
2006-01-01
For students to develop meaningful conceptions of fractions and fraction operations, they need to think of fractions in terms other than as just whole-number combinations. In this article, we suggest two powerful images for thinking about fractions that move beyond whole-number reasoning. (Contains 5 figures.)
Arbitrage with fractional Gaussian processes
NASA Astrophysics Data System (ADS)
Zhang, Xili; Xiao, Weilin
2017-04-01
While the arbitrage opportunity in the Black-Scholes model driven by fractional Brownian motion has a long history, the arbitrage strategy in the Black-Scholes model driven by general fractional Gaussian processes is in its infancy. The development of stochastic calculus with respect to fractional Gaussian processes allowed us to study such models. In this paper, following the idea of Shiryaev (1998), an arbitrage strategy is constructed for the Black-Scholes model driven by fractional Gaussian processes, when the stochastic integral is interpreted in the Riemann-Stieltjes sense. Arbitrage opportunities in some fractional Gaussian processes, including fractional Brownian motion, sub-fractional Brownian motion, bi-fractional Brownian motion, weighted-fractional Brownian motion and tempered fractional Brownian motion, are also investigated.
Four-Dimensional Patient Dose Reconstruction for Scanned Ion Beam Therapy of Moving Liver Tumors
Richter, Daniel; Saito, Nami; Chaudhri, Naved; Härtig, Martin; Ellerbrock, Malte; Jäkel, Oliver; Combs, Stephanie E.; Habermehl, Daniel; Herfarth, Klaus; Durante, Marco; Bert, Christoph
2014-05-01
Purpose: Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy. Methods and Materials: Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)–weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporal correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V{sub 95}) and 107% (V{sub 107}) of the planned doses. Results: 4D dose reconstruction based on daily measured data is possible in a clinical setting. V{sub 95} and V{sub 107} values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V{sub 95} > 87%, SD < 3%) and overdose (mean V{sub 107} < 4%, SD < 3%) with respect to the single-fraction dose for all analyzed patients. Conclusions: A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment.
The emergence of nonuniform spatiotemporal fractionation schemes within the standard BED model
Unkelbach, Jan Papp, Dávid
2015-05-15
Purpose: Nonuniform spatiotemporal radiotherapy fractionation schemes, i.e., delivering distinct dose distributions in different fractions can potentially improve the therapeutic ratio. This is possible if the dose distributions are designed such that similar doses are delivered to normal tissues (exploit the fractionation effect) while hypofractionating subregions of the tumor. In this paper, the authors develop methodology for treatment planning with nonuniform fractions and demonstrate this concept in the context of intensity-modulated proton therapy (IMPT). Methods: Treatment planning is performed by simultaneously optimizing (possibly distinct) IMPT dose distributions for multiple fractions. This is achieved using objective and constraint functions evaluated for the cumulative biologically equivalent dose (BED) delivered at the end of treatment. BED based treatment planning formulations lead to nonconvex optimization problems, such that local gradient based algorithms require adequate starting positions to find good local optima. To that end, the authors develop a combinatorial algorithm to initialize the pencil beam intensities. Results: The concept of nonuniform spatiotemporal fractionation schemes is demonstrated for a spinal metastasis patient treated in two fractions using stereotactic body radiation therapy. The patient is treated with posterior oblique beams with the kidneys being located in the entrance region of the beam. It is shown that a nonuniform fractionation scheme that hypofractionates the central part of the tumor allows for a skin and kidney BED reduction of approximately 10%–20%. Conclusions: Nonuniform spatiotemporal fractionation schemes represent a novel approach to exploit fractionation effects that deserves further exploration for selected disease sites.
Accelerated versus conventional radiation fractionation in early stage carcinoma larynx.
Alam, M S; Perween, R; Siddiqui, S A
2016-01-01
In our study, we have treated cases of early glottic carcinoma by two different dose-fractionation schedules in relation to overall treatment time. This is an analysis of 29 patients with invasive, previously untreated T1and T2squamous cell carcinoma of true vocal cord that was treated by radical radiation therapy. All patients were treated with a continuous course of radiation therapy with once-daily fractionation. All the patients were treated 5 days a week from Monday to Friday. The fractionation regime was either: (1) 62.5 Gy/25fractions/5 weeks at 2.5 Gy fractions (Regimen 1), (2) 70 Gy/35 fractions/7 weeks at 2 Gy/fraction (Regimen 2). Regimen 1 included 15/29 patients (51.72%) and Regimen 2 included 14/29 patients (48.27%). Patients were evaluated for: (1) Locoregional control, (2) acute and late radiation toxicities, (3) quality of voice. There was no significant difference in terms of locoregional control rate, acute and late radiation toxicities in both groups. Voice quality during and after radiation was comparable in both arms. Use of high dose per fraction schedule with shorter duration of treatment results in comparable local control as well as the quality of voice to the protracted course of radiotherapy without increase in treatment-related toxicities. Shorter overall treatment time can be of great advantage in terms of time, cost, comfort, and acceptability by the patients.
Floquet Fractional Chern Insulators
NASA Astrophysics Data System (ADS)
Grushin, Adolfo G.; Gómez-León, Álvaro; Neupert, Titus
2014-04-01
We show theoretically that periodically driven systems with short range Hubbard interactions offer a feasible platform to experimentally realize fractional Chern insulator states. We exemplify the procedure for both the driven honeycomb and the square lattice, where we derive the effective steady state band structure of the driven system by using the Floquet theory and subsequently study the interacting system with exact numerical diagonalization. The fractional Chern insulator state equivalent to the 1/3 Laughlin state appears at 7/12 total filling (1/6 filling of the upper band). The state also features spontaneous ferromagnetism and is thus an example of the spontaneous breaking of a continuous symmetry along with a topological phase transition. We discuss light-driven graphene and shaken optical lattices as possible experimental systems that can realize such a state.
Testing fractional action cosmology
NASA Astrophysics Data System (ADS)
Shchigolev, V. K.
2016-08-01
The present work deals with a combined test of the so-called Fractional Action Cosmology (FAC) on the example of a specific model obtained by the author earlier. In this model, the effective cosmological term is proportional to the Hubble parameter squared through the so-called kinematic induction. The reason of studying this cosmological model could be explained by its ability to describe two periods of accelerated expansion, that is in agreement with the recent observations and the cosmological inflation paradigm. First of all, we put our model through the theoretical tests, which gives a general conception of the influence of the model parameters on its behavior. Then, we obtain some restrictions on the principal parameters of the model, including the fractional index, by means of the observational data. Finally, the cosmography parameters and the observational data compared to the theoretical predictions are presented both analytically and graphically.
Fractional lattice charge transport
Flach, Sergej; Khomeriki, Ramaz
2017-01-01
We consider the dynamics of noninteracting quantum particles on a square lattice in the presence of a magnetic flux α and a dc electric field E oriented along the lattice diagonal. In general, the adiabatic dynamics will be characterized by Bloch oscillations in the electrical field direction and dispersive ballistic transport in the perpendicular direction. For rational values of α and a corresponding discrete set of values of E(α) vanishing gaps in the spectrum induce a fractionalization of the charge in the perpendicular direction - while left movers are still performing dispersive ballistic transport, the complementary fraction of right movers is propagating in a dispersionless relativistic manner in the opposite direction. Generalizations and the possible probing of the effect with atomic Bose-Einstein condensates and photonic networks are discussed. Zak phase of respective band associated with gap closing regime has been computed and it is found converging to π/2 value. PMID:28102302
NASA Technical Reports Server (NTRS)
McKay, David S.; Cooper, Bonnie L.
2010-01-01
This slide presentation describes new fractionation methods that are used to create dust that is respirable for testing the effects of inhalation of lunar dust in preparation for future manned lunar exploration. Because lunar dust is a very limited commodity, a method that does not result in loss of the material had to be developed. The dust separation system that is described incorporates some traditional methods, while preventing the dust from being contaminated or changed in reactivity properties while also limiting losses.
Fractional Galilean symmetries
NASA Astrophysics Data System (ADS)
Hosseiny, Ali; Rouhani, Shahin
2016-09-01
We generalize the differential representation of the operators of the Galilean algebras to include fractional derivatives. As a result a whole new class of scale invariant Galilean algebras are obtained. The first member of this class has dynamical index z = 2 similar to the Schrödinger algebra. The second member of the class has dynamical index z = 3 / 2, which happens to be the dynamical index Kardar-Parisi-Zhang equation.
Fractional statistics from gravitation
Cho, Y.M. ); Park, D.H. )
1994-06-15
We show that the solitons of the SO(3) nonlinear sigma model in 2+1 dimensions, when coupled to gravitation with the gravitational Chern-Simons interaction, become anyons in the absence of the Hopf term. In particular we calculate the fractional statistical factor of the gravitating anyons, and prove that the gravitational Chern-Simons term itself can be interpreted as the Hopf term of the topological current of [Pi][sub 2]([ital S][sup 2]).
