10 CFR 34.45 - Operating and emergency procedures.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.45 Operating and... that no person is likely to be exposed to radiation doses in excess of the limits established in 10 CFR...

10 CFR 34.45 - Operating and emergency procedures.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.45 Operating and... that no person is likely to be exposed to radiation doses in excess of the limits established in 10 CFR...

10 CFR 34.45 - Operating and emergency procedures.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.45 Operating and... that no person is likely to be exposed to radiation doses in excess of the limits established in 10 CFR...

10 CFR 34.45 - Operating and emergency procedures.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.45 Operating and... that no person is likely to be exposed to radiation doses in excess of the limits established in 10 CFR...

10 CFR 34.45 - Operating and emergency procedures.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.45 Operating and... that no person is likely to be exposed to radiation doses in excess of the limits established in 10 CFR...

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

Larner, J.

In this interactive session, lung SBRT patient cases will be presented to highlight real-world considerations for ensuring safe and accurate treatment delivery. An expert panel of speakers will discuss challenges specific to lung SBRT including patient selection, patient immobilization techniques, 4D CT simulation and respiratory motion management, target delineation for treatment planning, online treatment alignment, and established prescription regimens and OAR dose limits. Practical examples of cases, including the patient flow thought the clinical process are presented and audience participation will be encouraged. This panel session is designed to provide case demonstration and review for lung SBRT in terms ofmore » (1) clinical appropriateness in patient selection, (2) strategies for simulation, including 4D and respiratory motion management, and (3) applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent, and (4) image guidance in treatment delivery. Learning Objectives: Understand the established requirements for patient selection in lung SBRT Become familiar with the various immobilization strategies for lung SBRT, including technology for respiratory motion management Understand the benefits and pitfalls of applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent determination for lung SBRT Understand established prescription regimes and OAR dose limits.« less

Clinical validation and applications for CT-based atlas for contouring the lower cranial nerves for head and neck cancer radiation therapy.

PubMed

Mourad, Waleed F; Young, Brett M; Young, Rebekah; Blakaj, Dukagjin M; Ohri, Nitin; Shourbaji, Rania A; Manolidis, Spiros; Gámez, Mauricio; Kumar, Mahesh; Khorsandi, Azita; Khan, Majid A; Shasha, Daniel; Blakaj, Adriana; Glanzman, Jonathan; Garg, Madhur K; Hu, Kenneth S; Kalnicki, Shalom; Harrison, Louis B

2013-09-01

Radiation induced cranial nerve palsy (RICNP) involving the lower cranial nerves (CNs) is a serious complication of head and neck radiotherapy (RT). Recommendations for delineating the lower CNs on RT planning studies do not exist. The aim of the current study is to develop a standardized methodology for contouring CNs IX-XII, which would help in establishing RT limiting doses for organs at risk (OAR). Using anatomic texts, radiologic data, and guidance from experts in head and neck anatomy, we developed step-by-step instructions for delineating CNs IX-XII on computed tomography (CT) imaging. These structures were then contoured on five consecutive patients who underwent definitive RT for locally-advanced head and neck cancer (LAHNC). RT doses delivered to the lower CNs were calculated. We successfully developed a contouring atlas for CNs IX-XII. The median total dose to the planning target volume (PTV) was 70Gy (range: 66-70Gy). The median CN (IX-XI) and (XII) volumes were 10c.c (range: 8-12c.c) and 8c.c (range: 7-10c.c), respectively. The median V50, V60, V66, and V70 of the CN (IX-XI) and (XII) volumes were (85, 77, 71, 65) and (88, 80, 74, 64) respectively. The median maximal dose to the CN (IX-XI) and (XII) were 72Gy (range: 66-77) and 71Gy (range: 64-78), respectively. We have generated simple instructions for delineating the lower CNs on RT planning imaging. Further analyses to explore the relationship between lower CN dosing and the risk of RICNP are recommended in order to establish limiting doses for these OARs. Published by Elsevier Ltd.

An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma.

PubMed

von Tresckow, Bastian; Morschhauser, Franck; Ribrag, Vincent; Topp, Max S; Chien, Caly; Seetharam, Shobha; Aquino, Regina; Kotoulek, Sonja; de Boer, Carla J; Engert, Andreas

2015-04-15

This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. ©2015 American Association for Cancer Research.

Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

PubMed Central

Ayala, Victor I.; Trivett, Matthew T.; Barsov, Eugene V.; Jain, Sumiti; Piatak, Michael; Trubey, Charles M.; Alvord, W. Gregory; Chertova, Elena; Roser, James D.; Smedley, Jeremy; Komin, Alexander; Keele, Brandon F.; Ohlen, Claes

2016-01-01

ABSTRACT AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4+ T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. IMPORTANCE The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower. PMID:27558423

Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques.

PubMed

Ayala, Victor I; Trivett, Matthew T; Barsov, Eugene V; Jain, Sumiti; Piatak, Michael; Trubey, Charles M; Alvord, W Gregory; Chertova, Elena; Roser, James D; Smedley, Jeremy; Komin, Alexander; Keele, Brandon F; Ohlen, Claes; Ott, David E

2016-11-01

AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4 + T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A study to establish reasonable action limits for patient‐specific quality assurance in intensity‐modulated radiation therapy

PubMed Central

Alecu, Ionut M.; Stan, Andrada R.; Alecu, Marius; Ciura, Andrei; Hansen, Jeremy M.; Alecu, Rodica

2007-01-01

An effective patient quality assurance (QA) program for intensity‐modulated radiation therapy (IMRT) requires accurate and realistic plan acceptance criteria—that is, action limits. Based on dose measurements performed with a commercially available two‐dimensional (2D) diode array, we analyzed 747 fluence maps resulting from a routine patient QA program for IMRT plans. The fluence maps were calculated by three different commercially available (ADAC, CMS, Eclipse) treatment planning systems (TPSs) and were delivered using 6‐MV X‐ray beams produced by linear accelerators. To establish reasonably achievable and clinically acceptable limits for the dose deviations, the agreement between the measured and calculated fluence maps was evaluated in terms of percent dose error (PDE) for a few points and percent of passing points (PPP) for the isodose distribution. The analysis was conducted for each TPS used in the study (365 ADAC, 162 CMS, 220 Eclipse), for multiple treatment sites (prostate, pelvis, head and neck, spine, rectum, anus, lung, brain), at the normalization point for 3% percentage difference (%Diff) and 3‐mm distance to agreement (DTA) criteria. We investigated the treatment‐site dependency of PPP and PDE. The results show that, at 3% and 3‐mm criteria, a 95% PPP and 3% PDE can be achieved for prostate treatments and a 90% PPP and 5% PDE are attainable for any treatment site. PACS Numbers: 87.53Dq, 87.53Tf, 87.53Xd, 87.56Fc PMID:17592459

Chemical and radiological risk factors associated with waste from energy production.

PubMed

Christensen, T; Fuglestvedt, J; Benestad, C; Ehdwall, H; Hansen, H; Mustonen, R; Stranden, E

1992-04-01

We have tried to estimate the toxic potential of waste from nuclear power plants and from power plants burning fossil fuels. The potential risks have been expressed as 'risk potentials' or 'person equivalents.' These are purely theoretical units and represent only an attempt to quantify the potential impact of different sources and substances on human health. Existing concentration limits for effects on human health are used. The philosophy behind establishing limits for several carcinogenic chemicals is based on a linear dose-effect curve. That is, no lower concentration of no effect exists and one has to accept a certain small risk by accepting the concentration limit. This is in line with the establishment of limits for radiation. Waste products from coal combustion have the highest potential risk among the fossil fuel alternatives. The highest risk is caused by metals, and the fly ash represents the effluent stream giving the largest contribution to the potential risk. The waste from nuclear power production has a lower potential risk than coal if today's limit values re used. If one adjusts the limits for radiation dose and the concentration limit values so that a similar risk is accepted by the limits, nuclear waste seems to have a much higher potential risk than waste from fossil fuel. The possibility that such risk estimates may be used as arguments for safe storage of the different types of waste is discussed. In order to obtain the actual risk from the potential risk, the dispersion of the waste in the environment and its uptake and effects in man have to be taken into account.

Less than 3 doses of the HPV vaccine – Review of efficacy against virological and disease end points

PubMed Central

Basu, Partha; Bhatla, Neerja; Ngoma, Twalib; Sankaranarayanan, Rengaswamy

2016-01-01

ABSTRACT World Health Organization (WHO) recommended 2 doses of the Human Papillomavirus (HPV) vaccine for girls below 15 y on the basis of the immune-bridging studies demonstrating non-inferior immune response of 2 doses in the adolescent girls compared to 3 doses in the young adult women in whom the efficacy against disease is established. The biological nature of the antigens (virus-like particles) constituting the HPV vaccine is responsible for the vigorous antibody response that may make the third dose redundant. The protection offered by 2 doses has been demonstrated in non-randomized clinical trials to be comparable to that offered by 3 doses against incident and persistent infections of vaccine targeted HPV types. However, results emerging from the ecological and nested case-control studies embedded in the population based screening programs of different countries indicate reduced efficacy of 2 doses against virological and disease end points. Some recent studies observed the protective effect of single dose of the vaccine against incident and persistent infections of the vaccine targeted HPV types to be similar to 3 doses in spite of immunological inferiority. The sample size, duration of follow-ups and number of events were limited in these studies. Longer follow ups of the less than 3 doses cohorts in the ongoing studies as well as appropriately designed and ethically justifiable randomized studies are needed to establish the protection offered by the alternative schedules at least beyond 10 y of vaccination. PMID:26933961

Minimum Detectable Dose as a Measure of Bioassay Programme Capability

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

Carbaugh, Eugene H.

2003-01-01

This paper suggests that minimum detectable dose (MDD) be used to describe the capability of bioassay programs for which intakes are expected to be rare. This allows expression of the capability in units that correspond directly to primary dose limits. The concept uses the well-established analytical statistic minimum detectable amount (MDA) as the starting point and assumes MDA detection at a prescribed time post intake. The resulting dose can then be used as an indication of the adequacy or capability of the program for demonstrating compliance with the performance criteria. MDDs can be readily tabulated or plotted to demonstrate themore » effectiveness of different types of monitoring programs. The inclusion of cost factors for bioassay measurements can allow optimisation.« less

Minimum detectable dose as a measure of bioassay programme capability.

PubMed

Carbaugh, E H

2003-01-01

This paper suggests that minimum detectable dose (MDD) be used to describe the capability of bioassay programmes for which intakes are expected to be rare. This allows expression of the capability in units that correspond directly to primary dose limits. The concept uses the well established analytical statistic minimum detectable amount (MDA) as the starting point, and assumes MDA detection at a prescribed time post-intake. The resulting dose can then be used as an indication of the adequacy or capability of the programme for demonstrating compliance with the performance criteria. MDDs can be readily tabulated or plotted to demonstrate the effectiveness of different types of monitoring programmes. The inclusion of cost factors for bioassay measurements can allow optimisation.

Phase I Trial Using Patupilone (Epothilone B) and Concurrent Radiotherapy for Central Nervous System Malignancies

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

Fogh, Shannon; Machtay, Mitchell; Werner-Wasik, Maria

Purpose: Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials: The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicitymore » requiring hospitalization, occurred during treatment. Results: Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m{sup 2}, 4 at 2.0 mg/m{sup 2}, 4 at 2.5 mg/m{sup 2}, and 1 at 4 mg/m{sup 2}. Of 18 patients, 7 were treated in the 6-mg/m{sup 2} group, 6 in the 8-mg/m{sup 2} group, and 5 in the 10-mg/m{sup 2} group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m{sup 2} every 3 weeks. At the subsequent dose level (10 mg/m{sup 2}), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m{sup 2} every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m{sup 2} every 3 weeks.« less

The effects of temperature and pressure on airborne exposure concentrations when performing compliance evaluations using ACGIH TLVs and OSHA PELs.

PubMed

Stephenson, D J; Lillquist, D R

2001-04-01

Occupational hygienists perform air sampling to characterize airborne contaminant emissions, assess occupational exposures, and establish allowable workplace airborne exposure concentrations. To perform these air sampling applications, occupational hygienists often compare an airborne exposure concentration to a corresponding American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) or an Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL). To perform such comparisons, one must understand the physiological assumptions used to establish these occupational exposure limits, the relationship between a workplace airborne exposure concentration and its associated TLV or PEL, and the effect of temperature and pressure on the performance of an accurate compliance evaluation. This article illustrates the correct procedure for performing compliance evaluations using airborne exposure concentrations expressed in both parts per million and milligrams per cubic meter. In so doing, a brief discussion is given on the physiological assumptions used to establish TLVs and PELs. It is further shown how an accurate compliance evaluation is fundamentally based on comparison of a measured work site exposure dose (derived from the sampling site exposure concentration estimate) to an estimated acceptable exposure dose (derived from the occupational exposure limit concentration). In addition, this article correctly illustrates the effect that atmospheric temperature and pressure have on airborne exposure concentrations and the eventual performance of a compliance evaluation. This article also reveals that under fairly moderate conditions of temperature and pressure, 30 degrees C and 670 torr, a misunderstanding of how varying atmospheric conditions affect concentration values can lead to a 15 percent error in assessing compliance.

Phase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma

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

Drappatz, Jan; Norden, Andrew D.; Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital, Boston, MA

Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvantmore » TMZ, using a standard '3 + 3' dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of {>=}60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT. Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.« less

Tolerance limits and methodologies for IMRT measurement-based verification QA: Recommendations of AAPM Task Group No. 218.

PubMed

Miften, Moyed; Olch, Arthur; Mihailidis, Dimitris; Moran, Jean; Pawlicki, Todd; Molineu, Andrea; Li, Harold; Wijesooriya, Krishni; Shi, Jie; Xia, Ping; Papanikolaou, Nikos; Low, Daniel A

2018-04-01

Patient-specific IMRT QA measurements are important components of processes designed to identify discrepancies between calculated and delivered radiation doses. Discrepancy tolerance limits are neither well defined nor consistently applied across centers. The AAPM TG-218 report provides a comprehensive review aimed at improving the understanding and consistency of these processes as well as recommendations for methodologies and tolerance limits in patient-specific IMRT QA. The performance of the dose difference/distance-to-agreement (DTA) and γ dose distribution comparison metrics are investigated. Measurement methods are reviewed and followed by a discussion of the pros and cons of each. Methodologies for absolute dose verification are discussed and new IMRT QA verification tools are presented. Literature on the expected or achievable agreement between measurements and calculations for different types of planning and delivery systems are reviewed and analyzed. Tests of vendor implementations of the γ verification algorithm employing benchmark cases are presented. Operational shortcomings that can reduce the γ tool accuracy and subsequent effectiveness for IMRT QA are described. Practical considerations including spatial resolution, normalization, dose threshold, and data interpretation are discussed. Published data on IMRT QA and the clinical experience of the group members are used to develop guidelines and recommendations on tolerance and action limits for IMRT QA. Steps to check failed IMRT QA plans are outlined. Recommendations on delivery methods, data interpretation, dose normalization, the use of γ analysis routines and choice of tolerance limits for IMRT QA are made with focus on detecting differences between calculated and measured doses via the use of robust analysis methods and an in-depth understanding of IMRT verification metrics. The recommendations are intended to improve the IMRT QA process and establish consistent, and comparable IMRT QA criteria among institutions. © 2018 American Association of Physicists in Medicine.

Oligodendrocyte progenitor cell (OPC) transplantation is unlikely to offer a means of preventing X-irradiation induced damage in the CNS.

PubMed

Chari, Divya M; Gilson, Jennifer M; Franklin, Robin J M; Blakemore, William F

2006-03-01

Oligodendrocyte lineage cells [oligodendrocytes and their parent cells, the oligodendrocyte progenitor cells (OPCs)] are depleted by X-irradiation and progenitor cell transplantation has been proposed as a therapeutic strategy to counteract radiation induced myelopathy. Previous studies have demonstrated that oligodendrocyte progenitor cell (OPC) depletion is a prerequisite for establishing transplanted OPCs in normal tissue. One can therefore predict that the extent and timing of OPC depletion and regeneration following X-irradiation will be crucial factors in determining the feasibility of this therapeutic approach. To address this issue, we have examined the time course of OPC depletion and regeneration following a range of X-irradiation doses (5 to 40 Gy), and its relationship to establishing transplanted OPCs in X-irradiated tissue. Doses above 10 Gy resulted in rapid death of OPCs. With doses up to 20 Gy, surviving X-irradiated OPCs were capable of robust regeneration, restoring normal densities within 6 weeks. Transplanted OPCs could only be established in tissue that had been exposed to > or =20 Gy. Since 20 Gy is close to the ED50 for radiation necrosis, our findings demonstrate the limitation of OPC replacement strategies.

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

Unkelbach, J; Perko, Z; Wolfgang, J

Purpose: Stereotactic body radiotherapy (SBRT) has become an established treatment option for liver cancer. For patients with large tumors, the prescription dose is often limited by constraints on the mean liver dose, leading to tumor recurrence. In this work, we demonstrate that spatiotemporal fractionation schemes, ie delivering distinct dose distributions in different fractions, may allow for a 10% increase in biologically effective dose (BED) in the tumor compared to current practice where each fraction delivers the same dose distribution. Methods: We consider rotation therapy delivered with x-ray beams. Treatment plan optimization is performed using objective functions evaluated for the cumulativemore » BED delivered at the end of treatment. This allows for simultaneously optimizing multiple distinct treatment plans for different fractions. Results: The treatment that optimally exploits fractionation effects is designed such that each fraction delivers a similar dose bath to the uninvolved liver while delivering high single fraction doses to complementary parts of the target volume. Thereby, partial hypofractionation in the tumor is achieved along with near uniform fractionation in the surrounding liver - leading to an improvement in the therapeutic ratio. The benefit of such spatiotemporal fractionation schemes depends on tumor geometry and location as well as the number of fractions. For 5-fraction treatments (allowing for 5 distinct dose distributions) an improvement in the order of 10% is observed. Conclusion: Delivering distinct dose distributions in different fractions, purely motivated by fractionation effects rather than geometric changes, may improve the therapeutic ratio. For treatment sites where the prescriptions dose is limited by mean dose constraints in the surrounding organ, such as liver cancer, this approach may facilitate biological dose escalation and improved cure rates.« less

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m 2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor. Copyright © 2018 Elsevier Ltd. All rights reserved.

MO-E-BRB-03: Panel Member

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

Salter, B.

2016-06-15

In this interactive session, lung SBRT patient cases will be presented to highlight real-world considerations for ensuring safe and accurate treatment delivery. An expert panel of speakers will discuss challenges specific to lung SBRT including patient selection, patient immobilization techniques, 4D CT simulation and respiratory motion management, target delineation for treatment planning, online treatment alignment, and established prescription regimens and OAR dose limits. Practical examples of cases, including the patient flow thought the clinical process are presented and audience participation will be encouraged. This panel session is designed to provide case demonstration and review for lung SBRT in terms ofmore » (1) clinical appropriateness in patient selection, (2) strategies for simulation, including 4D and respiratory motion management, and (3) applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent, and (4) image guidance in treatment delivery. Learning Objectives: Understand the established requirements for patient selection in lung SBRT Become familiar with the various immobilization strategies for lung SBRT, including technology for respiratory motion management Understand the benefits and pitfalls of applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent determination for lung SBRT Understand established prescription regimes and OAR dose limits.« less

MO-E-BRB-01: Panel Member

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

Benedict, S.

2016-06-15

In this interactive session, lung SBRT patient cases will be presented to highlight real-world considerations for ensuring safe and accurate treatment delivery. An expert panel of speakers will discuss challenges specific to lung SBRT including patient selection, patient immobilization techniques, 4D CT simulation and respiratory motion management, target delineation for treatment planning, online treatment alignment, and established prescription regimens and OAR dose limits. Practical examples of cases, including the patient flow thought the clinical process are presented and audience participation will be encouraged. This panel session is designed to provide case demonstration and review for lung SBRT in terms ofmore » (1) clinical appropriateness in patient selection, (2) strategies for simulation, including 4D and respiratory motion management, and (3) applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent, and (4) image guidance in treatment delivery. Learning Objectives: Understand the established requirements for patient selection in lung SBRT Become familiar with the various immobilization strategies for lung SBRT, including technology for respiratory motion management Understand the benefits and pitfalls of applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent determination for lung SBRT Understand established prescription regimes and OAR dose limits.« less

MO-E-BRB-00: PANEL DISCUSSION: SBRT/SRS Case Studies - Lung

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

NONE

2016-06-15

In this interactive session, lung SBRT patient cases will be presented to highlight real-world considerations for ensuring safe and accurate treatment delivery. An expert panel of speakers will discuss challenges specific to lung SBRT including patient selection, patient immobilization techniques, 4D CT simulation and respiratory motion management, target delineation for treatment planning, online treatment alignment, and established prescription regimens and OAR dose limits. Practical examples of cases, including the patient flow thought the clinical process are presented and audience participation will be encouraged. This panel session is designed to provide case demonstration and review for lung SBRT in terms ofmore » (1) clinical appropriateness in patient selection, (2) strategies for simulation, including 4D and respiratory motion management, and (3) applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent, and (4) image guidance in treatment delivery. Learning Objectives: Understand the established requirements for patient selection in lung SBRT Become familiar with the various immobilization strategies for lung SBRT, including technology for respiratory motion management Understand the benefits and pitfalls of applying multi imaging modality (4D CT imaging, MRI, PET) for tumor volume delineation and motion extent determination for lung SBRT Understand established prescription regimes and OAR dose limits.« less

Biological dose estimation for charged-particle therapy using an improved PHITS code coupled with a microdosimetric kinetic model.

PubMed

Sato, Tatsuhiko; Kase, Yuki; Watanabe, Ritsuko; Niita, Koji; Sihver, Lembit

2009-01-01

Microdosimetric quantities such as lineal energy, y, are better indexes for expressing the RBE of HZE particles in comparison to LET. However, the use of microdosimetric quantities in computational dosimetry is severely limited because of the difficulty in calculating their probability densities in macroscopic matter. We therefore improved the particle transport simulation code PHITS, providing it with the capability of estimating the microdosimetric probability densities in a macroscopic framework by incorporating a mathematical function that can instantaneously calculate the probability densities around the trajectory of HZE particles with a precision equivalent to that of a microscopic track-structure simulation. A new method for estimating biological dose, the product of physical dose and RBE, from charged-particle therapy was established using the improved PHITS coupled with a microdosimetric kinetic model. The accuracy of the biological dose estimated by this method was tested by comparing the calculated physical doses and RBE values with the corresponding data measured in a slab phantom irradiated with several kinds of HZE particles. The simulation technique established in this study will help to optimize the treatment planning of charged-particle therapy, thereby maximizing the therapeutic effect on tumors while minimizing unintended harmful effects on surrounding normal tissues.

American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance.

PubMed

Manchikanti, Laxmaiah; Abdi, Salahadin; Atluri, Sairam; Balog, Carl C; Benyamin, Ramsin M; Boswell, Mark V; Brown, Keith R; Bruel, Brian M; Bryce, David A; Burks, Patricia A; Burton, Allen W; Calodney, Aaron K; Caraway, David L; Cash, Kimberly A; Christo, Paul J; Damron, Kim S; Datta, Sukdeb; Deer, Timothy R; Diwan, Sudhir; Eriator, Ike; Falco, Frank J E; Fellows, Bert; Geffert, Stephanie; Gharibo, Christopher G; Glaser, Scott E; Grider, Jay S; Hameed, Haroon; Hameed, Mariam; Hansen, Hans; Harned, Michael E; Hayek, Salim M; Helm, Standiford; Hirsch, Joshua A; Janata, Jeffrey W; Kaye, Alan D; Kaye, Adam M; Kloth, David S; Koyyalagunta, Dhanalakshmi; Lee, Marion; Malla, Yogesh; Manchikanti, Kavita N; McManus, Carla D; Pampati, Vidyasagar; Parr, Allan T; Pasupuleti, Ramarao; Patel, Vikram B; Sehgal, Nalini; Silverman, Sanford M; Singh, Vijay; Smith, Howard S; Snook, Lee T; Solanki, Daneshvari R; Tracy, Deborah H; Vallejo, Ricardo; Wargo, Bradley W

2012-07-01

Part 2 of the guidelines on responsible opioid prescribing provides the following recommendations for initiating and maintaining chronic opioid therapy of 90 days or longer. 1. A) Comprehensive assessment and documentation is recommended before initiating opioid therapy, including documentation of comprehensive history, general medical condition, psychosocial history, psychiatric status, and substance use history. ( good) B) Despite limited evidence for reliability and accuracy, screening for opioid use is recommended, as it will identify opioid abusers and reduce opioid abuse. ( limited) C) Prescription monitoring programs must be implemented, as they provide data on patterns of prescription usage, reduce prescription drug abuse or doctor shopping. ( good to fair) D) Urine drug testing (UDT) must be implemented from initiation along with subsequent adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. ( good) 2. A) Establish appropriate physical diagnosis and psychological diagnosis if available prior to initiating opioid therapy. ( good) B) Caution must be exercised in ordering various imaging and other evaluations, interpretation and communication with the patient, to avoid increased fear, activity restriction, requests for increased opioids, and maladaptive behaviors. ( good) C) Stratify patients into one of the 3 risk categories - low, medium, or high risk. D) A pain management consultation, may assist non-pain physicians, if high-dose opioid therapy is utilized. ( fair) 3. Essential to establish medical necessity prior to initiation or maintenance of opioid therapy. ( good) 4. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. ( good) 5. A) Long-acting opioids in high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids, as there is no significant difference between long-acting and short-acting opioids for their effectiveness or adverse effects. ( fair) B) The relative and absolute contraindications to opioid use in chronic non-cancer pain must be evaluated including respiratory instability, acute psychiatric instability, uncontrolled suicide risk, active or history of alcohol or substance abuse, confirmed allergy to opioid agents, coadministration of drugs capable of inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of controlled substances, and concomitant use of heavy doses of central nervous system depressants. ( fair to limited) 6. A robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion. ( fair) 7. A) Once medical necessity is established, opioid therapy may be initiated with low doses and short-acting drugs with appropriate monitoring to provide effective relief and avoid side effects. ( fair for short-term effectiveness, limited for long-term effectiveness) B) Up to 40 mg of morphine equivalent is considered as low dose, 41 to 90 mg of morphine equivalent as a moderate dose, and greater than 91 mg of morphine equivalence as high dose. ( fair) C) In reference to long-acting opioids, titration must be carried out with caution and overdose and misuse must be avoided. ( good) 8. A) Methadone is recommended for use in late stages after failure of other opioid therapy and only by clinicians with specific training in the risks and uses. ( limited) B) Monitoring recommendation for methadone prescription is that an electrocardiogram should be obtained prior to initiation, at 30 days and yearly thereafter. ( fair) 9. In order to reduce prescription drug abuse and doctor shopping, adherence monitoring by UDT and PMDPs provide evidence that is essential to the identification of those patients who are non-compliant or abusing prescription drugs or illicit drugs. ( fair) 10. Constipation must be closely monitored and a bowel regimen be initiated as soon as deemed necessary. ( good) 11. Chronic opioid therapy may be continued, with continuous adherence monitoring, in well-selected populations, in conjunction with or after failure of other modalities of treatments with improvement in physical and functional status and minimal adverse effects. ( fair). The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Esophageal Dose Tolerance in Patients Treated With Stereotactic Body Radiation Therapy.

PubMed

Nuyttens, Joost J; Moiseenko, Vitali; McLaughlin, Mark; Jain, Sheena; Herbert, Scott; Grimm, Jimm

2016-04-01

Mediastinal critical structures such as trachea, bronchus, esophagus, and heart are among the dose-limiting factors for stereotactic body radiation therapy (SBRT) to central lung lesions. The purpose of this study was to characterize the risk of esophagitis for patients treated with SBRT and to develop a statistical dose-response model to assess the equivalent uniform dose, D10%, D5cc, D1cc, and Dmax, to the esophagus and the risk of toxicity. Toxicity outcomes of a dose-escalation study of 56 patients who had taken CyberKnife treatment from 45-60Gy in 3-7 fractions at the Erasmus MC-Daniel den Hoed Cancer Center were utilized to create the dose-response model for esophagus. A total of 5 grade 2 esophageal complications were reported (Common Terminology Criteria for Adverse Events version 3.0); 4 complications were early effects and 1 complication was a late effect. All analyses were performed in terms of 5-fraction equivalent dosing. According to our study, D1cc at a dose of 32.9Gy and Dmax dose of 43.4Gy corresponded to a complication probability of 50% for grade 2 toxicity. In this series of 58 CyberKnife mediastinal lung cases, no grade 3 or higher esophageal toxicity occurred. Our estimates of esophageal toxicity are compared with the data in the literature. Further research needs to be performed to establish more reliable dose limits as longer follow-up and toxicity outcomes are reported in patients treated with SBRT for central lung lesions. Copyright © 2016 Elsevier Inc. All rights reserved.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

PubMed

Tahara, M; Araki, K; Okano, S; Kiyota, N; Fuse, N; Minashi, K; Yoshino, T; Doi, T; Zenda, S; Kawashima, M; Ogino, T; Hayashi, R; Minami, H; Ohtsu, A

2011-01-01

we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

PROBIT: A Probit Analysis Program for the DRES (Defence Research Establishment Suffield) Computer Facility,

DTIC Science & Technology

1986-07-01

p are are also discussed. When iteration is terminated, we can determine the effective dose at the A percentile level or EDX ; that is the dose at...corresponds to the lower limit, fl.. The fiducial or Fieller limits on x , i.e., the EDX are then f’ = exp If.1 (36) It can be readily shown that g = t2 v-1...4 .4+ 1W (n 0 CL C ~o 0 0 X U) -W CLW W 24W Q X C W C > VW U)w5 z C z 5memo f- G5555t (j) tSS a;C w CO W QZ 1 I- ~ ~ ~ C (. 5r 5W <A * a W Www w V

Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

PubMed

Takahashi, Shunji; Nakano, Kenji; Yokota, Tomoya; Shitara, Kohei; Muro, Kei; Sunaga, Yoshinori; Ecstein-Fraisse, Evelyne; Ura, Takashi

2016-08-27

In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m 2 ombrabulin with 75 mg/m 2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m 2 combined with cisplatin 75 mg/m 2 . The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

Definitions and outlook targeting x-ray exposure of patients in diagnostic imaging

NASA Astrophysics Data System (ADS)

Regulla, Dieter F.

2011-03-01

Computer tomography (CT) is vital and currently irreplaceable in diagnostic radiology. But CT operates with ionizing radiation which may cause cancer or non-cancer diseases in humans. The degree of radiation impact depends on the dose administered by an investigation. And this is the core issue: Even CT exams executed lege artis, administer doses to patients which by magnitude are far beyond the level of hitherto known doses of conventional film-screen techniques. Patients undergoing one or multiple CT examinations, digital angiographies or interventions will be exposed to effective doses between roughly several mSv and several 100 mSv depending on type and frequency of the diagnostic investigations. From the radiation protection point of view, there is therefore the worldwide problem of formulating firm rules for the control of these high-dose investigations, as dose limits can not be established for reasons of the medical benefit. This makes the difference compared with radiation protection for occupationally exposed persons. What remains is "software", namely "justification" and "optimization". Justification requires balancing the interests between the health benefit and the potential harm of an exam which has to be responsibly executed by the physician himself; therefore the radiologists' associations are in the duty to prepare practicable rules for justification. Optimization again needs a cooperative solution, and that is the establishment of reference doses for diagnostic examinations, to be checked by the technical service of the producers' companies. Experts and authorities have been aware of the high-dose dilemma in diagnostic imaging since long. It is time for the reflection of active solutions and their implementation into practice.

TU-C-18A-01: Models of Risk From Low-Dose Radiation Exposures: What Does the Evidence Say?

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

Bushberg, J; Boreham, D; Ulsh, B

2014-06-15

At dose levels of (approximately) 500 mSv or more, increased cancer incidence and mortality have been clearly demonstrated. However, at the low doses of radiation used in medical imaging, the relationship between dose and cancer risk is not well established. As such, assumptions about the shape of the dose-response curve are made. These assumptions, or risk models, are used to estimate potential long term effects. Common models include 1) the linear non-threshold (LNT) model, 2) threshold models with either a linear or curvilinear dose response above the threshold, and 3) a hormetic model, where the risk is initially decreased belowmore » background levels before increasing. The choice of model used when making radiation risk or protection calculations and decisions can have significant implications on public policy and health care decisions. However, the ongoing debate about which risk model best describes the dose-response relationship at low doses of radiation makes informed decision making difficult. This symposium will review the two fundamental approaches to determining the risk associated with low doses of ionizing radiation, namely radiation epidemiology and radiation biology. The strengths and limitations of each approach will be reviewed, the results of recent studies presented, and the appropriateness of different risk models for various real world scenarios discussed. Examples of well-designed and poorly-designed studies will be provided to assist medical physicists in 1) critically evaluating publications in the field and 2) communicating accurate information to medical professionals, patients, and members of the general public. Equipped with the best information that radiation epidemiology and radiation biology can currently provide, and an understanding of the limitations of such information, individuals and organizations will be able to make more informed decisions regarding questions such as 1) how much shielding to install at medical facilities, 2) at what dose level are risk vs. benefit discussions with patients appropriate, 3) at what dose level should we tell a pregnant woman that the baby’s health risk from a prenatal radiation exposure is “significant”, 4) is informed consent needed for patients undergoing medical imaging, and 5) at what dose level is evacuation appropriate after a radiological accident. Examples of the tremendous impact that choosing different risks models can have on the answers to these types of questions will be given.A moderated panel discussion will allow audience members to pose questions to the faculty members, each of whom is an established expert in his respective discipline. Learning Objectives: Understand the fundamental principles, strengths and limitations of radiation epidemiology and radiation biology for determining the risk from exposures to low doses of ionizing radiation Become familiar with common models of risk used to describe the dose-response relationship at low dose levels Learn to identify strengths and weaknesses in studies designed to measure the effect of low doses of ionizing radiation Understand the implications of different risk models on public policy and health care decisions.« less

Absorbed Dose Rate Due to Intake of Natural Radionuclides by Tilapia Fish (Tilapia nilotica,Linnaeus, 1758) Estimated Near Uranium Mining at Caetité, Bahia, Brazil

NASA Astrophysics Data System (ADS)

Pereira, Wagner de S.; Kelecom, Alphonse; Py Júnior, Delcy de Azevedo

2008-08-01

The uranium mining at Caetité (Uranium Concentrate Unit—URA) is in its operational phase. Aiming to estimate the radiological environmental impact of the URA, a monitoring program is underway. In order to preserve the biota of the deleterious effects from radiation and to act in a pro-active way as expected from a licensing body, the present work aims to use an environmental protection methodology based on the calculation of absorbed dose rate in biota. Thus, selected target organism was the Tilapia fish (Tilapia nilotica, Linnaeus, 1758) and the radionuclides were: uranium (U-238), thorium (Th-232), radium (Ra-226 and Ra-228) and lead (Pb-210). As, in Brazil there are no radiation exposure limits adopted for biota the value proposed by the Department of Energy (DOE) of the United States of 3.5×103 μGy y-1 has been used. The derived absorbed dose rate calculated for Tilapia was 2.51×100 μGy y-1, that is less than 0.1% of the dose limit established by DOE. The critical radionuclide was Ra-226, with 56% of the absorbed dose rate, followed by U-238 with 34% and Th-232 with 9%. This value of 0.1% of the limit allows to state that, in the operational conditions analyzed, natural radionuclides do not represent a radiological problem to biota.

Absorbed Dose Rate Due to Intake of Natural Radionuclides by Tilapia Fish (Tilapia nilotica,Linnaeus, 1758) Estimated Near Uranium Mining at Caetite, Bahia, Brazil

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

Pereira, Wagner de S; Universidade Federal Fluminense, Programa de Pos-graduacao em Biologia Marinha; Kelecom, Alphonse

2008-08-07

The uranium mining at Caetite (Uranium Concentrate Unit--URA) is in its operational phase. Aiming to estimate the radiological environmental impact of the URA, a monitoring program is underway. In order to preserve the biota of the deleterious effects from radiation and to act in a pro-active way as expected from a licensing body, the present work aims to use an environmental protection methodology based on the calculation of absorbed dose rate in biota. Thus, selected target organism was the Tilapia fish (Tilapia nilotica, Linnaeus, 1758) and the radionuclides were: uranium (U-238), thorium (Th-232), radium (Ra-226 and Ra-228) and lead (Pb-210).more » As, in Brazil there are no radiation exposure limits adopted for biota the value proposed by the Department of Energy (DOE) of the United States of 3.5x10{sup 3} {mu}Gy y{sup -1} has been used. The derived absorbed dose rate calculated for Tilapia was 2.51x10{sup 0} {mu}Gy y{sup -1}, that is less than 0.1% of the dose limit established by DOE. The critical radionuclide was Ra-226, with 56% of the absorbed dose rate, followed by U-238 with 34% and Th-232 with 9%. This value of 0.1% of the limit allows to state that, in the operational conditions analyzed, natural radionuclides do not represent a radiological problem to biota.« less

Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

PubMed

Czito, Brian G; Deming, Dustin A; Jameson, Gayle S; Mulcahy, Mary F; Vaghefi, Houman; Dudley, Matthew W; Holen, Kyle D; DeLuca, Angela; Mittapalli, Rajendar K; Munasinghe, Wijith; He, Lei; Zalcberg, John R; Ngan, Samuel Y; Komarnitsky, Philip; Michael, Michael

2017-06-01

Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. AbbVie Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hormesis as a biological hypothesis.

PubMed Central

Calabrese, E J; Baldwin, L A

1998-01-01

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of > 6 doses; with > 3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database. PMID:9539030

Mathematical optimization of high dose-rate brachytherapy—derivation of a linear penalty model from a dose-volume model

NASA Astrophysics Data System (ADS)

Morén, B.; Larsson, T.; Carlsson Tedgren, Å.

2018-03-01

High dose-rate brachytherapy is a method for cancer treatment where the radiation source is placed within the body, inside or close to a tumour. For dose planning, mathematical optimization techniques are being used in practice and the most common approach is to use a linear model which penalizes deviations from specified dose limits for the tumour and for nearby organs. This linear penalty model is easy to solve, but its weakness lies in the poor correlation of its objective value and the dose-volume objectives that are used clinically to evaluate dose distributions. Furthermore, the model contains parameters that have no clear clinical interpretation. Another approach for dose planning is to solve mixed-integer optimization models with explicit dose-volume constraints which include parameters that directly correspond to dose-volume objectives, and which are therefore tangible. The two mentioned models take the overall goals for dose planning into account in fundamentally different ways. We show that there is, however, a mathematical relationship between them by deriving a linear penalty model from a dose-volume model. This relationship has not been established before and improves the understanding of the linear penalty model. In particular, the parameters of the linear penalty model can be interpreted as dual variables in the dose-volume model.

Korean anatomical reference data for adults for use in radiological protection

NASA Astrophysics Data System (ADS)

Choi, Chansoo; Yeom, Yeon Soo; Nguyen, Thang Tat; Lee, Hanjin; Han, Haegin; Shin, Bangho; Zhang, Xujia; Kim, Chan Hyeong; Chung, Beom Sun

2018-01-01

For radiological protection from exposure to ionizing radiation, in which a population-averaged dose evaluation is used, establishing a system of reference anatomical and physiological data for a specific population of interest is important. Some studies were done in the past to establish Korean reference data; however, the data provided the mass values only for a limited number of organs/tissues. In addition, the standing height and total body mass are based on 20-year-old data. In the present study, a new set of Korean reference anatomical values was established for use in the radiological protection of Korean workers and members of the public. The established Korean reference data provide the masses of 58 organs/tissues, including those needed to calculate the effective dose, which were derived by collecting and analyzing various scientific reports in the literature and data. In addition, the data provide not only standing height and total body mass, but also 131 additional anthropometric parameters; these values were derived from the most recent Korean national survey project, 7 th Size Korea. The characteristics of the data were also compared with several other population data, including the Asian and the International Commission on Radiological Protection (ICRP) reference data.

A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors.

PubMed

Papadopoulos, Kyriakos P; Burris, Howard A; Gordon, Michael; Lee, Peter; Sausville, Edward A; Rosen, Peter J; Patnaik, Amita; Cutler, Richard E; Wang, Zhengping; Lee, Susan; Jones, Suzanne F; Infante, Jeffery R

2013-10-01

Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2-10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study. Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m(2) in week 1 of cycle 1 and 20, 27, or 36 mg/m(2) thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts. Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m(2) was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts. Carfilzomib 20/36 mg/m(2) was well tolerated when administered twice weekly by 2-10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.

Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed

NASA Astrophysics Data System (ADS)

Craig, A.; Klotz, James; Duringer, Jennifer

2015-02-01

Ergot-induced disease was known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mitigate migraine headaches and have had indications as anticarcinogens. Although ergot alkaloids have been used for centuries, basic pharmacokinetic data has not been documented for clinical disease. Consequently, a threshold dose and accurate dose-response data have yet to be established. Throughout the past several years, new detection techniques have emerged to detect these alkaloids at the parts per billion which have allowed for new efforts to be made with respect to determining threshold levels and making accurate clinical diagnoses. This perspectives article provides a critical initial step for establishing a uniform interpretation of ergot toxicosis from limited existing data.

Recent developments in clopidogrel pharmacology and their relation to clinical outcomes.

PubMed

Gurbel, Paul A; Antonino, Mark J; Tantry, Udaya S

2009-08-01

Oral antiplatelet therapy with clopidogrel and aspirin is an important and widely prescribed strategy to prevent ischemic events in patients with cardiovascular diseases. However, the occurrence of thrombotic events including stent thrombosis is still high (> 10%). Current practice guidelines are mainly based on large-scale trials focusing on clinical endpoints and 'one size fits all' strategies of treating all patients with the same clopidogrel doses. Pharmacodynamic studies have demonstrated that the latter strategy is associated with wide response variability where a substantial percentage of patients show nonresponsivenes. Translational research studies have established the relation between clopidogrel nonresponsivenes or high on-treatment platelet reactivity to adverse clinical events, thereby establishing clopidogrel nonresponsivenes as an important emerging clinical entity. Clopidogrel response variability is primarily a pharmacokinetic phenomenon associated with insufficient active metabolite generation that is secondary to i) limited intestinal absorption affected by an ABCB1 gene polymorphism; ii) functional variability in P450 isoenzyme activity; and iii) a genetic polymorphism of CYP450 isoenzymes. Personalized antiplatelet treatment with higher clopidogrel doses in selected patients or with newer more potent P2Y(12) receptor blockers based on individual platelet function measurement can overcome some of the limitations of current clopidogrel treatment.

Radiation exposure in interventional radiology

NASA Astrophysics Data System (ADS)

Pinto, N. G. V.; Braz, D.; Vallim, M. A.; Filho, L. G. P.; Azevedo, F. S.; Barroso, R. C.; Lopes, R. T.

2007-09-01

The aim of this study is to evaluate dose values in patients and staff involved in some interventional radiology procedures. Doses have been measured using thermoluminescent dosemeters for single procedures (such as renal and cerebral arteriography, transjungular intrahepatic portasystemic shunt (TIPS) and chemoembolization). The magnitude of doses through the hands of interventional radiologists has been studied. Dose levels were evaluated in three points for patients (eye, thyroid and gonads). The dose-area product (DAP) was also investigated using a Diamentor (PTW-M2). The dose in extremities was estimated for a professional who generally performed one TIPS, two chemoembolizations, two cerebral arteriographies and two renal arteriographies in a week. The estimated annual radiation dose was converted to effective dose as suggested by the 453-MS/Brazil norm The annual dose values were 137.25 mSv for doctors, 40.27 mSv for nurses and 51.95 mSv for auxiliary doctors, and all these annual dose values are below the limit established. The maximum values of the dose obtained for patients were 6.91, 10.92 and 15.34 mGy close to eye, thyroid and gonads, respectively. The DAP values were evaluated for patients in the same interventional radiology procedures. The dose and DAP values obtained are in agreement with values encountered in the literature.

The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

PubMed

Wu, Runhui; Luke, Koon Hung

2017-11-01

Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

Clinical applications of advanced rotational radiation therapy

NASA Astrophysics Data System (ADS)

Nalichowski, Adrian

Purpose: With a fast adoption of emerging technologies, it is critical to fully test and understand its limits and capabilities. In this work we investigate new graphic processing unit (GPU) based treatment planning algorithm and its applications in helical tomotherapy dose delivery. We explore the limits of the system by applying it to challenging clinical cases of total marrow irradiation (TMI) and stereotactic radiosurgery (SRS). We also analyze the feasibility of alternative fractionation schemes for total body irradiation (TBI) and TMI based on reported historical data on lung dose and interstitial pneumonitis (IP) incidence rates. Methods and Materials: An anthropomorphic phantom was used to create TMI plans using the new GPU based treatment planning system and the existing CPU cluster based system. Optimization parameters were selected based on clinically used values for field width, modulation factor and pitch. Treatment plans were also created on Eclipse treatment planning system (Varian Medical Systems Inc, Palo Alto, CA) using volumetric modulated arc therapy (VMAT) for dose delivery on IX treatment unit. A retrospective review was performed of 42 publications that reported IP rates along with lung dose, fractionation regimen, dose rate and chemotherapy. The analysis consisted of nearly thirty two hundred patients and 34 unique radiation regimens. Multivariate logistic regression was performed to determine parameters associated with IP and establish does response function. Results: The results showed very good dosimetric agreement between the GPU and CPU calculated plans. The results from SBRT study show that GPU planning system can maintain 90% target coverage while meeting all the constraints of RTOG 0631 protocol. Beam on time for Tomotherapy and flattening filter free RapidArc was much faster than for Vero or Cyberknife. Retrospective data analysis showed that lung dose and Cyclophosphomide (Cy) are both predictors of IP in TBI/TMI treatments. The dose rate was not found to be an independent risk factor for IP. The model failed to establish accurate dose response function, but the discrete data indicated a radiation dose threshold of 7.6Gy (EQD2_repair) and 120 mg/kg of Cy below which no IP cases were reported. Conclusion: The TomoTherapy GPU based dose engine is capable of calculating TMI treatment plans with plan quality nearly identical to plans calculated using the traditional CPU/cluster based system, while significantly reducing the time required for optimization and dose calculation. The new system was able to achieve more uniform dose distribution throughout the target volume and steeper dose fall off, resulting in superior OAR sparing when compared to Eclipse treatment planning system for VMAT delivery. The machine optimization parameters tested for TMI cases provide a comprehensive overview of the capabilities of the treatment planning station and associated helical delivery system. The new system also proved to be dosimetrically compatible with other leading modalities for treatments of small and complicated target volumes and was even superior when treatment delivery times were compared. These finding demonstrate that the advanced treatment planning and delivery system from TomoTherapy is well suitable for treatments of complicated cases such as TMI and SRS and it's often dosimetrically and/or logistically superior to other modalities. The new planning system can easily meet the constraint of threshold lung dose established in this study. The results presented here on the capabilities of Tomotherapy and on the identified lung dose threshold provide an opportunity to explore alternative fractionation schemes without sacrificing target coverage or lung toxicity. (Abstract shortened by ProQuest.).

Ultra-Low-Dose Fetal CT With Model-Based Iterative Reconstruction: A Prospective Pilot Study.

PubMed

Imai, Rumi; Miyazaki, Osamu; Horiuchi, Tetsuya; Asano, Keisuke; Nishimura, Gen; Sago, Haruhiko; Nosaka, Shunsuke

2017-06-01

Prenatal diagnosis of skeletal dysplasia by means of 3D skeletal CT examination is highly accurate. However, it carries a risk of fetal exposure to radiation. Model-based iterative reconstruction (MBIR) technology can reduce radiation exposure; however, to our knowledge, the lower limit of an optimal dose is currently unknown. The objectives of this study are to establish ultra-low-dose fetal CT as a method for prenatal diagnosis of skeletal dysplasia and to evaluate the appropriate radiation dose for ultra-low-dose fetal CT. Relationships between tube current and image noise in adaptive statistical iterative reconstruction and MBIR were examined using a 32-cm CT dose index (CTDI) phantom. On the basis of the results of this examination and the recommended methods for the MBIR option and the known relationship between noise and tube current for filtered back projection, as represented by the expression SD = (milliamperes) -0.5 , the lower limit of the optimal dose in ultra-low-dose fetal CT with MBIR was set. The diagnostic power of the CT images obtained using the aforementioned scanning conditions was evaluated, and the radiation exposure associated with ultra-low-dose fetal CT was compared with that noted in previous reports. Noise increased in nearly inverse proportion to the square root of the dose in adaptive statistical iterative reconstruction and in inverse proportion to the fourth root of the dose in MBIR. Ultra-low-dose fetal CT was found to have a volume CTDI of 0.5 mGy. Prenatal diagnosis was accurately performed on the basis of ultra-low-dose fetal CT images that were obtained using this protocol. The level of fetal exposure to radiation was 0.7 mSv. The use of ultra-low-dose fetal CT with MBIR led to a substantial reduction in radiation exposure, compared with the CT imaging method currently used at our institution, but it still enabled diagnosis of skeletal dysplasia without reducing diagnostic power.

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer.

PubMed

Takahashi, Shunji; Kobayashi, Takayuki; Tomomatsu, Junichi; Ito, Yoshinori; Oda, Hisanobu; Kajitani, Tatsuhiro; Kakizume, Tomoyuki; Tajima, Takeshi; Takeuchi, Hiromi; Maacke, Heiko; Esaki, Taito

2017-01-01

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. ClinicalTrials.gov NCT01911936.

Implications in dosimetry of the implementation of the revised dose limit to the lens of the eye.

PubMed

Broughton, J; Cantone, M C; Ginjaume, M; Shah, B; Czarwinski, R

2015-04-01

In 2012, International Radiation Protection Association (IRPA) established a Task Group to provide an assessment of the impact of the implementation of the ICRP-revised dose limit for the lens of the eye for occupational exposure. Associated Societies (ASs) of IRPA were asked to provide views and comments on the basis of a questionnaire addressing three principal topics: (i) implications for dosimetry, (ii) implications for methods of protection and (iii) wider implications of implementing the revised limits. A summary of the collated responses regarding dosimetry is presented and discussed. There is large agreement on the most critical aspects and difficulties in setting up an appropriate monitoring programme for the lens of the eyes. The recent international standards and technical documents provide guidance for some of the concerns but other challenges remain in terms of awareness, acceptance and practicalities. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Implications of the implementation of the revised dose limit to the lens of the eye: the view of IRPA professionals.

PubMed

Broughton, J; Cantone, M C; Ginjaume, M; Shah, B; Czarwinski, R

2015-06-01

In April 2011, the International Commission on Radiological Protection issued a statement on reduction of the equivalent dose limits for the lens of the eye, and strongly recommended its consideration in the revision of the International Atomic Energy Agency's International Basic Safety Standards on Radiation Protection. The reduced dose limit was incorporated in the final version of the Basic Safety Standards. As significant concern was expressed by radiation protection professionals worldwide, the International Radiation Protection Association (IRPA) established a task group to assess the impact of implementation of the revised dose limit for the lens of the eye for occupational exposure. IRPA Associate Societies (ASs) were asked for their views using a questionnaire addressing three topics: implications for dosimetry, implications for methods of protection, and wider implications. The responses received indicate various methods of approach and express different points of view, reflecting nuances of particular ASs or specific professional groups. Topic experts nominated by ASs were selected to assist with collation of responses, and a report was produced by the task group. Conclusions were drawn on the three issues, including potential cost implications. A number of recommendations were drawn from the responses received including: the request for more understanding about the relationship between exposure of the lens of the eye and cataract formation, and further guidance to assist implementation; the importance of economic and social considerations when introducing the limits into national regulations; the need to propose or define procedures related to employment of people with existing or pre-cataract conditions; and the practical aspects relating to dosimetry and protective equipment. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Short communication: a repeated simian human immunodeficiency virus reverse transcriptase/herpes simplex virus type 2 cochallenge macaque model for the evaluation of microbicides.

PubMed

Kenney, Jessica; Derby, Nina; Aravantinou, Meropi; Kleinbeck, Kyle; Frank, Ines; Gettie, Agegnehu; Grasperge, Brooke; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D; Zydowsky, Thomas M; Robbiani, Melissa

2014-11-01

Epidemiological studies suggest that prevalent herpes simplex virus type 2 (HSV-2) infection increases the risk of HIV acquisition, underscoring the need to develop coinfection models to evaluate promising prevention strategies. We previously established a single high-dose vaginal coinfection model of simian human immunodeficiency virus (SHIV)/HSV-2 in Depo-Provera (DP)-treated macaques. However, this model does not appropriately mimic women's exposure. Repeated limiting dose SHIV challenge models are now used routinely to test prevention strategies, yet, at present, there are no reports of a repeated limiting dose cochallenge model in which to evaluate products targeting HIV and HSV-2. Herein, we show that 20 weekly cochallenges with 2-50 TCID50 simian human immunodeficiency virus reverse transcriptase (SHIV-RT) and 10(7) pfu HSV-2 results in infection with both viruses (4/6 SHIV-RT, 6/6 HSV-2). The frequency and level of vaginal HSV-2 shedding were significantly greater in the repeated exposure model compared to the single high-dose model (p<0.0001). We used this new model to test the Council's on-demand microbicide gel, MZC, which is active against SHIV-RT in DP-treated macaques and HSV-2 and human papillomavirus (HPV) in mice. While MZC reduced SHIV and HSV-2 infections in our repeated limiting dose model when cochallenging 8 h after each gel application, a barrier effect of carrageenan (CG) that was not seen in DP-treated animals precluded evaluation of the significance of the antiviral activity of MZC. Both MZC and CG significantly (p<0.0001) reduced the frequency and level of vaginal HSV-2 shedding compared to no gel treatment. This validates the use of this repeated limiting dose cochallenge model for testing products targeting HIV and HSV-2.

The incidence of phlebitis with intravenous amiodarone at guideline dose recommendations.

PubMed

Slim, Ahmad M; Roth, Jason E; Duffy, Benjamin; Boyd, Sheri Y N; Rubal, Bernard J

2007-12-01

Postoperative atrial fibrillation following cardiothoracic surgery is common and frequently managed with intravenous (IV) amiodarone. Phlebitis is the most common complication with peripheral infusion of this agent. Current practice guidelines for peripheral IV administration of <2 mg/mL amiodarone were established to reduce the risk of phlebitis. The present study examines the incidence of phlebitis in a postoperative patient population given current dose recommendations. A total of 273 patient charts were reviewed. The incidence of phlebitis in patients given IV amiodarone (n = 36) was 13.9% (95% confidence interval, 2.6-25.2%; p = 0.001). Logistic regression analysis with backward elimination of other therapeutic risk factors suggests that the odds ratio for phlebitis using current dose regimens without IV filters is 19-fold greater than baseline risk in this population. Phlebitis remains a significant complication associated with peripheral infusion of amiodarone within recommended dosing limits.

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour-bearing dogs: A phase I dose finding study.

PubMed

Wouda, R M; Hocker, S E; Higginbotham, M L

2018-03-01

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg -1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m -2 . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m -2 . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m -2 IV every 21 days and approximately 2.75 mg kg -1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials. © 2017 John Wiley & Sons Ltd.

Characterization of adaptive statistical iterative reconstruction algorithm for dose reduction in CT: A pediatric oncology perspective

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

Brady, S. L.; Yee, B. S.; Kaufman, R. A.

Purpose: This study demonstrates a means of implementing an adaptive statistical iterative reconstruction (ASiR Trade-Mark-Sign ) technique for dose reduction in computed tomography (CT) while maintaining similar noise levels in the reconstructed image. The effects of image quality and noise texture were assessed at all implementation levels of ASiR Trade-Mark-Sign . Empirically derived dose reduction limits were established for ASiR Trade-Mark-Sign for imaging of the trunk for a pediatric oncology population ranging from 1 yr old through adolescence/adulthood. Methods: Image quality was assessed using metrics established by the American College of Radiology (ACR) CT accreditation program. Each image quality metricmore » was tested using the ACR CT phantom with 0%-100% ASiR Trade-Mark-Sign blended with filtered back projection (FBP) reconstructed images. Additionally, the noise power spectrum (NPS) was calculated for three common reconstruction filters of the trunk. The empirically derived limitations on ASiR Trade-Mark-Sign implementation for dose reduction were assessed using (1, 5, 10) yr old and adolescent/adult anthropomorphic phantoms. To assess dose reduction limits, the phantoms were scanned in increments of increased noise index (decrementing mA using automatic tube current modulation) balanced with ASiR Trade-Mark-Sign reconstruction to maintain noise equivalence of the 0% ASiR Trade-Mark-Sign image. Results: The ASiR Trade-Mark-Sign algorithm did not produce any unfavorable effects on image quality as assessed by ACR criteria. Conversely, low-contrast resolution was found to improve due to the reduction of noise in the reconstructed images. NPS calculations demonstrated that images with lower frequency noise had lower noise variance and coarser graininess at progressively higher percentages of ASiR Trade-Mark-Sign reconstruction; and in spite of the similar magnitudes of noise, the image reconstructed with 50% or more ASiR Trade-Mark-Sign presented a more smoothed appearance than the pre-ASiR Trade-Mark-Sign 100% FBP image. Finally, relative to non-ASiR Trade-Mark-Sign images with 100% of standard dose across the pediatric phantom age spectrum, similar noise levels were obtained in the images at a dose reduction of 48% with 40% ASIR Trade-Mark-Sign and a dose reduction of 82% with 100% ASIR Trade-Mark-Sign . Conclusions: The authors' work was conducted to identify the dose reduction limits of ASiR Trade-Mark-Sign for a pediatric oncology population using automatic tube current modulation. Improvements in noise levels from ASiR Trade-Mark-Sign reconstruction were adapted to provide lower radiation exposure (i.e., lower mA) instead of improved image quality. We have demonstrated for the image quality standards required at our institution, a maximum dose reduction of 82% can be achieved using 100% ASiR Trade-Mark-Sign ; however, to negate changes in the appearance of reconstructed images using ASiR Trade-Mark-Sign with a medium to low frequency noise preserving reconstruction filter (i.e., standard), 40% ASiR Trade-Mark-Sign was implemented in our clinic for 42%-48% dose reduction at all pediatric ages without a visually perceptible change in image quality or image noise.« less

Introduction of a deformable x-ray CT polymer gel dosimetry system

NASA Astrophysics Data System (ADS)

Maynard, E.; Heath, E.; Hilts, M.; Jirasek, A.

2018-04-01

This study introduces the first 3D deformable dosimetry system based on x-ray computed tomography (CT) polymer gel dosimetry and establishes the setup reproducibility, deformation characteristics and dose response of the system. A N-isopropylacrylamide (NIPAM)-based gel formulation optimized for x-ray CT gel dosimetry was used, with a latex balloon serving as the deformable container and low-density polyethylene and polyvinyl alcohol providing additional oxygen barrier. Deformable gels were irradiated with a 6 MV calibration pattern to determine dosimetric response and a dosimetrically uniform plan to determine the spatial uniformity of the response. Wax beads were added to each gel as fiducial markers to track the deformation and setup of the gel dosimeters. From positions of the beads on CT images the setup reproducibility and the limits and reproducibility of gel deformation were determined. Comparison of gel measurements with Monte Carlo dose calculations found excellent dosimetric accuracy, comparable to that of an established non-deformable dosimetry system, with a mean dose discrepancy of 1.5% in the low-dose gradient region and a gamma pass rate of 97.9% using a 3%/3 mm criterion. The deformable dosimeter also showed good overall spatial dose uniformity throughout the dosimeter with some discrepancies within 20 mm of the edge of the container. Tracking of the beads within the dosimeter found that sub-millimetre setup accuracy is achievable with this system. The dosimeter was able to deform and relax when externally compressed by up to 30 mm without sustaining any permanent damage. Internal deformations in 3D produced average marker movements of up to 12 mm along the direction of compression. These deformations were also shown to be reproducible over 100 consecutive deformations. This work has established several important characteristics of a new deformable dosimetry system which shows promise for future clinical applications, including the validation of deformable dose accumulation algorithms.

Dental radiography: tooth enamel EPR dose assessment from Rando phantom measurements

NASA Astrophysics Data System (ADS)

Aragno, D.; Fattibene, P.; Onori, S.; Aragno, D.; Fattibene, P.

2000-09-01

Electron paramagnetic resonance dosimetry of tooth enamel is now established as a suitable method for individual dose reconstruction following radiation accidents. The accuracy of the method is limited by some confounding factors, among which is the dose received due to medical x-ray irradiation. In the present paper the EPR response of tooth enamel to endoral examination was experimentally evaluated using an anthropomorphic phantom. The dose to enamel for a single exposure of a typical dental examination performed with a new x-ray generation unit working at 65 kVp gave rise to a CO2- signal of intensity similar to that induced by a dose of about 2 mGy of 60Co. EPR measurements were performed on the entire tooth with no attempt to separate buccal and lingual components. Also the dose to enamel for an orthopantomography exam was estimated. It was derived from TLD measurements as equivalent to 0.2 mGy of 60Co. In view of application to risk assessment analysis, in the present work the value for the ratio of the reference dose at the phantom surface measured with TLD to the dose at the tooth measured with EPR was determined.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessment of natural radionuclides and its radiological hazards from tiles made in Nigeria

NASA Astrophysics Data System (ADS)

Joel, E. S.; Maxwell, O.; Adewoyin, O. O.; Ehi-Eromosele, C. O.; Embong, Z.; Saeed, M. A.

2018-03-01

Activity concentration of 10 different brands of tiles made in Nigeria were analyzed using High purity Germanium gamma detector and its hazard indices such as absorbed dose rate, radium equivalent activity, external Hazard Index (Hex), internal Hazard Index (Hin), Annual Effective Dose (mSv/y), Gamma activity Index (Iγ) and Alpha Index (Iα) were determined. The result showed that the average activity concentrations of radionuclides (226Ra, 232Th and 40K) content are within the recommended limit. The average radium equivalent is within the recommended limit of 370 Bq/kg. The result obtained further showed that the mean values for the absorbed dose rate (D), external and internal hazard index, the annual effective dose (AEDR) equivalent, gamma activity index and Alpha Index were: 169.22 nGyh-1, 0.95 and 1.14, 1.59 mSv/y, 1.00 Sv yr-1 and 0.34 respectively. The result established that radiological hazards such as absorbed dose rate, internal hazard, annual effective dose rate, gamma activity index and Alpha Index for some samples are found to be slightly close or above international recommended values. The result for the present study was compared with tiles sample from others countries, it was observed that the concentration of tiles made in Nigeria and other countries are closer, however recommends proper radiation monitoring for some tiles made in Nigeria before usage due to the long term health effect.

A method for converting dose-to-medium to dose-to-tissue in Monte Carlo studies of gold nanoparticle-enhanced radiotherapy

NASA Astrophysics Data System (ADS)

Koger, B.; Kirkby, C.

2016-03-01

Gold nanoparticles (GNPs) have shown potential in recent years as a means of therapeutic dose enhancement in radiation therapy. However, a major challenge in moving towards clinical implementation is the exact characterisation of the dose enhancement they provide. Monte Carlo studies attempt to explore this property, but they often face computational limitations when examining macroscopic scenarios. In this study, a method of converting dose from macroscopic simulations, where the medium is defined as a mixture containing both gold and tissue components, to a mean dose-to-tissue on a microscopic scale was established. Monte Carlo simulations were run for both explicitly-modeled GNPs in tissue and a homogeneous mixture of tissue and gold. A dose ratio was obtained for the conversion of dose scored in a mixture medium to dose-to-tissue in each case. Dose ratios varied from 0.69 to 1.04 for photon sources and 0.97 to 1.03 for electron sources. The dose ratio is highly dependent on the source energy as well as GNP diameter and concentration, though this effect is less pronounced for electron sources. By appropriately weighting the monoenergetic dose ratios obtained, the dose ratio for any arbitrary spectrum can be determined. This allows complex scenarios to be modeled accurately without explicitly simulating each individual GNP.

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

PubMed

Fidias, Panos; Pennell, Nathan A; Boral, Anthony L; Shapiro, Geoffrey I; Skarin, Arthur T; Eder, Joseph P; Kwoh, T Jesse; Geary, Richard S; Johnson, Bruce E; Lynch, Thomas J; Supko, Jeffrey G

2009-09-01

A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

PubMed

Moore, Kathleen N; Borghaei, Hossein; O'Malley, David M; Jeong, Woondong; Seward, Shelly M; Bauer, Todd M; Perez, Raymond P; Matulonis, Ursula A; Running, Kelli L; Zhang, Xiaoyan; Ponte, Jose F; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-08-15

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. © 2017 American Cancer Society.

Dialysis Cannot be Dosed

PubMed Central

Meyer, Timothy W.; Sirich, Tammy L.; Hostetter, Thomas H.

2014-01-01

Adequate dialysis is difficult to define because we have not identified the toxic solutes that contribute most to uremic illness. Dialysis prescriptions therefore cannot be adjusted to control the levels of these solutes. The current solution to this problem is to define an adequate dose of dialysis on the basis of fraction of urea removed from the body. This has provided a practical guide to treatment as the dialysis population has grown over the past 25 years. Indeed, a lower limit to Kt/Vurea (or the related urea reduction ratio) is now established as a quality indicator by the Centers for Medicare and Medicaid for chronic hemodialysis patients in the United States. For the present, this urea-based standard provides a useful tool to avoid grossly inadequate dialysis. Dialysis dosing, however, based on measurement of a single, relatively nontoxic solute can provide only a very limited guide toward improved treatment. Prescriptions which have similar effects on the index solute can have widely different effects on other solutes. The dose concept discourages attempts to increase the removal of such solutes independent of the index solute. The dose concept further assumes that important solutes are produced at a constant rate relative to body size, and discourages attempts to augment dialysis treatment by reducing solute production. Identification of toxic solutes would provide a more rational basis for the prescription of dialysis and ultimately for improved treatment of patients with renal failure. PMID:21929590

ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.

PubMed

Miley, Galen P; Pou, Sovitj; Winter, Rolf; Nilsen, Aaron; Li, Yuexin; Kelly, Jane X; Stickles, Allison M; Mather, Michael W; Forquer, Isaac P; Pershing, April M; White, Karen; Shackleford, David; Saunders, Jessica; Chen, Gong; Ting, Li-Min; Kim, Kami; Zakharov, Lev N; Donini, Cristina; Burrows, Jeremy N; Vaidya, Akhil B; Charman, Susan A; Riscoe, Michael K

2015-09-01

ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure

PubMed Central

2012-01-01

Background According to a fundamental law of radiobiology (“Law of Bergonié and Tribondeau”, 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review. Results Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). Conclusions At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed. PMID:22540409

Establishing bounding internal dose estimates for thorium activities at Rocky Flats.

PubMed

Ulsh, Brant A; Rich, Bryce L; Chew, Melton H; Morris, Robert L; Sharfi, Mutty; Rolfes, Mark R

2008-07-01

As part of an evaluation of a Special Exposure Cohort petition filed on behalf of workers at the Rocky Flats Plant, the National Institute for Occupational Safety and Health (NIOSH) was required to demonstrate that bounding values could be established for radiation doses due to the potential intake of all radionuclides present at the facility. The main radioactive elements of interest at Rocky Flats were plutonium and uranium, but much smaller quantities of several other elements, including thorium, were occasionally handled at the site. Bounding potential doses from thorium has proven challenging at other sites due to the early historical difficulty in detecting this element through urinalysis methods and the relatively high internal dose delivered per unit intake. This paper reports the results of NIOSH's investigation of the uses of thorium at Rocky Flats and provides bounding dose reconstructions for these operations. During this investigation, NIOSH reviewed unclassified reports, unclassified extracts of classified materials, material balance and inventory ledgers, monthly progress reports from various groups, and health physics field logbooks, and conducted interviews with former Rocky Flats workers. Thorium operations included: (1) an experimental metal forming project with 240 kg of thorium in 1960; (2) the use of pre-formed parts in weapons mockups; (3) the removal of Th from U; (4) numerous analytical procedures involving trace quantities of thorium; and (5) the possible experimental use of thorium as a mold coating compound. The thorium handling operations at Rocky Flats were limited in scope, well-monitored and documented, and potential doses can be bounded.

BET 2: Low-dose ketamine for acute pain in the ED.

PubMed

Duncan, Colby; Riley, Brad

2016-12-01

A short cut review was carried out to establish whether low-dose ketamine is better than morphine at safely and effectively reducing pain scores in ED patients with acute pain who do not respond to conventional therapies. One hundred and thirty-two papers were found using the reported searches, of these three presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that the evidence is limited, but that ketamine can be an effective alternative or adjunct to intravenous opioid pain medications and in some instances may provide more effective pain relief when compared with opioids. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers

PubMed Central

Yap, Timothy A.; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P.; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A.; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P.; Swales, Karen; deSouza, Nandita M; Leach, Martin O.; Garrett, Michelle D.; Sullivan, Daniel M.; de Bono, Johann S.; Tolcher, Anthony W.

2014-01-01

Purpose Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60mg on alternate days (QOD). Due to a long half-life (60-80h), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design Patients with advanced cancers were enrolled onto a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers, and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy and intrinsic susceptibility-weighted MRI. Results Seventy-one patients were enrolled; 38 patients had 60mg MK-2206 QOD, while 33 received MK-2206 at 90mg, 135mg, 150mg, 200mg, 250mg, and 300mg QW. The QW MK-2206 MTD was established at 200mg following dose-limiting rash at 250mg and 300mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially-obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200mg QW is currently used in phase II MK-2206 monotherapy and combination studies. PMID:25239610

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PubMed

Yap, Timothy A; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P; Swales, Karen; deSouza, Nandita M; Leach, Martin O; Garrett, Michelle D; Sullivan, Daniel M; de Bono, Johann S; Tolcher, Anthony W

2014-11-15

Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). ©2014 American Association for Cancer Research.

The impact of various protective tools on the dose reduction in the eye lens in an interventional cardiology-clinical study.

PubMed

Domienik, J; Bissinger, A; Grabowicz, W; Jankowski, Ł; Kręcki, R; Makowski, M; Masiarek, K; Plewka, M; Lubiński, A; Peruga, J Z

2016-06-01

The aim of the study was to check, in clinical practice, the potential for the dose reduction of lead eyewear and a ceiling-suspended shield used to protect the eye lens of physicians working in interventional cardiology. To this end, for the lead eyewear, the dose reduction factors were derived to correct the readings from a dosimeter used routinely outside the glasses. Four types of lead eyewear with attached loose thermoluminescent dosimeters and EYE-D dosimeters were worn by physicians in two clinical centres, for two-month periods, during coronary angiography (CA), percutaneous coronary intervention (PCI), and pacemaker procedures. In order to analyse, separately, how a ceiling-suspended lead screen absorbs the scattered radiation, a series of measurements was carried out during single CA/PCI procedures performed with and without the protection. The lead eyewear may reduce the doses to the eye closest to the x-ray tube by a factor between 1.1 and 3.4, depending on its model and the physician's position. The effectiveness of the eyewear may, however, vary-even for the same model and physician-almost twofold between different working periods. The ceiling-suspended shield decreases the doses in clinical practice by a factor of 2.3. The annual eye lens doses without the eyewear estimated from routine measurements are high-above or close to the new eye lens dose limit established by the recent EU Basic Safety Standards, even though the ceiling-suspended shield was used. Therefore, to comply with the new dose limit that is set in the Directive, protection of the eyes of physicians with high workloads might require the use of both the eyewear and the ceiling-suspended shield.

A three-stage experimental strategy to evaluate and validate an interplate IC50 format.

PubMed

Rodrigues, Daniel J; Lyons, Richard; Laflin, Philip; Pointon, Wayne; Kammonen, Juha

2007-12-01

The serial dilution of compounds to establish potency against target enzymes or receptors can at times be a rate-limiting step in project progression. We have investigated the possibility of running 50% inhibitory concentration experiments in an interplate format, with dose ranges constructed across plates. The advantages associated with this format include a faster reformatting time for the compounds while also increasing the number of doses that can be potentially generated. These two factors, in particular, would lend themselves to a higher-throughput and more timely testing of compounds, while also maximizing chances to capture fully developed dose-response curves. The key objective from this work was to establish a strategy to assess the feasibility of an interplate format to ensure that the quality of data generated would be equivalent to historical formats used. A three-stage approach was adopted to assess and validate running an assay in an interplate format, compared to an intraplate format. Although the three-stage strategy was tested with two different assay formats, it would be necessary to investigate the feasibility for other assay types. The recommendation is that the three-stage experimental strategy defined here is used to assess feasibility of other assay formats used.

Web based scoring is useful for validation and harmonisation of scoring criteria within RENEB.

PubMed

Romm, Horst; Ainsbury, Elizabeth A; Barquinero, Joan Francesc; Barrios, Leonardo; Beinke, Christina; Cucu, Alexandra; Domene, Mercedes Moreno; Filippi, Silvia; Monteiro Gil, Octávia; Gregoire, Eric; Hadjidekova, Valeria; Hatzi, Vasia; Lindholm, Carita; M Kacher, Radhia; Montoro, Alegria; Moquet, Jayne; Noditi, Mihaela; Oestreicher, Ursula; Palitti, Fabrizio; Pantelias, Gabriel; Prieto, María Jesús; Popescu, Irina; Rothkamm, Kai; Sebastià, Natividad; Sommer, Sylwester; Terzoudi, Georgia; Testa, Antonella; Wojcik, Andrzej

2017-01-01

To establish a training data set of digital images and to investigate the scoring criteria and dose assessment of the dicentric assay within the European network of biodosimetry (RENEB), a web based scoring inter-comparison was undertaken by 17 RENEB partners. Two sets of 50 high resolution images were uploaded onto the RENEB website. One set included metaphases after a moderate exposure (1.3 Gy) and the other set consisted of metaphases after a high dose exposure (3.5 Gy). The laboratories used their own calibration curves for estimating doses based on observed aberration frequencies. The dose estimations and 95% confidence limits were compared to the actual doses and the corresponding z-values were satisfactory for the majority; only the dose estimations from two laboratories were too low or too high. The coefficients of variation were 17.6% for the moderate and 11.2% for the high dose. Metaphases with controversial results could be identified for training purposes. Overall, the web based scoring of the two galleries by the 17 laboratories produced very good results. Application of web based scoring for the dicentric assay may therefore be a relevant strategy for an operational biodosimetry assistance network.

The Elbmarsch leukemia cluster: are there conceptual limitations in controlling immission from nuclear establishments in Germany?

PubMed

Schmitz-Feuerhake, I; Dieckmann, H; Hoffmann, W; Lengfelder, E; Pflugbeil, S; Stevenson, A F

2005-11-01

The childhood leukemia cluster in the proximity of the German nuclear establishments of Geesthacht is unique in its spatial and temporal concentration. After a steep increase in cases in 1990, the cluster continues to show a significant increase up to the present. Early investigations of blood samples from a casual sample of local residents showed an increase in dicentric chromosomes in lymphocytes, indicating exposure exceeding dose limits. Analyses of the immission data revealed several unexpected deliveries of fission and activation products in the environment but provided no explanation of the source. Because of the observed overdispersion of dicentric chromosomes in cells, the idea of a contribution by densely ionizing emitters was compelling. The routine programs, however, do not include alpha emitters. These were measured in specific studies that proved contamination by transuranic nuclides. As shown in the present investigation, routine environmental surveillance programs support the occurrence of an accidental event near Geesthacht in September 1986. Until now, neither the cause nor the complete scenario of the activity release could be established. The ongoing discussion highlights limitations in the immission-control concept, which is predominantly based on gamma-radiation monitoring.

Alternative strawberry disease management strategy: combing low UV-C irradiation in dark, disabling pathogen’s UV-C repair mechanism, and preventing pathogen establishment with biocontrol agents

USDA-ARS?s Scientific Manuscript database

The limitations of current fungicides necessitate a search for new approaches. Low-dose or sub-lethal UV-C irradiation (12.36 J/m2) alone is not effective in controlling fungal diseases, especially when the plants are exposed to UV-C irradiation during the day. We found, however, that application ...

10 CFR 20.1207 - Occupational dose limits for minors.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Occupational dose limits for minors. 20.1207 Section 20.1207 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1207 Occupational dose limits for minors. The annual occupational dose limits for minors are...

10 CFR 20.1207 - Occupational dose limits for minors.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Occupational dose limits for minors. 20.1207 Section 20.1207 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1207 Occupational dose limits for minors. The annual occupational dose limits for minors are...

10 CFR 20.1207 - Occupational dose limits for minors.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Occupational dose limits for minors. 20.1207 Section 20.1207 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1207 Occupational dose limits for minors. The annual occupational dose limits for minors are...

10 CFR 20.1207 - Occupational dose limits for minors.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Occupational dose limits for minors. 20.1207 Section 20.1207 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1207 Occupational dose limits for minors. The annual occupational dose limits for minors are...

10 CFR 20.1207 - Occupational dose limits for minors.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Occupational dose limits for minors. 20.1207 Section 20.1207 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1207 Occupational dose limits for minors. The annual occupational dose limits for minors are...

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

PubMed Central

Awada, A; Punt, C J A; Piccart, M J; Tellingen, O Van; Manen, L Van; Kerger, J; Groot, Y; Wanders, J; Verweij, J; Wagener, D J Th

1999-01-01

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1–5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m−2. According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m−2, the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m−2. From the dose level 170 μg m−2, the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m−2. The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml−1) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaign PMID:10188890

A probabilistic safety analysis of incidents in nuclear research reactors.

PubMed

Lopes, Valdir Maciel; Agostinho Angelo Sordi, Gian Maria; Moralles, Mauricio; Filho, Tufic Madi

2012-06-01

This work aims to evaluate the potential risks of incidents in nuclear research reactors. For its development, two databases of the International Atomic Energy Agency (IAEA) were used: the Research Reactor Data Base (RRDB) and the Incident Report System for Research Reactor (IRSRR). For this study, the probabilistic safety analysis (PSA) was used. To obtain the result of the probability calculations for PSA, the theory and equations in the paper IAEA TECDOC-636 were used. A specific program to analyse the probabilities was developed within the main program, Scilab 5.1.1. for two distributions, Fischer and chi-square, both with the confidence level of 90 %. Using Sordi equations, the maximum admissible doses to compare with the risk limits established by the International Commission on Radiological Protection (ICRP) were obtained. All results achieved with this probability analysis led to the conclusion that the incidents which occurred had radiation doses within the stochastic effects reference interval established by the ICRP-64.

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

PubMed

Griffiths, Lisa A; Flatters, Sarah J L

2015-10-01

Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of high energy radiation on the mechanical properties of epoxy/graphite fiber reinforced composites

NASA Technical Reports Server (NTRS)

Fornes, R. E.; Gilbert, R. D.; Memory, J. D.

1986-01-01

The epoxy resin system formed by tetraglycidyl 4,4'-diamino diphenyl methane (TGDDM) and 4,4'-diamino diphenyl sulfone (DDS) was characterized by dynamic mechanical analysis and differential scanning calorimetry. Dynamic mechanical properties of graphite fiber epoxy composite specimens formulated with two different adhesive systems (NARMCO 5208, NARMCO 5209) were determined. The specimens were exposed to varying dose levels of ionizing radiation (0.5 MeV electrons) with a maximum absorbed dose of 10,000 Mrads. Following irradiation, property measurements were made to assess the influence of radiation on the epoxy and composite specimens. The results established that ionizing radiation has a limited effect on the properties of epoxy and composite specimens.

Recurrent Kikuchi-Fujimoto Disease Successfully Treated by the Concomitant Use of Hydroxychloroquine and Corticosteroids

PubMed Central

Honda, Fumika; Tsuboi, Hiroto; Toko, Hirofumi; Ohyama, Ayako; Takahashi, Hidenori; Abe, Saori; Yokosawa, Masahiro; Asashima, Hiromitsu; Hagiwara, Shinya; Hirota, Tomoya; Kondo, Yuya; Matsumoto, Isao; Sumida, Takayuki

2017-01-01

Kikuchi-Fujimoto disease (KFD) is a benign disease of unknown etiology characterized by lymphadenopathy and a fever. For the majority of patients with KFD, the course is self-limited; however, the optimum method of managing recurrent cases has not yet been established. We herein report a case of a 42-year-old Japanese woman with KFD (confirmed by a lymph node biopsy). Although high-dose prednisolone (PSL) rapidly induced remission, she experienced four recurrences on treatment tapering. Concomitant use of hydroxychloroquine (HCQ) with low-dose PSL induced continuous remission. This is the first case to suggest the effectiveness of HCQ for recurrent KFD in a Japanese patient. PMID:29021444

Recurrent Kikuchi-Fujimoto Disease Successfully Treated by the Concomitant Use of Hydroxychloroquine and Corticosteroids.

PubMed

Honda, Fumika; Tsuboi, Hiroto; Toko, Hirofumi; Ohyama, Ayako; Takahashi, Hidenori; Abe, Saori; Yokosawa, Masahiro; Asashima, Hiromitsu; Hagiwara, Shinya; Hirota, Tomoya; Kondo, Yuya; Matsumoto, Isao; Sumida, Takayuki

2017-12-15

Kikuchi-Fujimoto disease (KFD) is a benign disease of unknown etiology characterized by lymphadenopathy and a fever. For the majority of patients with KFD, the course is self-limited; however, the optimum method of managing recurrent cases has not yet been established. We herein report a case of a 42-year-old Japanese woman with KFD (confirmed by a lymph node biopsy). Although high-dose prednisolone (PSL) rapidly induced remission, she experienced four recurrences on treatment tapering. Concomitant use of hydroxychloroquine (HCQ) with low-dose PSL induced continuous remission. This is the first case to suggest the effectiveness of HCQ for recurrent KFD in a Japanese patient.

[TESTING STABILITY OF TABLETED ACETAMINOPHEN AND FUROSEMIDE AFTER 6-MONTH STORAGE IN SPACE FLIGHT].

PubMed

Bogomolov, V V; Kondratenko, S N; Kovachevich, I V

2015-01-01

It was shown that multiple spaceflight factors (i.e., acceleration, overvibration, microgravity etc.) do not impact stability of acetaminophen and furosemide tablets stored onboard the International space station over 6 months. Acetaminophen dose in a tablet was 496.44 ± 6.88 mg (99.29 ± 1.38%) before spaceflight (SF) and 481.77 ± 1 2.40 mg (96.35 ± 0.48%) after 6 mos. of storage; furosemide dose in a tablet was 40.19 ± 0.28 mg (100.47 ± 0.71%) before and 39.24 ± 0.72 mg (98.105 ± 1.80%) after SF remaining within the established limits.

Efficacy of high-dose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment.

PubMed

Tona, Francesco; Bellotto, Fabio; Laveder, Francesco; Meneghin, Alessia; Sinagra, Gianfranco; Marcolongo, Renzo

2003-01-01

Although idiopathic acute pericarditis is usually a self-limiting disease, in many patients it may recur over a period of months or years. Even if some evidence seems to suggest the possible role of a deranged immune reactivity in the pathogenesis of idiopathic recurrent pericarditis, the etiology of the disease is still unknown. Furthermore, while some trial data confirm the usefulness of colchicine, its medical treatment is not yet clearly established. We here report the clinical history of 2 patients with idiopathic recurrent pericarditis resistant to prednisone, colchicine and other immunosuppressive drugs, who have been successfully treated with high-dose intravenous immunoglobulins.

Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors

PubMed Central

Sasaki, Masao S.; Tachibana, Akira; Takeda, Shunichi

2014-01-01

Cancer risk at low doses of ionizing radiation remains poorly defined because of ambiguity in the quantitative link to doses below 0.2 Sv in atomic bomb survivors in Hiroshima and Nagasaki arising from limitations in the statistical power and information available on overall radiation dose. To deal with these difficulties, a novel nonparametric statistics based on the ‘integrate-and-fire’ algorithm of artificial neural networks was developed and tested in cancer databases established by the Radiation Effects Research Foundation. The analysis revealed unique features at low doses that could not be accounted for by nominal exposure dose, including (i) the presence of a threshold that varied with organ, gender and age at exposure, and (ii) a small but significant bumping increase in cancer risk at low doses in Nagasaki that probably reflects internal exposure to 239Pu. The threshold was distinct from the canonical definition of zero effect in that it was manifested as negative excess relative risk, or suppression of background cancer rates. Such a unique tissue response at low doses of radiation exposure has been implicated in the context of the molecular basis of radiation–environment interplay in favor of recently emerging experimental evidence on DNA double-strand break repair pathway choice and its epigenetic memory by histone marking. PMID:24366315

Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors.