Gottlieb, A; Schleibinger, H; Ketseridis, G; Wullenweber, M; Rüden, H
1983-01-01
Suspended particulate matter (PM) with a Dae less than 0.4 micron was collected from July 1981 till January 1982. The ether/benzene soluble extract (EEOM) and the acidic, basic and neutral fractions were determined and investigated for their mutagenic activities in the Ames bioassay. In addition particles (Dae) less than 10.2 micron derived in January were investigated. Five compounds of the basic fraction were determined by gaschromatography. The following results were obtained: Suspended particulate matter (Dae less than 0.4 micron) and the ether/benzene extract increase from July to January. The lowest rates occur in July (PM: 16.9 micron/m3) and August (EEOM: 3.0 micrograms/m3), the highest in January (PM: 48.9 micrograms/m3, EEOM: 10.5 micrograms/m3). The ether/benzene soluble portion of the suspended particulate matter increases from the average rate of 16.3% (July-September) to 22.7% (November-January). The neutral fraction amounts to 44.9%, the acidic fraction to 27.3% and the basic fraction to 3.5% of the organic matter (on an average). In experiments with metabolic activation 99% of the total mutagenicity during the period of July till September can be demonstrated by summing up the mutagenicity of the three fractions on the other hand only 59.7% from November till January. The EEOMs derived from winter exhibit without metabolic activation (250 micrograms/plate) distinctively higher numbers of revertants than the single fractions. Dose-response curves of extracts derived from back-up filters (Dae less than 0.4 micron) in January show that the acidic fraction has a slightly higher mutagenic activity than the neutral fraction (mean values of tests with and without S9-mix). The basic fraction shows no mutagenicity without S9-mix, with activation the mutagenic activity is lower than that of the other fractions. Mutagenicity expressed as rev./m3 air shows, that the neutral fraction is most efficient. The number of revertants per plate reveals-in relation to
Model Fractional Chern Insulators
NASA Astrophysics Data System (ADS)
Behrmann, Jörg; Liu, Zhao; Bergholtz, Emil J.
2016-05-01
We devise local lattice models whose ground states are model fractional Chern insulators—Abelian and non-Abelian topologically ordered states characterized by exact ground state degeneracies at any finite size and infinite entanglement gaps. Most saliently, we construct exact parent Hamiltonians for two distinct families of bosonic lattice generalizations of the Zk parafermion quantum Hall states: (i) color-entangled fractional Chern insulators at band filling fractions ν =k /(C +1 ) and (ii) nematic states at ν =k /2 , where C is the Chern number of the lowest band. In spite of a fluctuating Berry curvature, our construction is partially frustration free: the ground states reside entirely within the lowest band and exactly minimize a local (k +1 ) body repulsion term by term. In addition to providing the first known models hosting intriguing states such as higher Chern number generalizations of the Fibonacci anyon quantum Hall states, the remarkable stability and finite-size properties make our models particularly well suited for the study of novel phenomena involving, e.g., twist defects and proximity induced superconductivity, as well as being a guide for designing experiments.
Model Fractional Chern Insulators.
Behrmann, Jörg; Liu, Zhao; Bergholtz, Emil J
2016-05-27
We devise local lattice models whose ground states are model fractional Chern insulators-Abelian and non-Abelian topologically ordered states characterized by exact ground state degeneracies at any finite size and infinite entanglement gaps. Most saliently, we construct exact parent Hamiltonians for two distinct families of bosonic lattice generalizations of the Z_{k} parafermion quantum Hall states: (i) color-entangled fractional Chern insulators at band filling fractions ν=k/(C+1) and (ii) nematic states at ν=k/2, where C is the Chern number of the lowest band. In spite of a fluctuating Berry curvature, our construction is partially frustration free: the ground states reside entirely within the lowest band and exactly minimize a local (k+1) body repulsion term by term. In addition to providing the first known models hosting intriguing states such as higher Chern number generalizations of the Fibonacci anyon quantum Hall states, the remarkable stability and finite-size properties make our models particularly well suited for the study of novel phenomena involving, e.g., twist defects and proximity induced superconductivity, as well as being a guide for designing experiments.
Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit
2017-01-01
Purpose To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. Material and methods The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD2) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD2 verification with pair t-test statistical analysis using IBM SPSS Statistics version 22 (64-bit). Results Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D90%, 0.56% in the bladder, 1.74% in the rectum when determined by D2cc, and less than 1% in Pinnacle. The difference in the EQD2 between the software calculation and the manual calculation was not significantly different with 0.00% at p-values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR-CTV, bladder, and rectum, respectively. Conclusions The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT. PMID:28344603
Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit; Tharavichitkul, Ekkasit
2017-02-01
To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD2) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD2 verification with pair t-test statistical analysis using IBM SPSS Statistics version 22 (64-bit). Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D90%, 0.56% in the bladder, 1.74% in the rectum when determined by D2cc, and less than 1% in Pinnacle. The difference in the EQD2 between the software calculation and the manual calculation was not significantly different with 0.00% at p-values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR-CTV, bladder, and rectum, respectively. The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT.
Charkoftaki, Georgia; Dokoumetzidis, Aristides; Valsami, Georgia; Macheras, Panos
2012-11-01
To develop a dose dependent version of BCS and identify a critical dose after which the amount absorbed is independent from the dose. We utilized a mathematical model of drug absorption in order to produce simulations of the fraction of dose absorbed (F) and the amount absorbed as function of the dose for the various classes of BCS and the marginal cases in between classes. Simulations based on the mathematical model of F versus dose produced patterns of a constant F throughout a wide range of doses for drugs of Classes I, II and III, justifying biowaiver claim. For Classes I and III the pattern of a constant F stops at a critical dose Dose(cr) after which the amount of drug absorbed, is independent from the dose. For doses higher than Dose(cr), Class I drugs become Class II and Class III drugs become Class IV. Dose(cr) was used to define an in vivo effective solubility as S(eff) = Dose(cr)/250 ml. Literature data were used to support our simulation results. A new biopharmaceutic classification of drugs is proposed, based on F, separating drugs into three regions, taking into account the dose, and Dose(cr), while the regions for claiming biowaiver are clearly defined.
Spatially fractionated radiotherapy (GRID) using helical tomotherapy.
Zhang, Xin; Penagaricano, Jose; Yan, Yulong; Liang, Xiaoying; Morrill, Steven; Griffin, Robert J; Corry, Peter; Ratanatharathorn, Vaneerat
2016-01-08
Spatially fractionated radiotherapy (GRID) was designed to treat large tumors while sparing skin, and it is usually delivered with a linear accelerator using a commercially available block or multileaf collimator (LINAC-GRID). For deep-seated (skin to tumor distance (> 8 cm)) tumors, it is always a challenge to achieve adequate tumor dose coverage. A novel method to perform GRID treatment using helical tomotherapy (HT-GRID) was developed at our institution. Our approach allows treating patients by generating a patient-specific virtual GRID block (software-generated) and using IMRT technique to optimize the treatment plan. Here, we report our initial clinical experience using HT-GRID, and dosimetric comparison results between HT-GRID and LINAC-GRID. This study evaluates 10 previously treated patients who had deep-seated bulky tumors with complex geometries. Five of these patients were treated with HT-GRID and replanned with LINAC-GRID for comparison. Similarly, five other patients were treated with LINAC-GRID and replanned with HT-GRID for comparison. The prescription was set such that the maximum dose to the GTV is 20 Gy in a single fraction. Dosimetric parameters compared included: mean GTV dose (DGTV mean), GTV dose inhomogeneity (valley-to-peak dose ratio (VPR)), normal tissue doses (DNmean), and other organs-at-risk (OARs) doses. In addition, equivalent uniform doses (EUD) for both GTV and normal tissue were evaluated. In summary, HT-GRID technique is patient-specific, and allows adjustment of the GRID pattern to match different tumor sizes and shapes when they are deep-seated and cannot be adequately treated with LINAC-GRID. HT-GRID delivers a higher DGTV mean, EUD, and VPR compared to LINAC-GRID. HT-GRID delivers a higher DNmean and lower EUD for normal tissue compared to LINAC-GRID. HT-GRID plans also have more options for tumors with complex anatomical relationships between the GTV and the avoidance OARs (abutment or close proximity).