PubMed

Sasaki, Masao S; Tachibana, Akira; Takeda, Shunichi

2014-05-01

Cancer risk at low doses of ionizing radiation remains poorly defined because of ambiguity in the quantitative link to doses below 0.2 Sv in atomic bomb survivors in Hiroshima and Nagasaki arising from limitations in the statistical power and information available on overall radiation dose. To deal with these difficulties, a novel nonparametric statistics based on the 'integrate-and-fire' algorithm of artificial neural networks was developed and tested in cancer databases established by the Radiation Effects Research Foundation. The analysis revealed unique features at low doses that could not be accounted for by nominal exposure dose, including (i) the presence of a threshold that varied with organ, gender and age at exposure, and (ii) a small but significant bumping increase in cancer risk at low doses in Nagasaki that probably reflects internal exposure to (239)Pu. The threshold was distinct from the canonical definition of zero effect in that it was manifested as negative excess relative risk, or suppression of background cancer rates. Such a unique tissue response at low doses of radiation exposure has been implicated in the context of the molecular basis of radiation-environment interplay in favor of recently emerging experimental evidence on DNA double-strand break repair pathway choice and its epigenetic memory by histone marking.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study.

PubMed

Thomas, A L; Cox, G; Sharma, R A; Steward, W P; Shields, F; Jeyapalan, K; Muller, S; O'Byrne, K J

2000-12-01

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis.

Patient doses and occupational exposure in a hybrid operating room.

PubMed

Andrés, C; Pérez-García, H; Agulla, M; Torres, R; Miguel, D; Del Castillo, A; Flota, C M; Alonso, D; de Frutos, J; Vaquero, C

2017-05-01

This study aimed to characterize the radiation exposure to patients and workers in a new vascular hybrid operating room during X-ray-guided procedures. During one year, data from 260 interventions performed in a hybrid operating room equipped with a Siemens Artis Zeego angiography system were monitored. The patient doses were analysed using the following parameters: radiation time, kerma-area product, patient entrance reference point dose and peak skin dose. Staff radiation exposure and ambient dose equivalent were also measured using direct reading dosimeters and thermoluminescent dosimeters. The radiation time, kerma-area product, patient entrance reference point dose and peak skin dose were, on average, 19:15min, 67Gy·cm 2 , 0.41Gy and 0.23Gy, respectively. Although the contribution of the acquisition mode was smaller than 5% in terms of the radiation time, this mode accounted for more than 60% of the effective dose per patient. All of the worker dose measurements remained below the limits established by law. The working conditions in the hybrid operating room HOR are safe in terms of patient and staff radiation protection. Nevertheless, doses are highly dependent on the workload; thus, further research is necessary to evaluate any possible radiological deviation of the daily working conditions in the HOR. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Developability assessment of clinical drug products with maximum absorbable doses.

PubMed

Ding, Xuan; Rose, John P; Van Gelder, Jan

2012-05-10

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or D(abs), has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of D(abs), but in general D(abs) from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the D(abs) limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of D(abs) estimates to inform clinical formulation development strategies. Copyright © 2012 Elsevier B.V. All rights reserved.

Multiparametric Determination of Radiation Risk

NASA Technical Reports Server (NTRS)

Richmond, Robert C.

2003-01-01

Predicting risk of human cancer following exposure to ionizing space radiation is challenging in part because of uncertainties of low-dose distribution amongst cells, of unknown potentially synergistic effects of microgravity upon cellular protein-expression, and of processing dose-related damage within cells to produce rare and late-appearing malignant transformation, degrade the confidence of cancer risk-estimates. The NASA- specific responsibility to estimate the risks of radiogenic cancer in a limited number of astronauts is not amenable to epidemiologic study, thereby increasing this challenge. Developing adequately sensitive cellular biodosimeters that simultaneously report 1) the quantity of absorbed close after exposure to ionizing radiation, 2) the quality of radiation delivering that dose, and 3) the risk of developing malignant transformation by the cells absorbing that dose could be useful for resolving these challenges. Use of a multiparametric cellular biodosimeter is suggested using analyses of gene-expression and protein-expression whereby large datasets of cellular response to radiation-induced damage are obtained and analyzed for expression-profiles correlated with established end points and molecular markers predictive for cancer-risk. Analytical techniques of genomics and proteomics may be used to establish dose-dependency of multiple gene- and protein- expressions resulting from radiation-induced cellular damage. Furthermore, gene- and protein-expression from cells in microgravity are known to be altered relative to cells grown on the ground at 1g. Therefore, hypotheses are proposed that 1) macromolecular expression caused by radiation-induced damage in cells in microgravity may be different than on the ground, and 2) different patterns of macromolecular expression in microgravity may alter human radiogenic cancer risk relative to radiation exposure on Earth. A new paradigm is accordingly suggested as a national database wherein genomic and proteomic datasets are registered and interrogated in order to provide statistically significant dose-dependent risk estimation of radiogenic cancer in astronauts.

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

PubMed Central

Trippett, Tanya M.; Herzog, Cynthia; Whitlock, James A.; Wolff, Johannes; Kuttesch, John; Bagatell, Rochelle; Hunger, Stephen P.; Boklan, Jessica; Smith, Amy A.; Arceci, Robert J.; Katzenstein, Howard M.; Harbison, Christopher; Zhou, Xiaofei; Lu, Haolan; Langer, Christiane; Weber, Martin; Gore, Lia

2009-01-01

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen. PMID:19770383

SU-E-T-154: Establishment and Implement of 3D Image Guided Brachytherapy Planning System

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

Jiang, S; Zhao, S; Chen, Y

2014-06-01

Purpose: Cannot observe the dose intuitionally is a limitation of the existing 2D pre-implantation dose planning. Meanwhile, a navigation module is essential to improve the accuracy and efficiency of the implantation. Hence a 3D Image Guided Brachytherapy Planning System conducting dose planning and intra-operative navigation based on 3D multi-organs reconstruction is developed. Methods: Multi-organs including the tumor are reconstructed in one sweep of all the segmented images using the multiorgans reconstruction method. The reconstructed organs group establishs a three-dimensional visualized operative environment. The 3D dose maps of the three-dimentional conformal localized dose planning are calculated with Monte Carlo method whilemore » the corresponding isodose lines and isodose surfaces are displayed in a stereo view. The real-time intra-operative navigation is based on an electromagnetic tracking system (ETS) and the fusion between MRI and ultrasound images. Applying Least Square Method, the coordinate registration between 3D models and patient is realized by the ETS which is calibrated by a laser tracker. The system is validated by working on eight patients with prostate cancer. The navigation has passed the precision measurement in the laboratory. Results: The traditional marching cubes (MC) method reconstructs one organ at one time and assembles them together. Compared to MC, presented multi-organs reconstruction method has superiorities in reserving the integrality and connectivity of reconstructed organs. The 3D conformal localized dose planning, realizing the 'exfoliation display' of different isodose surfaces, helps make sure the dose distribution has encompassed the nidus and avoid the injury of healthy tissues. During the navigation, surgeons could observe the coordinate of instruments real-timely employing the ETS. After the calibration, accuracy error of the needle position is less than 2.5mm according to the experiments. Conclusion: The speed and quality of 3D reconstruction, the efficiency in dose planning and accuracy in navigation all can be improved simultaneously.« less

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

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

Corn, Paul G., E-mail: pcorn@mdanderson.org; Song, Danny Y.; Heath, Elisabeth

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles).more » A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.« less

PROPOSALS FOR THE ESTABLISHMENT OF NATIONAL DIAGNOSTIC REFERENCE LEVELS FOR RADIOGRAPHY FOR ADULT PATIENTS BASED ON REGIONAL DOSE SURVEYS IN RUSSIAN FEDERATION.

PubMed

Vodovatov, A V; Balonov, M I; Golikov, V Yu; Shatsky, I G; Chipiga, L A; Bernhardsson, C

2017-04-01

In 2009-2014, dose surveys aimed to collect adult patient data and parameters of most common radiographic examinations were performed in six Russian regions. Typical patient doses were estimated for the selected examinations both in entrance surface dose and in effective dose. 75%-percentiles of typical patient effective dose distributions were proposed as preliminary regional diagnostic reference levels (DRLs) for radiography. Differences between the 75%-percentiles of regional typical patient dose distributions did not exceed 30-50% for the examinations with standardized clinical protocols (skull, chest and thoracic spine) and a factor of 1.5 for other examinations. Two different approaches for establishing national DRLs were evaluated: as a 75%-percentile of a pooled regional sample of patient typical doses (pooled method) and as a median of 75%-percentiles of regional typical patient dose distributions (median method). Differences between pooled and median methods for effective dose did not exceed 20%. It was proposed to establish Russian national DRLs in effective dose using a pooled method. In addition, the local authorities were granted an opportunity to establish regional DRLs if the local radiological practice and typical patient dose distributions are significantly different. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis of the Body Distribution of Absorbed Dose in the Organs of Three Species of Fish from Sepetiba Bay

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

Pereira, Wagner de S; Universidade Federal Fluminense, Programa de Pos-graduacao em Biologia Marinha; Kelecom, Alphonse

2008-08-07

The body distribution of Polonium-210 in three fishes from the Sepetiba Bay (Macrodon ancylodon, Micropogonias furnieri and Mugil curema) has been studied under the approach of the Department of Energy of the United States of America (DOE) that set the limit of absorbed dose rate in biota equal to 3.5x10{sup 3} {mu}Gy/y, and that also established the relation between dose rate (D) and radionuclide concentration (c) on a fish muscle fresh weight basis, as follows: D = 5.05 ExNxC, assuming that the radionuclide distribution is homogenous among organs. Two hypotheses were tested here, using statistical tools: 1) is the bodymore » distribution of absorbed dose homogenous among organs? and 2) is the body distribution of absorbed dose identical among studied fishes? It was concluded, as expected, that the distribution among organs is heterogeneous; but, unexpectedly, that the three fishes display identical body distribution pattern, although they belong to different trophic levels. Hence, concerning absorbed dose calculation, the statement that data distribution is homogenous must be understood merely as an approximation, at least in the case of Polonium-210.« less

[High-dose magnesium sulfate in the treatment of aconite poisoning].

PubMed

Clara, A; Rauch, S; Überbacher, C A; Felgenhauer, N; Drüge, G

2015-05-01

This article reports the case of a 62-year-old male patient who ingested the roots of Monkshood (Aconitum napellus) and white hellebore (Veratrum album) dissolved in alcohol with a suicidal intention and suffered cardiotoxic and neurotoxic symptoms. After contacting the Poison Information Centre ventricular arrhythmia was treated with high-dose magnesium sulphate as the only antiarrhythmic agent and subsequently a stable sinus rhythm could be established after approximately 3 h. Aconitum napellus is considered the most poisonous plant in Europe and it is found in gardens, the Alps and the Highlands. Poisoning is mainly caused by the alkaloid aconite that leads to persistent opening and activation of voltage-dependent sodium channels resulting in severe cardiac and neurological toxicity. As no specific antidote is known so far, poisoning is associated with a high mortality. The therapy with high-dose magnesium sulphate is based on in vitro and animal experiments as well as limited clinical case reports.

Expression of Angiotensin II and Aldosterone in Radiation-induced Lung Injury.

PubMed

Cao, Shuo; Wu, Rong

2012-12-01

Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied. Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

PubMed

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

PubMed Central

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; Mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA- activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32%–87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition

PubMed Central

Jane Cassidy, Elizabeth; Vitt Meyling, Nicolai

2018-01-01

Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta—flour beetle Tenebrio molitor model—has been used extensively for ecological and evolutionary host–parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7–10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition. PMID:29401652

Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition.

PubMed

Dhakal, Suraj; Micki Buss, Sebastian; Jane Cassidy, Elizabeth; Vitt Meyling, Nicolai; Lund Fredensborg, Brian

2018-02-03

Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta -flour beetle Tenebrio molitor model-has been used extensively for ecological and evolutionary host-parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7-10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition.

Improved dosimetry techniques for intravascular brachytherapy

NASA Astrophysics Data System (ADS)

Sehgal, Varun

Coronary artery disease leads to the accumulation of atheromatous plaque leading to coronary stenosis. Coronary intervention techniques such as balloon angioplasty and atherectomy are used to address coronary stenosis and establish a stable lumen thus enhancing blood flow to the myocardium. Restenosis or re-blockage of the arteries is a major limitation of the above mentioned interventional techniques. Neointimal hyperplasia or proliferation of cells in response to the vascular injury as a result of coronary intervention is considered to be one of the major causes of restenosis. Recent studies indicated that irradiation of the coronary lesion site, with radiation doses ranging from 15 to 30 Gy, leads to diminishing neointimal hyperplasia with subsequent reduction in restenosis. The radiation dose is given by catheter-based radiation delivery systems using beta-emitters 90Sr/90Y, 32P and gamma-emitting 192Ir among others. However the dose schema used for dose prescription for these sources are relatively simplistic, and are based on calculations using uniform homogenous water or tissue media and simple cylinder geometry. Stenotic coronary vessels are invariably lined with atheromatous plaque of heterogeneous composition, the radiation dose distribution obtained from such dosimetry data can cause significant variations in the actual dose received by a given patient. Such discrepancies in dose calculation can introduce relatively large uncertainties in the limits of dose window for effective and safe application of intravascular brachytherapy, and consequently in the clinical evaluation of the efficacy of this modality. In this research study we investigated the effect of different geometrical and material heterogeneities, including residual plaque, catheter non-centering, lesion eccentricity and cardiac motion on the radiation dose delivered at the lesion site. Correction factors including dose perturbation factors and dose variation factors have been calculated using Monte Carlo-based radiation transport code MCNP and tabulated for a range of different coronary geometries and different radionuclides. A new technique using imaging techniques such as intravascular ultrasound and angiography to assess dosimetry for realistic coronary arteries is also introduced. The results indicate the need for accurate assessment of post-intervention clinical measurements such as minimal lumen diameter and residual plaque burden and incorporating them into dose calculations.

Embracing model-based designs for dose-finding trials

PubMed Central

Love, Sharon B; Brown, Sarah; Weir, Christopher J; Harbron, Chris; Yap, Christina; Gaschler-Markefski, Birgit; Matcham, James; Caffrey, Louise; McKevitt, Christopher; Clive, Sally; Craddock, Charlie; Spicer, James; Cornelius, Victoria

2017-01-01

Background: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). Methods: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. Conclusions: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia. PMID:28664918

A non-human primate model of human radiation-induced venocclusive liver disease and hepatocyte injury

PubMed Central

Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; Roy-Chowdhury, Jayanta; Locker, Joseph; Abe, Michio; Enke, Charles A.; Baranowska-Kortylewicz, Janina; Solberg, Timothy D.; Guha, Chandan; Fox, Ira J.

2014-01-01

Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Since the characteristic venocclusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic venocclusive disease. Methods We performed a dose escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses where radiation-induced liver disease was mild or non-existent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human venocclusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury. PMID:24315566

Ivermectin residues in squab.

PubMed

Bennett, D C; Cheng, K M

2012-11-01

No drugs have been approved for the treatment of parasitic nematodes in pigeons, but ivermectin, a broad-spectrum endectocide, has been used extra-label by prescription. Producers currently allow for a 2-wk withdrawal time before marketing squabs. However, because its use is extra-label there is no legal maximum residue limit for ivermectin in squab meat. The purpose of this study was to examine the depletion of ivermectin (passed by the parents to the squabs) from the tissues of squab. Adult pigeons brooding squab were treated with ivermectin in their drinking water (3.3 µg/mL) for 3 d. After dosing the parents, the ivermectin concentration of the breast meat and liver of squabs was found to be greater than the maximum residual limits established for livestock, indicating that ivermectin was transferred from the parents to the squabs. However, ivermectin was not detected in either the breast meat or the livers of squabs 1 wk after dosing. These results indicate that there is a rapid decline in tissue levels of ivermectin in squab.

Ethical issues related to professional exposure of pregnant women in the medical field: monitoring and limiting effective dose.

PubMed

Santos, J A M; Nunes, R

2011-03-01

The International Commission on Radiological Protection recommendations for occupational exposed pregnant women do not imply necessarily the complete avoidance of work with radiation or radioactive materials. Instead, a careful review of the exposure conditions, once the pregnancy is declared, as part of the exercise of the ICRP optimisation principle (based in a teleological ethics point of view) is suggested. The dose limitation (following a deontological ethics point of view) of the fetus/embryo is, however, not clearly well established as happens in the case of workers or members of the public. Also, the justification of practices (to continue to work or not with radiation or radioactive materials) is not clearly addressed in most national or international recommendations. An analysis of this justification (bearing in mind both teleological and deontological ethics) is examined in this work having in mind the best interest of the child-to-be as well as other existing social and economical factors.

Inadvertent Intruder Analysis For The Portsmouth On-Site Waste Disposal Facility (OSWDF)

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

Smith, Frank G.; Phifer, Mark A.

2014-01-22

The inadvertent intruder analysis considers the radiological impacts to hypothetical persons who are assumed to inadvertently intrude on the Portsmouth OSWDF site after institutional control ceases 100 years after site closure. For the purposes of this analysis, we assume that the waste disposal in the OSWDF occurs at time zero, the site is under institutional control for the next 100 years, and inadvertent intrusion can occur over the following 1,000 year time period. Disposal of low-level radioactive waste in the OSWDF must meet a requirement to assess impacts on such individuals, and demonstrate that the effective dose equivalent to anmore » intruder would not likely exceed 100 mrem per year for scenarios involving continuous exposure (i.e. chronic) or 500 mrem for scenarios involving a single acute exposure. The focus in development of exposure scenarios for inadvertent intruders was on selecting reasonable events that may occur, giving consideration to regional customs and construction practices. An important assumption in all scenarios is that an intruder has no prior knowledge of the existence of a waste disposal facility at the site. Results of the analysis show that a hypothetical inadvertent intruder at the OSWDF who, in the worst case scenario, resides on the site and consumes vegetables from a garden established on the site using contaminated soil (chronic agriculture scenario) would receive a maximum chronic dose of approximately 7.0 mrem/yr during the 1000 year period of assessment. This dose falls well below the DOE chronic dose limit of 100 mrem/yr. Results of the analysis also showed that a hypothetical inadvertent intruder at the OSWDF who, in the worst case scenario, excavates a basement in the soil that reaches the waste (acute basement construction scenario) would receive a maximum acute dose of approximately 0.25 mrem/yr during the 1000 year period of assessment. This dose falls well below the DOE acute dose limit of 500 mrem/yr. Disposal inventory constraints based on the intruder analysis are well above conservative estimates of the OSWDF inventory and, based on intruder disposal limits; about 7% of the disposal capacity is reached with the estimated OSWDF inventory.« less

Statistical analysis of nonmonotonic dose-response relationships: research design and analysis of nasal cell proliferation in rats exposed to formaldehyde.

PubMed

Gaylor, David W; Lutz, Werner K; Conolly, Rory B

2004-01-01

Statistical analyses of nonmonotonic dose-response curves are proposed, experimental designs to detect low-dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect nonmonotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm, with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose-response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.

A method of setting limits for the purpose of quality assurance

NASA Astrophysics Data System (ADS)

Sanghangthum, Taweap; Suriyapee, Sivalee; Kim, Gwe-Ya; Pawlicki, Todd

2013-10-01

The result from any assurance measurement needs to be checked against some limits for acceptability. There are two types of limits; those that define clinical acceptability (action limits) and those that are meant to serve as a warning that the measurement is close to the action limits (tolerance limits). Currently, there is no standard procedure to set these limits. In this work, we propose an operational procedure to set tolerance limits and action limits. The approach to establish the limits is based on techniques of quality engineering using control charts and a process capability index. The method is different for tolerance limits and action limits with action limits being categorized into those that are specified and unspecified. The procedure is to first ensure process control using the I-MR control charts. Then, the tolerance limits are set equal to the control chart limits on the I chart. Action limits are determined using the Cpm process capability index with the requirements that the process must be in-control. The limits from the proposed procedure are compared to an existing or conventional method. Four examples are investigated: two of volumetric modulated arc therapy (VMAT) point dose quality assurance (QA) and two of routine linear accelerator output QA. The tolerance limits range from about 6% larger to 9% smaller than conventional action limits for VMAT QA cases. For the linac output QA, tolerance limits are about 60% smaller than conventional action limits. The operational procedure describe in this work is based on established quality management tools and will provide a systematic guide to set up tolerance and action limits for different equipment and processes.

High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program

PubMed Central

Moningi, Shalini; Armour, Elwood P.; Terezakis, Stephanie A.; Efron, Jonathan E.; Gearhart, Susan L.; Bivalacqua, Trinity J.; Kumar, Rachit; Le, Yi; Kien Ng, Sook; Wolfgang, Christopher L.; Zellars, Richard C.; Ellsworth, Susannah G.; Ahuja, Nita

2014-01-01

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed. PMID:24790628

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

PubMed Central

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

2016-01-01

Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. Conclusion. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. PMID:27789778

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

2016-11-01

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

[Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

PubMed

Fronius, M

2016-04-01

Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

Is Dosing of Therapeutic Immunoglobulins Optimal? A Review of a Three-Decade Long Debate in Europe

PubMed Central

Kerr, Jacqueline; Quinti, Isabella; Eibl, Martha; Chapel, Helen; Späth, Peter J.; Sewell, W. A. Carrock; Salama, Abdulgabar; van Schaik, Ivo N.; Kuijpers, Taco W.; Peter, Hans-Hartmut

2014-01-01

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic “per kg” dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki’ disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases. PMID:25566244

High-dose transdermal nicotine replacement for tobacco cessation.

PubMed

Brokowski, Laurie; Chen, Jiahui; Tanner, Sara

2014-04-15

The safety and efficacy of high-dose transdermal nicotine-replacement therapy (NRT) for the treatment of tobacco-use cessation were reviewed. Transdermal nicotine doses of 7, 14, and 21 mg daily are approved by the Food and Drug Administration for use in tobacco cessation. However, studies have suggested that these doses are more adequate for people who smoke fewer than 20 cigarettes per day. A literature search was conducted to identify English-language studies that evaluated the use of transdermal nicotine doses of ≥42 mg daily. A total of 11 articles were identified, representing 10 separate trials. In terms of safety, the majority of the trials had no reports of serious adverse events related to transdermal NRT at doses of ≥42 mg daily. A dose-response relationship with adverse events occurred in most trials. In terms of efficacy, a numerically higher abstinence rate was achieved with high-dose transdermal NRT in all trials but 1. However, none of the studies showed significant differences in final abstinence rates at follow-up. Some reasons why statistical significance was not achieved in these trials may be related to the limitations of these trials, such as their small samples and the lack of a power calculation. A more robust trial is needed to support higher nicotine transdermal doses in tobacco cessation and to help elucidate which patient population would be most suitable for their use. The safety and efficacy of high-dose transdermal NRT for tobacco cessation have not been established in the medical literature.

Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors.

PubMed

Gandhi, Leena; Bahleda, Rastislav; Tolaney, Sara M; Kwak, Eunice L; Cleary, James M; Pandya, Shuchi S; Hollebecque, Antoine; Abbas, Richat; Ananthakrishnan, Revathi; Berkenblit, Anna; Krygowski, Mizue; Liang, Yali; Turnbull, Kathleen W; Shapiro, Geoffrey I; Soria, Jean-Charles

2014-01-10

Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Tapp, Tiffany; Trimmer, Ann; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to evaluate the efficacy and safety of reducing ciclosporin (CsA) dosing frequency from daily to every other day (EOD) or twice a week (TW) according to clinical response in cats with hypersensitivity dermatitis (HD) and treated with CsA. Methods One hundred and ninety-one cats with HD were given 7 mg/kg CsA daily for at least 4 weeks. Depending on clinical response, the dosing frequency was tapered from daily to EOD over the next 4 weeks and further to TW for an additional 4 weeks. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results The majority of cats were able to have their dose of CsA tapered to either EOD (15.5%) or TW (62.9%) according to the clinical response. Observed AEs were most frequently mild and self-limiting vomiting and diarrhea. A higher percentage of AEs occurred with daily administration (73%) compared with other dosing regimens (27%). Conclusions and relevance Following 4 weeks of daily dosing at 7 mg/kg, CsA may be tapered to EOD or TW while maintaining the desired therapeutic response in cats with HD. Additionally, CsA appears to be well tolerated with fewer AEs at EOD or TW dosing. Establishing the lowest effective dosing frequency of CsA improves the drug's safety profile.

Swallowing outcomes following Intensity Modulated Radiation Therapy (IMRT) for head & neck cancer - a systematic review.

PubMed

Roe, Justin W G; Carding, Paul N; Dwivedi, Raghav C; Kazi, Rehan A; Rhys-Evans, Peter H; Harrington, Kevin J; Nutting, Christopher M

2010-10-01

A systematic review to establish what evidence is available for swallowing outcomes following IMRT for head and neck cancer. Online electronic databases were searched to identify papers published in English from January 1998 to December 2009. Papers were independently appraised by two reviewers for methodological quality, method of swallowing evaluation and categorized according to the World Health Organisation's International Classification of Health Functions. The impact of radiation dose to dysphagia aspiration risk structures (DARS) was also evaluated. Sixteen papers met the inclusion criteria. The literature suggests that limiting the radiation dose to certain structures may result in favourable swallowing outcomes. Methodological limitations included variable assessment methods and outcome measures and heterogeneity of patients. There are only limited prospective data, especially where pre-treatment measures have been taken and compared to serial post-treatment assessment. Few studies have investigated the impact of IMRT on swallow function and the impact on everyday life. Initial studies have reported potential benefits but are limited in terms of study design and outcome data. Further well designed, prospective, longitudinal swallowing studies including multidimensional evaluation methods are required to enable a more comprehensive understanding of dysphagia complications and inform pre-treatment counselling and rehabilitation planning. Copyright © 2010 Elsevier Ltd. All rights reserved.

10 CFR 835.207 - Occupational dose limits for minors.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Occupational dose limits for minors. 835.207 Section 835.207 Energy DEPARTMENT OF ENERGY OCCUPATIONAL RADIATION PROTECTION Standards for Internal and External Exposure § 835.207 Occupational dose limits for minors. The dose limits for minors occupationally exposed...

Effects of a Rhodiola rosea L. extract on the acquisition, expression, extinction, and reinstatement of morphine-induced conditioned place preference in mice.

PubMed

Mattioli, Laura; Titomanlio, Federica; Perfumi, Marina

2012-05-01

Opioid addiction is a chronic, recurrent brain disease that is characterised by compulsive drug seeking and a high rate of relapse even after long periods of abstinence. Prevention of relapse is the primary goal of addiction treatment and is still the major limitation in drug therapy. The present study investigated the effects of a Rhodiola rosea L. hydroalcoholic extract (RHO), a well-known traditional oriental medicine, on establishment and reinstatement of morphine-induced conditioned place preference (CPP) in mice. CPP was induced by intraperitoneal injection of morphine (10 mg/kg) as an 8-day conditioning schedule. The effects of RHO on the rewarding properties of morphine were tested in mice receiving oral administration of RHO (10, 15, and 20 mg/kg) 60 min prior to each morphine injection (acquisition) or prior to the CPP test on day 9 (expression). Once established, CPP was extinguished by repeated testing, during which conditioned mice were injected daily with different doses of RHO. Finally, the efficacy of RHO in blocking reinstatement of CPP provoked by priming injections and physical stress was also evaluated. RHO administration showed dose dependency for prevention of establishment of CPP and was effective in facilitating extinction of morphine-induced CPP. RHO suppressed both priming- and stress-induced reinstatement of CPP in a dose-dependent manner. In conclusion, as RHO was effective for reducing craving and vulnerability to relapse, it might be a very effective natural remedy for the treatment of opioid addiction.

Preventing medication errors in cancer chemotherapy.

PubMed

Cohen, M R; Anderson, R W; Attilio, R M; Green, L; Muller, R J; Pruemer, J M

1996-04-01

Recommendations for preventing medication errors in cancer chemotherapy are made. Before a health care provider is granted privileges to prescribe, dispense, or administer antineoplastic agents, he or she should undergo a tailored educational program and possibly testing or certification. Appropriate reference materials should be developed. Each institution should develop a dose-verification process with as many independent checks as possible. A detailed checklist covering prescribing, transcribing, dispensing, and administration should be used. Oral orders are not acceptable. All doses should be calculated independently by the physician, the pharmacist, and the nurse. Dosage limits should be established and a review process set up for doses that exceed the limits. These limits should be entered into pharmacy computer systems, listed on preprinted order forms, stated on the product packaging, placed in strategic locations in the institution, and communicated to employees. The prescribing vocabulary must be standardized. Acronyms, abbreviations, and brand names must be avoided and steps taken to avoid other sources of confusion in the written orders, such as trailing zeros. Preprinted antineoplastic drug order forms containing checklists can help avoid errors. Manufacturers should be encouraged to avoid or eliminate ambiguities in drug names and dosing information. Patients must be educated about all aspects of their cancer chemotherapy, as patients represent a last line of defense against errors. An interdisciplinary team at each practice site should review every medication error reported. Pharmacists should be involved at all sites where antineoplastic agents are dispensed. Although it may not be possible to eliminate all medication errors in cancer chemotherapy, the risk can be minimized through specific steps. Because of their training and experience, pharmacists should take the lead in this effort.

Process Evaluation of a Blended Web-Based Intervention on Return to Work for Sick-Listed Employees with Common Mental Health Problems in the Occupational Health Setting.

PubMed

Volker, D; Zijlstra-Vlasveld, M C; Brouwers, E P M; van der Feltz-Cornelis, C M

2017-06-01

Purpose A blended web-based intervention, "eHealth module embedded in collaborative occupational health care" (ECO), aimed at return to work, was developed and found effective in sick-listed employees with common mental disorders. In order to establish the feasibility of ECO, a process evaluation was conducted. Methods Seven process components were investigated: recruitment, reach, dose delivered, dose received, fidelity, satisfaction and context. Quantitative and qualitative methods were used to collect data: an online questionnaire for the employees, website data, telephonic interviews with occupational physicians (OPs) and observations of the researchers. Results Recruitment was uncomplicated for the employees, but required several steps for the OPs. Reach was 100 % at the OP level and 76.3 % at the employee level. Dose delivered and received for OPs: 91.6 % received minimally one email message. Dose delivered and received for the employees: finishing of the different modules of ECO varied between 13 and 90 %. Fidelity: the support of the OP to the employee in ECO was lower than anticipated. Satisfaction: both employees and OPs were satisfied with the intervention. However, employees reported a need for more support in ECO. The context showed that OPs had limited time to support the employees and it was impossible for the employee to contact the OP outside their regular contacts. Conclusion Feasibility of ECO and satisfaction of employees and OPs with ECO were good. Fidelity of OPs was limited. For further implementation in the occupational health setting, especially contextual barriers regarding time limitation and accessibility of OPs for employees should be addressed.

An in vivo investigative protocol for HDR prostate brachytherapy using urethral and rectal thermoluminescence dosimetry.

PubMed

Toye, Warren; Das, Ram; Kron, Tomas; Franich, Rick; Johnston, Peter; Duchesne, Gillian

2009-05-01

To develop an in vivo dosimetry based investigative action level relevant for a corrective protocol for HDR brachytherapy boost treatment. The dose delivered to points within the urethra and rectum was measured using TLD in vivo dosimetry in 56 patients. Comparisons between the urethral and rectal measurements and TPS calculations showed differences, which are related to the relative position of the implant and TLD trains, and allowed shifts of implant position relative to the prostate to be estimated. Analysis of rectal dose measurements is consistent with implant movement, which was previously only identified with the urethral data. Shift corrected doses were compared with results from the TPS. Comparison of peak doses to the urethra and rectum has been assessed against the proposed corrective protocol to limit overdosing these critical structures. An initial investigative level of 20% difference between measured and TPS peak dose was established, which corresponds to 1/3 of patients which was practical for the caseload. These patients were assessed resulting in corrective action being applied for one patient. Multiple triggering for selective investigative action is outlined. The use of a single in vivo measurement in the first fraction optimizes patient benefit at acceptable cost.

Optimal allocation of the limited oral cholera vaccine supply between endemic and epidemic settings.

PubMed

Moore, Sean M; Lessler, Justin

2015-10-06

The World Health Organization (WHO) recently established a global stockpile of oral cholera vaccine (OCV) to be preferentially used in epidemic response (reactive campaigns) with any vaccine remaining after 1 year allocated to endemic settings. Hence, the number of cholera cases or deaths prevented in an endemic setting represents the minimum utility of these doses, and the optimal risk-averse response to any reactive vaccination request (i.e. the minimax strategy) is one that allocates the remaining doses between the requested epidemic response and endemic use in order to ensure that at least this minimum utility is achieved. Using mathematical models, we find that the best minimax strategy is to allocate the majority of doses to reactive campaigns, unless the request came late in the targeted epidemic. As vaccine supplies dwindle, the case for reactive use of the remaining doses grows stronger. Our analysis provides a lower bound for the amount of OCV to keep in reserve when responding to any request. These results provide a strategic context for the fulfilment of requests to the stockpile, and define allocation strategies that minimize the number of OCV doses that are allocated to suboptimal situations. © 2015 The Authors.

Minimum exposure limits and measured relationships between the vitamin D, erythema and international commission on non-ionizing radiation protection solar ultraviolet.

PubMed

Downs, Nathan; Parisi, Alfio; Butler, Harry; Turner, Joanna; Wainwright, Lisa

2015-01-01

The International Commission on Non-Ionizing Radiation Protection (ICNIRP) has established guidelines for exposure to ultraviolet radiation in outdoor occupational settings. Spectrally weighted ICNIRP ultraviolet exposures received by the skin or eye in an 8 h period are limited to 30 J m(-2). In this study, the time required to reach the ICNIRP exposure limit was measured daily in 10 min intervals upon a horizontal plane at a subtropical Australian latitude over a full year and compared with the effective Vitamin D dose received to one-quarter of the available skin surface area for all six Fitzpatrick skin types. The comparison of measured solar ultraviolet exposures for the full range of sky conditions in the 2009 measurement period, including a major September continental dust event, show a clear relationship between the weighted ICNIRP and the effective vitamin D dose. Our results show that the horizontal plane ICNIRP ultraviolet exposure may be used under these conditions to provide minimum guidelines for the healthy moderation of vitamin D, scalable to each of the six Fitzpatrick skin types. © 2014 The American Society of Photobiology.

Induction of potent local cellular immunity with low dose X4 SHIV{sub SF33A} vaginal exposure

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

Tasca, Silvana; Tsai, Lily; Trunova, Nataliya

2007-10-10

Intravaginal inoculation of rhesus macaques with varying doses of the CXCR4 (X4)-tropic SHIV{sub SF33A} isolate revealed a threshold inoculum for establishment of systemic virus infection and a dose dependency in overall viral burden and CD4+ T cell depletion. While exposure to inoculum size of 1000 or greater 50% tissue infectious dose (TCID{sub 50}) resulted in high viremia and precipitous CD4+ T cell loss, occult infection was observed in seven of eight macaques exposed to 500 TCID{sub 50} of the same virus. The latter was characterized by intermittent detection of low level virus with no evidence of seroconversion or CD4+ Tmore » cell decline, but with signs of an ongoing antiviral T cell immune response. Upon vaginal re-challenge with the same limiting dose 11-12 weeks after the first, classic pathogenic X4 SHIV{sub SF33A} infection was established in four of the seven previously exposed seronegative macaques, implying enhanced susceptibility to systemic infection with prior exposure. Pre-existing peripheral SIV gag-specific CD4+ T cells were more readily demonstrable in macaques that became systemically infected following re-exposure than those that were not. In contrast, early presence of circulating polyfunctional cytokine secreting CD8+ T cells or strong virus-specific proliferative responses in draining lymph nodes and in the gut associated lymphoid tissue (GALT) following the first exposure was associated with protection from systemic re-infection. These studies identify the gut and lymphoid tissues proximal to the genital tract as sites of robust CD8 T lymphocyte responses that contribute to containment of virus spread following vaginal transmission.« less

The observed correlation between in vivo clinical pharmacokinetic parameters and in vitro potency of VEGFR-2 inhibitors. Can this be used as a prospective guide for the development of novel compounds?

PubMed

Benjamin, B; Sahu, M; Bhatnagar, U; Abhyankar, D; Srinivas, N R

2012-04-01

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class. © Georg Thieme Verlag KG Stuttgart · New York.

Fieldable computer system for determining gamma-ray pulse-height distributions, flux spectra, and dose rates from Little Boy

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

Moss, C.E.; Lucas, M.C.; Tisinger, E.W.

1984-01-01

Our system consists of a LeCroy 3500 data acquisition system with a built-in CAMAC crate and eight bismuth-germanate detectors 7.62 cm in diameter and 7.62 cm long. Gamma-ray pulse-height distributions are acquired simultaneously for up to eight positions. The system was very carefully calibrated and characterized from 0.1 to 8.3 MeV using gamma-ray spectra from a variety of radioactive sources. By fitting the pulse-height distributions from the sources with a function containing 17 parameters, we determined theoretical repsonse functions. We use these response functions to unfold the distributions to obtain flux spectra. A flux-to-dose-rate conversion curve based on the workmore » of Dimbylow and Francis is then used to obtain dose rates. Direct use of measured spectra and flux-to-dose-rate curves to obtain dose rates avoids the errors that can arise from spectrum dependence in simple gamma-ray dosimeter instruments. We present some gamma-ray doses for the Little Boy assembly operated at low power. These results can be used to determine the exposures of the Hiroshima survivors and thus aid in the establishment of radation exposure limits for the nuclear industry.« less

A U.S. Multicenter Study of Recorded Occupational Radiation Badge Doses in Nuclear Medicine.

PubMed

Villoing, Daphnée; Yoder, R Craig; Passmore, Christopher; Bernier, Marie-Odile; Kitahara, Cari M

2018-05-01

Purpose To summarize occupational badge doses recorded for a sample of U.S. nuclear medicine technologists. Materials and Methods Nine large U.S. medical institutions identified 208 former and current nuclear medicine technologists certified after 1979 and linked these individuals to historic badge dose records maintained by a commercial dosimetry company (Landauer), yielding a total of 2618 annual dose records. The distributions of annual and cumulative occupational doses were described by using summary statistics. Results Between 1992 and 2015, the median annual personal dose equivalent per nuclear medicine technologist was 2.18 mSv (interquartile range [IQR], 1.25-3.47 mSv; mean, 2.69 mSv). Median annual personal dose equivalents remained relatively constant over this period (range, 1.40-3.30 mSv), while maximum values generally increased over time (from 8.00 mSv in 1992 to 13.9 mSv in 2015). The median cumulative personal dose equivalent was 32.9 mSv (IQR, 18.1-65.5 mSv; mean, 51.4 mSv) for 45 technologists who had complete information and remained employed through 2015. Conclusion Occupational radiation doses were well below the established occupational limits and were consistent with those observed for nuclear medicine technologists worldwide and were greater than those observed for nuclear and general medical workers in the United States These results should be informative for radiation monitoring and safety efforts in nuclear medicine departments. © RSNA, 2018 Online supplemental material is available for this article.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors.

PubMed

Krick, Erika L; Sorenmo, Karin U; Rankin, Shelley C; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A

2012-01-01

To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. 6 client-owned dogs. A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

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

Chau, Ricky; Teo, Peter; Kam, Michael

The aim of this study is to evaluate the deficiencies in target coverage and organ protection of 2-dimensional radiation therapy (2DRT) in the treatment of advanced T-stage (T3-4) nasopharyngeal carcinoma (NPC), and assess the extent of improvement that could be achieved with intensity modulated radiation therapy (IMRT), with special reference to of the dose to the planning organ-at-risk volume (PRV) of the brainstem and spinal cord. A dosimetric study was performed on 10 patients with advanced T-stage (T3-4 and N0-2) NPC. Computer tomography (CT) images of 2.5-mm slice thickness of the head and neck were acquired with the patient immobilizedmore » in semi-extended-head position. A 2D plan based on Ho's technique, and an IMRT plan based on a 7-coplanar portals arrangement, were established for each patient. 2DRT was planned with the field borders and shielding drawn on the simulator radiograph with reference to bony landmarks, digitized, and entered into a planning computer for reconstruction of the 3D dose distribution. The 2DRT and IMRT treatment plans were evaluated and compared with respect to the dose-volume histograms (DVHs) of the targets and the organs-at-risk (OARs), tumor control probability (TCP), and normal tissue complication probabilities (NTCPs). With IMRT, the dose coverage of the target was superior to that of 2DRT. The mean minimum dose of the GTV and PTV were increased from 33.7 Gy (2DRT) to 62.6 Gy (IMRT), and 11.9 Gy (2DRT) to 47.8 Gy (IMRT), respectively. The D{sub 95} of the GTV and PTV were also increased from 57.1 Gy (2DRT) to 67 Gy (IMRT), and 45 Gy (2DRT) to 63.6 Gy (IMRT), respectively. The TCP was substantially increased to 78.5% in IMRT. Better protection of the critical normal organs was also achieved with IMRT. The mean maximum dose delivered to the brainstem and spinal cord were reduced significantly from 61.8 Gy (2DRT) to 52.8 Gy (IMRT) and 56 Gy (2DRT) to 43.6 Gy (IMRT), respectively, which were within the conventional dose limits of 54 Gy for brainstem and of 45 Gy for spinal cord. The mean maximum doses deposited on the PRV of the brainstem and spinal cord were 60.7 Gy and 51.6 Gy respectively, which were above the conventional dose limits. For the chiasm, the mean dose maximum and the dose to 5% of its volume were reduced from 64.3 Gy (2DRT) to 53.7 Gy (IMRT) and from 62.8 Gy (2DRT) to 48.7 Gy (IMRT), respectively, and the corresponding NTCP was reduced from 18.4% to 2.1%. For the temporal lobes, the mean dose to 10% of its volume (about 4.6 cc) was reduced from 63.8 Gy (2DRT) to 55.4 Gy (IMRT) and the NTCP was decreased from 11.7% to 3.4%. The therapeutic ratio for T3-4 NPC tumors can be significantly improved with IMRT treatment technique due to improvement both in target coverage and the sparing of the critical normal organ. Although the maximum doses delivered to the brainstem and spinal cord in IMRT can be kept at or below their conventional dose limits, the maximum doses deposited on the PRV often exceed these limits due to the close proximity between the target and OARs. In other words, ideal dosimetric considerations cannot be fulfilled in IMRT planning for T3-4 NPC tumors. A compromise of the maximal dose limit to the PRV of the brainstem and spinal cord would need be accepted if dose coverage to the targets is not to be unacceptably compromised. Dosimetric comparison with 2DRT plans show that these dose limits to PRV were also frequently exceeded in 2DRT plans for locally advanced NPC. A dedicated retrospective study on the incidence of clinical injury to neurological organs in a large series of patients with T3-4 NPC treated by 2DRT may provide useful reference data in exploring how far the PRV dose constraints may be relaxed, to maximize the target coverage without compromising the normal organ function.« less

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

Fritz, Brad G.; Dirkes, Roger L.; Napier, Bruce A.