Statistical iterative reconstruction using adaptive fractional order regularization
Zhang, Yi; Wang, Yan; Zhang, Weihua; Lin, Feng; Pu, Yifei; Zhou, Jiliu
2016-01-01
In order to reduce the radiation dose of the X-ray computed tomography (CT), low-dose CT has drawn much attention in both clinical and industrial fields. A fractional order model based on statistical iterative reconstruction framework was proposed in this study. To further enhance the performance of the proposed model, an adaptive order selection strategy, determining the fractional order pixel-by-pixel, was given. Experiments, including numerical and clinical cases, illustrated better results than several existing methods, especially, in structure and texture preservation. PMID:27231604
Radiation fractionation: the search for isoeffect relationships and mechanisms.
Moulder, John E; Seymour, Colin
2017-10-02
Review the historical basis for the use of fractionated radiation in radiation oncology. The history of dose fractionation in radiation oncology is long and tortuous, and the radiobiologist's understanding of why fractionation worked came decades after radiation oncologists had adopted multi-week daily-dose fractionation as 'standard'. Central to the history is the search for 'isoeffective' formulas that would allow different radiation schedules to be compared. Initially, this meant dealing with different lengths of treatment, leading to the 1944 Strandqvist formulation that dominated thinking for decades. Concerns about the number of fractions, not just the total time, led to the 1967 Ellis NSD formulation that held sway through the 1980s. The development of experimental radiotherapy in 1970s (e.g. Fowler's work at the Gray Laboratory, and Fischer's work at Yale) led to biologically-based approaches that culminated with the Biologically Effective Dose (BED) concept. BED is the current dogma for treatment optimization, but it must be used with caution, as there are multiple formulations, and some parameters have debatable values. There is also a controversy about whether BED is biologically-based or a 'curve-fitting' exercise. These latter issues are beyond the scope of this article, but the history of fractionation models suggests that our current concepts are probably wrong, although when used with caution they are clearly useful.
Dynamically accumulated dose and 4D accumulated dose for moving tumors
Li, Heng; Li, Yupeng; Zhang, Xiaodong; Li, Xiaoqiang; Liu, Wei; Gillin, Michael T.; Zhu, X. Ronald
2012-01-01
Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove the principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a “pulsed beam”; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a “continuous beam.” A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose
Dynamically accumulated dose and 4D accumulated dose for moving tumors
Li Heng; Li Yupeng; Zhang Xiaodong; Li Xiaoqiang; Liu Wei; Gillin, Michael T.; Zhu, X. Ronald
2012-12-15
Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove the principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a 'pulsed beam'; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a 'continuous beam.' A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference
Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes
NASA Astrophysics Data System (ADS)
Carabe-Fernandez, A.; Dale, R. G.; Hopewell, J. W.; Jones, B.; Paganetti, H.
2010-10-01
The aim is to demonstrate the potential impact of changes in the value of the β parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBEmin is introduced into the LQ formulation to account for possible changes in the β radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBEmin = 1 and RBEmin ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBEmin better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBEmin ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBEmin ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the β parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations.
Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes.
Carabe-Fernandez, A; Dale, R G; Hopewell, J W; Jones, B; Paganetti, H
2010-10-07
The aim is to demonstrate the potential impact of changes in the value of the β parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBE(min) is introduced into the LQ formulation to account for possible changes in the β radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBE(min) = 1 and RBE(min) ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBE(min) better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBE(min) ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBE(min) ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the β parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations.
Acoustic dose and acoustic dose-rate.
Duck, Francis
2009-10-01
Acoustic dose is defined as the energy deposited by absorption of an acoustic wave per unit mass of the medium supporting the wave. Expressions for acoustic dose and acoustic dose-rate are given for plane-wave conditions, including temporal and frequency dependencies of energy deposition. The relationship between the acoustic dose-rate and the resulting temperature increase is explored, as is the relationship between acoustic dose-rate and radiation force. Energy transfer from the wave to the medium by means of acoustic cavitation is considered, and an approach is proposed in principle that could allow cavitation to be included within the proposed definitions of acoustic dose and acoustic dose-rate.
Fractionated radiotherapy and radiosurgery of intracranial meningiomas.
Biau, J; Khalil, T; Verrelle, P; Lemaire, J-J
2015-06-19
This review focuses on the role of radiosurgery and fractionated radiotherapy in the management of intracranial meningiomas, which are the most common benign intracranial tumors. Whenever feasible, surgery remains a cornerstone of treatment in effective health care treatment where modern radiotherapy plays an important role. Irradiation can be proposed as first-line treatment, as adjuvant treatment, or as a second-line treatment after recurrence. Stereotactic radiosurgery consists of delivering, a high-dose of radiation with high precision, to the tumor in a single-fraction with a minimal exposure of surrounding healthy tissue. Stereotactic radiosurgery, especially with the gamma knife technique, has reached a high level of success for the treatment of intracranial meningiomas with excellent local control and low morbidity. However, stereotactic radiosurgery is limited by tumor size,<3-4cm, and location, i.e. reasonable distance from the organs at risk. Fractionated radiation therapy is an interesting alternative (5 to 6weeks treatment time) for large inoperable tumors. The results of fractionated radiation therapy seem encouraging as regards both local control and morbidity although long-term prospective studies are still needed.
[Ablative and fractional lasers].
Beylot, C; Grognard, C; Michaud, T
2009-10-01
The use of pulsed or scanning Carbon Dioxide, and pulsed Erbium-YAG lasers allows the programmable and reproducible photocoagulation of thin layers of the epidermis and superficial dermis. Thermal damage depends on the type of laser and is greater with CO(2) lasers. The degree of neocollagenesis is proportional to the thermal damage and is better with CO(2) lasers. Their main indication is the correction of photoaged facial skin but they can also be used for corrective dermatology, e.g. for scars and genodermatosis. Results are highly satisfactory but the technique is invasive and the patient experiences a social hindrance of around two weeks. Fractionated techniques treat 25% of the defective skin area at each session in noncontiguous microzones; four sessions are therefore necessary to treat the entire cutaneous surface. The treatment is given under topical anesthesia and is much less invasive, particularly with nonablative fractional laser treatment in which photothermolysis does not penetrate below the epidermis and/or the effects are slight, with no or very little social isolation. However, the results are much less satisfactory than the results of ablative laser and there is no firming effect. Other zones than the face can be treated. With the fractional CO(2) and Erbium ablative lasers, which have multiplied over the past 2 years, the much wider impacts cause perforation of the epidermis and there is a zone of ablation by laser photovaporization, with a zone of thermal damage below. The results are better in correcting photoaging of the face, without, however, achieving the efficacy of ablative lasers, which remain the reference technique. However, the effects are not insignificant, requiring at least 5 days of social isolation.
Fractional Langevin equation and Riemann-Liouville fractional derivative.
Sau Fa, Kwok
2007-10-01
In this present work we consider a fractional Langevin equation with Riemann-Liouville fractional time derivative which modifies the classical Newtonian force, nonlocal dissipative force, and long-time correlation. We investigate the first two moments, variances and position and velocity correlation functions of this system. We also compare them with the results obtained from the same fractional Langevin equation which uses the Caputo fractional derivative.
Fractionated total body irradiation for metastatic neuroblastoma
Kun, L.E.; Casper, J.T.; Kline, R.W.; Piaskowski, V.D.
1981-11-01
Twelve patients over one year old with neuroblastoma (NBL) metastatic to bone and bone marrow entered a study of adjuvant low-dose, fractionated total body irradiation (TBI). Six children who achieved a ''complete clinical response'' following chemotherapy (cyclophosphamide and adriamycin) and surgical resection of the abdominal primary received TBI (10 rad/fraction to totals of 100-120 rad/10-12 fx/12-25 days). Two children received concurrent local irradiation for residual abdominal tumor. The intervals from cessation of chemotherapy to documented progression ranged from 2-16 months, not substatially different from patients receiving similar chemotherapy and surgery without TBI. Three additional children with progressive NBL received similar TBI (80-120 rad/8-12 fx) without objective response.
Preheating with fractional powers
NASA Astrophysics Data System (ADS)
Moghaddam, Hossein Bazrafshan; Brandenberger, Robert
2016-11-01
We consider preheating in models in which the potential for the inflaton is given by a fractional power, as is the case in axion monodromy inflation. We assume a standard coupling between the inflaton field and a scalar matter field. We find that in spite of the fact that the oscillation of the inflaton about the field value which minimizes the potential is anharmonic, there is nevertheless a parametric resonance instability, and we determine the Floquet exponent which describes this instability as a function of the parameters of the inflaton potential.
Solvent Fractionation of Lignin
Chatterjee, Sabornie; Saito, Tomonori
2014-01-01
Lignin is a highly abundant source of renewable carbon that can be considered as a valuable sustainable source of biobased materials. The major issues for the commercial production of value added high performance lignin products are lignin s physical and chemical heterogenities. To overcome these problems, a variety of procedures have been developed to produce pure lignin suitable for high performace applications such as lignin-derived carbon materials. However, most of the isolation procedures affect lignin s properties and structure. In this chapter, a short review of the effect of solvent fractionation on lignin s properties and structure is presented.
Fractional channel multichannel analyzer
Brackenbush, Larry W.; Anderson, Gordon A.
1994-01-01
A multichannel analyzer incorporating the features of the present invention obtains the effect of fractional channels thus greatly reducing the number of actual channels necessary to record complex line spectra. This is accomplished by using an analog-to-digital converter in the asynscronous mode, i.e., the gate pulse from the pulse height-to-pulse width converter is not synchronized with the signal from a clock oscillator. This saves power and reduces the number of components required on the board to achieve the effect of radically expanding the number of channels without changing the circuit board.
Fractional channel multichannel analyzer
Brackenbush, L.W.; Anderson, G.A.
1994-08-23
A multichannel analyzer incorporating the features of the present invention obtains the effect of fractional channels thus greatly reducing the number of actual channels necessary to record complex line spectra. This is accomplished by using an analog-to-digital converter in the asynchronous mode, i.e., the gate pulse from the pulse height-to-pulse width converter is not synchronized with the signal from a clock oscillator. This saves power and reduces the number of components required on the board to achieve the effect of radically expanding the number of channels without changing the circuit board. 9 figs.
NASA Astrophysics Data System (ADS)
Gallavotti, G.; Gentile, G.; Giuliani, A.
2006-01-01
The parametric equations of the surfaces on which highly resonant quasiperiodic motions develop (lower-dimensional tori) cannot be analytically continued, in general, in the perturbation parameter ɛ, i.e., they are not analytic functions of ɛ. However rather generally quasiperiodic motions whose frequencies satisfy only one rational relation ("resonances of order 1") admit formal perturbation expansions in terms of a fractional power of ɛ depending on the degeneration of the resonance. We find conditions for this to happen, and in such a case we prove that the formal expansion is convergent after suitable resummation.
Body Fractions: A Physical Approach to Fraction Learning
ERIC Educational Resources Information Center
Mills, Judith
2011-01-01
Many students experience great difficulty understanding the meaning of fractions. For many students who have spent their early mathematics lessons focusing on counting (whole) numbers, recognising that there are many numbers between those whole numbers called fractional numbers, is quite revolutionary. The foundation of understanding fractions is…
Akine, Y.; Tokita, N.; Ogino, T.; Kajiura, Y.; Tsukiyama, I.; Egawa, S. )
1990-12-01
By comparing the incidence of major radiation injury, we estimated doses clinically equivalent for high-dose-rate (HDR) to conventional low-dose-rate (LDR) intracavitary irradiation in patients with Stages IIb and IIIb cancer of the uterine cervix. We reviewed a total of 300 patients who were treated with external beam therapy to the pelvis (50 Gy in 5 weeks) followed either by low-dose-rate (253 patients) or high-dose-rate (47 patients) intracavitary treatment. The high-dose-rate intracavitary treatment was given 5 Gy per session to point A, 4 fractions in 2 weeks, with a total dose of 20 Gy. The low-dose-rate treatment was given with one or two application(s) delivering 11-52 Gy to the point A. The local control rates were similar in both groups. The incidence of major radiation injury requiring surgical intervention were 5.1% (13/253) and 4.3% (2/47) for low-dose-rate and high-dose-rate groups, respectively. The 4.3% incidence corresponded to 29.8 Gy with low-dose-rate irradiation, thus, it was concluded that the clinically equivalent dose for high-dose-rate irradiation was approximately 2/3 (20/29.8) of the dose used in low-dose-rate therapy.
Effects of fractionated radiation therapy on human brain tumor multicellular spheriods
Jih-Tsun Ho; Sarkar, A.; Kendal, L.E.; Hoshino, T.; Marton, L.J.; Deen, D.F. )
1993-01-15
We investigated the cytotoxic effects of fractionated radiation therapy on multicellular spheriods of human malignant glioma cell lines U-87 MG, U-251 MG, and U-373 MG. Graded doses of x-rays were administered in 1, 3, 8, 15, and 30 fractions over 15 days. The isoeffect dose for a 1 log cell kill ranged from 4-4.5 Gy for a single fraction to 7-8 Gy for an 8-fraction protocol; no additional dose-sparing was achieved with more fractions. Therefore, the effects of individual doses (1.56 Gy) of the 8-fraction protocol were studied in U-251 MG spheroids. A cell survival assay showed that the first dose of radiation killed 30-50% of the cells; subsequent doses usually killed fewer cells. The cell kill after all 8 doses was about 1.0 log. No consistent relationship between the intracellular glutathione level and fraction number was observed. The 24-hour labeling index of the spheroids did not decrease until after the second fraction. Thus, the higher cell kill of the first dose does not seem to be related to cell cycle synchrony. Multinuclear and mononuclear giant cells were limited almost entirely to the periphery of the spheriods and increased with the number of radiation fractions. We conclude that multicellular spheroids can be used to study the biological effects of fractionated radiation therapy on human brain tumor cells. Although this model cannot be used to evaluate the effect of radiation on normal tissue, it may be useful in developing more effective radiation therapy protocols for human brain tumors. 36 refs., 8 figs.
Fractional Vorticity Equations
NASA Astrophysics Data System (ADS)
Schertzer, D.; Tchguirinskaia, I.; Lovejoy, S.; Tuck, A.
2012-04-01
As a result of a thorough discussion (Schertzer et al., Atmos. Chem. Phys., 12, 327-336, 2012 ) of the limitations of the quasi-geostrophic approximation and turbulence, fractional vorticity equations were obtained. This was done with the help of an anisotropic scaling analysis, instead of the classical scale analysis, as done to derive the quasi-geostrophic approximation. This breaks the rotational symmetry of the classical 3D vorticity equations and a priori yields a (2 + Hz)-dimensional turbulence (0 ≤ Hz ≤ 1). This corresponds to a first step in the derivation of a dynamical alternative to the quasi-geostrophic approximation and turbulence. The corresponding precise definition of fractional dimensional turbulence already demonstrates that the classical 2-D and 3-D turbulence are not the main options to understand atmospheric and oceanic dynamics. Although (2 + Hz)-dimensional turbulence (with 0 < Hz < 1) has more common features with 3-D turbulence than with 2-D turbulence, it has nevertheless very distinctive features: its scaling anisotropy is in agreement with the layered pancake structure, which is typical of rotating and stratified turbulence, but not of the classical 3-D turbulence. In this presentation, we further discuss the properties of this set of deterministic-like equations, especially how they can generate a statistical scaling anisotropy, as well as the relevance of the theoretical value Hz = 5/9.
[Ablative and fractional lasers].
Beylot, C
2008-02-01
The use of pulsed or scanning Carbon Dioxide, and pulsed Erbium-YAG lasers allows the programmable and reproducible photocoagulation of thin layers of the epidermis and superficial dermis. Thermal damage depends on the type of laser and is greater with CO(2) lasers. The degree of neocollagenesis is proportional to the thermal damage and is better with CO(2) lasers. Their main indication is the correction of photoaged facial skin but they can also be used for corrective dermatology, e.g. for scars and genodermatosis. Results are highly satisfactory but the technique is invasive and the patient experiences a social hindrance of around two weeks. The fractional techniques such as Fraxel are used to treat non-adjacent microzones without ablation of the epidermis. Around 25 p. 100 of the affected region is treated per session without ablation of the epidermis. Each fraction is only mini-invasive and is performed under local anesthesia. Social hindrance is minimal. Nonetheless, the results are inferior to those obtained with ablative lasers, especially regarding deep wrinkles. The treatment is costly and four sessions are usually required to treat the whole affected area. Others regions of the face may also be treated. Encouraging results have been obtained with mélasma.
Absorbed Dose and Dose Equivalent Calculations for Modeling Effective Dose
NASA Technical Reports Server (NTRS)
Welton, Andrew; Lee, Kerry
2010-01-01
While in orbit, Astronauts are exposed to a much higher dose of ionizing radiation than when on the ground. It is important to model how shielding designs on spacecraft reduce radiation effective dose pre-flight, and determine whether or not a danger to humans is presented. However, in order to calculate effective dose, dose equivalent calculations are needed. Dose equivalent takes into account an absorbed dose of radiation and the biological effectiveness of ionizing radiation. This is important in preventing long-term, stochastic radiation effects in humans spending time in space. Monte carlo simulations run with the particle transport code FLUKA, give absorbed and equivalent dose data for relevant shielding. The shielding geometry used in the dose calculations is a layered slab design, consisting of aluminum, polyethylene, and water. Water is used to simulate the soft tissues that compose the human body. The results obtained will provide information on how the shielding performs with many thicknesses of each material in the slab. This allows them to be directly applicable to modern spacecraft shielding geometries.