The Hanford Reach National Monument (HRNM) was created by presidential proclamation in 2000. It is located along the Columbia River in south central Washington and consists of five distinct units. The McGee Ranch-Riverlands and the North Slope units are addressed in this report. North Slope refers to two of the HRNM units: the Saddle Mountain Unit and the Wahluke Slope Unit. The Saddle Mountain and Wahluke Slope Units are located north of the Columbia River, while the McGee Ranch-Riverlands Unit is located south of the Columbia River and north and west of Washington State Highway 24. To fulfill internal U.S.more » Department of Energy (DOE) requirements prior to any radiological clearance of land, the DOE must evaluate the potential for residual radioactive contamination on this land and determine compliance with the requirements of DOE Order 5400.5. Authorized limits for residual radioactive contamination were developed based on the DOE annual exposure limit to the public (100 mrem) using future potential land-use scenarios. The DOE Office of Environmental Management approved these authorized limits on March 1, 2004. Historical soil monitoring conducted on and around the HRNM indicated soil concentrations of radionuclides were well below the authorized limits (Fritz et al. 2003). However, the historical sampling was done at a limited number of sampling locations. Therefore, additional soil sampling was conducted to determine if the concentrations of radionuclides in soil on the McGee Ranch-Riverlands and North Slope units were below the authorized limits. Sixty-seven soil samples were collected from the McGee Ranch-Riverlands and North Slope units. A software package (Visual Sample Plan) was used to plan the collection to assure an adequate number of samples were collected. The number of samples necessary to decide with a high level of confidence (99%) that the soil concentrations of radionuclides on the North Slope and McGee Ranch-Riverlands units did not exceed the authorized limits was determined to be 27. Additional soil samples were collected from areas suspected to have a potential for accumulation of radionuclides. This included samples collected from the riparian zone along the Columbia River, Savage Island, and other locations across the North Slope and McGee Ranch-Riverlands units. The 67 soil samples collected from the McGee Ranch-Riverlands and North Slope units all had concentrations of radionuclides far below the authorized limits established by the DOE. Statistical analysis of the results concluded that the Authorized Limits were not exceeded when total uncertainty was considered. The calculated upper confidence limit for each radionuclide measured in this study (which represents the value at which 99% of the measurements reside below with a 99% confidence level) was lower than the Authorized Limit for each radionuclide. The maximum observed soil concentrations for the radionuclides included in the authorized limits would result in a potential annual dose of 0.23 mrem assuming the most probable use scenario, a recreational visitor. This potential dose is well below the DOE 100-mrem/year dose limit for members of the public. Furthermore, the results of the biota dose assessment screen, which used the RESRAD biota code, indicated that the sum of fractions is less than one. This assumed soil concentrations equal to the maximum concentrations of radionuclides measured on the McGee Ranch-Riverlands and North Slope units’ in this study. Since the sum of fractions was less than 1, dose to terrestrial biota will not exceed the recommended biota dose limit for the soil concentrations measured in this study.« less

Evaluation of dose variation during total skin electron irradiation using thermoluminescent dosimeters.

PubMed

Weaver, R D; Gerbi, B J; Dusenbery, K E

1995-09-30

To determine acceptable dose variation using thermoluminescent dosimeters (TLD) in the treatment of Mycosis Fungoides with total skin electron beam (TSEB) irradiation. From 1983 to 1993, 22 patients were treated with total skin electron beam therapy in the standing position. A six-field technique was used to deliver 2 Gy in two days, treating 4 days per week, to a total dose of 35 to 40 Gy using a degraded 9 MeV electron beam. Thermoluminescent dosimeters were placed on several locations of the body and the results recorded. The variations in these readings were analyzed to determine normal dose variation for various body locations during TSEB. The dose to flat surfaces of the body was essentially the same as the dose to the prescription point. The dose to tangential surfaces was within +/- 10% of the prescription dose, but the readings showed much more variation (up to 24%). Thin areas of the body showed large deviations from the prescription dose along with a large amount of variation in the readings (up to 22%). Special areas of the body, such as the perineum and eyelid, showed large deviations from the prescription dose with very large (up to 40%) variations in the readings. The TLD results of this study will be used as a quality assurance check for all new patients treated with TSEB. The results of the TLDs will be compared with this baseline study to determine if the delivered dose is within acceptable ranges. If the TLD results fall outside the acceptable limits established above, then the patient position can be modified or the technique itself evaluated.

[Possible role of autotransplantation in small cel bronchial carcinoma].

PubMed

Tiefengraber, E; Sebesta, C; Kier, P; Ruckser, R; Habertheuer, K H; Hinterberger, W

1995-01-01

Autologous bone marrow transplantation (ABMT) performed with recent achievements plays yet no established role in the treatment of small cell lung cancer (SCLC). The majority of treatment results obtained so far do not clearly suggest a superiority of high-dose therapy with autologous transplantation over conventional polychemo/radiotherapy. It is unknown, whether or not a subgroup of patients with, e.g., "limited disease" and chemosensitive tumor may benefit from ABMT. Randomized trials will be necessary to clarify this question.

Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

PubMed

Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

2016-01-01

EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

IMRT and RapidArc commissioning of a TrueBeam linear accelerator using TG-119 protocol cases.

PubMed

Wen, Ning; Zhao, Bo; Kim, Jinkoo; Chin-Snyder, Karen; Bellon, Maria; Glide-Hurst, Carri; Barton, Kenneth; Chen, Daiquan; Chetty, Indrin J

2014-09-08

The purpose of this study is to evaluate the overall accuracy of intensity-modulated radiation therapy (IMRT) and RapidArc delivery using both flattening filter (FF) and flattening filter-free (FFF) modalities based on test cases developed by AAPM Task Group 119. Institutional confidence limits (CLs) were established as the baseline for patient specific treatment plan quality assurance (QA). The effects of gantry range, gantry speed, leaf speed, dose rate, as well as the capability to capture intentional errors, were evaluated by measuring a series of Picket Fence (PF) tests using the electronic portal imaging device (EPID) and EBT3 films. Both IMRT and RapidArc plans were created in a Solid Water phantom (30 × 30 × 15 cm3) for the TG-119 test cases representative of normal clinical treatment sites for all five photon energies (6X, 10X, 15X, 6X-FFF, 10X-FFF) and the Exact IGRT couch was included in the dose calculation. One high-dose point in the PTV and one low-dose point in the avoidance structure were measured with an ion chamber in each case for each energy. Similarly, two GAFCHROMIC EBT3 films were placed in the coronal planes to measure planar dose distributions in both high- and low-dose regions. The confidence limit was set to have 95% of the measured data fall within the tolerance. The mean of the absolute dose deviation for variable dose rate and gantry speed during RapidArc delivery was within 0.5% for all energies. The corresponding results for leaf speed tests were all within 0.4%. The combinations of dynamic leaf gap (DLG) and MLC transmission factor were optimized based on the ion chamber measurement results of RapidArc delivery for each energy. The average 95% CLs for the high-dose point in the PTV were 0.030 ± 0.007 (range, 0.022-0.038) for the IMRT plans and 0.029 ± 0.011 (range, 0.016-0.043) for the RapidArc plans. For low-point dose in the avoidance structures, the CLs were 0.029 ± 0.006 (range, 0.024-0.039) for the IMRT plans and 0.027 ± 0.013 (range, 0.017-0.047) for the RapidArc plans. The average 95% CLs using 3%/3 mm gamma criteria in the high-dose region were 5.9 ± 2.7 (range, 1.4-8.6) and 3.9 ± 2.9 (range, 1.5-8.8) for IMRT and RapidArc plans, respectively. The average 95% CLs in the low-dose region were 5.3 ± 2.6 (range, 1.2-7.4) and 3.7 ± 2.8 (range, 1.8-8.3) for IMRT and RapidArc plans, respectively. Based on ion chamber, as well as film measurements, we have established CLs values to ensure the high precision of IMRT and RapidArc delivery for both FF and FFF modalities.

A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

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

Yannam, Govardhana Rao; Han, Bing; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi

Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevatedmore » alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.« less

Derivation of mean dose tolerances for new fractionation schemes and treatment modalities

NASA Astrophysics Data System (ADS)

Perkó, Zoltán; Bortfeld, Thomas; Hong, Theodore; Wolfgang, John; Unkelbach, Jan

2018-02-01

Avoiding toxicities in radiotherapy requires the knowledge of tolerable organ doses. For new, experimental fractionation schemes (e.g. hypofractionation) these are typically derived from traditional schedules using the biologically effective dose (BED) model. In this report we investigate the difficulties of establishing mean dose tolerances that arise since the mean BED depends on the entire spatial dose distribution, rather than on the dose level alone. A formula has been derived to establish mean physical dose constraints such that they are mean BED equivalent to a reference treatment scheme. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 24 liver cancer patients for whom both proton and photon IMRT treatment plans were available. The results show that the standard BED equation—neglecting the spatial dose distribution—can overestimate mean dose tolerances for hypofractionated treatments by up to 20%. The shape difference between photon and proton dose distributions can cause 30-40% differences in mean physical dose for plans having identical mean BEDs. Converting hypofractionated, 5/15-fraction proton doses to mean BED equivalent photon doses in traditional 35-fraction regimens resulted in up to 10 Gy higher doses than applying the standard BED formula. The dose shape effect should be accounted for to avoid overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. Additionally, tolerances established for one treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions, such as proton therapy. Last, protons may only allow marginal (5-10%) dose escalation if a fraction-size adjusted organ mean dose is constraining instead of a physical dose.

A pioneer experience in Malaysia on In-house Radio-labelling of (131)I-rituximab in the treatment of Non-Hodgkin's Lymphoma and a case report of high dose (131)I-rituximab-BEAM conditioning autologous transplant.

PubMed

Kuan, Jew Win; Law, Chiong Soon; Wong, Xiang Qi; Ko, Ching Tiong; Awang, Zool Hilmi; Chew, Lee Ping; Chang, Kian Meng

2016-10-01

Radioimmunotherapy is an established treatment modality in Non-Hodgkin's lymphoma. The only two commercially available radioimmunotherapies - (90)Y-ibritumomab tiuxetan is expensive and (131)I-tositumomab has been discontinued from commercial production. In resource limited environment, self-labelling (131)I-rituximab might be the only viable practical option. We reported our pioneer experience in Malaysia on self-labelling (131)I-rituximab, substituting autologous haematopoietic stem cell transplantation (HSCT) and a patient, the first reported case, received high dose (131)I-rituximab (6000MBq/163mCi) combined with BEAM conditioning for autologous HSCT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Statistical methods for analysis of radiation effects with tumor and dose location-specific information with application to the WECARE study of asynchronous contralateral breast cancer

PubMed Central

Langholz, Bryan; Thomas, Duncan C.; Stovall, Marilyn; Smith, Susan A.; Boice, John D.; Shore, Roy E.; Bernstein, Leslie; Lynch, Charles F.; Zhang, Xinbo; Bernstein, Jonine L.

2009-01-01

Summary Methods for the analysis of individually matched case-control studies with location-specific radiation dose and tumor location information are described. These include likelihood methods for analyses that just use cases with precise location of tumor information and methods that also include cases with imprecise tumor location information. The theory establishes that each of these likelihood based methods estimates the same radiation rate ratio parameters, within the context of the appropriate model for location and subject level covariate effects. The underlying assumptions are characterized and the potential strengths and limitations of each method are described. The methods are illustrated and compared using the WECARE study of radiation and asynchronous contralateral breast cancer. PMID:18647297

Estimation of parameters of dose volume models and their confidence limits

NASA Astrophysics Data System (ADS)

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

2003-07-01

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

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice.

PubMed

Schmohl, Kathrin A; Müller, Andrea M; Schwenk, Nathalie; Knoop, Kerstin; Rijntjes, Eddy; Köhrle, Josef; Heuer, Heike; Bartenstein, Peter; Göke, Burkhard; Nelson, Peter J; Spitzweg, Christine

2015-09-01

Due to the high variance in available protocols on iodide-131 ((131)I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of (131)I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T4 concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and (99m)Tc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) (131)I alone was not sufficient to abolish thyroidal T4 production, 500 µCi (18.5 MBq) (131)I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high (131)I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) (131)I decreased serum T4 concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. (99m)Tc-pertechnetate scintigraphy revealed absence of thyroidal (99m)Tc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene.

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

PubMed Central

Schmohl, Kathrin A.; Müller, Andrea M.; Schwenk, Nathalie; Knoop, Kerstin; Rijntjes, Eddy; Köhrle, Josef; Heuer, Heike; Bartenstein, Peter; Göke, Burkhard; Nelson, Peter J.; Spitzweg, Christine

2015-01-01

Due to the high variance in available protocols on iodide-131 (131I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of 131I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T4 concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and 99mTc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) 131I alone was not sufficient to abolish thyroidal T4 production, 500 µCi (18.5 MBq) 131I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high 131I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) 131I decreased serum T4 concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. 99mTc-pertechnetate scintigraphy revealed absence of thyroidal 99mTc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene. PMID:26601076

Occupational dose constraints for the lens of the eye for interventional radiologists and interventional cardiologists in the UK.

PubMed

Mairs, William DA

2016-06-01

The International Commission on Radiological Protection (ICRP) has recommended a 20 mSv year(-1) dose limit for the lens of the eye, which has been adopted in the European Union Basic Safety Standards. Interventional radiologists (IRs) and interventional cardiologists (ICs) are likely to be affected by this. The effects of radiation in the lens are somewhat uncertain, and the ICRP explicitly recommend optimization. Occupational dose constraints are part of the optimization process and define a level of dose which ought to be achievable in a well-managed practice. This commentary calls on the professional bodies to review a need for national constraints to guide local decisions. Consideration is given to developing such constraints using maximum expected doses in high-workload facilities with good radiation protection practices and application of a factor allowing for attenuation by lead glasses (LG). Doses are based on a Public Health England survey of eye dose in the UK. Maximum expected doses for ICs are approximately 21 mSv year(-1), neglecting LG. However, the extent of IR exposure is not yet fully known, and further evidence is required before conclusions are drawn. A Health and Safety Laboratory review of LG established a conservative dose reduction factor of 3 for models available in 2012. Application of this factor provides a dose constraint of 7 mSv year(-1) to the eye for ICs. To achieve this constraint, those employers with the most exposed ICs will have to provide and ensure the correct use of a ceiling-suspended eye shield and LG.

A case series of re-establishment of neuromuscular block with rocuronium after sugammadex reversal.

PubMed

Iwasaki, Hajime; Sasakawa, Tomoki; Takahoko, Kenichi; Takagi, Shunichi; Nakatsuka, Hideki; Suzuki, Takahiro; Iwasaki, Hiroshi

2016-06-01

We report the use of rocuronium to re-establish neuromuscular block after reversal with sugammadex. The aim of this study was to investigate the relationship between the dose of rocuronium needed to re-establish neuromuscular block and the time interval between sugammadex administration and re-administration of rocuronium. Patients who required re-establishment of neuromuscular block within 12 h after the reversal of rocuronium-induced neuromuscular block with sugammadex were included. After inducing general anesthesia and placing the neuromuscular monitor, the protocol to re-establish neuromuscular block was as follows. An initial rocuronium dose of 0.6 mg/kg was followed by additional 0.3 mg/kg doses every 2 min until train-of-four responses were abolished. A total of 11 patients were enrolled in this study. Intervals between sugammadex and second rocuronium were 12-465 min. Total dose of rocuronium needed to re-establish neuromuscular block was 0.6-1.2 mg/kg. 0.6 mg/kg rocuronium re-established neuromuscular block in all patients who received initial sugammadex more than 3 h previously. However, when the interval between sugammadex and second rocuronium was less than 2 h, more than 0.6 mg/kg rocuronium was necessary to re-establish neuromuscular block.

Developing better mouse models to study cisplatin-induced kidney injury.

PubMed

Sharp, Cierra N; Siskind, Leah J

2017-10-01

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. Copyright © 2017 the American Physiological Society.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

PubMed

Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

2015-04-01

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. © 2014 American Cancer Society.

Calculation of out-of-field dose distribution in carbon-ion radiotherapy by Monte Carlo simulation.

PubMed

Yonai, Shunsuke; Matsufuji, Naruhiro; Namba, Masao

2012-08-01

Recent radiotherapy technologies including carbon-ion radiotherapy can improve the dose concentration in the target volume, thereby not only reducing side effects in organs at risk but also the secondary cancer risk within or near the irradiation field. However, secondary cancer risk in the low-dose region is considered to be non-negligible, especially for younger patients. To achieve a dose estimation of the whole body of each patient receiving carbon-ion radiotherapy, which is essential for risk assessment and epidemiological studies, Monte Carlo simulation plays an important role because the treatment planning system can provide dose distribution only in∕near the irradiation field and the measured data are limited. However, validation of Monte Carlo simulations is necessary. The primary purpose of this study was to establish a calculation method using the Monte Carlo code to estimate the dose and quality factor in the body and to validate the proposed method by comparison with experimental data. Furthermore, we show the distributions of dose equivalent in a phantom and identify the partial contribution of each radiation type. We proposed a calculation method based on a Monte Carlo simulation using the PHITS code to estimate absorbed dose, dose equivalent, and dose-averaged quality factor by using the Q(L)-L relationship based on the ICRP 60 recommendation. The values obtained by this method in modeling the passive beam line at the Heavy-Ion Medical Accelerator in Chiba were compared with our previously measured data. It was shown that our calculation model can estimate the measured value within a factor of 2, which included not only the uncertainty of this calculation method but also those regarding the assumptions of the geometrical modeling and the PHITS code. Also, we showed the differences in the doses and the partial contributions of each radiation type between passive and active carbon-ion beams using this calculation method. These results indicated that it is essentially important to include the dose by secondary neutrons in the assessment of the secondary cancer risk of patients receiving carbon-ion radiotherapy with active as well as passive beams. We established a calculation method with a Monte Carlo simulation to estimate the distribution of dose equivalent in the body as a first step toward routine risk assessment and an epidemiological study of carbon-ion radiotherapy at NIRS. This method has the advantage of being verifiable by the measurement.

Equivalence of Gyn GEC-ESTRO guidelines for image guided cervical brachytherapy with EUD-based dose prescription

PubMed Central

2013-01-01

Background To establish a generalized equivalent uniform dose (gEUD) -based prescription method for Image Guided Brachytherapy (IGBT) that reproduces the Gyn GEC-ESTRO WG (GGE) prescription for cervix carcinoma patients on CT images with limited soft tissue resolution. Methods The equivalence of two IGBT planning approaches was investigated in 20 patients who received external beam radiotherapy (EBT) and 5 concomitant high dose rate IGBT treatments. The GGE planning strategy based on dose to the most exposed 2 cm3 (D2cc) was used to derive criteria for the gEUD-based planning of the bladder and rectum. The safety of gEUD constraints in terms of GGE criteria was tested by maximizing dose to the gEUD constraints for individual fractions. Results The gEUD constraints of 3.55 Gy for the rectum and 5.19 Gy for the bladder were derived. Rectum and bladder gEUD-maximized plans resulted in D2cc averages very similar to the initial GGE criteria. Average D2ccs and EUDs from the full treatment course were comparable for the two techniques within both sets of normal tissue constraints. The same was found for the tumor doses. Conclusions The derived gEUD criteria for normal organs result in GGE-equivalent IGBT treatment plans. The gEUD-based planning considers the entire dose distribution of organs in contrast to a single dose-volume-histogram point. PMID:24225184

A dose of nature: Tree cover, stress reduction, and gender differences

Treesearch

Bin Jiang; Chun-Yen Chang; William C. Sullivan

2014-01-01

Although it is well established that exposure to nearby nature can help reduce stress in individuals, the shape of the dose-response curve is entirely unclear. To establish this dose-response curve, we recruited 160 individuals for a laboratory experiment. Participants engaged in the Trier Social Stress Test (TSST) to induce psychological stress, and were then randomly...

Impact of wind turbine noise in the Netherlands.

PubMed

Verheijen, Edwin; Jabben, Jan; Schreurs, Eric; Smith, Kevin B

2011-01-01

The Dutch government aims at an increase of wind energy up to 6 000 MW in 2020 by placing new wind turbines on land or offshore. At the same time, the existing noise legislation for wind turbines is being reconsidered. For the purpose of establishing a new noise reception limit value expressed in L den , the impact of wind turbine noise under the given policy targets needs to be explored. For this purpose, the consequences of different reception limit values for the new Dutch noise legislation have been studied, both in terms of effects on the population and regarding sustainable energy policy targets. On the basis of a nation-wide noise map containing all wind turbines in The Netherlands, it is calculated that 3% of the inhabitants of The Netherlands are currently exposed to noise from wind turbines above 28 dB(A) at the faηade. Newly established dose-response relationships indicate that about 1500 of these inhabitants are likely to be severely annoyed inside their dwellings. The available space for new wind turbines strongly depends on the noise limit value that will be chosen. This study suggests an outdoor A-weighted reception limit of L den = 45 dB as a trade-off between the need for protection against noise annoyance and the feasibility of national targets for renewable energy.

In vivo dosimetry for total body irradiation: five‐year results and technique comparison

PubMed Central

Warry, Alison J.; Eaton, David J.; Collis, Christopher H.; Rosenberg, Ivan

2014-01-01

The aim of this work is to establish if the new CT‐based total body irradiation (TBI) planning techniques used at University College London Hospital (UCLH) and Royal Free Hospital (RFH) are comparable to the previous technique at the Middlesex Hospital (MXH) by analyzing predicted and measured diode results. TBI aims to deliver a homogeneous dose to the entire body, typically using extended SSD fields with beam modulation to limit doses to organs at risk. In vivo dosimetry is used to verify the accuracy of delivered doses. In 2005, when the Middlesex Hospital was decommissioned and merged with UCLH, both UCLH and the RFH introduced updated CT‐planned TBI techniques, based on the old MXH technique. More CT slices and in vivo measurement points were used by both; UCLH introduced a beam modulation technique using MLC segments, while RFH updated to a combination of lead compensators and bolus. Semiconductor diodes were used to measure entrance and exit doses in several anatomical locations along the entire body. Diode results from both centers for over five years of treatments were analyzed and compared to the previous MXH technique for accuracy and precision of delivered doses. The most stable location was the field center with standard deviations of 4.1% (MXH), 3.7% (UCLH), and 1.7% (RFH). The least stable position was the ankles. Mean variation with fraction number was within 1.5% for all three techniques. In vivo dosimetry can be used to verify complex modulated CT‐planned TBI, and demonstrate improvements and limitations in techniques. The results show that the new UCLH technique is no worse than the previous MXH one and comparable to the current RFH technique. PACS numbers: 87.55.Qr, 87.56.N‐ PMID:25207423

In vivo dosimetry for total body irradiation: five-year results and technique comparison.

PubMed

Patel, Reshma P; Warry, Alison J; Eaton, David J; Collis, Christopher H; Rosenberg, Ivan

2014-07-08

The aim of this work is to establish if the new CT-based total body irradiation (TBI) planning techniques used at University College London Hospital (UCLH) and Royal Free Hospital (RFH) are comparable to the previous technique at the Middlesex Hospital (MXH) by analyzing predicted and measured diode results. TBI aims to deliver a homogeneous dose to the entire body, typically using extended SSD fields with beam modulation to limit doses to organs at risk. In vivo dosimetry is used to verify the accuracy of delivered doses. In 2005, when the Middlesex Hospital was decommissioned and merged with UCLH, both UCLH and the RFH introduced updated CT-planned TBI techniques, based on the old MXH technique. More CT slices and in vivo measurement points were used by both; UCLH introduced a beam modulation technique using MLC segments, while RFH updated to a combination of lead compensators and bolus. Semiconductor diodes were used to measure entrance and exit doses in several anatomical locations along the entire body. Diode results from both centers for over five years of treatments were analyzed and compared to the previous MXH technique for accuracy and precision of delivered doses. The most stable location was the field center with standard deviations of 4.1% (MXH), 3.7% (UCLH), and 1.7% (RFH). The least stable position was the ankles. Mean variation with fraction number was within 1.5% for all three techniques. In vivo dosimetry can be used to verify complex modulated CT-planned TBI, and demonstrate improvements and limitations in techniques. The results show that the new UCLH technique is no worse than the previous MXH one and comparable to the current RFH technique.

Mixture toxicity revisited from a toxicogenomic perspective.

PubMed

Altenburger, Rolf; Scholz, Stefan; Schmitt-Jansen, Mechthild; Busch, Wibke; Escher, Beate I

2012-03-06

The advent of new genomic techniques has raised expectations that central questions of mixture toxicology such as for mechanisms of low dose interactions can now be answered. This review provides an overview on experimental studies from the past decade that address diagnostic and/or mechanistic questions regarding the combined effects of chemical mixtures using toxicogenomic techniques. From 2002 to 2011, 41 studies were published with a focus on mixture toxicity assessment. Primarily multiplexed quantification of gene transcripts was performed, though metabolomic and proteomic analysis of joint exposures have also been undertaken. It is now standard to explicitly state criteria for selecting concentrations and provide insight into data transformation and statistical treatment with respect to minimizing sources of undue variability. Bioinformatic analysis of toxicogenomic data, by contrast, is still a field with diverse and rapidly evolving tools. The reported combined effect assessments are discussed in the light of established toxicological dose-response and mixture toxicity models. Receptor-based assays seem to be the most advanced toward establishing quantitative relationships between exposure and biological responses. Often transcriptomic responses are discussed based on the presence or absence of signals, where the interpretation may remain ambiguous due to methodological problems. The majority of mixture studies design their studies to compare the recorded mixture outcome against responses for individual components only. This stands in stark contrast to our existing understanding of joint biological activity at the levels of chemical target interactions and apical combined effects. By joining established mixture effect models with toxicokinetic and -dynamic thinking, we suggest a conceptual framework that may help to overcome the current limitation of providing mainly anecdotal evidence on mixture effects. To achieve this we suggest (i) to design studies to establish quantitative relationships between dose and time dependency of responses and (ii) to adopt mixture toxicity models. Moreover, (iii) utilization of novel bioinformatic tools and (iv) stress response concepts could be productive to translate multiple responses into hypotheses on the relationships between general stress and specific toxicity reactions of organisms.

Radiation Specifications for Fission Power Conversion Component Materials

NASA Technical Reports Server (NTRS)

Bowman, Cheryl L.; Shin, E. Eugene; Mireles, Omar R.; Radel, Ross F.; Qualls, A. Louis

2011-01-01

NASA has been supporting design studies and technology development that could provide power to an outpost on the moon, Mars, or an asteroid. One power-generation system that is independent of sunlight or power-storage limitations is a fission-based power plant. There is a wealth of terrestrial system heritage that can be transferred to the design and fabrication of a fission power system for space missions, but there are certain design aspects that require qualification. The radiation tolerance of the power conversion system requires scrutiny because the compact nature of a space power plant restricts the dose reduction methodologies compared to those used in terrestrial systems. An integrated research program has been conducted to establish the radiation tolerance of power conversion system-component materials. The radiation limit specifications proposed for a Fission Power System power convertor is 10 Mrad ionizing dose and 5 x 10(exp 14) neutron per square centimeter fluence for a convertor operating at 150 C. Specific component materials and their radiation tolerances are discussed. This assessment is for the power convertor hardware; electronic components are not covered here.

MO-E-18A-01: Imaging: Best Practices In Pediatric Imaging

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

Willis, C; Strauss, K; MacDougall, R

This imaging educational program will focus on solutions to common pediatric imaging challenges. The speakers will present collective knowledge on best practices in pediatric imaging from their experience at dedicated children's hospitals. Areas of focus will include general radiography, the use of manual and automatic dose management in computed tomography, and enterprise-wide radiation dose management in the pediatric practice. The educational program will begin with a discussion of the complexities of exposure factor control in pediatric projection radiography. Following this introduction will be two lectures addressing the challenges of computed tomography (CT) protocol optimization in the pediatric population. The firstmore » will address manual CT protocol design in order to establish a managed radiation dose for any pediatric exam on any CT scanner. The second CT lecture will focus on the intricacies of automatic dose modulation in pediatric imaging with an emphasis on getting reliable results in algorithmbased technique selection. The fourth and final lecture will address the key elements needed to developing a comprehensive radiation dose management program for the pediatric environment with particular attention paid to new regulations and obligations of practicing medical physicists. Learning Objectives: To understand how general radiographic techniques can be optimized using exposure indices in order to improve pediatric radiography. To learn how to establish diagnostic dose reference levels for pediatric patients as a function of the type of examination, patient size, and individual design characteristics of the CT scanner. To learn how to predict the patient's radiation dose prior to the exam and manually adjust technique factors if necessary to match the patient's dose to the department's established dose reference levels. To learn how to utilize manufacturer-provided automatic dose modulation technology to consistently achieve patient doses within the department's established size-based diagnostic reference range. To understand the key components of an enterprise-wide pediatric dose management program that integrates the expanding responsibilities of medial physicists in the new era of dose monitoring.« less

Monte Carlo study of out-of-field exposure in carbon-ion radiotherapy with a passive beam: Organ doses in prostate cancer treatment.

PubMed

Yonai, Shunsuke; Matsufuji, Naruhiro; Akahane, Keiichi

2018-04-23

The aim of this work was to estimate typical dose equivalents to out-of-field organs during carbon-ion radiotherapy (CIRT) with a passive beam for prostate cancer treatment. Additionally, sensitivity analyses of organ doses for various beam parameters and phantom sizes were performed. Because the CIRT out-of-field dose depends on the beam parameters, the typical values of those parameters were determined from statistical data on the target properties of patients who received CIRT at the Heavy-Ion Medical Accelerator in Chiba (HIMAC). Using these typical beam-parameter values, out-of-field organ dose equivalents during CIRT for typical prostate treatment were estimated by Monte Carlo simulations using the Particle and Heavy-Ion Transport Code System (PHITS) and the ICRP reference phantom. The results showed that the dose decreased with distance from the target, ranging from 116 mSv in the testes to 7 mSv in the brain. The organ dose equivalents per treatment dose were lower than those either in 6-MV intensity-modulated radiotherapy or in brachytherapy with an Ir-192 source for organs within 40 cm of the target. Sensitivity analyses established that the differences from typical values were within ∼30% for all organs, except the sigmoid colon. The typical out-of-field organ dose equivalents during passive-beam CIRT were shown. The low sensitivity of the dose equivalent in organs farther than 20 cm from the target indicated that individual dose assessments required for retrospective epidemiological studies may be limited to organs around the target in cases of passive-beam CIRT for prostate cancer. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system.

PubMed

Aldelaijan, Saad; Devic, Slobodan

2018-05-01

Different dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation. Pieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis. Response functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy. Although reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

PubMed Central

Krick, Erika L.; Sorenmo, Karin U.; Rankin, Shelley C.; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A.

2015-01-01

Objective To establish the maximum tolerated dose of Clostridium novyi–NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. Animals 6 client-owned dogs. Procedures A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C novyi–NT spores IV. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. Results The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C novyi–NT infection; both required surgical intervention. Clostridium novyi–NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Conclusions and Clinical Relevance Results indicated that C novyi–NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology. PMID:22204296

Spline-based procedures for dose-finding studies with active control

PubMed Central

Helms, Hans-Joachim; Benda, Norbert; Zinserling, Jörg; Kneib, Thomas; Friede, Tim

2015-01-01

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentration d*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:25319931

Exjade® (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion

PubMed Central

Cappellini, Maria Domenica

2007-01-01

Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Although the current reference standard iron chelator deferoxamine has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Deferasirox (Exjade®, ICL670, Novartis Pharma AG, Basel, Switzerland) is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in adult and pediatric patients. The efficacy and safety of deferasirox have been established in a comprehensive clinical development program involving patients with various transfusion-dependent anemias. Deferasirox has a dose-dependent effect on iron burden, and is as efficacious as deferoxamine at comparable therapeutic doses. Deferasirox therapy can be tailored to a patient’s needs, as response is related to both dose and iron intake. Since deferasirox has a long half-life and is present in the plasma for 24 hours with once-daily dosing, it is unique in providing constant chelation coverage with a single dose. The availability of this convenient, effective, and well tolerated therapy represents a significant advance in the management of transfusional iron overload. PMID:18360637

The Study of External Dose Rate and Retained Body Activity of Patients Receiving 131I Therapy for Differentiated Thyroid Carcinoma

PubMed Central

Zhang, Haiying; Jiao, Ling; Cui, Songye; Wang, Liang; Tan, Jian; Zhang, Guizhi; He, Yajing; Ruan, Shuzhou; Fan, Saijun; Zhang, Wenyi

2014-01-01

Radiation safety is an integral part of targeted radionuclide therapy. The aim of this work was to study the external dose rate and retained body activity as functions of time in differentiated thyroid carcinoma patients receiving 131I therapy. Seventy patients were stratified into two groups: the ablation group (A) and the follow-up group (FU). The patients’ external dose rate was measured, and simultaneously, their retained body radiation activity was monitored at various time points. The equations of the external dose rate and the retained body activity, described as a function of hours post administration, were fitted. Additionally, the release time for patients was calculated. The reduction in activity in the group receiving a second or subsequent treatment was more rapid than the group receiving only the initial treatment. Most important, an expeditious method was established to indirectly evaluate the retained body activity of patients by measuring the external dose rate with a portable radiation survey meter. By this method, the calculated external dose rate limits are 19.2, 8.85, 5.08 and 2.32 μSv·h−1 at 1, 1.5, 2 and 3 m, respectively, according to a patient’s released threshold level of retained body activity <400 MBq. This study is beneficial for radiation safety decision-making. PMID:25337944

Establishment and validation of a method for multi-dose irradiation of cells in 96-well microplates

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

Abatzoglou, Ioannis; Zois, Christos E.; Pouliliou, Stamatia

2013-02-15

Highlights: ► We established a method for multi-dose irradiation of cell cultures within a 96-well plate. ► Equations to adjust to preferable dose levels are produced and provided. ► Up to eight different dose levels can be tested in one microplate. ► This method results in fast and reliable estimation of radiation dose–response curves. -- Abstract: Microplates are useful tools in chemistry, biotechnology and molecular biology. In radiobiology research, these can be also applied to assess the effect of a certain radiation dose delivered to the whole microplate, to test radio-sensitivity, radio-sensitization or radio-protection. Whether different radiation doses can bemore » accurately applied to a single 96-well plate to further facilitate and accelerated research by one hand and spare funds on the other, is a question dealt in the current paper. Following repeated ion-chamber, TLD and radiotherapy planning dosimetry we established a method for multi-dose irradiation of cell cultures within a 96-well plate, which allows an accurate delivery of desired doses in sequential columns of the microplate. Up to eight different dose levels can be tested in one microplate. This method results in fast and reliable estimation of radiation dose–response curves.« less

Space radiation risk limits and Earth-Moon-Mars environmental models

NASA Astrophysics Data System (ADS)

Cucinotta, Francis A.; Hu, Shaowen; Schwadron, Nathan A.; Kozarev, K.; Townsend, Lawrence W.; Kim, Myung-Hee Y.

2010-12-01

We review NASA's short-term and career radiation limits for astronauts and methods for their application to future exploration missions outside of low Earth orbit. Career limits are intended to restrict late occurring health effects and include a 3% risk of exposure-induced death from cancer and new limits for central nervous system and heart disease risks. Short-term dose limits are used to prevent in-flight radiation sickness or death through restriction of the doses to the blood forming organs and to prevent clinically significant cataracts or skin damage through lens and skin dose limits, respectively. Large uncertainties exist in estimating the health risks of space radiation, chiefly the understanding of the radiobiology of heavy ions and dose rate and dose protraction effects, and the limitations in human epidemiology data. To protect against these uncertainties NASA estimates the 95% confidence in the cancer risk projection intervals as part of astronaut flight readiness assessments and mission design. Accurate organ dose and particle spectra models are needed to ensure astronauts stay below radiation limits and to support the goal of narrowing the uncertainties in risk projections. Methodologies for evaluation of space environments, radiation quality, and organ doses to evaluate limits are discussed, and current projections for lunar and Mars missions are described.

76 FR 53847 - New International Commission on Radiological Protection; Recommendations on the Annual Dose Limit...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-30

... Radiological Protection; Recommendations on the Annual Dose Limit to the Lens of the Eye AGENCY: Nuclear... Protection (ICRP) recommendations for the limitation of annual dose to the lens of the eye. This significant... might be lower than previously considered. For the lens of the eye, the threshold in absorbed dose for...

Technical Note: Dosimetric evaluation of Monte Carlo algorithm in iPlan for stereotactic ablative body radiotherapy (SABR) for lung cancer patients using RTOG 0813 parameters.

PubMed

Pokhrel, Damodar; Badkul, Rajeev; Jiang, Hongyu; Kumar, Pravesh; Wang, Fen

2015-01-08

For stereotactic ablative body radiotherapy (SABR) in lung cancer patients, Radiation Therapy Oncology Group (RTOG) protocols currently require radiation dose to be calculated using tissue heterogeneity corrections. Dosimetric criteria of RTOG 0813 were established based on the results obtained from non-Monte Carlo (MC) algorithms, such as superposition/convolutions. Clinically, MC-based algorithms are now routinely used for lung SABR dose calculations. It is essential to confirm that MC calculations in lung SABR meet RTOG guidelines. This report evaluates iPlan MC plans for SABR in lung cancer patients using dose-volume histogram normalization per current RTOG 0813 compliance criteria. Eighteen Stage I-II non-small cell lung cancer (NSCLC) patients with centrally located tumors, who underwent MC-based lung SABR with heterogeneity correction using X-ray Voxel Monte Carlo (XVMC) algorithm (BrainLAB iPlan version 4.1.2), were analyzed. Total dose of 60 Gy in 5 fractions was delivered to planning target volume (PTV) with at least V100% = 95%. Internal target volumes (ITVs) were delineated on maximum intensity projection (MIP) images of 4D CT scans. PTV (ITV + 5 mm margin) volumes ranged from 10.0 to 99.9 cc (mean = 36.8 ± 20.7 cc). Organs at risk (OARs) were delineated on average images of 4D CT scans. Optimal clinical MC SABR plans were generated using a combination of non-coplanar conformal arcs and beams for the Novalis-TX consisting of high definition multileaf collimators (MLCs) and 6 MV-SRS (1000 MU/min) mode. All plans were evaluated using the RTOG 0813 high and intermediate dose spillage criteria: conformity index (R100%), ratio of 50% isodose volume to the PTV (R50%), maximum dose 2 cm away from PTV in any direction (D2 cm), and percent of normal lung receiving 20 Gy (V20) or more. Other organs-at-risk (OARs) doses were tabulated, including the volume of normal lung receiving 5 Gy (V5), maximum cord dose, dose to < 15 cc of heart, and dose to <5 cc of esophagus. Only six out of 18 patients met all RTOG 0813 compliance criteria. Eight of 18 patients had minor deviations in R100%, four in R50%, and nine in D2 cm. However, only one patient had minor deviation in V20. All other OARs doses, such as maximum cord dose, dose to < 15 cc of heart, and dose to < 5 cc of esophagus, were satisfactory for RTOG criteria, except for one patient, for whom the dose to < 15 cc of heart was higher than RTOG guidelines. The preliminary results for our limited iPlan XVMC dose calculations indicate that the majority (i.e., 2/3) of our patients had minor deviations in the dosimetric guidelines set by RTOG 0813 protocol in one way or another. When using an exclusive highly sophisticated XVMC algorithm, the RTOG 0813 dosimetric compliance criteria such as R100% and D2 cm may need to be revisited. Based on our limited number of patient datasets, in general, about 6% for R100% and 9% for D2 cm corrections could be applied to pass the RTOG 0813 compliance criteria in most of those patients. More patient plans need to be evaluated to make recommendation for R50%. No adjustment is necessary for OAR dose tolerances, including normal lung V20. In order to establish new MC specific dose parameters, further investigation with a large cohort of patients including central, as well as peripheral lung tumors, is anticipated and strongly recommended.

A harmonization effort for acceptable daily exposure application to pharmaceutical manufacturing - Operational considerations.