Ejection Fraction Heart Failure Measurement
... Thromboembolism Aortic Aneurysm More Ejection Fraction Heart Failure Measurement Updated:Feb 15,2017 The ejection fraction (EF) is an important measurement in determining how well your heart is pumping ...
Positive fractional linear electrical circuits
NASA Astrophysics Data System (ADS)
Kaczorek, Tadeusz
2013-10-01
The positive fractional linear systems and electrical circuits are addressed. New classes of fractional asymptotically stable and unstable electrical circuits are introduced. The Caputo and Riemann-Liouville definitions of fractional derivatives are used to analysis of the positive electrical circuits composed of resistors, capacitors, coils and voltage (current) sources. The positive fractional electrical and specially unstable different types electrical circuits are analyzed. Some open problems are formulated.
Fractional Hopfield Neural Networks: Fractional Dynamic Associative Recurrent Neural Networks.
Pu, Yi-Fei; Yi, Zhang; Zhou, Ji-Liu
2017-10-01
This paper mainly discusses a novel conceptual framework: fractional Hopfield neural networks (FHNN). As is commonly known, fractional calculus has been incorporated into artificial neural networks, mainly because of its long-term memory and nonlocality. Some researchers have made interesting attempts at fractional neural networks and gained competitive advantages over integer-order neural networks. Therefore, it is naturally makes one ponder how to generalize the first-order Hopfield neural networks to the fractional-order ones, and how to implement FHNN by means of fractional calculus. We propose to introduce a novel mathematical method: fractional calculus to implement FHNN. First, we implement fractor in the form of an analog circuit. Second, we implement FHNN by utilizing fractor and the fractional steepest descent approach, construct its Lyapunov function, and further analyze its attractors. Third, we perform experiments to analyze the stability and convergence of FHNN, and further discuss its applications to the defense against chip cloning attacks for anticounterfeiting. The main contribution of our work is to propose FHNN in the form of an analog circuit by utilizing a fractor and the fractional steepest descent approach, construct its Lyapunov function, prove its Lyapunov stability, analyze its attractors, and apply FHNN to the defense against chip cloning attacks for anticounterfeiting. A significant advantage of FHNN is that its attractors essentially relate to the neuron's fractional order. FHNN possesses the fractional-order-stability and fractional-order-sensitivity characteristics.
The Small Wonders of Fractions.
ERIC Educational Resources Information Center
May, Lola
1996-01-01
Presents five math activities designed to help students understand fractions, keep students motivated, and help them maintain their math skills. The activities are "What's in a Name?""Fractured Words,""Egyptian Fractions,""More Fractured Fractions,""Name the Parts," and "Timely Device."…
Fractional diffusion on bounded domains
Defterli, Ozlem; D'Elia, Marta; Du, Qiang; ...
2015-03-13
We found that the mathematically correct specification of a fractional differential equation on a bounded domain requires specification of appropriate boundary conditions, or their fractional analogue. In this paper we discuss the application of nonlocal diffusion theory to specify well-posed fractional diffusion equations on bounded domains.
Fractional diffusion on bounded domains
Defterli, Ozlem; D'Elia, Marta; Du, Qiang; Gunzburger, Max Donald; Lehoucq, Richard B.; Meerschaert, Mark M.
2015-03-13
We found that the mathematically correct specification of a fractional differential equation on a bounded domain requires specification of appropriate boundary conditions, or their fractional analogue. In this paper we discuss the application of nonlocal diffusion theory to specify well-posed fractional diffusion equations on bounded domains.
How Weird Are Weird Fractions?
ERIC Educational Resources Information Center
Stuffelbeam, Ryan
2013-01-01
A positive rational is a weird fraction if its value is unchanged by an illegitimate, digit-based reduction. In this article, we prove that each weird fraction is uniquely weird and initiate a discussion of the prevalence of weird fractions.
How Weird Are Weird Fractions?
ERIC Educational Resources Information Center
Stuffelbeam, Ryan
2013-01-01
A positive rational is a weird fraction if its value is unchanged by an illegitimate, digit-based reduction. In this article, we prove that each weird fraction is uniquely weird and initiate a discussion of the prevalence of weird fractions.
The random continued fraction transformation
NASA Astrophysics Data System (ADS)
Kalle, Charlene; Kempton, Tom; Verbitskiy, Evgeny
2017-03-01
We introduce a random dynamical system related to continued fraction expansions. It uses random combinations of the Gauss map and the Rényi (or backwards) continued fraction map. We explore the continued fraction expansions that this system produces, as well as the dynamical properties of the system.
Numerical approaches to fractional calculus and fractional ordinary differential equation
NASA Astrophysics Data System (ADS)
Li, Changpin; Chen, An; Ye, Junjie
2011-05-01
Nowadays, fractional calculus are used to model various different phenomena in nature, but due to the non-local property of the fractional derivative, it still remains a lot of improvements in the present numerical approaches. In this paper, some new numerical approaches based on piecewise interpolation for fractional calculus, and some new improved approaches based on the Simpson method for the fractional differential equations are proposed. We use higher order piecewise interpolation polynomial to approximate the fractional integral and fractional derivatives, and use the Simpson method to design a higher order algorithm for the fractional differential equations. Error analyses and stability analyses are also given, and the numerical results show that these constructed numerical approaches are efficient.
Use of radiation protraction to escalate biologically effective dose to the treatment target
Kuperman, V. Y.; Spradlin, G. S.
2011-12-15
Purpose: The aim of this study is to evaluate how simultaneously increasing fraction time and dose per fraction affect biologically effective dose for the target (BED{sub tar}) while biologically effective dose for the normal tissue (BED{sub nt}) is fixed. Methods: In this investigation, BED{sub tar} and BED{sub nt} were studied by assuming mono-exponential repair of sublethal damage with tissue dependent repair half-time. Results: Our results demonstrate that under certain conditions simultaneously increasing fraction time and dose per fraction result in increased BED{sub tar} while BED{sub nt} is fixed. The dependence of biologically effective dose on fraction time is influenced by the dose rate. In this investigation we analytically determined time-varying dose rate R-tilde which minimizes BED. Changes in BED with fraction time were compared for constant dose rate and for R-tilde. Conclusions: A number of recent experimental and theoretical studies have demonstrated that slow delivery of radiation (known as radiation protraction) leads to reduced therapeutic effect because of increased repair of sublethal damage. In contrast, our analysis shows that under certain conditions simultaneously increasing fraction time and dose per fraction are radiobiologically advantageous.
Concept for quantifying the dose from image guided radiotherapy.
Schneider, Uwe; Hälg, Roger; Besserer, Jürgen
2015-09-17
Radiographic image guidance is routinely used for patient positioning in radiotherapy. All radiographic guidance techniques can give a significant radiation dose to the patient. The dose from diagnostic imaging is usually managed by using effective dose minimization. In contrast, image-guided radiotherapy adds the imaging dose to an already high level of therapeutic radiation which cannot be easily managed using effective dose. The purpose of this work is the development of a concept of IGRT dose quantification which allows a comparison of imaging dose with commonly accepted variations of therapeutic dose. It is assumed that dose variations of the treatment beam which are accepted in the spirit of the ALARA convention can also be applied to the additional imaging dose. Therefore we propose three dose categories: Category I: The imaging dose is lower than a 2% variation of the therapy dose. Category II: The imaging dose is larger than in category I, but lower than the therapy dose variations between different treatment techniques. Category III: The imaging dose is larger than in Category II. For various treatment techniques dose measurements are used to define the dose categories. The imaging devices were categorized according to the measured dose. Planar kV-kV imaging is a category I imaging procedure. kV-MV imaging is located at the edge between category I and II and is for increasing fraction size safely a category I imaging technique. MV-MV imaging is for all imaging technologies a category II procedure. MV fan beam CT for localization is a category I technology. Low dose protocols for kV CBCT are located between category I and II and are for increasing fraction size a category I imaging technique. All other investigated Pelvis-CBCT protocols are category II procedures. Fan beam CT scout views are category I technology. Live imaging modalities are category III for conventional fractionation, but category II for stereotactic treatments. Dose from radiotherapy
Fractional chemotaxis diffusion equations.