PubMed

Hayes, Eileen P; Jolly, Robert A; Faria, Ellen C; Barle, Ester Lovsin; Bercu, Joel P; Molnar, Lance R; Naumann, Bruce D; Olson, Michael J; Pecquet, Alison M; Sandhu, Reena; Shipp, Bryan K; Sussman, Robert G; Weideman, Patricia A

2016-08-01

A European Union (EU) regulatory guideline came into effect for all new pharmaceutical products on June 1st, 2015, and for all existing pharmaceutical products on December 1st, 2015. This guideline centers around the use of the Acceptable Daily Exposure (ADE) [synonymous with the Permitted Daily Exposure (PDE)] and operational considerations associated with implementation are outlined here. The EU guidance states that all active pharmaceutical ingredients (API) require an ADE; however, other substances such as starting materials, process intermediates, and cleaning agents may benefit from an ADE. Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE. Established methodologies such as occupational exposure limits or bands (OELs or OEBs) and the threshold of toxicological concern (TTC) can be used or adjusted for use as interim ADEs when only limited data are available and until a more formal ADE can be established. Once formal ADEs are derived, it is important that the documents are routinely updated and that these updates are communicated to appropriate stakeholders. Another key operational consideration related to data-poor substances includes the use of maximum daily dose (MDD) in setting cross-contamination limits. The MDD is an important part of the maximum allowable/safe concentration (MAC/MSC) calculation and there are important considerations for its use and definition. Finally, other considerations discussed include operational aspects of setting ADEs for pediatrics, considerations for large molecules, and risk management in shared facilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Dose-related beneficial and harmful effects of gabapentin in postoperative pain management – post hoc analyses from a systematic review with meta-analyses and trial sequential analyses

PubMed Central

Fabritius, Maria Louise; Wetterslev, Jørn; Mathiesen, Ole; Dahl, Jørgen B

2017-01-01

Background During the last 15 years, gabapentin has become an established component of postoperative pain treatment. Gabapentin has been employed in a wide range of doses, but little is known about the optimal dose, providing the best balance between benefit and harm. This systematic review with meta-analyses aimed to explore the beneficial and harmful effects of various doses of gabapentin administered to surgical patients. Materials and methods Data in this paper were derived from an original review, and the subgroup analyses were predefined in an International Prospective Register of Systematic Reviews published protocol: PROSPERO (ID: CRD42013006538). The methods followed Cochrane guidelines. The Cochrane Library’s CENTRAL, PubMed, EMBASE, Science Citation Index Expanded, Google Scholar, and FDA database were searched for relevant trials. Randomized clinical trials comparing gabapentin versus placebo were included. Four different dose intervals were investigated: 0–350, 351–700, 701–1050, and >1050 mg. Primary co-outcomes were 24-hour morphine consumption and serious adverse events (SAEs), with emphasis put on trials with low risk of bias. Results One hundred and twenty-two randomized clinical trials, with 8466 patients, were included. Sixteen were overall low risk of bias. No consistent increase in morphine-sparing effect was observed with increasing doses of gabapentin from the trials with low risk of bias. Analyzing all trials, the smallest and the highest dose subgroups demonstrated numerically the most prominent reduction in morphine consumption. Twenty-seven trials reported 72 SAEs, of which 83% were reported in the >1050 mg subgroup. No systematic increase in SAEs was observed with increasing doses of gabapentin. Conclusion Data were sparse, and the small number of trials with low risk of bias is a major limitation for firm conclusions. Taking these limitations into account, we were not able to demonstrate a clear relationship between the dosage of gabapentin and opioid-sparing or harmful effects. These subgroup analyses are exploratory and hypothesis-generating for future trialists. PMID:29138592

Three-dimensional radiation dosimetry using polymer gel and solid radiochromic polymer: From basics to clinical applications

PubMed Central

Watanabe, Yoichi; Warmington, Leighton; Gopishankar, N

2017-01-01

Accurate dose measurement tools are needed to evaluate the radiation dose delivered to patients by using modern and sophisticated radiation therapy techniques. However, the adequate tools which enable us to directly measure the dose distributions in three-dimensional (3D) space are not commonly available. One such 3D dose measurement device is the polymer-based dosimeter, which changes the material property in response to radiation. These are available in the gel form as polymer gel dosimeter (PGD) and ferrous gel dosimeter (FGD) and in the solid form as solid plastic dosimeter (SPD). Those are made of a continuous uniform medium which polymerizes upon irradiation. Hence, the intrinsic spatial resolution of those dosimeters is very high, and it is only limited by the method by which one converts the dose information recorded by the medium to the absorbed dose. The current standard methods of the dose quantification are magnetic resonance imaging, optical computed tomography, and X-ray computed tomography. In particular, magnetic resonance imaging is well established as a method for obtaining clinically relevant dosimetric data by PGD and FGD. Despite the likely possibility of doing 3D dosimetry by PGD, FGD or SPD, the tools are still lacking wider usages for clinical applications. In this review article, we summarize the current status of PGD, FGD, and SPD and discuss the issue faced by these for wider acceptance in radiation oncology clinic and propose some directions for future development. PMID:28396725

Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children.

PubMed

Brady, Rebecca C; Hu, Wilson; Houchin, Vonda G; Eder, Frank S; Jackson, Kenneth C; Hartel, Gunter F; Sawlwin, Daphne C; Albano, Frank R; Greenberg, Michael

2014-12-12

A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons≥18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population≥6 months to <18 years of age. Subjects were stratified as follows: Cohort A (≥6 months to <3 years); Cohort B (≥3 years to <9 years); and Cohort C (≥9 years to <18 years). The subject's age and influenza vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Emergency Dosimetry Using Ceramic Components in Personal Electronic Devices

NASA Astrophysics Data System (ADS)

Kouroukla, E. C.; Bailiff, I. K.; Terry, I.

2014-02-01

The rapid assessment of radiation dose to members of the public exposed to significant levels of ionizing radiation during a radiological incident presents a significant difficulty in the absence of planned radiation monitoring. However, within most personal electronic devices components such as resistors with alumina substrates can be found that have potentially suitable properties as solid state dosimeters using luminescence measurement techniques. The suitability of several types of ceramic-based components (e.g., resonators, inductors and resistors) has been previously examined using optically stimulated luminescence (OSL) and thermoluminescence (TL) techniques to establish their basic characteristics for the retrospective determination of absorbed dose. In this paper, we present results obtained with aluminum oxide surface mount resistors extracted from mobile phones that further extend this work. Very encouraging results have been obtained related to the measurement of luminescence sensitivity, dose response, reusability, limit of detection, signal reproducibility and known-dose recovery. However, the alumina exhibits a rapid loss of the latent luminescence signal with time following irradiation attributed to athermal (or anomalous) fading. The issues related to obtaining a reliable correction protocol for this loss and the detailed examinations required of the fading behavior are discussed.

Compendium of Single Event Effects, Total Ionizing Dose, and Displacement Damage for Candidate Spacecraft Electronics for NASA

NASA Technical Reports Server (NTRS)

LaBel, Kenneth A.; OBryan, Martha V.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Pellish, Jonathan A.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Topper, Alyson D.; Ladbury, Raymond L.;

Specific immune response genes of new inbred strains of guinea pigs.

PubMed

Chiba, J; Egashira, Y

1978-01-01

Distribution of specific immune-response (Ir) genes controlling responsiveness to synthetic polypeptide antigens, homopolymer of poly-L-lysine (PLL), copolymer of L-glutamic acid and L-alanine (GA) and copolymer of L-glutamic acid and L-tyrosine (GT), and limiting doses of 2,4-dinitrophenyl guinea pig serum albumin (DNP-GPA) was surveyed in new inbred strains of guinea pigs, JY 1, JY 2, JY 9 and JY 10, established in this Institute. The PLL gene was not found in any of the guinea pigs. The GA gene was found in JY 1 and JY 2 guinea pigs and the GT gene in all the guinea pigs. The gene controlling responsiveness to low doses (1 microgram) of DNP-GPA was found in JY 1, JY 9 and JY 10 guinea pigs. The associated (Ia) antigens was discussed.

Interactive dose shaping part 2: proof of concept study for six prostate patients

NASA Astrophysics Data System (ADS)

Kamerling, Cornelis Ph; Ziegenhein, Peter; Sterzing, Florian; Oelfke, Uwe

2016-03-01

Recently we introduced interactive dose shaping (IDS) as a new IMRT planning strategy. This planning concept is based on a hierarchical sequence of local dose modification and recovery operations. The purpose of this work is to provide a feasibility study for the IDS planning strategy based on a small set of six prostate patients. The IDS planning paradigm aims to perform interactive local dose adaptations of an IMRT plan without compromising already established valuable dose features in real-time. Various IDS tools were developed in our in-house treatment planning software Dynaplan and were utilized to create IMRT treatment plans for six patients with an adeno-carcinoma of the prostate. The sequenced IDS treatment plans were compared to conventionally optimized clinically approved plans (9 beams, co-planar). For each patient, several IDS plans were created, with different trade-offs between organ sparing and target coverage. The reference dose distributions were imported into Dynaplan. For each patient, the IDS treatment plan with a similar or better trade-off between target coverage and OAR sparing was selected for plan evaluation, guided by a physician. For this initial study we were able to generate treatment plans for prostate geometries in 15-45 min. Individual local dose adaptations could be performed in less than one second. The average differences compared to the reference plans were for the mean dose: 0.0 Gy (boost) and 1.2 Gy (PTV), for {{D}98%}:-1.1 Gy and for {{D}2%}:1.1 Gy (both target volumes). The dose-volume quality indicators were well below the Quantec constraints. However, we also observed limitations of our currently implemented approach. Most prominent was an increase of the non-tumor integral dose by 16.4% on average, demonstrating that further developments of our planning strategy are required.

Absolute dosimetry on a dynamically scanned sample for synchrotron radiotherapy using graphite calorimetry and ionization chambers

NASA Astrophysics Data System (ADS)

Lye, J. E.; Harty, P. D.; Butler, D. J.; Crosbie, J. C.; Livingstone, J.; Poole, C. M.; Ramanathan, G.; Wright, T.; Stevenson, A. W.

2016-06-01

The absolute dose delivered to a dynamically scanned sample in the Imaging and Medical Beamline (IMBL) on the Australian Synchrotron was measured with a graphite calorimeter anticipated to be established as a primary standard for synchrotron dosimetry. The calorimetry was compared to measurements using a free-air chamber (FAC), a PTW 31 014 Pinpoint ionization chamber, and a PTW 34 001 Roos ionization chamber. The IMBL beam height is limited to approximately 2 mm. To produce clinically useful beams of a few centimetres the beam must be scanned in the vertical direction. In practice it is the patient/detector that is scanned and the scanning velocity defines the dose that is delivered. The calorimeter, FAC, and Roos chamber measure the dose area product which is then converted to central axis dose with the scanned beam area derived from Monte Carlo (MC) simulations and film measurements. The Pinpoint chamber measures the central axis dose directly and does not require beam area measurements. The calorimeter and FAC measure dose from first principles. The calorimetry requires conversion of the measured absorbed dose to graphite to absorbed dose to water using MC calculations with the EGSnrc code. Air kerma measurements from the free air chamber were converted to absorbed dose to water using the AAPM TG-61 protocol. The two ionization chambers are secondary standards requiring calibration with kilovoltage x-ray tubes. The Roos and Pinpoint chambers were calibrated against the Australian primary standard for air kerma at the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Agreement of order 2% or better was obtained between the calorimetry and ionization chambers. The FAC measured a dose 3-5% higher than the calorimetry, within the stated uncertainties.

First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours.

PubMed

Rodon, Jordi; Postel-Vinay, Sophie; Hollebecque, Antoine; Nuciforo, Paolo; Azaro, Analia; Cattan, Valérie; Marfai, Lucie; Sudey, Isabelle; Brendel, Karl; Delmas, Audrey; Malasse, Stéphanie; Soria, Jean-Charles

2017-08-01

S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. ISRCTN00759419. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Using fractional polynomials to estimate the safety threshold of fluoride in drinking water].

PubMed

Pan, Shenling; An, Wei; Li, Hongyan; Yang, Min

2014-01-01

To study the dose-response relationship between fluoride content in drinking water and prevalence of dental fluorosis on the national scale, then to determine the safety threshold of fluoride in drinking water. Meta-regression analysis was applied to the 2001-2002 national endemic fluorosis survey data of key wards. First, fractional polynomial (FP) was adopted to establish fixed effect model, determining the best FP structure, after that restricted maximum likelihood (REML) was adopted to estimate between-study variance, then the best random effect model was established. The best FP structure was first-order logarithmic transformation. Based on the best random effect model, the benchmark dose (BMD) of fluoride in drinking water and its lower limit (BMDL) was calculated as 0.98 mg/L and 0.78 mg/L. Fluoride in drinking water can only explain 35.8% of the variability of the prevalence, among other influencing factors, ward type was a significant factor, while temperature condition and altitude were not. Fractional polynomial-based meta-regression method is simple, practical and can provide good fitting effect, based on it, the safety threshold of fluoride in drinking water of our country is determined as 0.8 mg/L.

Radon in indoor air of primary schools: determinant factors, their variability and effective dose.

PubMed

Madureira, Joana; Paciência, Inês; Rufo, João; Moreira, André; de Oliveira Fernandes, Eduardo; Pereira, Alcides

2016-04-01

Radon is a radioactive gas, abundant in granitic areas, such as in the city of Porto at the north-east of Portugal. This gas is a recognized carcinogenic agent, being appointed by the World Health Organization as the leading cause of lung cancer after smoking. The aim of this preliminary survey was to determine indoor radon concentrations in public primary schools, to analyse the main factors influencing their indoor concentration levels and to estimate the effective dose in students and teachers in primary schools. Radon concentrations were measured in 45 classrooms from 13 public primary schools located in Porto, using CR-39 passive radon detectors for about 2-month period. In all schools, radon concentrations ranged from 56 to 889 Bq/m(3) (mean = 197 Bq/m(3)). The results showed that the limit of 100 Bq/m(3) established by WHO IAQ guidelines was exceeded in 92 % of the measurements, as well as 8 % of the measurements exceeded the limit of 400 Bq/m(3) established by the national legislation. Moreover, the mean annual effective dose was calculated as 1.25 mSv/y (ranging between 0.58 and 3.07 mSv/y), which is below the action level (3-10 mSv). The considerable variability of radon concentration observed between and within floors indicates a need to monitor concentrations in several rooms for each floor. A single radon detector for each room can be used, provided that the measurement error is considerably lower than variability of radon concentration between rooms. The results of the present survey will provide useful baseline data for adopting safety measures and dealing effectively with radiation emergencies. In particular, radon remediation techniques should be used in buildings located in the highest radon risk areas of Portugal. The results obtained in the current study concerning radon levels and their variations will be useful to optimize the design of future research surveys.

Dynamically accumulated dose and 4D accumulated dose for moving tumors

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

Li Heng; Li Yupeng; Zhang Xiaodong

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 themore » 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 between the dynamic dose and 4D dose as a function of number of deliveries and/or total deliver time was also established.« less

Center of cancer systems biology second annual workshop--tumor metronomics: timing and dose level dynamics.

PubMed

Hahnfeldt, Philip; Hlatky, Lynn; Klement, Giannoula Lakka

2013-05-15

Metronomic chemotherapy, the delivery of doses in a low, regular manner so as to avoid toxic side effects, was introduced over 12 years ago in the face of substantial clinical and preclinical evidence supporting its tumor-suppressive capability. It constituted a marked departure from the classic maximum-tolerated dose (MTD) strategy, which, given its goal of rapid eradication, uses dosing sufficiently intense to require rest periods between cycles to limit toxicity. Even so, upfront tumor eradication is frequently not achieved with MTD, whereupon a de facto goal of longer-term tumor control is often pursued. As metronomic dosing has shown tumor control capability, even for cancers that have become resistant to the same drug delivered under MTD, the question arises whether it may be a preferable alternative dosing approach from the outset. To date, however, our knowledge of the coupled dynamics underlying metronomic dosing is neither sufficiently well developed nor widely enough disseminated to establish its actual potential. Meeting organizers thus felt the time was right, armed with new quantitative approaches, to call a workshop on "Tumor Metronomics: Timing and Dose Level Dynamics" to explore prospects for gaining a deeper, systems-level appreciation of the metronomics concept. The workshop proved to be a forum in which experts from the clinical, biologic, mathematical, and computational realms could work together to clarify the principles and underpinnings of metronomics. Among other things, the need for significant shifts in thinking regarding endpoints to be used as clinical standards of therapeutic progress was recognized. ©2013 AACR.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

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

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

Adulticidal Susceptibility Evaluation of Aedes albopictus Using New Diagnostic Doses in Penang Island, Malaysia.

PubMed

Rahim, Junaid; Ahmad, Abu H; Ahmad, Hamdan; Ishak, Intan H; Rus, Adanan Che; Maimusa, Hamisu A

2017-09-01

Insecticide-based vector control approaches are facing challenges due to the development of resistance in vector mosquitoes. Therefore, a proper resistance surveillance program using baseline lethal concentrations is crucial for resistance management strategies. Currently, the World Health Organization's (WHO) diagnostic doses established for Aedes aegypti and Anopheles species are being used to study the resistance status of Aedes albopictus. In this study, we established the diagnostic doses for permethrin, deltamethrin, and malathion using a known susceptible reference strain. Five field-collected populations were screened against these doses, following the WHO protocol. This study established the diagnostic dose of malathion at 2.4%, permethrin at 0.95%, and deltamethrin at 0.28%, which differ from the WHO doses for Aedes aegypti and Anopheles spp. Among the insecticides tested on the 5 wild populations, only deltamethrin showed high effectiveness. Different susceptibility and resistance patterns were observed with permethrin, malathion, and dichloro-diphenyl-trichloroethane (DDT) at 4%. This study may assist the health authorities to improve future chemical-based vector control operations in dengue-endemic areas.

Setting Occupational Exposure Limits for Chemical Allergens—Understanding the Challenges

PubMed Central

Dotson, G. S.; Maier, A.; Siegel, P. D.; Anderson, S. E.; Green, B. J.; Stefaniak, A. B.; Codispoti, C. D.; Kimber, I.

2015-01-01

Chemical allergens represent a significant health burden in the workplace. Exposures to such chemicals can cause the onset of a diverse group of adverse health effects triggered by immune-mediated responses. Common responses associated with workplace exposures to low molecular weight (LMW) chemical allergens range from allergic contact dermatitis to life-threatening cases of asthma. Establishing occupational exposure limits (OELs) for chemical allergens presents numerous difficulties for occupational hygiene professionals. Few OELs have been developed for LMW allergens because of the unique biological mechanisms that govern the immune-mediated responses. The purpose of this article is to explore the primary challenges confronting the establishment of OELs for LMW allergens. Specific topics include: (1) understanding the biology of LMW chemical allergies as it applies to setting OELs; (2) selecting the appropriate immune-mediated response (i.e., sensitization versus elicitation); (3) characterizing the dose (concentration)-response relationship of immune-mediated responses; (4) determining the impact of temporal exposure patterns (i.e., cumulative versus acute exposures); and (5) understanding the role of individual susceptibility and exposure route. Additional information is presented on the importance of using alternative exposure recommendations and risk management practices, including medical surveillance, to aid in protecting workers from exposures to LMW allergens when OELs cannot be established. PMID:26583909

The reference individual of radiation protection

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

Eckerman, K.F.; Cristy, M.

1995-12-31

The 70-kg {open_quotes}standard man{close_quotes} representing a typical Western adult male has been used in physiological models since at least the 1920s. In 1949 at the Chalk River conference, health physicists from the U.S., UK, and Canada agreed on the concept of a standard man to facilitate comparison of internal dose estimates. The 70-kg standard man included specifications of the masses of 25 organs and tissues, total body content of 15 elements, total water intake and output, water content of the body, and some anatomical and physiological data for the respiratory and gastrointestinal tracts. In 1959, in its Publication 2{sup 2}more » on permissible doses for internal radiation the International Commission on Radiological Protection (ICRP) modified standard man. In 1963 the ICRP established a task group to revise and extend the standard man concept. The name was changed later to Reference Man and the task group`s work was published in 1975 as ICRP Publication 23{sup 3}. Publication 23 similar to Publication 2, updates and documents the sources of the data. Data on women, children, and fetuses were also collected, where available, but these data were limited primarily to anatomical data and only a few reference values were established for these groups. Information assembled during the course of the effort on the Reference Man report was used at Oak Ridge National Laboratory (ORNL) to construct a mathematical representation of the body (a phantom) that was suitable for use with Monte Carlo methods in the calculation of organ doses. That effort was undertaken to improve estimates of dose from photon-emitting radionuclides residing within organs, so-called internal emitters. The phantom, although updated throughout the years, remains today as the basis for organ dose estimates in nuclear medicine and radiation protection and underlies the radiation risk data derived from the epidemiologic studies of the atomic bomb survivors of Hiroshima and Nagasaki.« less

Heavy metals in aromatic spices by inductively coupled plasma-mass spectrometry.

PubMed

Bua, Daniel Giuseppe; Annuario, Giovanni; Albergamo, Ambrogina; Cicero, Nicola; Dugo, Giacomo

2016-09-01

Objective of this study was to determine the content of Cd, Hg, As and Pb in common spices traded in the Italian market, using inductively coupled plasma-mass spectrometry (ICP-MS). The results were compared with the maximum limits established by the national Legislative Decree (LD) no. 107 implementing the Council Directive 88/388/EEC and by international organisations, such as Food and Agriculture Organization (FAO) and World Health Organization (WHO). Food safety for spices was assessed considering the tolerable weekly intake (TWI) and the provisional tolerable weekly intake (PTWI), respectively, for Cd and Hg and the 95% lower confidence limit of the benchmark dose of 1% extra risk (BMDL01) for As and Pb. Investigated elements in all samples were within the maximum limits as set by the national and international normative institutions. Nevertheless, the heavy metal content of some spices exceeded the PTWI, TWI and BMDL01, which needs attention when considering consumer's health.

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

Hickey, Ryan; Mulcahy, Mary F.; Lewandowski, Robert J.

Purpose: Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ({sup 90}Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of {sup 90}Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Methods and Materials: Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the secondmore » cycle, whole-liver {sup 90}Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after {sup 90}Y infusion. If a DLT was not observed, the {sup 90}Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of {sup 90}Y with full-dose capecitabine. Results: Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing {sup 90}Y MTD were not met, indicating an MTD of >170 Gy. Conclusion: The MTD of {sup 90}Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest {sup 90}Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.« less

Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors

PubMed Central

Jimeno, Antonio; Weiss, Glen J.; Miller, Wilson H.; Gettinger, Scott; Eigl, Bernard J.C.; Chang, Anne Lynne S.; Dunbar, Joi; Devens, Shannon; Faia, Kerrie; Skliris, Georgios; Kutok, Jeff; Lewis, Karl D.; Tibes, Raoul; Sharfman, William H.; Ross, Robert W.; Rudin, Charles M.

2013-01-01

Purpose To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). Experimental Design Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day −7 and day 22 of cycle 1. Results Ninety-four patients (32F, 62M; ages, 39–87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (Tmax = 2–8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg. Conclusions IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor–naïve patients with BCC. PMID:23575478

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

PubMed

Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Developing and implementing a high precision setup system

NASA Astrophysics Data System (ADS)

Peng, Lee-Cheng

The demand for high-precision radiotherapy (HPRT) was first implemented in stereotactic radiosurgery using a rigid, invasive stereotactic head frame. Fractionated stereotactic radiotherapy (SRT) with a frameless device was developed along a growing interest in sophisticated treatment with a tight margin and high-dose gradient. This dissertation establishes the complete management for HPRT in the process of frameless SRT, including image-guided localization, immobilization, and dose evaluation. The most ideal and precise positioning system can allow for ease of relocation, real-time patient movement assessment, high accuracy, and no additional dose in daily use. A new image-guided stereotactic positioning system (IGSPS), the Align RT3C 3D surface camera system (ART, VisionRT), which combines 3D surface images and uses a real-time tracking technique, was developed to ensure accurate positioning at the first place. The uncertainties of current optical tracking system, which causes patient discomfort due to additional bite plates using the dental impression technique and external markers, are found. The accuracy and feasibility of ART is validated by comparisons with the optical tracking and cone-beam computed tomography (CBCT) systems. Additionally, an effective daily quality assurance (QA) program for the linear accelerator and multiple IGSPSs is the most important factor to ensure system performance in daily use. Currently, systematic errors from the phantom variety and long measurement time caused by switching phantoms were discovered. We investigated the use of a commercially available daily QA device to improve the efficiency and thoroughness. Reasonable action level has been established by considering dosimetric relevance and clinic flow. As for intricate treatments, the effect of dose deviation caused by setup errors remains uncertain on tumor coverage and toxicity on OARs. The lack of adequate dosimetric simulations based on the true treatment coordinates from the treatment planning system (TPS) has limited adaptive treatments. A reliable and accurate dosimetric simulation using TPS and in-house software in uncorrected errors has been developed. In SRT, the calculated dose deviation is compared to the original treatment dose with the dose-volume histogram to investigate the dose effect of rotational errors. In summary, this work performed a quality assessment to investigate the overall accuracy of current setup systems. To reach the ideal HPRT, the reliable dosimetric simulation, an effective daily QA program and effective, precise setup systems were developed and validated.

A CONCEPTUAL FRAMEWORK FOR MANAGING RADIATION DOSE TO PATIENTS IN DIAGNOSTIC RADIOLOGY USING REFERENCE DOSE LEVELS.

PubMed

Almén, Anja; Båth, Magnus

2016-06-01

The overall aim of the present work was to develop a conceptual framework for managing radiation dose in diagnostic radiology with the intention to support optimisation. An optimisation process was first derived. The framework for managing radiation dose, based on the derived optimisation process, was then outlined. The outset of the optimisation process is four stages: providing equipment, establishing methodology, performing examinations and ensuring quality. The optimisation process comprises a series of activities and actions at these stages. The current system of diagnostic reference levels is an activity in the last stage, ensuring quality. The system becomes a reactive activity only to a certain extent engaging the core activity in the radiology department, performing examinations. Three reference dose levels-possible, expected and established-were assigned to the three stages in the optimisation process, excluding ensuring quality. A reasonably achievable dose range is also derived, indicating an acceptable deviation from the established dose level. A reasonable radiation dose for a single patient is within this range. The suggested framework for managing radiation dose should be regarded as one part of the optimisation process. The optimisation process constitutes a variety of complementary activities, where managing radiation dose is only one part. This emphasises the need to take a holistic approach integrating the optimisation process in different clinical activities. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A biological study establishing the endotoxin limit of biomaterials for bone regeneration in cranial and femoral implantation of rats.

PubMed

Haishima, Yuji; Hasegawa, Chie; Todoki, Kazuo; Sasaki, Kazuo; Niimi, Shingo; Ozono, Satoru

2017-08-01

The purpose of this study was to accurately quantify the risk of endotoxin contamination in biomaterials for bone regeneration in order to establish the acceptable endotoxin limit. Collagen sheets containing varying amounts of purified endotoxin from Escherichia coli and dried, heat-killed E. coli or Staphylococcus aureus cells were implanted into cranial or femoral defects in rats. These defects were artificially prepared to a size of 5 × 5 mm or a diameter of 1 mm, respectively. The degree of osteoanagenesis was assessed by soft X-ray radiography and histopathology at 1 and 4 weeks after implantation. The collagen sheet containing the dried E. coli cells showed a dose-dependent delay in cranial and/or femoral osteoanagenesis at endotoxin activities of more than 33.6 EU/mg, at which no inflammatory response was observed. In contrast, no such observation occurred with the collagen sheet containing S. aureus cells. These results suggest that endotoxins may affect the process of osteoanagenesis. Additionally, the no-observed-adverse-effect level was 9.6 EU/mg, corresponding to 255 EU/kg body weight in rats. Interestingly, no delay in osteoanagenesis was induced by the implantation of collagen sheets containing purified endotoxin at any dose tested. This suggested that pure endotoxin implanted into tissues having poor circulation of bodily fluids without bleeding may not be recognized as a foreign substance and may not induce a significant biological response. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1514-1524, 2017. © 2016 Wiley Periodicals, Inc.

Effect of Embolization Material in the Calculation of Dose Deposition in Arteriovenous Malformations

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

De la Cruz, O. O. Galvan; Moreno-Jimenez, S.; Larraga-Gutierrez, J. M.

2010-12-07

In this work it is studied the impact of the incorporation of high Z materials (embolization material) in the dose calculation for stereotactic radiosurgery treatment for arteriovenous malformations. A statistical analysis is done to establish the variables that may impact in the dose calculation. To perform the comparison pencil beam (PB) and Monte Carlo (MC) calculation algorithms were used. The comparison between both dose calculations shows that PB overestimates the dose deposited. The statistical analysis, for the quantity of patients of the study (20), shows that the variable that may impact in the dose calculation is the volume of themore » high Z material in the arteriovenous malformation. Further studies have to be done to establish the clinical impact with the radiosurgery result.« less

Defining the upper age limit of luminescence dating: A case study using long lacustrine records from Chew Bahir, Ethiopia

NASA Astrophysics Data System (ADS)

Chapot, Melissa S.; Roberts, Helen M.; Lamb, Henry F.; Schäbitz, Frank; Asrat, Asfawossen; Trauth, Martin H.

2017-04-01

Optically stimulated luminescence (OSL) dating is a family of numerical chronometric techniques applied to quartz or feldspar mineral grains to assess the time since these grains were last exposed to sunlight (i.e. deposited), based on the amount of energy they absorbed from ambient radiation during burial. The maximum limit of any OSL dating technique is not defined by a fixed upper age limit, but instead by the maximum radiation dose the sample can accurately record before the OSL signal saturates. The challenge is to assess this upper limit of accurate age determination without necessitating comparison to independent age control. Laboratory saturation of OSL signals can be observed using a dose response curve (DRC) plotting OSL signal intensity against absorbed laboratory radiation dose. When a DRC is fitted with a single saturating exponential, one of the equation's parameters can be used to define a pragmatic upper limit beyond which uncertainties become large and asymmetric (Wintle and Murray, 2006). However, many sub-samples demonstrate DRCs that are best defined by double saturating exponential equations, which cannot be used to define this upper limit. To investigate the reliability of luminescence ages approaching saturation, Chapot et al. (2012) developed the Natural DRC concept, which uses expected ages derived from independent age control, combined with sample-specific measurements of ambient radioactivity, to calculate expected doses of absorbed radiation during burial. Natural OSL signal intensity is then plotted against these expected doses and compared to laboratory-generated DRCs. Using this approach, discrepancies between natural and laboratory DRCs have been observed for the same mineral material as natural OSL signal intensities saturate at absorbed radiation doses lower than the pragmatic upper limit defined by laboratory DRCs, leading to increasing age underestimation with depth without a metric for questioning the age reliability. The present study explores a means of defining the upper limit for reliable luminescence ages for sedimentary records without an established chronologic framework, using a long ( 280m; Cohen et al., 2016) lacustrine record from Chew Bahir, Ethiopia, drilled as part of the Hominin Sites and Paleolakes Drilling Project (HSPDP) of the International Continental Scientific Drilling Programme (ICDP) and CRC806 "Our way to Europe". Natural saturation of OSL signals is explored by plotting natural signal intensity against depth, creating a pseudo-Natural DRC that can be compared to laboratory DRCs. Unlike the homogenous deposits of the Chinese Loess Plateau where the Natural DRC concept was developed, the 280m composite core from Chew Bahir shows significant variation in lithology enabling investigation of the effects of sample to sample variability on Natural DRC construction, and facilitating comparison between signals from fine-quartz, fine-polymineral, and coarse-potassium feldspar grains. This work demonstrates how the concepts of Natural DRCs can be used to define the upper dating limit of sample suites without independent age control, providing valuable information for long sedimentary sequences such as the lacustrine deposits from Chew Bahir. Chapot M.S., et al. (2012), Radiation Measurements 47: 1045-1052. Cohen A, et al. (2016), Scientific Drilling 21: 1-16. Wintle, A.G., Murray, A.S. (2006) Radiation Measurements 41: 369-391.

10 CFR 20.1302 - Compliance with dose limits for individual members of the public.

Code of Federal Regulations, 2013 CFR

2013-01-01

... public. 20.1302 Section 20.1302 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation Dose Limits for Individual Members of the Public § 20.1302 Compliance with dose limits..., surveys of radiation levels in unrestricted and controlled areas and radioactive materials in effluents...

10 CFR 20.1302 - Compliance with dose limits for individual members of the public.

Code of Federal Regulations, 2014 CFR

2014-01-01

... public. 20.1302 Section 20.1302 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation Dose Limits for Individual Members of the Public § 20.1302 Compliance with dose limits..., surveys of radiation levels in unrestricted and controlled areas and radioactive materials in effluents...

10 CFR 20.1302 - Compliance with dose limits for individual members of the public.

Code of Federal Regulations, 2012 CFR

2012-01-01

... public. 20.1302 Section 20.1302 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation Dose Limits for Individual Members of the Public § 20.1302 Compliance with dose limits..., surveys of radiation levels in unrestricted and controlled areas and radioactive materials in effluents...

10 CFR 20.1302 - Compliance with dose limits for individual members of the public.

Code of Federal Regulations, 2011 CFR

2011-01-01

... public. 20.1302 Section 20.1302 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation Dose Limits for Individual Members of the Public § 20.1302 Compliance with dose limits..., surveys of radiation levels in unrestricted and controlled areas and radioactive materials in effluents...

10 CFR 20.1302 - Compliance with dose limits for individual members of the public.

Code of Federal Regulations, 2010 CFR

2010-01-01

... public. 20.1302 Section 20.1302 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Radiation Dose Limits for Individual Members of the Public § 20.1302 Compliance with dose limits..., surveys of radiation levels in unrestricted and controlled areas and radioactive materials in effluents...

Analysis of Exposure-Dose Variation of Inhaled Particles in Adult Subjects.

EPA Science Inventory

Although internal dose is a key factor for determining the health risk of inhaled pollutant particles, available dose information is largely limited to young healthy adults under a few typical exposure conditions. Extrapolation of the limited dose information to different populat...

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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

Peters, Diane E.; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA; Hoover, Benjamin

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor activity of protease-activated anthrax toxins were evaluated. • All anthrax toxin variants exhibited potent systemic anti-tumor activity in mice. • A dual MMP/uPA-activated anthrax toxin displayed a superior safety profile. • Clinical development of a dual MMP/uPA-activated anthrax toxin is feasible.« less

Compendium of Current Single Event Effects for Candidate Spacecraft Electronics for NASA

NASA Technical Reports Server (NTRS)

O'Bryan, Martha V.; Label, Kenneth A.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Lauenstein, Jean-Marie; Pellish, Jonathan A.; Ladbury, Raymond L.; Berg, Melanie D.

2015-01-01

NASA spacecraft are subjected to a harsh space environment that includes exposure to various types of ionizing radiation. The performance of electronic devices in a space radiation environment are often limited by their susceptibility to single event effects (SEE). Ground-based testing is used to evaluate candidate spacecraft electronics to determine risk to spaceflight applications. Interpreting the results of radiation testing of complex devices is and adequate understanding of the test condition is critical. Studies discussed herein were undertaken to establish the application-specific sensitivities of candidate spacecraft and emerging electronic devices to single-event upset (SEU), single-event latchup (SEL), single-event gate rupture (SEGR), single-event burnout (SEB), and single-event transient (SET). For total ionizing dose (TID) and displacement damage dose (DDD) results, see a companion paper submitted to the 2015 Institute of Electrical and Electronics Engineers (IEEE) Nuclear and Space Radiation Effects Conference (NSREC) Radiation Effects Data Workshop (REDW) entitled "compendium of Current Total Ionizing Dose and Displacement Damage for Candidate Spacecraft Electronics for NASA by M. Campola, et al.

Decongestion: Diuretics and other therapies for hospitalized heart failure

PubMed Central

Vazir, Ali; Cowie, Martin R.

2016-01-01

Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Often the syndrome is characterized by congestion, and is associated with long hospital admissions and high risk of readmission and further healthcare expenditure. Despite a limited evidence-base, diuretics remain the first-line treatment for congestion. Loop diuretics are typically the first-line diuretic strategy with some evidence that initial treatment with continuous infusion or boluses of high-dose loop diuretic is superior to an initial lower dose strategy. In patients who have impaired responsiveness to diuretics, the addition of an oral thiazide or thiazide-like diuretic to induce sequential nephron blockade can be beneficial. The use of intravenous low-dose dopamine is no longer supported in heart failure patients with preserved systolic blood pressure and its use to assist diuresis in patients with low systolic blood pressures requires further study. Mechanical ultrafiltration has been used to treat patients with heart failure and fluid retention, but the evidence-base is not robust, and its place in clinical practice is yet to be established. Several novel pharmacological agents remain under investigation. PMID:27056656

Recommended treatment for urinary tract infection in pregnancy.

PubMed

Vercaigne, L M; Zhanel, G G

1994-02-01

To establish and recommend a therapeutic regimen for the treatment of urinary tract infection (UTI) in pregnancy based on the published studies. An English-language literature search employing MEDLINE, Index Medicus, and bibliographic reviews of the references obtained were searched (key terms: urinary tract infection, UTI, pregnancy, bacteriuria). All identified human studies dealing with bacteriuria or UTI in pregnancy were analyzed. Limited data are available regarding the appropriate antibiotic management of UTI in pregnancy. Single-dose cure rates with amoxicillin are approximately 80 percent. Trimethoprim/sulfamethoxazole provides cure rates of greater than 80 percent. Cephalosporins and nitrofurantoin produce variable results. We recommend separating pregnant subjects with UTI into two groups. Those with asymptomatic bacteriuria can be treated with a single dose of an antimicrobial to which the organism is susceptible. For those with symptomatic UTI, we recommend amoxicillin 500 mg tid for three days. Urine cultures should be repeated seven days following therapy to assess cure or failure. Well-designed studies need to be performed, comparing single-dose and three-day therapy for UTI in pregnancy.

Dose limits to the lens of the eye: International Basic Safety Standards and related guidance.

PubMed

Boal, T J; Pinak, M

2015-06-01

The International Atomic Energy Agency (IAEA) safety requirements: 'General Safety Requirements Part 3--Radiation protection and safety of radiation sources: International Basic Safety Standards' (BSS) was approved by the IAEA Board of Governors at its meeting in September 2011, and was issued as General Safety Requirements Part 3 in July 2014. The equivalent dose limit for the lens of the eye for occupational exposure in planned exposure situations was reduced from 150 mSv year(-1) to 20 mSv year(-1), averaged over defined periods of 5 years, with no annual dose in a single year exceeding 50 mSv. This reduction in the dose limit for the lens of the eye followed the recommendation of the International Commission on Radiological Protection in its statement on tissue reactions of 21 April 2011. IAEA has developed guidance on the implications of the new dose limit for the lens of the eye. This paper summarises the process that led to the inclusion of the new dose limit for the lens of the eye in the BSS, and the implications of the new dose limit. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

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

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Safety of docosahexaenoic acid (DHA) administered as DHA ethyl ester in a 9-month toxicity study in dogs.

PubMed

Dahms, Irina; Beilstein, Paul; Bonnette, Kimberly; Salem, Norman

2016-06-01

DHA Ethyl Ester (DHA-EE) is a 90% concentrated ethyl ester of docosahexaenoic acid manufactured from the microalgal oil. The objective of the 9-month study was to evaluate safety of DHA-EE administered to beagle dogs at dose levels 150, 1000 and 2000 mg/kg bw/day by oral gavage and to determine reversibility of any findings after a 2-month recovery period. DHA-EE was well tolerated at all doses. There were observations of dry flaky skin with occasional reddened areas at doses ≥1000 mg/kg bw/day. These findings lacked any microscopic correlate and were no longer present after the recovery period. There were no toxicologically relevant findings in body weights, body weight gains, food consumption, ophthalmological examinations, and ECG measurements. Test article-related changes in hematology parameters were limited to decreases in reticulocyte count in the high-dose males and considered non-adverse. In clinical chemistry parameters, dose-related decreases in cholesterol and triglycerides levels were observed at all doses in males and females and attributed to the known lipid-lowering effects of DHA. There were no effects on other clinical chemistry, urinalysis or coagulation parameters. There were no abnormal histopathology findings attributed to test article. The No-Observable-Adverse-Effect Level of DHA-EE was established at 2000 mg/kg bw/day for both genders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Vaxchora: A Single-Dose Oral Cholera Vaccine.

PubMed

Cabrera, Adriana; Lepage, Jayne E; Sullivan, Karyn M; Seed, Sheila M

2017-07-01

To review trials evaluating the efficacy and safety of Vaxchora, a reformulated, single-dose, oral, lyophilized Vibrio cholerae CVD 103-HgR vaccine for the prevention of travel-related cholera caused by V cholerae serogroup O1. A literature search was conducted using MEDLINE (1946 to January week 3, 2017) and EMBASE (1996 to 2017 week 3). Keywords included oral cholera vaccine, single-dose, Vaxchora, and CVD 103-HgR. Limits included human, clinical trials published in English since 2010. ClinicalTrials.gov was used as a source for unpublished data. Additional data sources were obtained through bibliographic review of selected articles. Studies that addressed the safety and efficacy of Vaxchora, the reformulated, single-dose oral CVD 103-HgR cholera vaccine, were selected for analysis. Approval of Vaxchora, was based on efficacy of the vaccine in human trials demonstrating 90.3% protection among those challenged with V cholerae 10 days after vaccination and in immunogenicity studies with 90% systemic vibriocidal antibody conversion at 6 months after a single-dose of vaccine. Tolerability was acceptable, with the most common adverse effects reported to be fatigue, headache, and abdominal pain. Vaxchora is the only FDA-approved, single-dose oral vaccine for the prevention of cholera caused by V cholerae serogroup O1 in adult travelers from the United States going to cholera-affected areas. Safety and efficacy has not been established in children, immunocompromised persons, and pregnant or breastfeeding women or those living in cholera-endemic areas.

Combined ionizing radiation and thermal injury in the rat. Evaluation of early excision and closure of the burn wound

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

Hirsch, E.F.; Vezina, R.; Corbett, S.

1990-01-01

The present study was undertaken to establish an animal model of combined whole-body irradiation and thermal injury and to determine the effectiveness of early excision and closure of the burn wound in such a model. Whole-body irradiation over a range of doses resulted in a predictable mortality rate, with an LD50/30 of 783 rad with 95% confidence limits of 737 and 823 rad. A controlled 10% body surface area full-thickness thermal injury resulted in no deaths in 30 animals. When combined with a standard nonlethal 10% thermal injury, varying doses of whole-body irradiation resulted in widely differing LD50/30 values inmore » three separate cohorts of rats. Excision and closure of a 10% burn 24 hours after exposure to 200 rads did not improve survival.« less

A note on the tissue star dose in personnel radiation monitoring in space

NASA Technical Reports Server (NTRS)

Schaefer, H. J.

1978-01-01

Secondaries from nuclear interactions of high energy primaries in the body tissues themselves contribute substantially to the astronaut's radiation exposure in space. The so-called tissue star dose is assessed from the prong number distribution of disintegration stars in emulsion. Prong counts of 1,000 emulsion stars from the Apollo-Soyuz mission reported earlier were re-evaluated. The original scores were divided into sets of 250, 500, 750, and 1,000 emulsion stars and the respective prong number distributions established. The statistical error of the gelatin star number for the four consecutively larger was found to vary, on the 67 percent confidence level, from + or - 25 percent for the count of 250 emulsion stars to + or - 11 percent for 1,000 stars. Seen in the context of the other limitations of the experimental design, the lowest effort of prong-counting 250 stars appears entirely appropriate.

Comparison of radium-228 determination in water among Australian laboratories.

PubMed

Zawadzki, Atun; Cook, Megan; Cutmore, Brodie; Evans, Fiona; Fierro, Daniela; Gedz, Alicea; Harrison, Jennifer J; Loosz, Tom; Medley, Peter; Mokhber-Shahin, Lida; Mullins, Sarah; Sdraulig, Sandra

2017-11-01

The National Health and Medical Research Council and Natural Resource Management Ministerial Council of Australia developed the current Australian Drinking Water Guidelines which recommend an annual radiation dose value of 1 mSv year -1 . One of the potential major contributors to the radiation dose from drinking water is radium-228, a naturally occurring radionuclide arising from the thorium decay series. Various methods of analysing for radium-228 in water have been established and adapted by analytical radiochemistry laboratories. Seven laboratories in Australia participated in analysing radium-228 spiked water samples with activity concentrations ranging from 6 mBq L -1 to 20 Bq L -1 . The aim of the exercise was to compare and evaluate radium-228 results reported by the participating laboratories, the methods used and the detection limits. This paper presents the outcome of the exercise. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Lawrence Livermore National Laboratory and Sandia National Laboratory Nuclear Accident Dosimetry Support of IER 252 and the Dose Characterization of the Flattop Reactor at the DAF

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

Hickman, D. P.; Jeffers, K. L.; Radev, R. P.

In support of IER 252 “Characterization of the Flattop Reactor at the NCERC”, LLNL performed ROSPEC measurements of the neutron spectrum and deployed 129 Personnel Nuclear Accident Dosimeters (PNAD) to establish the need for height corrections and verification of neutron spectrum evaluation of the fluences and dose. A very limited number of heights (typically only one or two heights) can be measured using neutron spectrometers, therefore it was important to determine if any height correction would be needed in future intercomparisons and studies. Specific measurement positions around the Flatttop reactor are provided in Figure 1. Table 1 provides run andmore » position information for LLNL measurements. The LLNL ROSPEC (R2) was used for run numbers 1 – 7, and vi. PNADs were positioned on trees during run numbers 9, 11, and 13.« less

Radiation exposure control from the application of nuclear gauges in the mining industry in Ghana.

PubMed

Faanu, A; Darko, E O; Awudu, A R; Schandorf, C; Emi-Reynolds, G; Yeboah, J; Glover, E T; Kattah, V K

2010-05-01

The use of nuclear gauges for process control and elemental analysis in the mining industry in Ghana, West Africa, is wide spread and on the increase in recent times. The Ghana Radiation Protection Board regulates nuclear gauges through a system of notification and authorization by registration or licensing, inspection, and enforcement. Safety assessments for authorization and enforcement have been established to ensure the safety and security of radiation sources as well as protection of workers and the general public. Appropriate training of mine staff is part of the efforts to develop the necessary awareness about the safety and security of radiation sources. The knowledge and skills acquired will ensure the required protection and safety at the workplaces. Doses received by workers monitored over a period between 1998 and 2007 are well below the annual dose limit of 20 mSv recommended by the International Commission on Radiological Protection.

A reassessment of Galileo radiation exposures in the Jupiter magnetosphere.

PubMed

Atwell, William; Townsend, Lawrence; Miller, Thomas; Campbell, Christina

2005-01-01

Earlier particle experiments in the 1970s on Pioneer-10 and -11 and Voyager-1 and -2 provided Jupiter flyby particle data, which were used by Divine and Garrett to develop the first Jupiter trapped radiation environment model. This model was used to establish a baseline radiation effects design limit for the Galileo onboard electronics. Recently, Garrett et al. have developed an updated Galileo Interim Radiation Environment (GIRE) model based on Galileo electron data. In this paper, we have used the GIRE model to reassess the computed radiation exposures and dose effects for Galileo. The 34-orbit 'as flown' Galileo trajectory data and the updated GIRE model were used to compute the electron and proton spectra for each of the 34 orbits. The total ionisation doses of electrons and protons have been computed based on a parametric shielding configuration, and these results are compared with previously published results.

Film Dosimetry for Intensity Modulated Radiation Therapy

NASA Astrophysics Data System (ADS)

Benites-Rengifo, J.; Martínez-Dávalos, A.; Celis, M.; Lárraga, J.

2004-09-01

Intensity Modulated Radiation Therapy (IMRT) is an oncology treatment technique that employs non-uniform beam intensities to deliver highly conformal radiation to the targets while minimizing doses to normal tissues and critical organs. A key element for a successful clinical implementation of IMRT is establishing a dosimetric verification process that can ensure that delivered doses are consistent with calculated ones for each patient. To this end we are developing a fast quality control procedure, based on film dosimetry techniques, to be applied to the 6 MV Novalis linear accelerator for IMRT of the Instituto Nacional de Neurología y Neurocirugía (INNN) in Mexico City. The procedure includes measurements of individual fluence maps for a limited number of fields and dose distributions in 3D using extended dose-range radiographic film. However, the film response to radiation might depend on depth, energy and field size, and therefore compromise the accuracy of measurements. In this work we present a study of the dependence of Kodak EDR2 film's response on the depth, field size and energy, compared with those of Kodak XV2 film. The first aim is to devise a fast and accurate method to determine the calibration curve of film (optical density vs. doses) commonly called a sensitometric curve. This was accomplished by using three types of irradiation techniques: Step-and-shoot, dynamic and static fields.

An epidermal growth factor receptor variant III–targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme

PubMed Central

Sampson, John H.; Archer, Gary E.; Mitchell, Duane A.; Heimberger, Amy B.; Herndon, James E.; Lally-Goss, Denise; McGehee-Norman, Sharon; Paolino, Alison; Reardon, David A.; Friedman, Allan H.; Friedman, Henry S.; Bigner, Darell D.

2010-01-01

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacyis ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)–based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 × 107 ± 2.9 × 107 SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 ± 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.95), 2.5–8.8], and median survival time from vaccination was 18.7 months (C.I.95, 14.5–25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.95, 17.5–29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy. PMID:19825799

SU-E-T-649: Quality Assurances for Proton Therapy Delivery Equipment

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

Arjomandy, B; Kase, Y; Flanz, J

2015-06-15

Purpose: The number of proton therapy centers has increased dramatically over the past decade. Currently, there is no comprehensive set of guidelines that addresses quality assurance (QA) procedures for the different technologies used for proton therapy. The AAPM has charged task group 224 (TG-224) to provide recommendations for QA required for accurate and safe dose delivery, using existing and next generation proton therapy delivery equipment. Methods: A database comprised of QA procedures and tolerance limits was generated from many existing proton therapy centers in and outside of the US. These consist of proton therapy centers that possessed double scattering, uniformmore » scanning, and pencil beams delivery systems. The diversity in beam delivery systems as well as the existing devices to perform QA checks for different beam parameters is the main subject of TG-224. Based on current practice at the clinically active proton centers participating in this task group, consensus QA recommendations were developed. The methodologies and requirements of the parameters that must be verified for consistency of the performance of the proton beam delivery systems are discussed. Results: TG-224 provides procedures and QA checks for mechanical, imaging, safety and dosimetry requirements for different proton equipment. These procedures are categorized based on their importance and their required frequencies in order to deliver a safe and consistent dose. The task group provides daily, weekly, monthly, and annual QA check procedures with their tolerance limits. Conclusions: The procedures outlined in this protocol provide sufficient information to qualified medical physicists to perform QA checks for any proton delivery system. Execution of these procedures should provide confidence that proton therapy equipment is functioning as commissioned for patient treatment and delivers dose safely and accurately within the established tolerance limits. The report will be published in late 2015.« less

Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

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

Brachman, David G., E-mail: david.brachman@dignityhealth.org; Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; Pugh, Stephanie L.

Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, amore » 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.« less

Pharmacokinetics of low-dose nedaplatin and validation of AUC prediction in patients with non-small-cell lung carcinoma.

PubMed

Niioka, Takenori; Uno, Tsukasa; Yasui-Furukori, Norio; Takahata, Takenori; Shimizu, Mikiko; Sugawara, Kazunobu; Tateishi, Tomonori

2007-04-01

The aim of this study was to determine the pharmacokinetics of low-dose nedaplatin combined with paclitaxel and radiation therapy in patients having non-small-cell lung carcinoma and establish the optimal dosage regimen for low-dose nedaplatin. We also evaluated predictive accuracy of reported formulas to estimate the area under the plasma concentration-time curve (AUC) of low-dose nedaplatin. A total of 19 patients were administered a constant intravenous infusion of 20 mg/m(2) body surface area (BSA) nedaplatin for an hour, and blood samples were collected at 1, 2, 3, 4, 6, 8, and 19 h after the administration. Plasma concentrations of unbound platinum were measured, and the actual value of platinum AUC (actual AUC) was calculated based on these data. The predicted value of platinum AUC (predicted AUC) was determined by three predictive methods reported in previous studies, consisting of Bayesian method, limited sampling strategies with plasma concentration at a single time point, and simple formula method (SFM) without measured plasma concentration. Three error indices, mean prediction error (ME, measure of bias), mean absolute error (MAE, measure of accuracy), and root mean squared prediction error (RMSE, measure of precision), were obtained from the difference between the actual and the predicted AUC, to compare the accuracy between the three predictive methods. The AUC showed more than threefold inter-patient variation, and there was a favorable correlation between nedaplatin clearance and creatinine clearance (Ccr) (r = 0.832, P < 0.01). In three error indices, MAE and RMSE showed significant difference between the three AUC predictive methods, and the method of SFM had the most favorable results, in which %ME, %MAE, and %RMSE were 5.5, 10.7, and 15.4, respectively. The dosage regimen of low-dose nedaplatin should be established based on Ccr rather than on BSA. Since prediction accuracy of SFM, which did not require measured plasma concentration, was most favorable among the three methods evaluated in this study, SFM could be the most practical method to predict AUC of low-dose nedaplatin in a clinical situation judging from its high accuracy in predicting AUC without measured plasma concentration.

Fenoterol delivery by Respimat soft mist inhaler versus CFC metered dose inhaler: cumulative dose-response study in asthma patients.

PubMed

Vincken, Walter; Dewberry, Helen; Moonen, Diane

2003-09-01

Respimat (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 microg/actuation, RMT50; or 100 microg/actuation. RMT100) and MDI (100 microg/actuation; MDI100). A total of 41 asthma patients received cumulative doses of fenoterol 600 microg (RMT50) or 1200 microg (RMT100 and MDI100) on 3 test days. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of +/- 0.15L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. CONCLUSIONS; The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.

Maintaining radiation exposures as low as reasonably achievable (ALARA) for dental personnel operating portable hand-held x-ray equipment.

PubMed

McGiff, Thomas J; Danforth, Robert A; Herschaft, Edward E

2012-08-01

Clinical experience indicates that newly available portable hand-held x-ray units provide advantages compared to traditional fixed properly installed and operated x-ray units in dental radiography. However, concern that hand-held x-ray units produce higher operator doses than fixed x-ray units has caused regulatory agencies to mandate requirements for use of hand-held units that go beyond those recommended by the manufacturer and can discourage the use of this technology. To assess the need for additional requirements, a hand-held x-ray unit and a pair of manikins were used to measure the dose to a simulated operator under two conditions: exposures made according to the manufacturer's recommendations and exposures made according to manufacturer's recommendation except for the removal of the x-ray unit's protective backscatter shield. Dose to the simulated operator was determined using an array of personal dosimeters and a pair of pressurized ion chambers. The results indicate that the dose to an operator of this equipment will be less than 0.6 mSv y⁻¹ if the device is used according to the manufacturer's recommendations. This suggests that doses to properly trained operators of well-designed, hand-held dental x-ray units will be below 1.0 mSv y⁻¹ (2% of the annual occupational dose limit) even if additional no additional operational requirements are established by regulatory agencies. This level of annual dose is similar to those reported as typical dental personnel using fixed x-ray units and appears to satisfy the ALARA principal for this class of occupational exposures.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

PubMed

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Uchida, Toshiki; Suzuki, Tatsuya; Kobayashi, Yukio; Mori, Masakazu; Terui, Yasuhito; Yokoyama, Masahiro; Hotta, Tomomitsu

2013-01-01

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. © 2012 Japanese Cancer Association.

Classification of radiation effects for dose limitation purposes: history, current situation and future prospects

PubMed Central

Hamada, Nobuyuki; Fujimichi, Yuki

2014-01-01

Radiation exposure causes cancer and non-cancer health effects, each of which differs greatly in the shape of the dose–response curve, latency, persistency, recurrence, curability, fatality and impact on quality of life. In recent decades, for dose limitation purposes, the International Commission on Radiological Protection has divided such diverse effects into tissue reactions (formerly termed non-stochastic and deterministic effects) and stochastic effects. On the one hand, effective dose limits aim to reduce the risks of stochastic effects (cancer/heritable effects) and are based on the detriment-adjusted nominal risk coefficients, assuming a linear-non-threshold dose response and a dose and dose rate effectiveness factor of 2. On the other hand, equivalent dose limits aim to avoid tissue reactions (vision-impairing cataracts and cosmetically unacceptable non-cancer skin changes) and are based on a threshold dose. However, the boundary between these two categories is becoming vague. Thus, we review the changes in radiation effect classification, dose limitation concepts, and the definition of detriment and threshold. Then, the current situation is overviewed focusing on (i) stochastic effects with a threshold, (ii) tissue reactions without a threshold, (iii) target organs/tissues for circulatory disease, (iv) dose levels for limitation of cancer risks vs prevention of non-life-threatening tissue reactions vs prevention of life-threatening tissue reactions, (v) mortality or incidence of thyroid cancer, and (vi) the detriment for tissue reactions. For future discussion, one approach is suggested that classifies radiation effects according to whether effects are life threatening, and radiobiological research needs are also briefly discussed. PMID:24794798

Enzymes in cleaning products: an overview of toxicological properties and risk assessment/management.

PubMed

Basketter, David; Berg, Ninna; Broekhuizen, Cees; Fieldsend, Mark; Kirkwood, Sheila; Kluin, Cornelia; Mathieu, Sophie; Rodriguez, Carlos

2012-10-01

Enzymes used in cleaning products have an excellent safety profile, with little ability to cause adverse responses in humans. For acute toxicity, genotoxicity, sub-acute and repeated dose toxicity, enzymes are unremarkable. Reproductive toxicity and carcinogenicity are also not endpoints of concern. Exceptions are the ability of some proteases to produce irritating effects at high concentrations and more importantly, the intrinsic potential of these bacterial/fungal proteins to act as respiratory sensitizers. It is a reasonable assumption that the majority of enzyme proteins possess this hazard. However, methods for characterising the respiratory sensitisation hazard of enzymes are lacking and the information required for risk assessment and risk management, although sufficient, remains limited. Previously, most data was generated in animal models and in in vitro immunoassays that assess immunological cross-reactivity. Nevertheless, by the establishment of strict limits on airborne exposure (based on a defined minimal effect limit of 60ng active enzyme protein/m(3)) and air and health monitoring, occupational safety can be assured. Similarly, by ensuring that airborne exposure is kept similarly low, coupled with knowledge of the fate of these enzymes on skin and fabrics, it has proven possible to establish a long history of safe consumer use of enzyme containing products. Copyright © 2012 Elsevier Inc. All rights reserved.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

On-line data collection platform for national dose surveys in diagnostic and interventional radiology.

PubMed

Vassileva, J; Simeonov, F; Avramova-Cholakova, S

2015-07-01

According to the Bulgarian regulation for radiation protection at medical exposure, the National Centre of Radiobiology and Radiation Protection (NCRRP) is responsible for performing national dose surveys in diagnostic and interventional radiology and nuclear medicine and for establishing of national diagnostic reference levels (DRLs). The next national dose survey is under preparation to be performed in the period of 2015-16, with the aim to cover conventional radiography, mammography, conventional fluoroscopy, interventional and fluoroscopy guided procedures and CT. It will be performed electronically using centralised on-line data collection platform established by the NCRRP. The aim is to increase the response rate and to improve the accuracy by reducing human errors. The concept of the on-line dose data collection platform is presented. Radiological facilities are provided with a tool to determine local typical patient doses, and the NCRRP to establish national DRLs. Future work will include automatic retrieval of dose data from hospital picture archival and communicating system. The on-line data collection platform is expected to facilitate the process of dose audit and optimisation of radiological procedures in Bulgarian hospitals. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Philosophy on astronaut protection: A physician`s perspective

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

Holloway, H

The National Aeronautics and Space Administration has a responsibility to assure that proper ethical standards are applied in establishing and applying limits for the control of radiation doses to the astronauts. Such a responsibility obviously includes assuring that the astronauts are properly informed of the hazards associated with individuals missions and that they agree to accept the associated risks. The responsibility, however, does not end there. It includes a need to discuss how to initiate a discourse for developing the related ethical standards and how to determine who should be involved in their establishment. To assure that such proper communicationsmore » on matters that encompass the realms of policy, science, politics, and ethics. There is also a need to mesh public perceptions with those of the scientific and technical community. This will be a monumental undertaking.« less

Obtaining the Optimal Dose in Alcohol Dependence Studies

PubMed Central

Wages, Nolan A.; Liu, Lei; O’Quigley, John; Johnson, Bankole A.

2012-01-01

In alcohol dependence studies, the treatment effect at different dose levels remains to be ascertained. Establishing this effect would aid us in identifying the best dose that has satisfactory efficacy while minimizing the rate of adverse events. We advocate the use of dose-finding methodology that has been successfully implemented in the cancer and HIV settings to identify the optimal dose in a cost-effective way. Specifically, we describe the continual reassessment method (CRM), an adaptive design proposed for cancer trials to reconcile the needs of dose-finding experiments with the ethical demands of established medical practice. We are applying adaptive designs for identifying the optimal dose of medications for the first time in the context of pharmacotherapy research in alcoholism. We provide an example of a topiramate trial as an illustration of how adaptive designs can be used to locate the optimal dose in alcohol treatment trials. It is believed that the introduction of adaptive design methods will enable the development of medications for the treatment of alcohol dependence to be accelerated. PMID:23189064

Allogeneic blood stem cell transplantation: considerations for donors.

PubMed

Anderlini, P; Körbling, M; Dale, D; Gratwohl, A; Schmitz, N; Stroncek, D; Howe, C; Leitman, S; Horowitz, M; Gluckman, E; Rowley, S; Przepiorka, D; Champlin, R

1997-08-01

Allogeneic transplantation of cytokine-mobilized peripheral blood stem cells (PBSCs) is now being increasingly performed, but safety considerations for hematologically normal PBSC donors have not been fully addressed. Progenitors are generally mobilized for collection from normal donors using recombinant human granulocyte colony-stimulating factor (rhG-CSF). Although the short-term safety profile of rhG-CSF seems acceptable, experience remains limited and its optimal dose and schedule have not been defined. Minimal data exist regarding long-term safety of rhG-CSF, primarily derived from experience in patients with chronic neutropenia or cancer. An "ad hoc" workshop was recently convened among a group of investigators actively involved in the field of allogeneic stem cell transplantation to discuss the safety issues pertaining to normal PBSC donors. There was agreement on the following points: (1) On the basis of available data, it appears that rhG-CSF treatment and PBSC collection have an acceptable short-term safety profile in normal donors. However, the need for continued safety monitoring was recognized. (2) rhG-CSF doses up to 10 microg/kg/d show a consistent dose-response relationship with the mobilization (and collection) of CD34+ progenitor cells, and this dose is acceptable for routine clinical use. Whether higher doses are superior (or cost effective) remains to be determined, and they may produce more severe side effects. The potential risks of marked leukocytosis (arbitrarily defined as a leukocyte count of more than 70 x 10(9)/L) have been a concern, and rhG-CSF dose reduction is performed by many centers to maintain leukocyte counts below this level. (3) Transient post donation cytopenias, involving granulocytes, lymphocytes, and platelets, may occur and are at least partly related to the leukapheresis procedure. These are generally asymptomatic and self-limited; follow-up blood counts are not necessarily required. Reinfusion of autologous platelet-rich plasma should be considered for donors with expected postdonation thrombocytopenia (platelet count < 80 to 100 x 10(9)/L). (4) Donors should meet the eligibility criteria which apply to donors of apheresis platelets, with the exception that pediatric donors may also be considered. Any deviation from these criteria should have supporting documentation. There is insufficient information at this time to clearly establish definite contraindications for PBSC collection in a hematologically normal donor. Potential contraindications include the presence of inflammatory, autoimmune, or rheumatologic disorders, as well as atherosclerotic or cerebrovascular disease. (5) The creation of an International PBSC Donor Registry is desirable to facilitate monitoring the long-term effects of the procedure. Individual institutions or donor centers are encouraged to establish their own PBSC donor follow-up system, preferably with a standardized approach to data collection.

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.

PubMed

Heery, Christopher R; O'Sullivan-Coyne, Geraldine; Madan, Ravi A; Cordes, Lisa; Rajan, Arun; Rauckhorst, Myrna; Lamping, Elizabeth; Oyelakin, Israel; Marté, Jennifer L; Lepone, Lauren M; Donahue, Renee N; Grenga, Italia; Cuillerot, Jean-Marie; Neuteboom, Berend; Heydebreck, Anja von; Chin, Kevin; Schlom, Jeffrey; Gulley, James L

2017-05-01

Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. National Cancer Institute and Merck KGaA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dose received by occupationally exposed workers at a nuclear medicine department

NASA Astrophysics Data System (ADS)

Ávila, O.; Sánchez-Uribe, N. A.; Rodríguez-Laguna, A.; Medina, L. A.; Estrada, E.; Buenfil, A. E.; Brandan, M. E.

2012-10-01

Personal Dose Equivalent (PDE) values were determined for occupational exposed workers (OEW) at the Nuclear Medicine Department (NMD) of "Instituto Nacional de Cancerología" (INCan), Mexico, using TLD-100 thermoluminescent dosemeters. OEW at NMD, INCan make use of radiopharmaceuticals for diagnosis and treatment of diseases. Radionuclides associated to a pharmaceutical compound used at this Department are 131I, 18F, 68Ga, 99mTc, 111In and 11C with main gamma emission energies between 140 and 511 keV. Dosemeter calibration was performed at the metrology department of "Instituto Nacional de Investigaciones Nucleares" (ININ), Mexico. Every occupational worker used dark containers with three dosimeters which were replaced monthly for a total of 5 periods. Additionally, control dosemeters were also placed at a site free of radioactive sources in order to determine the background radiation. Results were adjusted to find PDE/day and estimating annual PDE values in the range between 2 mSv (background) and 9 mSv. The mean annual value is 3.51 mSv and the standard deviation SD is 0.78 mSv. Four of the 16 OEW received annual doses higher than the average +1 SD (4.29 mSv). Results depend on OEW daily activities and were consistent for each OEW for the 5 studied periods as well as with PDE values reported by the firm that performs the monthly service. All obtained values are well within the established annual OEW dose limit stated in the "Reglamento General de Seguridad Radiológica", México (50 mSv), as well as within the lower limit recommended by the "International Commission on Radiation Protection" (ICRP), report no.60 (20 mSv). These results verify the adequate compliance of the NMD at INCan, Mexico with the norms given by the national regulatory commission.

Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene-induced genotoxicity in vivo.

PubMed

Masumura, Kenichi; Toyoda-Hokaiwado, Naomi; Niimi, Naoko; Grúz, Petr; Wada, Naoko A; Takeiri, Akira; Jishage, Kou-Ichi; Mishima, Masayuki; Nohmi, Takehiko

2017-12-01

DNA polymerase kappa (Polk) is a specialized DNA polymerase involved in translesion DNA synthesis. To understand the protective roles against genotoxins in vivo, we established inactivated Polk knock-in gpt delta (inactivated Polk KI) mice that possessed reporter genes for mutations and expressed inactive Polk. In this study, we examined genotoxicity of benzo[a]pyrene (BP) to determine whether Polk actually suppressed BP-induced genotoxicity as predicted by biochemistry and in vitro cell culture studies. Seven-week-old inactivated Polk KI and wild-type (WT) mice were treated with BP at doses of 5, 15, or 50 mg/(kg·day) for three consecutive days by intragastric gavage, and mutations in the colon and micronucleus formation in the peripheral blood were examined. Surprisingly, no differences were observed in the frequencies of mutations and micronucleus formation at 5 or 50 mg/kg doses. Inactivated Polk KI mice exhibited approximately two times higher gpt mutant frequency than did WT mice only at the 15 mg/kg dose. The frequency of micronucleus formation was slightly higher in inactivated Polk KI than in WT mice at the same dose, but it was statistically insignificant. The results suggest that Polk has a limited ability to suppress BP-induced genotoxicity in the colon and bone marrow and also that the roles of specialized DNA polymerases in mutagenesis and carcinogenesis should be examined not only by in vitro assays but also by in vivo mouse studies. We also report the spontaneous mutagenesis in inactivated Polk KI mice at young and old ages. Environ. Mol. Mutagen. 58:644-653, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism.

PubMed

Philbrick, Kenneth A; Wong, Carmen P; Branscum, Adam J; Turner, Russell T; Iwaniec, Urszula T

2017-03-01

Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood-brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally mediated actions of the hormone on energy metabolism. Leptin was infused (0, 4, 12, 40, 140 or 400 ng/h) for 12 days into 6-week-old female ob/ob mice (n = 8/group) using sc-implanted osmotic pumps. Treatment resulted in a dose-associated increase in serum leptin. Bone formation parameters were increased at EC 50 infusion rates of 7-17 ng/h, whereas higher levels (EC 50 , 40-80 ng/h) were required to similarly influence indices of energy metabolism. We then analyzed gene expression in tibia and hypothalamus at dose rates of 0, 12 and 140 ng/h; the latter dose resulted in serum leptin levels similar to WT mice. Infusion with 12 ng/h leptin increased the expression of genes associated with Jak/Stat signaling and bone formation in tibia with minimal effect on Jak/Stat signaling and neurotransmitters in hypothalamus. The results suggest that leptin acts peripherally to couple bone acquisition to energy availability and that limited transport across the BBB insures that the growth-promoting actions of peripheral leptin are not curtailed by the hormone's CNS-mediated anorexigenic actions. © 2017 Society for Endocrinology.

Unexplained overexposures on physical dosimetry reported by biological dosimetry.

PubMed

Montoro, A; Almonacid, M; Villaescusa, J I; Verdu, G

2009-01-01

The Medical Service of the Radiation Protection Service from the University Hospital La Fe (Valencia, Spain), carries out medical examinations of the workers occupationally exposed to ionising radiation. The Biological Dosimetry Laboratory is developing its activity since 2001. Up to now, the activities have been focused in performing biological dosimetry studies of Interventionists workers from La Fe Hospital. Recently, the Laboratory has been authorized by the Health Authority in the Valencian Community. Unexplained overexposures of workers and patients are also studied. Workers suspected of being overexposed to ionising radiation were referred for investigation by cytogenetic analysis. Two of these were from Hospitals of the Valencian Community and one belonged to an uranium mine from Portugal. Hospital workers had a physical dose by thermoluminiscence dosimeters (TLD) that exceeded the established limit. The worker of the uranium mine received a dose from a lost source of Cesium 137 with an activity of 170 mCi. All three cases showed normal values after the hematological analysis. Finally, the aim of this study consist to determine whether the dose showed by the dosimeter is reliable or not. In the case of workers that wore dosimeter, it is concluded that the doses measured by dosimeter are not corresponding to real doses. Hospital worker with a physical dose of 2.6 Sv and 0.269 Sv had an estimated absorbed dose by biological dosimetry of 0.076 Gy (0-0.165 Gy) and 0 Gy (0-0.089 Gy), respectively. In case of the mine worker an estimated absorbed dose of 0.073 Gy (0-0.159 Gy) was obtained by biological dosimetry. In all cases we used the odds ratio to present the results due to a very low frequency of observed aberrations [1].

Plasma Membrane Permeabilization by 60- and 600-ns Electric Pulses Is Determined by the Absorbed Dose

PubMed Central

Ibey, Bennett L.; Xiao, Shu; Schoenbach, Karl H.; Murphy, Michael R.; Pakhomov, Andrei G.

2008-01-01

We explored how the effect of plasma membrane permeabilization by nanosecond-duration electric pulses (nsEP) depends on the physical characteristics of exposure. The resting membrane resistance (Rm) and membrane potential (MP) were measured in cultured GH3 and CHO cells by conventional whole-cell patch-clamp technique. Intact cells were exposed to a single nsEP (60 or 600 ns duration, 0-22 kV/cm), followed by patch-clamp measurements after a 2-3 min delay. Consistent with earlier findings, nsEP caused long-lasting Rm decrease, accompanied by the loss of MP. The threshold for these effects was about 6 kV/cm for 60 ns pulses, and about 1 kV/cm for 600 ns pulses. Further analysis established that it was neither pulse duration nor the E-field amplitude per se, but the absorbed dose that determined the magnitude of the biological effect. In other words, exposure to nsEP at either pulse duration caused equal effects if the absorbed doses were equal. The threshold absorbed dose to produce plasma membrane effects in either GH3 or CHO cells at either pulse duration was found to be at or below 10 mJ/g. Despite being determined by the dose, the nsEP effect clearly is not thermal, as the maximum heating at the threshold dose is less than 0.01 °C. The use of the absorbed dose as a universal exposure metric may help to compare and quantify nsEP sensitivity of different cell types and of cells in different physiological conditions. The absorbed dose may also prove to be a more useful metric than the incident E-field in determining safety limits for high peak, lowaverage power EMF emissions. PMID:18839412

Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics.

PubMed

Freise, Kevin J; Hu, Beibei; Salem, Ahmed Hamed

2018-04-01

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (C max ) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C max and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors.

PubMed

Calvo, E; Vermorken, J B; Hiret, S; Rodon, J; Cortes, J; Senellart, H; Van den Brande, J; Dyck, J; Pétain, A; Ferre, P; Bennouna, J

2012-06-01

Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe. In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations. Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%. Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future.

PubMed

Sargent, Edward V; Flueckiger, Andreas; Barle, Ester Lovsin; Luo, Wendy; Molnar, Lance R; Sandhu, Reena; Weideman, Patricia A

2016-08-01

Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations. Copyright © 2016 Elsevier Inc. All rights reserved.

Limited chemotherapy and shrinking field radiotherapy for Osteolymphoma (primary bone lymphoma): results from the trans-Tasman Radiation Oncology Group 99.04 and Australasian Leukaemia and Lymphoma Group LY02 prospective trial.

PubMed

Christie, David; Dear, Keith; Le, Thai; Barton, Michael; Wirth, Andrew; Porter, David; Roos, Daniel; Pratt, Gary

2011-07-15

To establish benchmark outcomes for combined modality treatment to be used in future prospective studies of osteolymphoma (primary bone lymphoma). In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking field technique. The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma. Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen. Copyright © 2011 Elsevier Inc. All rights reserved.

The HZE radiation problem. [highly-charged energetic galactic cosmic rays

NASA Technical Reports Server (NTRS)

Schimmerling, Walter

1990-01-01

Radiation-exposure limits have yet to be established for missions envisioned in the framework of the Space Exploration Initiative. The radiation threat outside the earth's magnetosphere encompasses protons from solar particle events and the highly charged energetic particles constituting galactic cosmic rays; radiation biology entails careful consideration of the extremely nonuniform patterns of such particles' energy deposition. The ability to project such biological consequences of exposure to energetic particles as carcinogenicity currently involves great uncertainties from: (1) different regions of space; (2) the effects of spacecraft structures; and (3) the dose-effect relationships of single traversals of energetic particles.

Synthesis of modified steroids as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agents.

PubMed

Mohareb, Rafat M; Elmegeed, Gamal A; Abdel-Salam, Omar M E; Doss, Senot H; William, Marian G

2011-01-01

The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study. Copyright © 2011 Elsevier Inc. All rights reserved.

A normal tissue dose response model of dynamic repair processes.

PubMed

Alber, Markus; Belka, Claus

2006-01-07

A model is presented for serial, critical element complication mechanisms for irradiated volumes from length scales of a few millimetres up to the entire organ. The central element of the model is the description of radiation complication as the failure of a dynamic repair process. The nature of the repair process is seen as reestablishing the structural organization of the tissue, rather than mere replenishment of lost cells. The interactions between the cells, such as migration, involved in the repair process are assumed to have finite ranges, which limits the repair capacity and is the defining property of a finite-sized reconstruction unit. Since the details of the repair processes are largely unknown, the development aims to make the most general assumptions about them. The model employs analogies and methods from thermodynamics and statistical physics. An explicit analytical form of the dose response of the reconstruction unit for total, partial and inhomogeneous irradiation is derived. The use of the model is demonstrated with data from animal spinal cord experiments and clinical data about heart, lung and rectum. The three-parameter model lends a new perspective to the equivalent uniform dose formalism and the established serial and parallel complication models. Its implications for dose optimization are discussed.

MO-FG-CAMPUS-IeP1-03: Establishment of Provincial Diagnostic Reference Levels in Pediatric Imaging

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

Tonkopi, E; Queen Elizabeth II Health Sciences Ctr; O’Brien, K

Purpose: To establish provincial diagnostic reference levels (DRLs) in pediatric general radiography and computed tomography (CT) as a tool for the optimization of exposure parameters. Methods: Patient dose survey was conducted in the only pediatric hospital in the province of Nova Scotia. The DRLs were established as the 75th percentile of patient dose distributions in different age groups. For routine radiography projections the DRLs were determined in terms of entrance surface dose (ESD) calculated from the radiation output measurements and the tube current-exposure time product (mAs) recorded for each examination. Patient thickness was measured by the technologist during the examination.more » The CR and DR systems, employing respectively a fixed technique and phototiming, were evaluated separately; a two-tailed Student’s t-test was used to determine the significance of differences between the means of dose distributions. The CT studies included routine head, chest, abdomen/pelvis, and chest/abdomen/pelvis. The volume CT dose index (CTDIvol) and dose-length product (DLP) values were extracted retrospectively from PACS. The correction factors based on the effective diameter of the patient were applied to the CT dosimetry metrics based on the standard phantoms. Results: The provincial DRLs were established in the following age groups: newborn, 1, 5, 10, and 15 year olds. In general radiography the DR systems demonstrated slightly lower dose than the CR for all views, however the differences were not statistically significant (p > 0.05) for all examinations. In CT the provincial DRLs were lower than the published data, except for head DLPs in all age categories. This might be due to the small patient sample size in the survey. Future work will include additional CT data collection over an extended period of time. Conclusion: Provincial DRLs were established in the dedicated children’s hospital to provide guidance for the other facilities in examinations of pediatric patients.« less

Clinical Outcomes of Fixed Versus As-Needed Use of Artificial Tears in Dry Eye Disease: A 6-Week, Observer-Masked Phase 4 Clinical Trial.

PubMed

Asbell, Penny; Vingrys, Algis J; Tan, Jacqueline; Ogundele, Abayomi; Downie, Laura E; Jerkins, Gary; Shettle, Lee

2018-05-01

To evaluate the clinical effects of using fixed (four times daily [QID]) versus as-needed (PRN) dosing of an artificial tear product (polyethylene glycol/propylene glycol [PEG/PG]; Systane Ultra) in individuals with dry eye disease. In this prospective, multicenter, observer-masked, active-control, parallel-group trial, participants were randomized (1:2 allocation) to receive 1 drop of PEG/PG QID (n = 34) or PRN (n = 63) for 28 days. The primary endpoint was change from baseline in the total ocular surface staining (TOSS) score (according to the Oxford scale) at day 28. At day 28, the change from baseline in least squares mean (LSM) TOSS scores for QID and PRN groups were -1.19 and -0.94, respectively (treatment difference [TD]: -0.26; 95% confidence interval [CI]: -∞ to 0.21; P = 0.184); superiority of QID versus PRN dosing was not established, as the upper limit of one-sided 95% CI for TD was not <0 (prespecified limit). At day 28, for QID and PRN groups, the LSM change from baseline in Impact of Dry Eye on Everyday Life (IDEEL) scores was symptom-bother, -7.0 and -2.94 (TD: -4.06, P = 0.037); treatment effectiveness, 2.43 and 0.16 (TD: 2.28, P = 0.278); and treatment-related inconvenience, -11.56 and -2.77 (TD: -8.8, P = 0.996), respectively. Incidence of adverse events was low (≤3.2%) in both the groups; no serious adverse events were reported. QID dosing of PEG/PG was not superior to PRN dosing in terms of ocular staining. The IDEEL symptom-bother score favored QID dosing, suggesting that regular use of artificial tears may provide better symptomatic relief than PRN use. (ClinicalTrials.gov number, NCT02446015.).

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

PubMed Central

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O’Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-01-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ. PMID:24991840

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

PubMed

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O'Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Liquid Medication Dosing Errors by Hispanic Parents: Role of Health Literacy and English Proficiency

PubMed Central

Harris, Leslie M.; Dreyer, Benard; Mendelsohn, Alan; Bailey, Stacy C.; Sanders, Lee M.; Wolf, Michael S.; Parker, Ruth M.; Patel, Deesha A.; Kim, Kwang Youn A.; Jimenez, Jessica J.; Jacobson, Kara; Smith, Michelle; Yin, H. Shonna

2016-01-01

Objective Hispanic parents in the US are disproportionately affected by low health literacy and limited English proficiency (LEP). We examined associations between health literacy, LEP, and liquid medication dosing errors in Hispanic parents. Methods Cross-sectional analysis of data from a multisite randomized controlled experiment to identify best practices for the labeling/dosing of pediatric liquid medications (SAFE Rx for Kids study); 3 urban pediatric clinics. Analyses were limited to Hispanic parents of children <8 years, with health literacy and LEP data (n=1126). Parents were randomized to 5 groups that varied by pairing of units of measurement on the label/dosing tool. Each parent measured 9 doses [3 amounts (2.5,5,7.5 mL) using 3 tools (2 syringes (0.2,0.5 mL increment), 1 cup)] in random order. Dependent variable: Dosing error=>20% dose deviation. Predictor variables: health literacy (Newest Vital Sign) [limited=0–3; adequate=4–6], LEP (speaks English less than “very well”). Results 83.1% made dosing errors (mean(SD) errors/parent=2.2(1.9)). Parents with limited health literacy and LEP had the greatest odds of making a dosing error compared to parents with adequate health literacy who were English proficient (% trials with errors/parent=28.8 vs. 12.9%; AOR=2.2[1.7–2.8]). Parents with limited health literacy who were English proficient were also more likely to make errors (% trials with errors/parent=18.8%; AOR=1.4[1.1–1.9]). Conclusion Dosing errors are common among Hispanic parents; those with both LEP and limited health literacy are at particular risk. Further study is needed to examine how the redesign of medication labels and dosing tools could reduce literacy and language-associated disparities in dosing errors. PMID:28477800

SU-E-T-190: First Integration of Steriotactic Radiotherapy Planning System Iplan with Elekta Linear Accelerator

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

Biplab, S; Soumya, R; Paul, S

2014-06-01

Purpose: For the first time in the world, BrainLAB has integrated its iPlan treatment planning system for clinical use with Elekta linear accelerator (Axesse with a Beam Modulator). The purpose of this study was to compare the calculated and measured doses with different chambers to establish the calculation accuracy of iPlan system. Methods: The iPlan has both Pencil beam (PB) and Monte Carlo (MC) calculation algorithms. Beam data include depth doses, profiles and output measurements for different field sizes. Collected data was verified by vendor and beam modelling was done. Further QA tests were carried out in our clinic. Dosemore » calculation accuracy verified point, volumetric dose measurement using ion chambers of different volumes (0.01cc and 0.125cc). Planner dose verification was done using diode array. Plans were generated in iPlan and irradiated in Elekta Axesse linear accelerator. Results: Dose calculation accuracies verified using ion chamber for 6 and 10 MV beam were 3.5+/-0.33(PB), 1.7%+/-0.7(MC) and 3.9%+/-0.6(PB), 3.4%+/-0.6(MC) respectively. Using a pin point chamber, dose calculation accuracy for 6MV and 10MV was 3.8%+/-0.06(PB), 1.21%+/-0.2(MC) and 4.2%+/-0.6(PB), 3.1%+/-0.7(MC) respectively. The calculated planar dose distribution for 10.4×10.4 cm2 was verified using a diode array and the gamma analysis for 2%-2mm criteria yielded pass rates of 88 %(PB) and 98.8%(MC) respectively. 3mm-3% yields 100% passing for both MC and PB algorithm. Conclusion: Dose calculation accuracy was found to be within acceptable limits for MC for 6MV beam. PB for both beams and MC for 10 MV beam were found to be outside acceptable limits. The output measurements were done twice for conformation. The lower gamma matching was attributed to meager number of measured profiles (only two profiles for PB) and coarse measurement resolution for diagonal profile measurement (5mm). Based on these measurements we concluded that 6 MV MC algorithm is suitable for patient treatment.« less

Key Performance Indicators in the Evaluation of the Quality of Radiation Safety Programs.

PubMed

Schultz, Cheryl Culver; Shaffer, Sheila; Fink-Bennett, Darlene; Winokur, Kay

2016-08-01

Beaumont is a multiple hospital health care system with a centralized radiation safety department. The health system operates under a broad scope Nuclear Regulatory Commission license but also maintains several other limited use NRC licenses in off-site facilities and clinics. The hospital-based program is expansive including diagnostic radiology and nuclear medicine (molecular imaging), interventional radiology, a comprehensive cardiovascular program, multiple forms of radiation therapy (low dose rate brachytherapy, high dose rate brachytherapy, external beam radiotherapy, and gamma knife), and the Research Institute (including basic bench top, human and animal). Each year, in the annual report, data is analyzed and then tracked and trended. While any summary report will, by nature, include items such as the number of pieces of equipment, inspections performed, staff monitored and educated and other similar parameters, not all include an objective review of the quality and effectiveness of the program. Through objective numerical data Beaumont adopted seven key performance indicators. The assertion made is that key performance indicators can be used to establish benchmarks for evaluation and comparison of the effectiveness and quality of radiation safety programs. Based on over a decade of data collection, and adoption of key performance indicators, this paper demonstrates one way to establish objective benchmarking for radiation safety programs in the health care environment.

Enhancement of Structured Reporting - an Integration Reporting Module with Radiation Dose Collection Supporting.