Langlands, T A M; Henry, B I
2010-05-01
We introduce mesoscopic and macroscopic model equations of chemotaxis with anomalous subdiffusion for modeling chemically directed transport of biological organisms in changing chemical environments with diffusion hindered by traps or macromolecular crowding. The mesoscopic models are formulated using continuous time random walk equations and the macroscopic models are formulated with fractional order differential equations. Different models are proposed depending on the timing of the chemotactic forcing. Generalizations of the models to include linear reaction dynamics are also derived. Finally a Monte Carlo method for simulating anomalous subdiffusion with chemotaxis is introduced and simulation results are compared with numerical solutions of the model equations. The model equations developed here could be used to replace Keller-Segel type equations in biological systems with transport hindered by traps, macromolecular crowding or other obstacles.
NASA Technical Reports Server (NTRS)
Greenberg, Paul S.; Ku, Jerry C.
1994-01-01
A new technique is described for the full-field determination of soot volume fractions via laser extinction measurements. This technique differs from previously reported point-wise methods in that a two-dimensional array (i.e., image) of data is acquired simultaneously. In this fashion, the net data rate is increased, allowing the study of time-dependent phenomena and the investigation of spatial and temporal correlations. A telecentric imaging configuration is employed to provide depth-invariant magnification and to permit the specification of the collection angle for scattered light. To improve the threshold measurement sensitivity, a method is employed to suppress undesirable coherent imaging effects. A discussion of the tomographic inversion process is provided, including the results obtained from numerical simulation. Results obtained with this method from an ethylene diffusion flame are shown to be in close agreement with those previously obtained by sequential point-wise interrogation.
Fraction Reduction in Membrane Systems
Zhang, Hong
2014-01-01
Fraction reduction is a basic computation for rational numbers. P system is a new computing model, while the current methods for fraction reductions are not available in these systems. In this paper, we propose a method of fraction reduction and discuss how to carry it out in cell-like P systems with the membrane structure and the rules with priority designed. During the application of fraction reduction rules, synchronization is guaranteed by arranging some special objects in these rules. Our work contributes to performing the rational computation in P systems since the rational operands can be given in the form of fraction. PMID:24772037
Absorbed fractions for electrons in ellipsoidal volumes.
Amato, E; Lizio, D; Baldari, S
2011-01-21
We applied a Monte Carlo simulation in Geant4 in order to calculate the absorbed fractions for monoenergetic electrons in the energy interval between 10 keV and 2 MeV, uniformly distributed in ellipsoids made from soft tissue. For each volume, we simulated a spherical shape, four oblate and four prolate ellipsoids, and one scalene shape. For each energy and for every geometrical configuration, an analytical relationship between the absorbed fraction and a 'generalized radius' was found, and the dependence of the fit parameters from electron energy is discussed and fitted by proper parametric functions. With the proposed formulation, the absorbed fraction for electrons in the 10-2000 keV energy range can be calculated for all volumes and for every ellipsoidal shape of practical interest. This method can be directly applied to evaluation of the absorbed fraction from the radionuclide emission of monoenergetic electrons, such as Auger or conversion electrons. The average deposited energy per disintegration in the case of extended beta spectra can be evaluated through integration. Two examples of application to a pure beta emitter such as (90)Y and to (131)I, whose emission include monoenergetic and beta electrons plus gamma photons, are presented. This approach represent a generalization of our previous studies, allowing a comprehensive treatment of absorbed fractions from electron and photon sources uniformly distributed in ellipsoidal volumes of any ellipticity and volume, in the whole range of practical interest for internal dosimetry in nuclear medicine applications, as well as in radiological protection estimations of doses from an internal contamination.
Absorbed fractions for electrons in ellipsoidal volumes
NASA Astrophysics Data System (ADS)
Amato, E.; Lizio, D.; Baldari, S.
2011-01-01
We applied a Monte Carlo simulation in Geant4 in order to calculate the absorbed fractions for monoenergetic electrons in the energy interval between 10 keV and 2 MeV, uniformly distributed in ellipsoids made from soft tissue. For each volume, we simulated a spherical shape, four oblate and four prolate ellipsoids, and one scalene shape. For each energy and for every geometrical configuration, an analytical relationship between the absorbed fraction and a 'generalized radius' was found, and the dependence of the fit parameters from electron energy is discussed and fitted by proper parametric functions. With the proposed formulation, the absorbed fraction for electrons in the 10-2000 keV energy range can be calculated for all volumes and for every ellipsoidal shape of practical interest. This method can be directly applied to evaluation of the absorbed fraction from the radionuclide emission of monoenergetic electrons, such as Auger or conversion electrons. The average deposited energy per disintegration in the case of extended beta spectra can be evaluated through integration. Two examples of application to a pure beta emitter such as 90Y and to 131I, whose emission include monoenergetic and beta electrons plus gamma photons, are presented. This approach represent a generalization of our previous studies, allowing a comprehensive treatment of absorbed fractions from electron and photon sources uniformly distributed in ellipsoidal volumes of any ellipticity and volume, in the whole range of practical interest for internal dosimetry in nuclear medicine applications, as well as in radiological protection estimations of doses from an internal contamination.
Radiation Dose-Volume Effects in the Lung
Marks, Lawrence B.; Bentzen, Soren M. D.Sc.; Deasy, Joseph O.; Kong, F.-M.; Bradley, Jeffrey D.; Vogelius, Ivan S.; El Naqa, Issam; Hubbs, Jessica L. M.S.; Lebesque, Joos V.; Timmerman, Robert D.; Martel, Mary K.; Jackson, Andrew
2010-03-01
The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold 'tolerance dose-volume' levels. There are strong volume and fractionation effects.
Low dose neutron late effects: Cataractogenesis
Worgul, B.V.
1991-12-01
The work is formulated to resolve the uncertainty regarding the relative biological effectiveness (RBE) of low dose neutron radiation. The study exploits the fact that cataractogenesis is sensitive to the inverse dose-rate effect as has been observed with heavy ions and was an endpoint considered in the follow-up of the A-bomb survivors. The neutron radiations were initiated at the Radiological Research Accelerator facility (RARAF) of the Nevis Laboratory of Columbia University. Four week old ({plus minus} 1 day) rats were divided into eight dose groups each receiving single or fractionated total doses of 0.2, 1.0, 5.0 and 25.0 cGy of monoenergetic 435 KeV neutrons. Special restraining jigs insured that the eye, at the midpoint of the lens, received the appropriate energy and dose with a relative error of {plus minus}5%. The fractionation regimen consisted of four exposures, each administered at three hour ({plus minus}) intervals. The neutron irradiated groups are being compared to rats irradiated with 250kVp X-rays in doses ranging from 0.5 to 7 Gy. The animals are being examined on a biweekly basis utilizing conventional slit-lamp biomicroscopy and the Scheimpflug Slit Lamp Imaging System (Zeiss). The follows-ups, entering their second year, will continue throughout the life-span of the animals. This is essential inasmuch as given the extremely low doses which are being utilized clinically detectable opacities were not anticipated until a significant fraction of the life span has lapsed. Current data support this contention. At this juncture cataracts in the irradiated groups are beginning to exceed control levels.
Effect of Fractionation in Stereotactic Body Radiation Therapy Using the Linear Quadratic Model
Yang, Jun; Lamond, John; Fowler, Jack; Lanciano, Rachelle; Feng, Jing; Brady, Luther
2013-05-01
Purpose: To examine the fractionation effect of stereotactic body radiation therapy with a heterogeneous dose distribution. Methods: Derived from the linear quadratic formula with measurements from a hypothetical 2-cm radiosurgical tumor, the threshold percentage was defined as (α/β{sub tissue}/α/β{sub tumor}), the balance α/β ratio was defined as (prescription dose/tissue tolerance*α/β{sub tumor}), and the balance dose was defined as (tissue tolerance/threshold percentage). Results: With increasing fractions and equivalent peripheral dose to the target, the biological equivalent dose of “hot spots” in a target decreases. The relative biological equivalent doses of serial organs decrease only when the relative percentage of its dose to the prescription dose is above the threshold percentage. The volume of parallel organs at risk decreases only when the tumor's α/β ratio is above the balance α/β ratio and the prescription dose is lower than balance dose. Conclusions: The potential benefits of fractionation in stereotactic body radiation therapy depend on the complex interplay between the total dose, α/β ratios, and dose differences between the target and the surrounding normal tissues.
The radiobiology of prostate cancer including new aspects of fractionated radiotherapy.