PubMed

Lee, Ming-Che; Chuang, Kei-Shih; Hsu, Tien-Cheng; Lee, Chien-Ding

2016-11-01

Collection of radiation dose derived from radiological examination is necessary not only for radiation protection, but also for fulfillment of structured reports. However, the material regarding of radiation dose cannot be directly utilized by the Radiological Information System (RIS) since it is generated and only stored in the Picture Archiving and Communication System (PACS). In this paper, an integration reporting module is proposed to facilitate handling of dose information and structured reporting by providing two functionalities. First, a gateway is established to automatically collect the related information from PACS for further analyzing and monitoring the accumulated radiation. Second, the designated structured reporting patterns with corresponding radiation dose measurements can be acquired by radiologists as necessary. In the design, the radiation dose collection gateway and the well-established pattern are collocated to achieve that there is no need to do manual entry for structured reporting, thus increasing productivity and medical quality.

New Stochastic Annual Limits on Intake for Selected Radionuclides

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

Carbaugh, Eugene H.

Annual limits on intake (ALI) have historically been tabulated by the International Commission on Radiological Protection (e.g., ICRP 1979, 1961) and also by the Environmental Protection Agency (EPA 1988). These compilations have been rendered obsolete by more recent ICRP dosimetry methods, and, rather than provide new ALIs, the ICRP has opted instead to provide committed dose coefficients from which an ALI can be determined by a user for a specific set of conditions. The U.S. Department of Energy historically has referenced compilations of ALIs and has defined their method of calculation in its radiation protection regulation (10 CFDR 835), butmore » has never provided a specific compilation. Under June 2007 amendments to 10 CFR 835, ALIs can be calculated by dividing an appropriate dose limit, either 5-rem (0.05 Sv) effective dose or 50 rem (0.5 Sv) equivalent dose to an individual organ or tissue, by an appropriate committed dose coefficient. When based on effective dose, the ALI is often referred to as a stochastic annual limit on intake (SALI), and when based on the individual organ or tissue equivalent limit, it has often been called a deterministic annual limit on intake (DALI).« less

Maywood Interim Storage Site environmental report for calendar year 1992, 100 West Hunter Avenue, Maywood, New Jersey. Formerly Utilized Sites Remedial Action Program (FUSRAP)

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

Not Available

1993-05-01

This report describes the environmental surveillance program at the Maywood Interim Storage Site (MISS) and provides the results for 1992. Environmental monitoring of MISS began in 1984, when the site was assigned to DOE by Congress through the Energy and Water Development Appropriations Act and was placed under DOE`s Formerly Utilized Sites Remedial Action Program (FUSRAP). FUSRAP was established to identify and decontaminate or otherwise control sites where residual radioactive materials remain from the early years of the nation`s atomic energy program or from commercial operations causing conditions that Congress has authorized DOE to remedy. MISS is part of amore » National Priorities List (NPL) site. The environmental surveillance program at MISS includes sampling networks for radon and thoron in air; external gamma radiation exposure; and radium-226, radium-228, thorium-232, and total uranium in surface water, sediment, and groundwater. Additionally, chemical analysis includes metals and organic compounds in surface water and groundwater and metals in sediments. This program assists in fulfilling the DOE objective of measuring and monitoring effluents from DOE activities and calculating hypothetical doses to members of the general public. Monitoring results are compared with applicable Environmental Protection Agency (EPA) and state standards, DOE derived concentration guides (DCGs), dose limits, and other DOE requirements. Environmental standards are established to protect public health and the environment. The radiological data for all media sampled support the conclusion that doses to the public are not distinguishable from natural background radiation.« less

Assessment of the benefits and impacts in the U.S. Nuclear Power Industry of hypothesized lower occupational dose limits

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

Andersen, R.L.; Schmitt, J.F.

1995-03-01

The International Commission on Radiological Protection and the National Council on Radiation Protection and Measurements have issued recommendations that would limit occupational exposure of individuals to doses lower than regulatory limits contained in the Nuclear Regulatory Commission`s 10 CFR Part 20, {open_quotes}Standards for Protection Against Radiation{close_quotes}. Because of this situation, there is interest in the potential benefits and impacts that would be associated with movement of the NRC regulatory limits toward the advisory bodies recommendations. The records of occupational worker doses in the U.S. commercial nuclear power industry show that the vast majority of these workers have doses that aremore » significantly below the regulatory limit of 50 mSv (5 rem) per year. Some workers doses do approach the limits, however. This is most common in the case of specially skilled workers, especially those with skills utilized in support of plant outage work. Any consideration of the potential benefits and impacts of hypothesized lower dose limits must address these workers as an important input to the overall assessment. There are also, of course, many other areas in which the benefits and impacts must be evaluated. To prepare to provide valid, constructive input on this matter, the U.S. nuclear power industry is undertaking an assessment, facilitated by the Nuclear Energy Institute (NEI), of the potential benefits and impacts at its facilities associated with hypothesized lower occupational dose limits. Some preliminary results available to date from this assessment are provided.« less

Development of a Spect-Based Three-Dimensional Treatment Planner for Radionuclide Therapy with Iodine -131.

NASA Astrophysics Data System (ADS)

Giap, Huan Bosco

Accurate calculation of absorbed dose to target tumors and normal tissues in the body is an important requirement for establishing fundamental dose-response relationships for radioimmunotherapy. Two major obstacles have been the difficulty in obtaining an accurate patient-specific 3-D activity map in-vivo and calculating the resulting absorbed dose. This study investigated a methodology for 3-D internal dosimetry, which integrates the 3-D biodistribution of the radionuclide acquired from SPECT with a dose-point kernel convolution technique to provide the 3-D distribution of absorbed dose. Accurate SPECT images were reconstructed with appropriate methods for noise filtering, attenuation correction, and Compton scatter correction. The SPECT images were converted into activity maps using a calibration phantom. The activity map was convolved with an ^{131}I dose-point kernel using a 3-D fast Fourier transform to yield a 3-D distribution of absorbed dose. The 3-D absorbed dose map was then processed to provide the absorbed dose distribution in regions of interest. This methodology can provide heterogeneous distributions of absorbed dose in volumes of any size and shape with nonuniform distributions of activity. Comparison of the activities quantitated by our SPECT methodology to true activities in an Alderson abdominal phantom (with spleen, liver, and spherical tumor) yielded errors of -16.3% to 4.4%. Volume quantitation errors ranged from -4.0 to 5.9% for volumes greater than 88 ml. The percentage differences of the average absorbed dose rates calculated by this methodology and the MIRD S-values were 9.1% for liver, 13.7% for spleen, and 0.9% for the tumor. Good agreement (percent differences were less than 8%) was found between the absorbed dose due to penetrating radiation calculated from this methodology and TLD measurement. More accurate estimates of the 3 -D distribution of absorbed dose can be used as a guide in specifying the minimum activity to be administered to patients to deliver a prescribed absorbed dose to tumor without exceeding the toxicity limits of normal tissues.

An adaptive two-stage dose-response design method for establishing proof of concept.

PubMed

Franchetti, Yoko; Anderson, Stewart J; Sampson, Allan R

2013-01-01

We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics. The stage-wise test results are then combined to establish "global" PoC using a conditional error function. Our simulation studies showed good and more robust power in our design method compared to conventional and fixed designs.

A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children’s Oncology Group Phase I Consortium Report

PubMed Central

Bender, Julia Glade; Blaney, Susan M.; Borinstein, Scott; Reid, Joel M.; Baruchel, Sylvain; Ahern, Charlotte; Ingle, Ashish M.; Yamashiro, Darrell J.; Chen, Alice; Weigel, Brenda; Adamson, Peter C.; Park, Julie R.

2012-01-01

Background Aflibercept is a novel decoy receptor that efficiently neutralizes circulating vascular endothelial growth factor (VEGF). A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of aflibercept. Methods Cohorts of 3–6 children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5 or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were performed with the initial dose. Results 21 eligible patients were enrolled; 18 were fully evaluable for toxicity. One of 6 patients receiving 2.0 mg/kg/dose developed dose-limiting intra-tumoral hemorrhage and 2 of 6 receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the 6 patients receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD. The most common non-dose limiting toxicities were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free to bound aflibercept serum concentration was 2.10 on day 8, but only 0.44 by day 15. A rapid decrease in VEGF (p<0.05) and increase in PlGF (p<0.05) from baseline was observed in response to aflibercept by day 2. Conclusion The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower that the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of anti-tumor activity, but were dose-limiting. PMID:22791883

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

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

Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh

2016-01-01

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed themore » dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.« less

A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054)

PubMed Central

Rampling, Roy; Sanson, Marc; Gorlia, Thiery; Lacombe, Denis; Lai, Christina; Gharib, Myriam; Taal, Walter; Stoffregen, Clemens; Decker, Rodney; van den Bent, Martin J.

2012-01-01

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m2 for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels. PMID:22291006

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma.

PubMed

Friedberg, Joseph S; Mick, Rosemarie; Stevenson, James; Metz, James; Zhu, Timothy; Buyske, Jo; Sterman, Daniel H; Pass, Harvey I; Glatstein, Eli; Hahn, Stephen M

2003-03-01

Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Analgesic Efficacy and Safety of Buprenorphine in Chinchillas (Chinchilla lanigera).

PubMed

Fox, Lana; Mans, Christoph

2018-05-01

Buprenorphine is routinely used in chinchillas at reported doses of 0.01 to 0.1 mg/kg IM or SC. However, these dose recommendations are based on anecdotal reports or extrapolation from studies in other species. Therefore, the purpose of this study was to evaluate the analgesic efficacy and safety of subcutaneously administered buprenorphine in chinchillas. Using a randomized, blind, controlled, complete crossover design, we evaluated buprenorphine at a single dose of 0.05, 0.1 or 0.2 mg/kg SC (experiment A) and 0.2 mg/kg SC (experiment B). Analgesic efficacy was determined by measuring limb withdrawal latencies in response to a thermal noxious stimulus (Hargreaves method) at 0, 3, 6, 12, and 24 h (experiment A) and at 0, 1, 2, 4, and 8 h (experiment B). In a third experiment, food intake and fecal output were monitored after repeated administration of buprenorphine (0.2 mg/kg SC every 6 h for 3 doses). Buprenorphine at 0.2 mg/kg SC, but not at 0.05 or 0.1 mg/kg SC, significantly increased limb withdrawal latencies for less than 4 h. Self-limiting reduction in food intake and fecal output occurred after administration at the 0.2-mg/kg dose in animals undergoing algesiometry. In chinchillas not undergoing algesiometry, the administration of 3 doses at 0.2 mg/kg SC every 6 h did not reduce food intake but significantly decreased fecal output for the first 24 h. Additional studies are needed to evaluate buprenorphine in different algesiometry models and to establish its pharmacokinetic profile in chinchillas.

Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.

PubMed

Kamstrup, Maria R; Gniadecki, Robert; Iversen, Lars; Skov, Lone; Petersen, Peter Meidahl; Loft, Annika; Specht, Lena

2015-05-01

Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT. Copyright © 2015 Elsevier Inc. All rights reserved.

Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

PubMed

Abma, E; Peremans, K; De Vos, F; Bosmans, T; Kitshoff, A M; Daminet, S; Ni, Y; Dockx, R; de Rooster, H

2018-01-04

Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 μSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients. © 2018 John Wiley & Sons Ltd.

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

PubMed Central

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P.; Snyder, David S.; Khoury, Jean; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C.; Rutkoski, Thomas J.; Smith, Bryan D.; Flynn, Daniel L.; Kantarjian, Hagop M.; Rosen, Oliver; Van Etten, Richard A.

2017-01-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138). PMID:27927766

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

PubMed

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P; Snyder, David S; Khoury, Jean; Bhalla, Kapil N; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C; Rutkoski, Thomas J; Smith, Bryan D; Flynn, Daniel L; Kantarjian, Hagop M; Rosen, Oliver; Van Etten, Richard A

2017-03-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib ( clinicaltrials.gov Identifier:00827138 ). Copyright© Ferrata Storti Foundation.

Biomarkers of exposure, sensitivity and disease

NASA Technical Reports Server (NTRS)

Brooks, A. L.

1999-01-01

PURPOSE: This review is to evaluate the use of biomarkers as an indication of past exposure to radiation or other environmental insults, individual sensitivity and risk for the development of late occurring disease. OVERVIEW: Biomarkers can be subdivided depending on their applications. Markers of exposure and dose can be used to reconstruct and predict past accidental or occupational exposures when limited or no physical measurements were available. Markers of risk or susceptibility can help identify sensitivity individuals that are at increased risk for development of spontaneous disease and may help predict the increased risk in sensitive individuals associated with environmental or therapeutic radiation exposures. Markers of disease represent the initial cellular or molecular changes that occur during disease development. Each of these types of biomarkers serves a unique purpose. OUTLINE: This paper concentrates on biomarkers of dose and exposure and provides a brief review of biomarkers of sensitivity and disease. The review of biomarkers of dose and exposure will demonstrate the usefulness of biomarkers in evaluation of physical factors associated with radiation exposure, such as LET, doserate and dose distribution. It will also evaluate the use of biomarkers to establish relationships that exist between exposure parameters such as energy deposition, environmental concentration of radioactive materials, alpha traversals and dose. In addition, the importance of biological factors on the magnitude of the biomarker response will be reviewed. Some of the factors evaluated will be the influence of species, tissue, cell types and genetic background. The review will demonstrate that markers of sensitivity and disease often have little usefulness in dose-reconstruction and, by the same token, many markers of dose or exposure may not be applicable for prediction of sensitivity or risk.

Low-Dose (10-Gy) Total Skin Electron Beam Therapy for Cutaneous T-Cell Lymphoma: An Open Clinical Study and Pooled Data Analysis

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

Kamstrup, Maria R., E-mail: mkam0004@bbh.regionh.dk; Gniadecki, Robert; Iversen, Lars

2015-05-01

Purpose: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. Methods and Materials: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gymore » in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. Results: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Conclusions: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.« less

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

Sterilization validation for medical devices at IRASM microbiological laboratory—Practical approaches

NASA Astrophysics Data System (ADS)

Trandafir, Laura; Alexandru, Mioara; Constantin, Mihai; Ioniţă, Anca; Zorilă, Florina; Moise, Valentin

2012-09-01

EN ISO 11137 established regulations for setting or substantiating the dose for achieving the desired sterility assurance level. The validation studies can be designed in particular for different types of products. Each product needs distinct protocols for bioburden determination and sterility testing. The Microbiological Laboratory from Irradiation Processing Center (IRASM) deals with different types of products, mainly for the VDmax25 method. When it comes to microbiological evaluation the most challenging was cotton gauze. A special situation for establishing the sterilization validation method appears in cases of cotton packed in large quantities. The VDmax25 method cannot be applied for items with average bioburden more than 1000 CFU/pack, irrespective of the weight of the package. This is a method limitation and implies increased costs for the manufacturer when choosing other methods. For microbiological tests, culture condition should be selected in both cases of the bioburden and sterility testing. Details about choosing criteria are given.

Characterization of MOSFET dosimeters for low-dose measurements in maxillofacial anthropomorphic phantoms.

PubMed

Koivisto, Juha H; Wolff, Jan E; Kiljunen, Timo; Schulze, Dirk; Kortesniemi, Mika

2015-07-08

The aims of this study were to characterize reinforced metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters to assess the measurement uncertainty, single exposure low-dose limit with acceptable accuracy, and the number of exposures required to attain the corresponding limit of the thermoluminescent dosimeters (TLD). The second aim was to characterize MOSFET dosimeter sensitivities for two dental photon energy ranges, dose dependency, dose rate dependency, and accumulated dose dependency. A further aim was to compare the performance of MOSFETs with those of TLDs in an anthropomorphic phantom head using a dentomaxillofacial CBCT device. The uncertainty was assessed by exposing 20 MOSFETs and a Barracuda MPD reference dosimeter. The MOSFET dosimeter sensitivities were evaluated for two photon energy ranges (50-90 kVp) using a constant dose and polymethylmethacrylate backscatter material. MOSFET and TLD comparative point-dose measurements were performed on an anthropomorphic phantom that was exposed with a clinical CBCT protocol. The MOSFET single exposure low dose limit (25% uncertainty, k = 2) was 1.69 mGy. An averaging of eight MOSFET exposures was required to attain the corresponding TLD (0.3 mGy) low-dose limit. The sensitivity was 3.09 ± 0.13 mV/mGy independently of the photon energy used. The MOSFET dosimeters did not present dose or dose rate sensitivity but, however, presented a 1% decrease of sensitivity per 1000 mV for accumulated threshold voltages between 8300 mV and 17500 mV. The point doses in an anthropomorphic phantom ranged for MOSFETs between 0.24 mGy and 2.29 mGy and for TLDs between 0.25 and 2.09 mGy, respectively. The mean difference was -8%. The MOSFET dosimeters presented statistically insignificant energy dependency. By averaging multiple exposures, the MOSFET dosimeters can achieve a TLD-comparable low-dose limit and constitute a feasible method for diagnostic dosimetry using anthropomorphic phantoms. However, for single in vivo measurements (<1.7 mGy) the sensitivity is too low.

Treatment of Established Status Epilepticus.

PubMed

Falco-Walter, Jessica J; Bleck, Thomas

2016-04-25

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE.

Treatment of Established Status Epilepticus

PubMed Central

Falco-Walter, Jessica J.; Bleck, Thomas

2016-01-01

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE. PMID:27120626

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet
.

PubMed

Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene

2017-11-01

To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (C_max), and plasma concentrations at the end of the dosing interval (C_τ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 - 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed. The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance.
.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

Time-resolved MR angiography of renal artery stenosis in a swine model at 3 Tesla using gadobutrol with digital subtraction angiography correlation.

PubMed

Morelli, John N; Ai, Fei; Runge, Val M; Zhang, Wei; Li, Xiaoming; Schmitt, Peter; McNeal, Gary; Michaely, Henrick J; Schoenberg, Stefan O; Miller, Matthew; Gerdes, Clint M; Sincleair, Spencer T; Spratt, Heidi; Attenberger, Ulrike I

2012-09-01

To establish the minimum dose required for detection of renal artery stenosis using high temporal resolution, contrast enhanced MR angiography (MRA) in a porcine model. Surgically created renal artery stenoses were imaged with 3 Tesla MR and digital subtraction angiography (DSA) in 12 swine in this IACUC approved protocol. Gadobutrol was injected intravenously at doses of 0.5, 1, 2, and 4 mL for time-resolved MRA (1.5 × 1.5 mm(2) spatial resolution). Region of interest analysis was performed together with stenosis assessment and qualitative evaluation by two blinded readers. Mean signal to noise ratio (SNR) and contrast to noise ratio (CNR) values were statistically significantly less with the 0.5-mL protocol (P < 0.001). There were no statistically significant differences among the other evaluated doses. Both readers found 10/12 cases with the 0.5-mL protocol to be of inadequate diagnostic quality (κ = 1.0). All other scans were found to be adequate for diagnosis. Accuracies in distinguishing between mild/insignificant (<50%) and higher grade stenoses (>50%) were comparable among the higher-dose protocols (sensitivities 73-93%, specificities 62-100%). Renal artery stenosis can be assessed with very low doses (~0.025 mmol/kg bodyweight) of a high concentration, high relaxivity gadolinium chelate formulation in a swine model, results which are promising with respect to limiting exposure to gadolinium based contrast agents. Copyright © 2012 Wiley Periodicals, Inc.

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

Quality correction factors of composite IMRT beam deliveries: theoretical considerations.

PubMed

Bouchard, Hugo

2012-11-01

In the scope of intensity modulated radiation therapy (IMRT) dosimetry using ionization chambers, quality correction factors of plan-class-specific reference (PCSR) fields are theoretically investigated. The symmetry of the problem is studied to provide recommendable criteria for composite beam deliveries where correction factors are minimal and also to establish a theoretical limit for PCSR delivery k(Q) factors. The concept of virtual symmetric collapsed (VSC) beam, being associated to a given modulated composite delivery, is defined in the scope of this investigation. Under symmetrical measurement conditions, any composite delivery has the property of having a k(Q) factor identical to its associated VSC beam. Using this concept of VSC, a fundamental property of IMRT k(Q) factors is demonstrated in the form of a theorem. The sensitivity to the conditions required by the theorem is thoroughly examined. The theorem states that if a composite modulated beam delivery produces a uniform dose distribution in a volume V(cyl) which is symmetric with the cylindrical delivery and all beams fulfills two conditions in V(cyl): (1) the dose modulation function is unchanged along the beam axis, and (2) the dose gradient in the beam direction is constant for a given lateral position; then its associated VSC beam produces no lateral dose gradient in V(cyl), no matter what beam modulation or gantry angles are being used. The examination of the conditions required by the theorem lead to the following results. The effect of the depth-dose gradient not being perfectly constant with depth on the VSC beam lateral dose gradient is found negligible. The effect of the dose modulation function being degraded with depth on the VSC beam lateral dose gradient is found to be only related to scatter and beam hardening, as the theorem holds also for diverging beams. The use of the symmetry of the problem in the present paper leads to a valuable theorem showing that k(Q) factors of composite IMRT beam deliveries are close to unity under specific conditions. The theoretical limit k(Q(pcsr),Q(msr) ) (f(pcsr),f(msr) )=1 is determined based on the property of PCSR deliveries to provide a uniform dose in the target volume. The present approach explains recent experimental observations and proposes ideal conditions for IMRT reference dosimetry. The result of this study could potentially serve as a theoretical basis for reference dosimetry of composite IMRT beam deliveries or for routine IMRT quality assurance.

Decongestion: Diuretics and other therapies for hospitalized heart failure.

PubMed

Vazir, Ali; Cowie, Martin R

2016-04-01

Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Often the syndrome is characterized by congestion, and is associated with long hospital admissions and high risk of readmission and further healthcare expenditure. Despite a limited evidence-base, diuretics remain the first-line treatment for congestion. Loop diuretics are typically the first-line diuretic strategy with some evidence that initial treatment with continuous infusion or boluses of high-dose loop diuretic is superior to an initial lower dose strategy. In patients who have impaired responsiveness to diuretics, the addition of an oral thiazide or thiazide-like diuretic to induce sequential nephron blockade can be beneficial. The use of intravenous low-dose dopamine is no longer supported in heart failure patients with preserved systolic blood pressure and its use to assist diuresis in patients with low systolic blood pressures requires further study. Mechanical ultrafiltration has been used to treat patients with heart failure and fluid retention, but the evidence-base is not robust, and its place in clinical practice is yet to be established. Several novel pharmacological agents remain under investigation. Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

PubMed Central

Campone, M; Levy, V; Bourbouloux, E; Berton Rigaud, D; Bootle, D; Dutreix, C; Zoellner, U; Shand, N; Calvo, F; Raymond, E

2009-01-01

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m−2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33–69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m−2, warranting further clinical investigation. PMID:19127256

10 CFR 835.202 - Occupational dose limits for general employees.

Code of Federal Regulations, 2010 CFR

2010-01-01

... tissue other than the skin or the lens of the eye of 50 rems (0.5 Sv); (3) An equivalent dose to the lens of the eye of 15 rems (0.15 Sv); and (4) The sum of the equivalent dose to the skin or to any... 10 Energy 4 2010-01-01 2010-01-01 false Occupational dose limits for general employees. 835.202...

10 CFR 835.202 - Occupational dose limits for general employees.

Code of Federal Regulations, 2014 CFR

2014-01-01

... tissue other than the skin or the lens of the eye of 50 rems (0.5 Sv); (3) An equivalent dose to the lens of the eye of 15 rems (0.15 Sv); and (4) The sum of the equivalent dose to the skin or to any... 10 Energy 4 2014-01-01 2014-01-01 false Occupational dose limits for general employees. 835.202...

10 CFR 835.202 - Occupational dose limits for general employees.

Code of Federal Regulations, 2012 CFR

2012-01-01

... tissue other than the skin or the lens of the eye of 50 rems (0.5 Sv); (3) An equivalent dose to the lens of the eye of 15 rems (0.15 Sv); and (4) The sum of the equivalent dose to the skin or to any... 10 Energy 4 2012-01-01 2012-01-01 false Occupational dose limits for general employees. 835.202...

10 CFR 835.202 - Occupational dose limits for general employees.

Code of Federal Regulations, 2013 CFR

2013-01-01

... tissue other than the skin or the lens of the eye of 50 rems (0.5 Sv); (3) An equivalent dose to the lens of the eye of 15 rems (0.15 Sv); and (4) The sum of the equivalent dose to the skin or to any... 10 Energy 4 2013-01-01 2013-01-01 false Occupational dose limits for general employees. 835.202...

10 CFR 835.202 - Occupational dose limits for general employees.

Code of Federal Regulations, 2011 CFR

2011-01-01

... tissue other than the skin or the lens of the eye of 50 rems (0.5 Sv); (3) An equivalent dose to the lens of the eye of 15 rems (0.15 Sv); and (4) The sum of the equivalent dose to the skin or to any... 10 Energy 4 2011-01-01 2011-01-01 false Occupational dose limits for general employees. 835.202...

Review of the technical bases of 40 CFR Part 190.

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

Kelly, John E.; McMahon, Kevin A.; Siegel, Malcolm Dean

2010-07-01

The dose limits for emissions from the nuclear fuel cycle were established by the Environmental Protection Agency in 40 CFR Part 190 in 1977. These limits were based on assumptions regarding the growth of nuclear power and the technical capabilities of decontamination systems as well as the then-current knowledge of atmospheric dispersion and the biological effects of ionizing radiation. In the more than thirty years since the adoption of the limits, much has changed with respect to the scale of nuclear energy deployment in the United States and the scientific knowledge associated with modeling health effects from radioactivity release. Sandiamore » National Laboratories conducted a study to examine and understand the methodologies and technical bases of 40 CFR 190 and also to determine if the conclusions of the earlier work would be different today given the current projected growth of nuclear power and the advances in scientific understanding. This report documents the results of that work.« less

10 CFR 20.1201 - Occupational dose limits for adults.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Occupational dose limits for adults. 20.1201 Section 20.1201 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose... surveys or other radiation measurements for the purpose of demonstrating compliance with the occupational...

10 CFR 20.1201 - Occupational dose limits for adults.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Occupational dose limits for adults. 20.1201 Section 20.1201 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose... surveys or other radiation measurements for the purpose of demonstrating compliance with the occupational...

10 CFR 20.1201 - Occupational dose limits for adults.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Occupational dose limits for adults. 20.1201 Section 20.1201 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose... surveys or other radiation measurements for the purpose of demonstrating compliance with the occupational...

10 CFR 20.1201 - Occupational dose limits for adults.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Occupational dose limits for adults. 20.1201 Section 20.1201 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose... surveys or other radiation measurements for the purpose of demonstrating compliance with the occupational...

10 CFR 20.1201 - Occupational dose limits for adults.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Occupational dose limits for adults. 20.1201 Section 20.1201 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose... surveys or other radiation measurements for the purpose of demonstrating compliance with the occupational...

Absorbed dose thresholds and absorbed dose rate limitations for studies of electron radiation effects on polyetherimides

NASA Technical Reports Server (NTRS)

Long, Edward R., Jr.; Long, Sheila Ann T.; Gray, Stephanie L.; Collins, William D.

1989-01-01

The threshold values of total absorbed dose for causing changes in tensile properties of a polyetherimide film and the limitations of the absorbed dose rate for accelerated-exposure evaluation of the effects of electron radiation in geosynchronous orbit were studied. Total absorbed doses from 1 kGy to 100 MGy and absorbed dose rates from 0.01 MGy/hr to 100 MGy/hr were investigated, where 1 Gy equals 100 rads. Total doses less than 2.5 MGy did not significantly change the tensile properties of the film whereas doses higher than 2.5 MGy significantly reduced elongation-to-failure. There was no measurable effect of the dose rate on the tensile properties for accelerated electron exposures.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

NASA Astrophysics Data System (ADS)

Said, M. A.; Ashhar, Z. N.; Suhaimi, N. E. F.; Zainon, R.

2016-01-01

In routine radiopharmaceutical Iodine-131 (131I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle 131I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the 131I. The new fabricated of low cost 131I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of 131 I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the 131I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of 131I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

Stochastic Modeling of Radioactive Material Releases

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

Andrus, Jason; Pope, Chad

2015-09-01

Nonreactor nuclear facilities operated under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA was developed using the MATLAB coding framework. The software application has a graphical user input. SODA can be installed on both Windows and Mac computers and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC, rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The work was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

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

Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org; Won, Minhee; Wen, Patrick Y.

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established dailymore » dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.« less

A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas.

PubMed

Infante, Jeffrey R; Cassier, Philippe A; Gerecitano, John F; Witteveen, Petronella O; Chugh, Rashmi; Ribrag, Vincent; Chakraborty, Abhijit; Matano, Alessandro; Dobson, Jason R; Crystal, Adam S; Parasuraman, Sudha; Shapiro, Geoffrey I

2016-12-01

Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb + ). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb + advanced solid tumors or lymphomas. Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. ©2016 AACR. ©2016 American Association for Cancer Research.

Harnessing the theoretical foundations of the exponential and beta-Poisson dose-response models to quantify parameter uncertainty using Markov Chain Monte Carlo.

PubMed

Schmidt, Philip J; Pintar, Katarina D M; Fazil, Aamir M; Topp, Edward

2013-09-01

Dose-response models are the essential link between exposure assessment and computed risk values in quantitative microbial risk assessment, yet the uncertainty that is inherent to computed risks because the dose-response model parameters are estimated using limited epidemiological data is rarely quantified. Second-order risk characterization approaches incorporating uncertainty in dose-response model parameters can provide more complete information to decisionmakers by separating variability and uncertainty to quantify the uncertainty in computed risks. Therefore, the objective of this work is to develop procedures to sample from posterior distributions describing uncertainty in the parameters of exponential and beta-Poisson dose-response models using Bayes's theorem and Markov Chain Monte Carlo (in OpenBUGS). The theoretical origins of the beta-Poisson dose-response model are used to identify a decomposed version of the model that enables Bayesian analysis without the need to evaluate Kummer confluent hypergeometric functions. Herein, it is also established that the beta distribution in the beta-Poisson dose-response model cannot address variation among individual pathogens, criteria to validate use of the conventional approximation to the beta-Poisson model are proposed, and simple algorithms to evaluate actual beta-Poisson probabilities of infection are investigated. The developed MCMC procedures are applied to analysis of a case study data set, and it is demonstrated that an important region of the posterior distribution of the beta-Poisson dose-response model parameters is attributable to the absence of low-dose data. This region includes beta-Poisson models for which the conventional approximation is especially invalid and in which many beta distributions have an extreme shape with questionable plausibility. © Her Majesty the Queen in Right of Canada 2013. Reproduced with the permission of the Minister of the Public Health Agency of Canada.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

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

Said, M. A.; Suhaimi, N. E. F.; Ashhar, Z. N., E-mail: aminhpj@gmail.com

In routine radiopharmaceutical Iodine-131 ({sup 131}I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle {sup 131}I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the {sup 131}I. The new fabricated of low cost {sup 131}I dispenser was tested and the dose received by personnel were evaluated. The body of leadmore » material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of {sup 131} I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the {sup 131}I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of {sup 131}I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.« less

Radiopharmaceutical considerations for using Tc-99m MAA in lung transplant patients.

PubMed

Ponto, James A

2010-01-01

To elucidate radiopharmaceutical considerations for using technetium Tc-99m albumin aggregated (Tc-99m MAA) in lung transplant patients and to establish an appropriate routine dose and preparation procedure. Tertiary care academic hospital during May 2007 to May 2009. Nuclear pharmacist working in nuclear medicine department. Radiopharmaceutical considerations deemed important for the use of Tc-99m MAA in lung transplant patients included radioactivity dose, particulate dose, rate of the radiolabeling reaction (preparation time), and final radiochemical purity. Evaluation of our initial 12-month experience, published literature, and professional practice guidelines provided the basis for establishing an appropriate dose and preparation procedure of Tc-99m MAA for use in lung transplant patients. Radiochemical purity at typical incubation times and image quality in subsequent lung transplant patients imaged during the next 12 months. Based on considerations of radioactivity dose, particulate dose, rate of the radiolabeling reaction (preparation time), and final radiochemical purity, a routine dose consisting of 3 mCi (111 MBq) and 100,000 particles of Tc-99m MAA for planar perfusion lung imaging of adult lung transplant patients was established as reasonable and appropriate. MAA kits were prepared with a more reasonable amount of Tc-99m and yielded high radiochemical purity values in typical incubation times. Images have continued to be of high diagnostic quality. Tc-99m MAA used for lung transplant imaging can be readily prepared with high radiochemical purity to provide a dose of 3 mCi (111 GBq)/100,000 particles, which provides images of high diagnostic quality.

Radiation-induced cataracts: the Health Protection Agency's response to the ICRP statement on tissue reactions and recommendation on the dose limit for the eye lens.

PubMed

Bouffler, Simon; Ainsbury, Elizabeth; Gilvin, Phil; Harrison, John

2012-12-01

This paper presents the response of the Health Protection Agency (HPA) to the 2011 statement from the International Commission on Radiological Protection (ICRP) on tissue reactions and recommendation of a reduced dose limit for the lens of the eye. The response takes the form of a brief review of the most recent epidemiological and mechanistic evidence. This is presented together with a discussion of dose limits in the context of the related risk and the current status of eye dosimetry, which is relevant for implementation of the limits. It is concluded that although further work is desirable to quantify better the risk at low doses and following protracted exposures, along with research into the mechanistic basis for radiation cataractogenesis to inform selection of risk projection models, the HPA endorses the conclusion reached by the ICRP in their 2011 statement that the equivalent dose limit for the lens of the eye should be reduced from 150 to 20 mSv per year, averaged over a five year period, with no year's dose exceeding 50 mSv.

The skin: its structure and response to ionizing radiation.

PubMed

Hopewell, J W

1990-04-01

The response of the skin to ionizing radiation has important implications both for the treatment of malignant disease by radiation and for radiological protection. The structural organization of human skin is described and compared with that of the pig, with which it shows many similarities, in order that the response of the skin to ionizing radiation may be more fully understood. Acute radiation damage to the skin is primarily a consequence of changes in the epidermis; the timing of the peak of the reaction is related to the kinetic organization of this layer. The rate of development of damage is independent of the radiation dose, since this is related to the natural rate of loss of cells from the basal layer of the epidermis. Recovery of the epidermis occurs as a result of the proliferation of surviving clonogenic basal cells from within the irradiated area. The presence of clonogenic cells in the canal of the hair follicle is important, particularly after non-uniform irradiation from intermediate energy beta-emitters. The migration of viable cells from the edges of the irradiated site is also significant when small areas of skin are irradiated. Late damage to the skin is primarily a function of radiation effects on the vasculature; this produces a wave of dermal atrophy after 16-26 weeks. Dermal necrosis develops at this time after high doses. A second phase of dermal thinning is seen to develop after greater than 52 weeks, and this later phase of damage is associated with the appearance of telangiectasia. Highly localized irradiation of the skin, either to a specific layer (as may result from exposure to very low energy beta-emitters) or after exposure to small highly radioactive particles, 'hot particles', produces gross effects that become visibly manifest within 2 weeks of exposure. These changes result from the direct killing of the cells of the skin in interphase after doses greater than 100 Gy. Dose-effect curves have been established for the majority of these deterministic endpoints in the skin from the results of both experimental and clinical studies. These are of value in the establishment of safe radiation dose limits for the skin.

Assessment of the occupational eye lens dose for clinical staff in interventional radiology, cardiology and neuroradiology.

PubMed

Omar, Artur; Kadesjö, Nils; Palmgren, Charlotta; Marteinsdottir, Maria; Segerdahl, Tony; Fransson, Annette

2017-03-20

In accordance with recommendations by the International Commission on Radiological Protection, the current European Basic Safety Standards has adopted a reduced occupational eye lens dose limit of 20 mSv yr -1 . The radiation safety implications of this dose limit is of concern for clinical staff that work with relatively high dose x-ray angiography and interventional radiology. Presented in this work is a thorough assessment of the occupational eye lens dose based on clinical measurements with active personal dosimeters worn by staff during various types of procedures in interventional radiology, cardiology and neuroradiology. Results are presented in terms of the estimated equivalent eye lens dose for various medical professions. In order to compare the risk of exceeding the regulatory annual eye lens dose limit for the widely different clinical situations investigated in this work, the different medical professions were separated into categories based on their distinct work pattern: staff that work (a) regularly beside the patient, (b) in proximity to the patient and (c) typically at a distance from the patient. The results demonstrate that the risk of exceeding the annual eye lens dose limit is of concern for staff category (a), i.e. mainly the primary radiologist/cardiologist. However, the results also demonstrate that the risk can be greatly mitigated if radiation protection shields are used in the clinical routine. The results presented in this work cover a wide range of clinical situations, and can be used as a first indication of the risk of exceeding the annual eye lens dose limit for staff at other medical centres.

Treatment of AA amyloidosis in rheumatoid arthritis.

PubMed

Balakrishnan, C; Sule, A; Mittal, G; Gaitonde, S; Pathan, E; Rajadhyaksha, S; Deshpande, R B; Gurmeet, M; Samant, R; Joshi, V R

2002-07-01

Four patients of rheumatoid arthritis (RA) with biopsy confirmed AA amyloidosis were treated with chlorambucil. All had established but uncontrolled RA with a persistently raised ESR. Moderate (> 1 gm, < 3.5 gm/d) to nephrotic range (> 3.5 gm/d) proteinuria and a relatively well preserved renal function was noted in three patients. One patient had deranged renal function and required dialysis. On chlorambucil, there was complete recovery, partial improvement and no improvement in one patient each. The fourth patient required haemodialysis, did not tolerate chlorambucil and succumbed to the illness. Therapy with chlorambucil can benefit some patients of RA with AA amyloidosis. Leucopenia is the most important dose limiting side effect.

Health risk assessment of potable water containing small amount of tritium oxide

NASA Astrophysics Data System (ADS)

Momot, O. A.; Synzynys, B. I.; Oudalova, A. A.

2017-01-01

The problem of groundwater pollution with tritium in a vicinity of radiation-dangerous facilities in Obninsk is considered. The information on the specific activity of tritium in Obninsk water sources is provided. The formula for the calculation of the β-radiation absorbed dose from tritium ingestion is proposed, reflecting the biological behavior of tritium in a human body. To establish the extent of tritium effects on human, the health risk is assessed. It is shown that if the specific activity of tritium in drinking water amounts to 10 Bq/l, the risk of stochastic effects of radiation will not exceed the limit of the individual lifetime risk.

The biological effect of prolonged radiation and ways of selecting new anti-radiation drugs effective in this kind of radiation injury

NASA Technical Reports Server (NTRS)

Rogozkin, V. D.; Chertkov, K. S.; Nikolov, I.

1974-01-01

The basic characteristics of prolonged radiation - increased tolerance of radiation injury - are attributed to cellular kinetics; as dose rate is reduced, the population rate is not disturbed, particularly that of stem cells which makes it possible for the organism to tolerate higher radiation loads. It is concluded that this effect makes approved radio protectors, whose effect contains an established cytostatic component, unsuitable for prolonged radiation. It is better to correct the stem pool formation process by either accelerating the proliferation of cells or limiting the effect of stimuli causing cells to lose colony forming properties.

[How to screen for pheochromocytoma, primary aldosteronism and Cushing's syndrome].

PubMed

Meyer, Patrick

2009-01-07

Pheochromocytoma, primary aldosteronism and Cushing's syndrome are uncommon disorders and are difficult to diagnose because laboratory tests lack validation and specificity. Despite these limitations, practice guidelines are proposed to standardize the screening procedure. The most reliable method to diagnose pheochromocytoma is the measurement of plasmatic and/or urinary metanephrines and normetanephrines depending on the pre-test probability of the disease. The approach for detection of primary aldosteronism is based on the aldosterone-renin ratio under standard conditions. Finally, three tests are available to establish the diagnosis of Cushing's syndrome: 24-h urinary free cortisol excretion, low-dose dexamethasone suppression test and the recent and promising late evening salivary cortisol.

The benefits of exercise for patients with non-alcoholic fatty liver disease.

PubMed

Keating, Shelley E; George, Jacob; Johnson, Nathan A

2015-01-01

As exercise is now an established therapy for the management of non-alcoholic fatty liver disease (NAFLD), recent investigations have sought to identify the optimal dose (type, intensity and amount) of exercise for hepatic benefit. Here, the authors discuss the following: the role of aerobic exercise for the modulation of hepatic steatosis; the limited evidence for the role of resistance training in reducing liver fat; the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis; and the benefits of exercise for patients with NAFLD, beyond steatosis. Based on current evidence, the authors provide recommendations for exercise prescription for patients with NAFLD.

Portal scatter to primary dose ratio of 4 to 18 MV photon spectra incident on heterogeneous phantoms

NASA Astrophysics Data System (ADS)

Ozard, Siobhan R.

Electronic portal imagers designed and used to verify the positioning of a cancer patient undergoing radiation treatment can also be employed to measure the in vivo dose received by the patient. This thesis investigates the ratio of the dose from patient-scattered particles to the dose from primary (unscattered) photons at the imaging plane, called the scatter to primary dose ratio (SPR). The composition of the SPR according to the origin of scatter is analyzed more thoroughly than in previous studies. A new analytical method for calculating the SPR is developed and experimentally verified for heterogeneous phantoms. A novel technique that applies the analytical SPR method for in vivo dosimetry with a portal imager is evaluated. Monte Carlo simulation was used to determine the imager dose from patient-generated electrons and photons that scatter one or more times within the object. The database of SPRs reported from this investigation is new since the contribution from patient-generated electrons was neglected by previous Monte Carlo studies. The SPR from patient-generated electrons was found here to be as large as 0.03. The analytical SPR method relies on the established result that the scatter dose is uniform for an air gap between the patient and the imager that is greater than 50 cm. This method also applies the hypothesis that first-order Compton scatter only, is sufficient for scatter estimation. A comparison of analytical and measured SPRs for neck, thorax, and pelvis phantoms showed that the maximum difference was within +/-0.03, and the mean difference was less than +/-0.01 for most cases. This accuracy was comparable to similar analytical approaches that are limited to homogeneous phantoms. The analytical SPR method could replace lookup tables of measured scatter doses that can require significant time to measure. In vivo doses were calculated by combining our analytical SPR method and the convolution/superposition algorithm. Our calculated in vivo doses agreed within +/-3% with the doses measured in the phantom. The present in vivo method was faster compared to other techniques that use convolution/superposition. Our method is a feasible and satisfactory approach that contributes to on-line patient dose monitoring.