Fowler, Jack F
2005-01-01
Total radiation dose is not a reliable measure of biological effect when dose-per-fraction or dose-rate is changed. Large differences in biological effectiveness (per gray) are seen between the 2 Gy doses of external beam radiotherapy and the large boost doses given at high dose-rate from afterloading sources. The effects are profoundly different in rapidly or slowly proliferating tissues, that is for most tumors versus late complications. These differences work the opposite way round for prostate tumors versus late complications compared with most other types of tumor. Using the Linear-Quadratic formula it is aimed to explain these differences, especially for treatments of prostate cancer. The unusually slow growth rate of prostate cancers is associated with their high sensitivity to increased fraction size, so a large number of small fractions, such as 35 or 40 "daily" doses of 2 Gy, is not an optimum treatment. Theoretical modeling shows a stronger enhancement of tumor effect than of late complications for larger (and fewer) fractions, in prostate tumors uniquely. Biologically Effective Doses and Normalized Total Doses (in 2 Gy fraction equivalents) are given for prostate tumor, late rectal reactions, and--a new development--acute rectal mucosa. Tables showing the change of fraction-size sensitivity (the alpha/beta ratio) with proliferation rates of tissues lead to the association of slow cell doubling times in prostate tumors with small alpha/beta ratios. Clinical evidence to confirm this biological expectation is reviewed. The alpha/beta ratios of prostate tumors appear to be as low as 1.5 Gy (95% confidence interval 1.3-1.8 Gy), in contrast with the value of about 10 Gy for most other types of tumor. The important point is that alpha/beta =1.5 Gy appears to be significantly less than the alpha/beta =3 Gy for late complications in rectal tissues. Such differences are also emerging from recent clinical results. From this important difference stems the superior
Peripheral doses from pediatric IMRT
Klein, Eric E.; Maserang, Beth; Wood, Roy; Mansur, David
2006-07-15
from 0.47-0.94) doses {approx}[0.4-1.8 cGy]/[0.9-2.9 cGy]/fraction, respectively. Prior phantom reports are for fields 10 cm or greater, while pediatric central nervous system fields range from 4 to 7 cm, and effectively much smaller for IMRT (2-6 cm). Peripheral dose in close proximity (<10 cm from the field edge) is dominated by internal scatter; therefore, field-size differences overwhelm phantom size affects and increased MU. Distant peripheral dose, dominated by head leakage, was higher than predicted, even when accounting for MUs ({approx}factor of 3) likely due to the pediatric phantom size. The ratio of the testes dose ranged from 3.3-5.3 for IMRT/conventional. PD to OAR for pediatric IMRT cannot be predicted from large-field full phantom studies. For regional OAR, doses are likely lower than predicted by existing ''large field'' data, while the distant PD is higher.
Fractionally charged skyrmions in fractional quantum Hall effect.
Balram, Ajit C; Wurstbauer, U; Wójs, A; Pinczuk, A; Jain, J K
2015-11-26
The fractional quantum Hall effect has inspired searches for exotic emergent topological particles, such as fractionally charged excitations, composite fermions, abelian and nonabelian anyons and Majorana fermions. Fractionally charged skyrmions, which support both topological charge and topological vortex-like spin structure, have also been predicted to occur in the vicinity of 1/3 filling of the lowest Landau level. The fractional skyrmions, however, are anticipated to be exceedingly fragile, suppressed by very small Zeeman energies. Here we show that, slightly away from 1/3 filling, the smallest manifestations of the fractional skyrmion exist in the excitation spectrum for a broad range of Zeeman energies, and appear in resonant inelastic light scattering experiments as well-defined resonances slightly below the long wavelength spin wave mode. The spectroscopy of these exotic bound states serves as a sensitive tool for investigating the residual interaction between composite fermions, responsible for delicate new fractional quantum Hall states in this filling factor region.
Fractionally charged skyrmions in fractional quantum Hall effect
Balram, Ajit C.; Wurstbauer, U.; Wójs, A.; Pinczuk, A.; Jain, J. K.
2015-11-26
The fractional quantum Hall effect has inspired searches for exotic emergent topological particles, such as fractionally charged excitations, composite fermions, abelian and nonabelian anyons and Majorana fermions. Fractionally charged skyrmions, which support both topological charge and topological vortex-like spin structure, have also been predicted to occur in the vicinity of 1/3 filling of the lowest Landau level. The fractional skyrmions, however, are anticipated to be exceedingly fragile, suppressed by very small Zeeman energies. Here we show that, slightly away from 1/3 filling, the smallest manifestations of the fractional skyrmion exist in the excitation spectrum for a broad range of Zeeman energies, and appear in resonant inelastic light scattering experiments as well-defined resonances slightly below the long wavelength spin wave mode. The spectroscopy of these exotic bound states serves as a sensitive tool for investigating the residual interaction between composite fermions, responsible for delicate new fractional quantum Hall states in this filling factor region.
Effect-independent measures of tissue responses to fractionated irradiation.
Thames, H D
1984-01-01
Tissue repair factors measure the sparing that can be achieved from dose fractionation in the absence of proliferation. Four repair factors are analysed in these terms: FR, Frec, the ratio of linear-quadratic survival model parameters beta/alpha, and the half-time T1/2 for intracellular repair processes. A desirable feature of any repair factor is that it be independent of the level of injury induced in the tissue (or its single-dose equivalent, D1), since the comparison of tissues on the basis of the factor would not be meaningful, if they were characterized by differing D1S. Theoretically, FR and Frec are increasing functions of D1, and thus depend on level of effect. This is confirmed by analysis of skin reactions after multifractionated radiation. By contrast, beta/alpha is effect-independent as a measure of repair capacity in skin, gut, and bone marrow, tissues for which it is reasonable to assume that survival of identifiable target cells is the primary determinant of the endpoint. For a functional endpoint not clearly connected with the depletion of a specific target-cell population (late fibrotic reactions in the kidney), there was an increase in beta/alpha with increased levels of injury, but this was statistically insignificant. Effect-independence is defined for T1/2 as independence from size of dose per fraction. T1/2 is independent of fraction size in skin, gut, and spinal cord, and is longer (1.5 hours) in the late-reacting tissues (lung and spinal cord) than in those that react acutely (T1/2 less than 1 hour), with skin as the exception (T1/2 approximately 1.3 hours). Therefore, early and late-responding normal tissues may be distinguished in terms of both repair capacity and repair kinetics: repair is slower in late-responding tissues, which are also more sensitive to changes in dose fractionation. If generally true, these results imply that the potential for a therapeutic gain from hyperfractionation to spare late effects differentially would be
NASA Astrophysics Data System (ADS)
Hanin, Leonid; Zaider, Marco
2014-08-01
We revisit a long-standing problem of optimization of fractionated radiotherapy and solve it in considerable generality under the following three assumptions only: (1) repopulation of clonogenic cancer cells between radiation exposures follows linear birth-and-death Markov process; (2) clonogenic cancer cells do not interact with each other; and (3) the dose response function s(D) is decreasing and logarithmically concave. Optimal schedules of fractionated radiation identified in this work can be described by the following ‘greedy’ principle: give the maximum possible dose as soon as possible. This means that upper bounds on the total dose and the dose per fraction reflecting limitations on the damage to normal tissue, along with a lower bound on the time between successive fractions of radiation, determine the optimal radiation schedules completely. Results of this work lead to a new paradigm of dose delivery which we term optimal biologically-based adaptive boosting (OBBAB). It amounts to (a) subdividing the target into regions that are homogeneous with respect to the maximum total dose and maximum dose per fraction allowed by the anatomy and biological properties of the normal tissue within (or adjacent to) the region in question and (b) treating each region with an individual optimal schedule determined by these constraints. The fact that different regions may be treated to different total dose and dose per fraction mean that the number of fractions may also vary between regions. Numerical evidence suggests that OBBAB produces significantly larger tumor control probability than the corresponding conventional treatments.
An improved fractional divider for fractional-N frequency synthesizers
NASA Astrophysics Data System (ADS)
Zhang, Wei; Liu, Yang; Zhou, Yongqi
2009-07-01
This paper presents an improved fractional divider used in 1.8~2GHz fractional-N frequency synthesizers. A new clock setting for delta-sigma modulator (DSM) is proposed to prevent the potential problems of traditional fractional dividers: the DSM output would be wrongly loaded and the action of DSM circuit may affect the phase-detection of phase-frequency-detector (PFD). Simulation result shows the effectiveness of this improvement.
Fractional variational calculus in terms of Riesz fractional derivatives
NASA Astrophysics Data System (ADS)
Agrawal, O. P.
2007-06-01
This paper presents extensions of traditional calculus of variations for systems containing Riesz fractional derivatives (RFDs). Specifically, we present generalized Euler-Lagrange equations and the transversality conditions for fractional variational problems (FVPs) defined in terms of RFDs. We consider two problems, a simple FVP and an FVP of Lagrange. Results of the first problem are extended to problems containing multiple fractional derivatives, functions and parameters, and to unspecified boundary conditions. For the second problem, we present Lagrange-type multiplier rules. For both problems, we develop the Euler-Lagrange-type necessary conditions which must be satisfied for the given functional to be extremum. Problems are considered to demonstrate applications of the formulations. Explicitly, we introduce fractional momenta, fractional Hamiltonian, fractional Hamilton equations of motion, fractional field theory and fractional optimal control. The formulations presented and the resulting equations are similar to the formulations for FVPs given in Agrawal (2002 J. Math. Anal. Appl. 272 368, 2006 J. Phys. A: Math. Gen. 39 10375) and to those that appear in the field of classical calculus of variations. These formulations are simple and can be extended to other problems in the field of fractional calculus of variations.
Radiotherapy for laryngeal cancer—technical aspects and alternate fractionation
Suzuki, Gen; Nakamura, Satoaki; Yoshida, Ken; Konishi, Koji; Teshima, Teruki; Ogawa, Kazuhiko
2017-01-01
Abstract Early laryngeal, especially glottic, cancer is a good candidate for radiotherapy because obvious early symptoms (e.g. hoarseness) make earlier treatment possible and with highly successful localized control. This type of cancer is also a good model for exploring the basic principles of radiation oncology and several key findings (e.g. dose, fractionation, field size, patient fixation, and overall treatment time) have been noted. For example, unintended poor outcomes have been reported during transition from 60Cobalt to linear accelerator installation in the 1960s, with usage of higher energy photons causing poor dose distribution. In addition, shell fixation made precise dose delivery possible, but simultaneously elevated toxicity if a larger treatment field was necessary. Of particular interest to the radiation therapy community was altered fractionation gain as a way to improve local tumor control and survival rate. Unfortunately, this interest ceased with advancements in chemotherapeutic agents because alternate fractionation could not improve outcomes in chemoradiotherapy settings. At present, no form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy. In addition, the substantial workload associated with this technique made it difficult to add extra fractionation routinely in busy clinical hospitals. Hypofractionation, on the other hand, uses a larger single fractionation dose (2–3 Gy), making it a reasonable and attractive option for T1–T2 early glottic cancer because it can improve local control without the additional workload. Recently, Japan Clinical Oncology Group study 0701 reprised its role in early T1–T2 glottic cancer research, demonstrating that this strategy could be an optional standard therapy. Herein, we review radiotherapy history from 60Cobalt to modern linear accelerator, with special focus on the role of alternate fractionation. PMID:28898958
Radiotherapy for laryngeal cancer-technical aspects and alternate fractionation.
Yamazaki, Hideya; Suzuki, Gen; Nakamura, Satoaki; Yoshida, Ken; Konishi, Koji; Teshima, Teruki; Ogawa, Kazuhiko
2017-07-01
Early laryngeal, especially glottic, cancer is a good candidate for radiotherapy because obvious early symptoms (e.g. hoarseness) make earlier treatment possible and with highly successful localized control. This type of cancer is also a good model for exploring the basic principles of radiation oncology and several key findings (e.g. dose, fractionation, field size, patient fixation, and overall treatment time) have been noted. For example, unintended poor outcomes have been reported during transition from 60Cobalt to linear accelerator installation in the 1960s, with usage of higher energy photons causing poor dose distribution. In addition, shell fixation made precise dose delivery possible, but simultaneously elevated toxicity if a larger treatment field was necessary. Of particular interest to the radiation therapy community was altered fractionation gain as a way to improve local tumor control and survival rate. Unfortunately, this interest ceased with advancements in chemotherapeutic agents because alternate fractionation could not improve outcomes in chemoradiotherapy settings. At present, no form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy. In addition, the substantial workload associated with this technique made it difficult to add extra fractionation routinely in busy clinical hospitals. Hypofractionation, on the other hand, uses a larger single fractionation dose (2-3 Gy), making it a reasonable and attractive option for T1-T2 early glottic cancer because it can improve local control without the additional workload. Recently, Japan Clinical Oncology Group study 0701 reprised its role in early T1-T2 glottic cancer research, demonstrating that this strategy could be an optional standard therapy. Herein, we review radiotherapy history from 60Cobalt to modern linear accelerator, with special focus on the role of alternate fractionation. © The Author 2017. Published by Oxford University Press on behalf of The
Ir-192 HDR transit dose and radial dose function determination using alanine/EPR dosimetry
NASA Astrophysics Data System (ADS)
Guzmán Calcina, Carmen S.; de Almeida, Adelaide; Oliveira Rocha, José R.; Abrego, Felipe Chen; Baffa, Oswaldo
2005-03-01
Source positioning close to the tumour in high dose rate (HDR) brachytherapy is not instantaneous. An increment of dose will be delivered during the movement of the source in the trajectory to its static position. This increment is the transit dose, often not taken into account in brachytherapeutic treatment planning. The transit dose depends on the prescribed dose, number of treatment fractions, velocity and activity of the source. Combining all these factors, the transit dose can be 5% higher than the prescribed absorbed dose value (Sang-Hyun and Muller-Runkel, 1994 Phys. Med. Biol. 39 1181 8, Nath et al 1995 Med. Phys. 22 209 34). However, it cannot exceed this percentage (Nath et al 1995). In this work, we use the alanine-EPR (electron paramagnetic resonance) dosimetric system using analysis of the first derivative of the signal. The transit dose was evaluated for an HDR system and is consistent with that already presented for TLD dosimeters (Bastin et al 1993 Int. J. Radiat. Oncol. Biol. Phys. 26 695 702). Also using the same dosimetric system, the radial dose function, used to evaluate the geometric dose degradation around the source, was determined and its behaviour agrees better with those obtained by Monte Carlo simulations (Nath et al 1995, Williamson and Nath 1991 Med. Phys. 18 434 48, Ballester et al 1997 Med. Phys. 24 1221 8, Ballester et al 2001 Phys. Med. Biol. 46 N79 90) than with TLD measurements (Nath et al 1990 Med. Phys. 17 1032 40).
Yang, Haihua; Tu, Yu; Wang, Wei; Hu, Wei; Ding, Weijun; Yu, Changhui; Zhou, Chao
2013-11-04
The purpose of this study was to compare anatomical and dosimetric variations in first 15 fractions, and between fractions 16 and 25, during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). Twenty-three NPC patients who received IMRT in 33 fractions were enrolled. Each patient had two repeat computed tomography (CT) scans before the 16th and 25th fraction. Hybrid IMRT plans were generated to evaluate the dosimetric changes. There was a significant decrease of the transverse diameter of nasopharyngeal and neck as well as gross tumor volume (GTV) in the primary nasopharyngeal carcinoma (GTVnx) and involved lymph nodes (GTVnd) during the first 15 fractions, and between fraction 16 and 25 (p < 0.05). Consequently, there was a significant reduction of the percentage of the volume receiving the prescribed dose (V100) of CTV1 and GTVnd, which was more prominent after the first 15 fractions treatment compared to that between fraction 16 and 25 (p < 0.05). Additionally, there was a significant increase in the mean dose (Dmean) and percentage of volume receiving ≥ 30 Gy (V30) to the bilateral parotid in the first 15 fractions (p < 0.05), but not between fraction 16 and 25. While the maximum dose to the spinal cord was significantly increased both in the first 15 fractions, and between fraction 16 and 25 (p < 0.05), the increase of the percent of spinal cord volume receiving ≥ 40 Gy (V40) was significantly higher in the first 15 fractions compared to that between fraction 16 and 25 (p < 0.05). Based on the dose constraint criterion in the RTOG0225 protocol, a total 39.1% (9/23) of phantom plan 1 (generated by applying the beam configurations of the original IMRT treatment plan to the anatomy of the second CT scan) and 17.4% (4/23) of phantom 2 (generated by applying the beam configurations of the replan 1 to the anatomy of the third CT scan) were out of limit for the dose to the normal critical structures. In conclusion, our data indicated that
Variability of Marker-Based Rectal Dose Evaluation in HDR Cervical Brachytherapy
Wang Zhou; Jaggernauth, Wainwright; Malhotra, Harish K.; Podgorsak, Matthew B.
2010-01-01
In film-based intracavitary brachytherapy for cervical cancer, position of the rectal markers may not accurately represent the anterior rectal wall. This study was aimed at analyzing the variability of rectal dose estimation as a result of interfractional variation of marker placement. A cohort of five patients treated with multiple-fraction tandem and ovoid high-dose-rate (HDR) brachytherapy was studied. The cervical os point and the orientation of the applicators were matched among all fractional plans for each patient. Rectal points obtained from all fractions were then input into each clinical treated plan. New fractional rectal doses were obtained and a new cumulative rectal dose for each patient was calculated. The maximum interfractional variation of distances between rectal dose points and the closest source positions was 1.1 cm. The corresponding maximum variability of fractional rectal dose was 65.5%. The percentage difference in cumulative rectal dose estimation for each patient was 5.4%, 19.6%, 34.6%, 23.4%, and 1