Skin notation in the context of workplace exposure standards

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

Scansetti, G.; Piolatto, G.; Rubino, G.F.

1988-01-01

In the establishment of workplace exposure standards, the potential for cutaneous absorption is taken into consideration through the addition of skin notation to the relevant substance. In the TLVs Documentation (ACGIH, 1986) dermal lethal dose to 50% (LD50) or human data are the bases for the assignment of skin notation to 91 of 168 substances. For the other substances, the skin attribution seems to be based on undocumented statements in 24 (14.5%), skin effects in 13 (8%), and analogy in 7 (4%), while in the remaining 33 (20%) any reference is lacking as to the basis for notation of themore » cutaneous route of entry. Furthermore, since the established cut-off value of 2 g/kg is sometimes bypassed when a notation is added or omitted, the use of dermal LD50 is perplexing. Given the relevance of the skin notation for the validation of threshold limit values (TLVs) in the workplace, a full examination and citation of all available scientific data are recommended when establishing the TLV of substances absorbable through the skin.« less

Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies

NASA Astrophysics Data System (ADS)

Lee, Choonik; Jung, Jae Won; Pelletier, Christopher; Pyakuryal, Anil; Lamart, Stephanie; Kim, Jong Oh; Lee, Choonsik

2015-03-01

Organ dose estimation for retrospective epidemiological studies of late effects in radiotherapy patients involves two challenges: radiological images to represent patient anatomy are not usually available for patient cohorts who were treated years ago, and efficient dose reconstruction methods for large-scale patient cohorts are not well established. In the current study, we developed methods to reconstruct organ doses for radiotherapy patients by using a series of computational human phantoms coupled with a commercial treatment planning system (TPS) and a radiotherapy-dedicated Monte Carlo transport code, and performed illustrative dose calculations. First, we developed methods to convert the anatomy and organ contours of the pediatric and adult hybrid computational phantom series to Digital Imaging and Communications in Medicine (DICOM)-image and DICOM-structure files, respectively. The resulting DICOM files were imported to a commercial TPS for simulating radiotherapy and dose calculation for in-field organs. The conversion process was validated by comparing electron densities relative to water and organ volumes between the hybrid phantoms and the DICOM files imported in TPS, which showed agreements within 0.1 and 2%, respectively. Second, we developed a procedure to transfer DICOM-RT files generated from the TPS directly to a Monte Carlo transport code, x-ray Voxel Monte Carlo (XVMC) for more accurate dose calculations. Third, to illustrate the performance of the established methods, we simulated a whole brain treatment for the 10 year-old male phantom and a prostate treatment for the adult male phantom. Radiation doses to selected organs were calculated using the TPS and XVMC, and compared to each other. Organ average doses from the two methods matched within 7%, whereas maximum and minimum point doses differed up to 45%. The dosimetry methods and procedures established in this study will be useful for the reconstruction of organ dose to support retrospective epidemiological studies of late effects in radiotherapy patients.

SU-E-I-33: Establishment of CT Diagnostic Reference Levels in Province Nova Scotia

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

Tonkopi, E; Abdolell, M; Duffy, S

2015-06-15

Purpose: To evaluate patient radiation dose from the most frequently performed CT examinations and to establish provincial diagnostic reference levels (DRLs) as a tool for protocol optimization. Methods: The study investigated the following CT examinations: head, chest, abdomen/pelvis, and chest/abdomen/pelvis (CAP). Dose data, volume CT dose index (CTDIvol) and dose-length product (DLP), were collected from 15 CT scanners installed during 2004–2014 in 11 hospital sites of Nova Scotia. All scanners had dose modulation options and multislice capability (16–128 detector rows). The sample for each protocol included 15 average size patients (70±20 kg). Provincial DRLs were calculated as the 75th percentilemore » of patient dose distributions. The differences in dose between hospitals were evaluated with a single factor ANOVA statistical test. Generalized linear modeling was used to determine the factors associated with higher radiation dose. A sample of 36 abdominal studies performed on three different scanners was blinded and randomized for an assessment by an experienced radiologist who graded the imaging quality of anatomic structures. Results: Data for 900 patients were collected. The DRLs were proposed using CTDIvol (mGy) and DLP (mGy*cm) values for CT head (67 and 1049, respectively), chest (12 and 393), abdomen/pelvis (16 and 717), and CAP (14 and 1034). These DRLs were lower than the published national data except for the head CTDIvol. The differences between the means of the dose distributions from each scanner were statistically significant (p<0.05) for all examinations. A very weak correlation was found between the dose and the scanner age or the number of slices with Pearson’s correlation coefficients of 0.011–0.315. The blinded analysis of image quality demonstrated no clinically significant difference except for the noise category. Conclusion: Provincial DRLs were established for typical CT examinations. The variations in dose between the hospitals suggested a large potential for optimization of examinations. Radiology Research Foundation grant.« less

Limited Chemotherapy and Shrinking Field Radiotherapy for Osteolymphoma (Primary Bone Lymphoma): Results From the Trans-Tasman Radiation Oncology Group 99.04 and Australasian Leukaemia and Lymphoma Group LY02 Prospective Trial;Bone; Lymphoma; Radiotherapy; Chemotherapy; Clinical trial

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

Christie, David, E-mail: david.christie@premion.com.au; Dear, Keith; Le, Thai

2011-07-15

Purpose: To establish benchmark outcomes for combined modality treatment to be used in future prospective studies of osteolymphoma (primary bone lymphoma). Methods and Materials: In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking fieldmore » technique. Results: The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma. Conclusions: Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen.« less

PAEDIATRIC CT EXPOSURE PRACTICE IN THE COUNTY OF RIO DE JANEIRO: THE NEED TO ESTABLISH DIAGNOSTIC REFERENCE LEVELS.

PubMed

de Jesus, Fillipe M; Magalhães, Luis A G; Kodlulovich, Simone

2016-11-01

A pilot study of dose indicators in paediatric computed tomography (CT) was conducted to prove the need to establish diagnostic reference levels (DRLs) for the county of Rio de Janeiro. The dose descriptors were estimated from the beam dosimetry by applying the protocols used in each examination. The total patient sample included 279 children. Regarding the comparison of the dose-length product values among the hospitals, the high-resolution chest CT scans were distinguished among the three types of examinations, due to the discrepancies of 1148 % (1-5 y age group) and 2248 % (5-10 y age group) presented in Hospital A's dose-length product values relative to Hospital D's dose-length product values. The results showed that without DRL, the dose variation can be significant between hospitals in the same county for the same age group in the same examination. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Regulating exposure of the lens of the eye to ionising radiations.

PubMed

Thorne, M C

2012-06-01

The International Commission on Radiological Protection (ICRP) has reviewed recent epidemiological evidence suggesting that, for the lens of the eye, the threshold in absorbed dose for the induction of deleterious health effects is about 0.5 Gy. On this basis, the Commission recommends that for occupational exposure in planned exposure situations, the equivalent dose limit for the lens of the eye should be 20 mSv in a year, averaged over defined periods of 5 yr, with exposure not exceeding 50 mSv in any single year. This paper summarises the data that have been taken into account by the ICRP and critically examines whether the proposed downward revision of the dose limit is justified. Overall, it is concluded that the accumulating radiobiological and epidemiological evidence makes it more appropriate to treat cataract induction as a stochastic rather than a deterministic effect. Within this framework, it is illogical to have the same dose limit for the lens of the eye as for the whole body irradiated uniformly. This could be addressed either by removing the special dose limit for the lens of the eye, assigning it an appropriate tissue weighting factor and including it in the computation of the effective dose, or through a composite approach involving the use of a tissue weighting factor for effective dose computations together with a special limit on the equivalent dose to the lens of the eye to ensure that no individual was subject to an unacceptably high risk of induction of clinically significant cataracts.

User Guide for GoldSim Model to Calculate PA/CA Doses and Limits

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

Smith, F.

2016-10-31

A model to calculate doses for solid waste disposal at the Savannah River Site (SRS) and corresponding disposal limits has been developed using the GoldSim commercial software. The model implements the dose calculations documented in SRNL-STI-2015-00056, Rev. 0 “Dose Calculation Methodology and Data for Solid Waste Performance Assessment (PA) and Composite Analysis (CA) at the Savannah River Site”.

The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification

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

Timchalk, Charles; Weber, Thomas J.; Smith, Jordan N.

Advancements in Exposure Science involving the development and deployment of biomarkers of exposure and biological response are anticipated to significantly (and positively) influence health outcomes associated with occupational, environmental and clinical exposure to chemicals/drugs. To achieve this vision, innovative strategies are needed to develop multiplex sensor platforms capable of quantifying individual and mixed exposures (i.e. systemic dose) by measuring biomarkers of dose and biological response in readily obtainable (non-invasive) biofluids. Secondly, the use of saliva (alternative to blood) for biomonitoring coupled with the ability to rapidly analyze multiple samples in real-time offers an innovative opportunity to revolutionize biomonitoring assessments. Inmore » this regard, the timing and number of samples taken for biomonitoring will not be limited as is currently the case. In addition, real-time analysis will facilitate identification of work practices or conditions that are contributing to increased exposures and will make possible a more rapid and successful intervention strategy. The initial development and application of computational models for evaluation of saliva/blood analyte concentration at anticipated exposure levels represents an important opportunity to establish the limits of quantification and robustness of multiplex sensor systems by exploiting a unique computational modeling framework. The use of these pharmacokinetic models will also enable prediction of an exposure dose based on the saliva/blood measurement. This novel strategy will result in a more accurate prediction of exposures and, once validated, can be employed to assess dosimetry to a broad range of chemicals in support of biomonitoring and epidemiology studies.« less

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Availability and dose response of phytophenols from a wheat bran rich cereal product in healthy human volunteers.

PubMed

Neacsu, Madalina; McMonagle, Jolene; Fletcher, Reg J; Hulshof, Toine; Duncan, Sylvia H; Scobbie, Lorraine; Duncan, Gary J; Cantlay, Louise; Horgan, Graham; de Roos, Baukje; Duthie, Garry G; Russell, Wendy R

2017-03-01

Phytophenols present in cereals are metabolised to compounds that could be partly responsible for the reduced risk of chronic diseases and all-cause mortality associated with fibre-rich diets. The bioavailability, form and in vivo concentrations of these metabolites require to be established. Eight healthy volunteers consumed a test meal containing a recommended dose (40 g) and high dose (120 g) of ready-to-eat wheat bran cereal and the systemic and colonic metabolites determined quantitatively by LC-MS. Analysis of the systemic metabolomes demonstrated that a wide range of phytophenols were absorbed/excreted (43 metabolites) within 5 h of consumption. These included 16 of the 21 major parent compounds identified in the intervention product and several of these were also found to be significantly increased in the colon. Not all of the metabolites were increased with the higher dose, suggesting some limitation in absorption due to intrinsic factors and/or the food matrix. Many compounds identified (e.g. ferulic acid and major metabolites) exhibit anti-inflammatory activity and impact on redox pathways. The combination of postprandial absorption and delivery to the colon, as well as hepatic recycling of the metabolites at these concentrations, is likely to be beneficial to both systemic and gut health. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

PubMed

Xu, Lijuan; Wang, Hao; Yang, Xianle; Lu, Liqun

2013-06-25

Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.

Plasma metabolic profiling analysis of nephrotoxicity induced by acyclovir using metabonomics coupled with multivariate data analysis.

PubMed

Zhang, Xiuxiu; Li, Yubo; Zhou, Huifang; Fan, Simiao; Zhang, Zhenzhu; Wang, Lei; Zhang, Yanjun

2014-08-01

Acyclovir (ACV) is an antiviral agent. However, its use is limited by adverse side effect, particularly by its nephrotoxicity. Metabonomics technology can provide essential information on the metabolic profiles of biofluids and organs upon drug administration. Therefore, in this study, mass spectrometry-based metabonomics coupled with multivariate data analysis was used to identify the plasma metabolites and metabolic pathways related to nephrotoxicity caused by intraperitoneal injection of low (50mg/kg) and high (100mg/kg) doses of acyclovir. Sixteen biomarkers were identified by metabonomics and nephrotoxicity results revealed the dose-dependent effect of acyclovir on kidney tissues. The present study showed that the top four metabolic pathways interrupted by acyclovir included the metabolisms of arachidonic acid, tryptophan, arginine and proline, and glycerophospholipid. This research proves the established metabonomic approach can provide information on changes in metabolites and metabolic pathways, which can be applied to in-depth research on the mechanism of acyclovir-induced kidney injury. Copyright © 2014 Elsevier B.V. All rights reserved.

NEUTRON CHARACTERIZATION OF ENSA-DPT TYPE SPENT FUEL CASK AT TRILLO NUCLEAR POWER PLANT.

PubMed

Méndez-Villafañe, Roberto; Campo-Blanco, Xandra; Embid, Miguel; Yéboles, César A; Morales, Ramón; Novo, Manuel; Sanz, Javier

2018-04-23

The Neutron Standards Laboratory of CIEMAT has conducted the characterization of the independent spent fuel storage installation at the Trillo Nuclear Power Plant. At this facility, the spent fuel assemblies are stored in ENSA-DPT type dual purpose casks. Neutron characterization was performed by dosimetry measurements with a neutron survey meter (LB6411) inside the facility, around an individual cask and between stored casks, and outside the facility. Spectra measurements were also performed with a Bonner sphere system in order to determine the integral quantities and validate the use of the neutron monitor at the different positions. Inside the facility, measured neutron spectra and neutron ambient dose equivalent rate are consistent with the casks spatial distribution and neutron emission rates, and measurements with both instruments are consistent with each other. Outside the facility, measured neutron ambient dose equivalent rates are well below the 0.5 μSv/h limit established by the nuclear regulatory authority.

[Identification of irradiated abalone by ESR spectroscopy].

PubMed

Song, Yeping; Wang, Chuanxian; Yang, Zhenyu; Zhong, Weike; Geng, Jinpei; Lu, Di; Ding, Zhuoping

2012-05-01

To establish an analytical method for the detection and identification of irradiated abalone by electron spin resonance spectroscopy. Electron spin resonance (ESR) was used to study the spectral characteristics of abalone and the characteristic peak for quantitation. There were obvious different ESR spectra between unirradiated and irradiated abalone. The g factor for unirradiated abalone was 2.0055-2.0060, the g1 and g2 factor for irradiated abalone were (2.0027 +/- 0.0001) and (1.9994 +/- 0.0001), respectively. The ESR signal intensity of characteristic peak was positively correlated with absorbed dose in the range of 0.5 - 10 kGy, left peak was the characteristic peak for quantitation and the detection limit was < or = 0.5 kGy. It was difficult to quantitate when the absorbed dose was over 10 kGy. ESR characteristic peak and g factor were able to qualitatively determine the irradiation of abalone. ESR spectroscopy is an effective method to determine whether the abalone being irradiated or not.

Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase.

PubMed

Scarlatti, Francesca; Sala, Giusy; Ricci, Clara; Maioli, Claudio; Milani, Franco; Minella, Marco; Botturi, Marco; Ghidoni, Riccardo

2007-08-08

Radiotherapy is an established therapeutic modality for prostate cancer. Since it is well known that radiotherapy is limited due to its severe toxicity towards normal cells at high dose and minimal effect at low dose, the search for biological compounds that increase the sensitivity of tumors cells to radiation may improve the efficacy of therapy. Resveratrol, a natural antioxidant, was shown to inhibit carcinogenesis in animal models, and to block the process of tumor initiation and progression. The purpose of this study was to examine whether or not resveratrol can sensitize DU145, an androgen-independent human prostate cancer cell line, to ionizing radiation. We report here that DU145 cells are resistant to ionizing radiation-induced cell death, but pretreatment with resveratrol significantly enhances cell death. Resveratrol acts synergistically with ionizing radiation to inhibit cell survival in vitro. Resveratrol also potentiates ionizing radiation-induced ceramide accumulation, by promoting its de novo biosynthesis. This confirms ceramide as an effective mediator of the anticancer potential induced by resveratrol.

Development of a Geant4 application to characterise a prototype neutron detector based on three orthogonal 3He tubes inside an HDPE sphere.

PubMed

Gracanin, V; Guatelli, S; Prokopovich, D; Rosenfeld, A B; Berry, A

2017-01-01

The Bonner Sphere Spectrometer (BSS) system is a well-established technique for neutron dosimetry that involves detection of thermal neutrons within a range of hydrogenous moderators. BSS detectors are often used to perform neutron field surveys in order to determine the ambient dose equivalent H*(10) and estimate health risk to personnel. There is a potential limitation of existing neutron survey techniques, since some detectors do not consider the direction of the neutron field, which can result in overly conservative estimates of dose in neutron fields. This paper shows the development of a Geant4 simulation application to characterise a prototype neutron detector based on three orthogonal 3 He tubes inside a single HDPE sphere built at the Australian Nuclear Science and Technology Organisation (ANSTO). The Geant4 simulation has been validated with respect to experimental measurements performed with an Am-Be source. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Influence of very low doses of mediators on fungal laccase activity - nonlinearity beyond imagination

PubMed Central

Malarczyk, Elzbieta; Kochmanska-Rdest, Janina; Jarosz-Wilkolazka, Anna

2009-01-01

Laccase, an enzyme responsible for aerobic transformations of natural phenolics, in industrial applications requires the presence of low-molecular substances known as mediators, which accelerate oxidation processes. However, the use of mediators is limited by their toxicity and the high costs of exploitation. The activation of extracellular laccase in growing fungal culture with highly diluted mediators, ABTS and HBT is described. Two high laccase-producing fungal strains, Trametes versicolor and Cerrena unicolor, were used in this study as a source of enzyme. Selected dilutions of the mediators significantly increased the activity of extracellular laccase during 14 days of cultivation what was distinctly visible in PAGE technique and in colorimetric tests. The same mediator dilutions increased demethylation properties of laccase, which was demonstrated during incubation of enzyme with veratric acid. It was established that the activation effect was assigned to specific dilutions of mediators. Our dose-response dilution process smoothly passes into the range of action of homeopathic dilutions and is of interest for homeopaths. PMID:19732425

Dose-dependent establishment of Trichuris suis larvae in Göttingen minipigs.

PubMed

Vejzagić, Nermina; Roepstorff, Allan; Kringel, Helene; Thamsborg, Stig Milan; Nielsen, Mads Pårup; Kapel, Christian M O

2015-03-15

Embryonated eggs of the pig whipworm Trichuris suis (TSOee) constitute the active pharmaceutical ingredient (API) in a medicinal product explored in human clinical trials against several immune-mediated diseases. The measurement of TSO biological potency (hatchability and infectivity) is a requirement for the assessment of TSO's pharmacological potency in human clinical trials. The present study aims to validate the dose-dependent establishment of T. suis larvae in Göttingen minipigs and eventual clinical implication of a dose range (1000-10,000 TSO). Four groups of 5 minipigs were inoculated with doses of 1000, 2500, 7500, and 10,000 TSOee, respectively, to evaluate a range of concentrations of TSOee in a minipig infectivity model. Unembryonated eggs (TSOue) were added to keep the total egg number in the inoculum constant at 10,000 eggs. Two groups received 2500 and 7500 TSOee per pig without the addition of TSOue as controls. The intestinal larval establishment at 21 days post inoculation (dpi) demonstrated a clear positive linear dose-response relationship between numbers of inoculated TSOee and recovered larvae. There was a low level of variation in larval counts in all study groups. Thus, the infectivity model in minipigs within the tested dose range offers a reliable, sensitive and accurate assay for testing biological potency of TSO. Copyright © 2015 Elsevier B.V. All rights reserved.

Accuracy and Radiation Dose Reduction of Limited-Range CT in the Evaluation of Acute Appendicitis in Pediatric Patients.

PubMed

Jin, Michael; Sanchez, Thomas R; Lamba, Ramit; Fananapazir, Ghaneh; Corwin, Michael T

2017-09-01

The purpose of this article is to determine the accuracy and radiation dose reduction of limited-range CT prescribed from the top of L2 to the top of the pubic symphysis in children with suspected acute appendicitis. We performed a retrospective study of 210 consecutive pediatric patients from December 11, 2012, through December 11, 2014, who underwent abdominopelvic CT for suspected acute appendicitis. Two radiologists independently reviewed the theoretic limited scans from the superior L2 vertebral body to the top of the pubic symphysis, to assess for visualization of the appendix, acute appendicitis, alternative diagnoses, and incidental findings. Separately, the same parameters were assessed on the full scan by the same two reviewers. Whole-body effective doses were determined for the full- and limited-range scans and were compared using the paired t test. The appendix or entire cecum was visualized on the limited scan in all cases, and no cases of acute appendicitis were missed on the simulated limited scan compared with the full scan. Two alternative diagnoses were missed with the limited scan: one case of hydronephrosis and one of acute acalculous cholecystitis. The mean effective dose for the original scan was 5.6 mSv and that for the simulated limited scan was 3.0 mSv, resulting in a dose reduction of 46.4% (p < 0.001). A limited-range CT examination performed from the top of L2 to the top of the pubic symphysis is as accurate as a full-range abdominopelvic CT in evaluating pediatric patients with suspected appendicitis and reduces the dose by approximately 46%.

Organ doses for reference pediatric and adolescent patients undergoing computed tomography estimated by Monte Carlo simulation

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

Lee, Choonsik; Kim, Kwang Pyo; Long, Daniel J.

Purpose: To establish an organ dose database for pediatric and adolescent reference individuals undergoing computed tomography (CT) examinations by using Monte Carlo simulation. The data will permit rapid estimates of organ and effective doses for patients of different age, gender, examination type, and CT scanner model. Methods: The Monte Carlo simulation model of a Siemens Sensation 16 CT scanner previously published was employed as a base CT scanner model. A set of absorbed doses for 33 organs/tissues normalized to the product of 100 mAs and CTDI{sub vol} (mGy/100 mAs mGy) was established by coupling the CT scanner model with age-dependentmore » reference pediatric hybrid phantoms. A series of single axial scans from the top of head to the feet of the phantoms was performed at a slice thickness of 10 mm, and at tube potentials of 80, 100, and 120 kVp. Using the established CTDI{sub vol}- and 100 mAs-normalized dose matrix, organ doses for different pediatric phantoms undergoing head, chest, abdomen-pelvis, and chest-abdomen-pelvis (CAP) scans with the Siemens Sensation 16 scanner were estimated and analyzed. The results were then compared with the values obtained from three independent published methods: CT-Expo software, organ dose for abdominal CT scan derived empirically from patient abdominal circumference, and effective dose per dose-length product (DLP). Results: Organ and effective doses were calculated and normalized to 100 mAs and CTDI{sub vol} for different CT examinations. At the same technical setting, dose to the organs, which were entirely included in the CT beam coverage, were higher by from 40 to 80% for newborn phantoms compared to those of 15-year phantoms. An increase of tube potential from 80 to 120 kVp resulted in 2.5-2.9-fold greater brain dose for head scans. The results from this study were compared with three different published studies and/or techniques. First, organ doses were compared to those given by CT-Expo which revealed dose differences up to several-fold when organs were partially included in the scan coverage. Second, selected organ doses from our calculations agreed to within 20% of values derived from empirical formulae based upon measured patient abdominal circumference. Third, the existing DLP-to-effective dose conversion coefficients tended to be smaller than values given in the present study for all examinations except head scans. Conclusions: A comprehensive organ/effective dose database was established to readily calculate doses for given patients undergoing different CT examinations. The comparisons of our results with the existing studies highlight that use of hybrid phantoms with realistic anatomy is important to improve the accuracy of CT organ dosimetry. The comprehensive pediatric dose data developed here are the first organ-specific pediatric CT scan database based on the realistic pediatric hybrid phantoms which are compliant with the reference data from the International Commission on Radiological Protection (ICRP). The organ dose database is being coupled with an adult organ dose database recently published as part of the development of a user-friendly computer program enabling rapid estimates of organ and effective dose doses for patients of any age, gender, examination types, and CT scanner model.« less

Reformulation of a clinical-dose system for carbon-ion radiotherapy treatment planning at the National Institute of Radiological Sciences, Japan

NASA Astrophysics Data System (ADS)

Inaniwa, Taku; Kanematsu, Nobuyuki; Matsufuji, Naruhiro; Kanai, Tatsuaki; Shirai, Toshiyuki; Noda, Koji; Tsuji, Hiroshi; Kamada, Tadashi; Tsujii, Hirohiko

2015-04-01

At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical-dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose-averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with αr = 0.764 Gy-1 and β = 0.0615 Gy-2 as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C-equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within ±1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS.

Rare earth elements (REEs): effects on germination and growth of selected crop and native plant species.

PubMed

Thomas, Philippe J; Carpenter, David; Boutin, Céline; Allison, Jane E

2014-02-01

The phytotoxicity of rare earth elements (REEs) is still poorly understood. The exposure-response relationships of three native Canadian plant species (common milkweed, Asclepias syriaca L., showy ticktrefoil, Desmodium canadense (L.) DC. and switchgrass, Panicum virgatum L.) and two commonly used crop species (radish, Raphanus sativus L., and tomato, Solanum lycopersicum L.) to the REEs lanthanum (La), yttrium (Y) and cerium (Ce) were tested. In separate experiments, seven to eight doses of each element were added to the soil prior to sowing seeds. Effects of REE dose on germination were established through measures of total percent germination and speed of germination; effects on growth were established through determination of above ground biomass. Ce was also tested at two pH levels and plant tissue analysis was conducted on pooled samples. Effects on germination were mostly observed with Ce at low pH. However, effects on growth were more pronounced, with detectable inhibition concentrations causing 10% and 25% reductions in biomass for the two native forb species (A. syriaca and D. canadense) with all REEs and on all species tested with Ce in both soil pH treatments. Concentration of Ce in aboveground biomass was lower than root Ce content, and followed the dose-response trend. From values measured in natural soils around the world, our results continue to support the notion that REEs are of limited toxicity and not considered extremely hazardous to the environment. However, in areas where REE contamination is likely, the slow accumulation of these elements in the environment could become problematic. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

SU-F-BRD-05: Dosimetric Comparison of Protocol-Based SBRT Lung Treatment Modalities: Statistically Significant VMAT Advantages Over Fixed- Beam IMRT

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

Best, R; Harrell, A; Geesey, C

2014-06-15

Purpose: The purpose of this study is to inter-compare and find statistically significant differences between flattened field fixed-beam (FB) IMRT with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT) for stereotactic body radiation therapy SBRT. Methods: SBRT plans using FB IMRT and FFF VMAT were generated for fifteen SBRT lung patients using 6 MV beams. For each patient, both IMRT and VMAT plans were created for comparison. Plans were generated utilizing RTOG 0915 (peripheral, 10 patients) and RTOG 0813 (medial, 5 patients) lung protocols. Target dose, critical structure dose, and treatment time were compared and tested for statistical significance. Parametersmore » of interest included prescription isodose surface coverage, target dose heterogeneity, high dose spillage (location and volume), low dose spillage (location and volume), lung dose spillage, and critical structure maximum- and volumetric-dose limits. Results: For all criteria, we found equivalent or higher conformality with VMAT plans as well as reduced critical structure doses. Several differences passed a Student's t-test of significance: VMAT reduced the high dose spillage, evaluated with conformality index (CI), by an average of 9.4%±15.1% (p=0.030) compared to IMRT. VMAT plans reduced the lung volume receiving 20 Gy by 16.2%±15.0% (p=0.016) compared with IMRT. For the RTOG 0915 peripheral lesions, the volumes of lung receiving 12.4 Gy and 11.6 Gy were reduced by 27.0%±13.8% and 27.5%±12.6% (for both, p<0.001) in VMAT plans. Of the 26 protocol pass/fail criteria, VMAT plans were able to achieve an average of 0.2±0.7 (p=0.026) more constraints than the IMRT plans. Conclusions: FFF VMAT has dosimetric advantages over fixed beam IMRT for lung SBRT. Significant advantages included increased dose conformity, and reduced organs-at-risk doses. The overall improvements in terms of protocol pass/fail criteria were more modest and will require more patient data to establish difference trends of more statistical significance.« less

Characterization of MOSFET dosimeters for low‐dose measurements in maxillofacial anthropomorphic phantoms

PubMed Central

Wolff, Jan E.; Kiljunen, Timo; Schulze, Dirk; Kortesniemi, Mika

2015-01-01

The aims of this study were to characterize reinforced metal‐oxide‐semiconductor field‐effect transistor (MOSFET) dosimeters to assess the measurement uncertainty, single exposure low‐dose limit with acceptable accuracy, and the number of exposures required to attain the corresponding limit of the thermoluminescent dosimeters (TLD). The second aim was to characterize MOSFET dosimeter sensitivities for two dental photon energy ranges, dose dependency, dose rate dependency, and accumulated dose dependency. A further aim was to compare the performance of MOSFETs with those of TLDs in an anthropomorphic phantom head using a dentomaxillofacial CBCT device. The uncertainty was assessed by exposing 20 MOSFETs and a Barracuda MPD reference dosimeter. The MOSFET dosimeter sensitivities were evaluated for two photon energy ranges (50–90 kVp) using a constant dose and polymethylmethacrylate backscatter material. MOSFET and TLD comparative point‐dose measurements were performed on an anthropomorphic phantom that was exposed with a clinical CBCT protocol. The MOSFET single exposure low dose limit (25% uncertainty, k=2) was 1.69 mGy. An averaging of eight MOSFET exposures was required to attain the corresponding TLD (0.3 mGy) low‐dose limit. The sensitivity was 3.09±0.13 mV/mGy independently of the photon energy used. The MOSFET dosimeters did not present dose or dose rate sensitivity but, however, presented a 1% decrease of sensitivity per 1000 mV for accumulated threshold voltages between 8300 mV and 17500 mV. The point doses in an anthropomorphic phantom ranged for MOSFETs between 0.24 mGy and 2.29 mGy and for TLDs between 0.25 and 2.09 mGy, respectively. The mean difference was −8%. The MOSFET dosimeters presented statistically insignificant energy dependency. By averaging multiple exposures, the MOSFET dosimeters can achieve a TLD‐comparable low‐dose limit and constitute a feasible method for diagnostic dosimetry using anthropomorphic phantoms. However, for single in vivo measurements (<1.7 mGy) the sensitivity is too low. PACS number: 87.50.wj PMID:26219008

Occupational Radiation Exposure to the Extremities of Medical Staff during Hysterosalpingography and Radionuclide Bone Scan Procedures in Several Nigerian Hospitals.

PubMed

Jibiri, Nnamdi Norbert; Akintunde, Tawakalitu Oluwatoyin; Dambele, Musa Yusuf; Olowookere, Christopher Jimoh

2016-10-05

The practice of regular dose measurement helps to ascertain the level of occupational dose delivered to the staff involved in diagnostic procedures. This study was carried out to evaluate the dose exposed to the hands of radiologists and a radiologic technologist carrying out HSG and radionuclide bone scan examinations in several hospitals in Nigeria. Radiation doses exposed to the hands of radiologists and a technician carrying out hysterosalpingography (HSG) and bone scan procedures were measured using calibrated thermo-luminescent dosimeters. Five radiologists and a radiologic technologist were included in the study for dose measurement. The study indicates that each radiologist carried out approximately 2 examinations per week with the mean dose ranging between 0.49-0.62 mSv per week, resulting in an annual dose of 191 mSv. Similarly, the occupational dose delivered to both the left and right hands of a radiologic technologist administering 99mTc-methylene diphosphonate (MDP) without cannula and with cannula were 10.68 (720.2) and 13.82 (556.4) mSv per week (and per annum), respectively. It was determined that the left hand of the personnel received higher doses than their right hand. The estimated annual dose during HSG is far below the annual dose limit for deterministic effects, however, it is greater than 10% of the applicable annual dose limit. Hence, routine monitoring is required to ensure adequate protection of the personnel. The total annual dose received during the bone scan exceeds the annual dose limit for both hands, and the dose to either left or right hand is greater than the dose limit of 500 mSv/yr. The radiologists monitored are not expected to incur any deterministic effects during HSG examinations, however, accumulated doses arising from the scattered radiation to the eyes, legs, and neck could be substantial and might lead to certain effects. More staff are required to administer 99mTc-MDP in Nigerian institutions to prevent excessive doses to personnel.

Occupational Radiation Exposure to the Extremities of Medical Staff during Hysterosalpingography and Radionuclide Bone Scan Procedures in Several Nigerian Hospitals

PubMed Central

Jibiri, Nnamdi Norbert; Akintunde, Tawakalitu Oluwatoyin; Dambele, Musa Yusuf; Olowookere, Christopher Jimoh

2016-01-01

Objective: The practice of regular dose measurement helps to ascertain the level of occupational dose delivered to the staff involved in diagnostic procedures. This study was carried out to evaluate the dose exposed to the hands of radiologists and a radiologic technologist carrying out HSG and radionuclide bone scan examinations in several hospitals in Nigeria. Methods: Radiation doses exposed to the hands of radiologists and a technician carrying out hysterosalpingography (HSG) and bone scan procedures were measured using calibrated thermo-luminescent dosimeters. Five radiologists and a radiologic technologist were included in the study for dose measurement. Results: The study indicates that each radiologist carried out approximately 2 examinations per week with the mean dose ranging between 0.49-0.62 mSv per week, resulting in an annual dose of 191 mSv. Similarly, the occupational dose delivered to both the left and right hands of a radiologic technologist administering 99mTc-methylene diphosphonate (MDP) without cannula and with cannula were 10.68 (720.2) and 13.82 (556.4) mSv per week (and per annum), respectively. It was determined that the left hand of the personnel received higher doses than their right hand. Conclusion: The estimated annual dose during HSG is far below the annual dose limit for deterministic effects, however, it is greater than 10% of the applicable annual dose limit. Hence, routine monitoring is required to ensure adequate protection of the personnel. The total annual dose received during the bone scan exceeds the annual dose limit for both hands, and the dose to either left or right hand is greater than the dose limit of 500 mSv/yr. The radiologists monitored are not expected to incur any deterministic effects during HSG examinations, however, accumulated doses arising from the scattered radiation to the eyes, legs, and neck could be substantial and might lead to certain effects. More staff are required to administer 99mTc-MDP in Nigerian institutions to prevent excessive doses to personnel. PMID:27751973

Decontamination issues for chemical and biological warfare agents: how clean is clean enough?

PubMed

Raber, E; Jin, A; Noonan, K; McGuire, R; Kirvel, R D

2001-06-01

The objective of this assessment is to determine what level of cleanup will be required to meet regulatory and stakeholder needs in the case of a chemical and/or biological incident at a civilian facility. A literature review for selected, potential chemical and biological warfare agents shows that dose information is often lacking or controversial. Environmental regulatory limits or other industrial health guidelines that could be used to help establish cleanup concentration levels for such agents are generally unavailable or not applicable for a public setting. Although dose information, cleanup criteria, and decontamination protocols all present challenges to effective planning, several decontamination approaches are available. Such approaches should be combined with risk-informed decision making to establish reasonable cleanup goals for protecting health, property, and resources. Key issues during a risk assessment are to determine exactly what constitutes a safety hazard and whether decontamination is necessary or not for a particular scenario. An important conclusion is that cleanup criteria are site dependent and stakeholder specific. The results of a modeling exercise for two outdoor scenarios are presented to reinforce this conclusion. Public perception of risk to health, public acceptance of recommendations based on scientific criteria, political support, time constraints, and economic concerns must all be addressed in the context of a specific scenario to yield effective and acceptable decontamination.

A flow-through chromatography process for influenza A and B virus purification.

PubMed

Weigel, Thomas; Solomaier, Thomas; Peuker, Alessa; Pathapati, Trinath; Wolff, Michael W; Reichl, Udo

2014-10-01

Vaccination is still the most efficient measure to protect against influenza virus infections. Besides the seasonal wave of influenza, pandemic outbreaks of bird or swine flu represent a high threat to human population. With the establishment of cell culture-based processes, there is a growing demand for robust, economic and efficient downstream processes for influenza virus purification. This study focused on the development of an economic flow-through chromatographic process avoiding virus strain sensitive capture steps. Therefore, a three-step process consisting of anion exchange chromatography (AEC), Benzonase(®) treatment, and size exclusion chromatography with a ligand-activated core (LCC) was established, and tested for purification of two influenza A virus strains and one influenza B virus strain. The process resulted in high virus yields (≥68%) with protein contamination levels fulfilling requirements of the European Pharmacopeia for production of influenza vaccines for human use. DNA was depleted by ≥98.7% for all strains. The measured DNA concentrations per dose were close to the required limits of 10ng DNA per dose set by the European Pharmacopeia. In addition, the added Benzonase(®) could be successfully removed from the product fraction. Overall, the presented downstream process could potentially represent a simple, robust and economic platform technology for production of cell culture-derived influenza vaccines. Copyright © 2014 Elsevier B.V. All rights reserved.

LNT IS THE BEST WE CAN DO - TO-DAY

EPA Science Inventory

Abstract

The form of the dose-response curve for radiation-induced cancers, particularly at low doses, is the subject of an ongoing and spirited debate. The present review describes the current data base and basis for establishing a low dose, linear no threshold (LNT) mode...

ANALYSIS OF UNCERTAINTIES IN DOSE RECONSTRUCTION FROM BIOMARKERS: IMPACT ON STUDY DESIGN

EPA Science Inventory

The absorbed dose is defined as the quantity which has passed through the barriers (skin, GI tract, The absorbed dose of a pesticide can be estimated from its established urinary biomarker. ungs). For an exposure study, there are several options for biomarker collection, each w...

MO-DE-204-01: Radiation Doses in Over 50 Developing Countries of Asia, Africa, Eastern European and Latin America

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

Rehani, M.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

MO-DE-204-00: International Symposium: Patient Dose Reduction in Diagnostic Radiology

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

NONE

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

MO-DE-204-02: Optimization of the Patient CT Dose in Europe

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

Tsapaki, V.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

MO-DE-204-03: Radiology Dose Optimisation - An Australian Perspective

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

Schick, D.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

PubMed

Fathi, Amir T; Wander, Seth A; Blonquist, Traci M; Brunner, Andrew M; Amrein, Philip C; Supko, Jeffrey; Hermance, Nicole M; Manning, Amity L; Sadrzadeh, Hossein; Ballen, Karen K; Attar, Eyal C; Graubert, Timothy A; Hobbs, Gabriela; Joseph, Christelle; Perry, Ashley M; Burke, Meghan; Silver, Regina; Foster, Julia; Bergeron, Meghan; Ramos, Aura Y; Som, Tina T; Fishman, Kaitlyn M; McGregor, Kristin L; Connolly, Christine; Neuberg, Donna S; Chen, Yi-Bin

2017-04-01

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. ( clinicaltrials.gov Identifier:01779843 ). Copyright© Ferrata Storti Foundation.

Yield responses of ruderal plants to sucrose in invasive-dominated sagebrush steppe of the northern Great Basin

USGS Publications Warehouse

Brunson, Jessi; Pyke, David A.; Perakis, Steven S.

2010-01-01

Restoration of sagebrush-steppe plant communities dominated by the invasive ruderals Bromus tectorum (cheatgrass) and Taeniatherum caput-medusae (medusahead) can be facilitated by adding carbon (C) to the soil, stimulating microbes to immobilize nitrogen (N) and limit inorganic N availability. Our objectives were to determine responses in (1) cheatgrass and medusahead biomass and seed production; (2) soil microbial biomass C and N; and (3) inorganic soil N to a range of C doses and to calculate the lowest dose that yielded a significant response. In November 2005, we applid 12 C doses ranging from 0 to 2,400 kg C/ha as sucrose to plots sown with cheatgrass and medusahead at two sites in the northern Great Basin. Other ruderal plants established in our plots, and this entire ruderal community was negatively affected by C addition. End-of-year biomass of the ruderal community decreased approximately by approximately 6% at each site for an increase in C dose of 100 kg C/ha. For the same increase in C, microbial biomass C increased by 2–4 mg/kg in November 2005 and March 2006, but not in July 2006. There was little, if any, microbial soil N uptake, as microbial biomass N increased by 0.3 mg/kg at only one site at the earliest date, in November 2005. Soil nitrate (NO3−) measured via resin capsules placed in situ for the study duration decreased at both sites with increasing C. Although we found no threshold dose of C, for a significant reduction in ruderal biomass, we calculated lowest significant doses of 240–640 kg C/ha.

Improving the Accuracy of a Heliocentric Potential (HCP) Prediction Model for the Aviation Radiation Dose

NASA Astrophysics Data System (ADS)

Hwang, Junga; Yoon, Kyoung-Won; Jo, Gyeongbok; Noh, Sung-Jun

2016-12-01

The space radiation dose over air routes including polar routes should be carefully considered, especially when space weather shows sudden disturbances such as coronal mass ejections (CMEs), flares, and accompanying solar energetic particle events. We recently established a heliocentric potential (HCP) prediction model for real-time operation of the CARI-6 and CARI-6M programs. Specifically, the HCP value is used as a critical input value in the CARI-6/6M programs, which estimate the aviation route dose based on the effective dose rate. The CARI-6/6M approach is the most widely used technique, and the programs can be obtained from the U.S. Federal Aviation Administration (FAA). However, HCP values are given at a one month delay on the FAA official webpage, which makes it difficult to obtain real-time information on the aviation route dose. In order to overcome this critical limitation regarding the time delay for space weather customers, we developed a HCP prediction model based on sunspot number variations (Hwang et al. 2015). In this paper, we focus on improvements to our HCP prediction model and update it with neutron monitoring data. We found that the most accurate method to derive the HCP value involves (1) real-time daily sunspot assessments, (2) predictions of the daily HCP by our prediction algorithm, and (3) calculations of the resultant daily effective dose rate. Additionally, we also derived the HCP prediction algorithm in this paper by using ground neutron counts. With the compensation stemming from the use of ground neutron count data, the newly developed HCP prediction model was improved.

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

Fury, Matthew G.; Department of Medicine, Weill Cornell Medical College, New York, New York; Lee, Nancy Y.

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neckmore » cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.« less

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.

PubMed

Brohl, Andrew S; Khushalani, Nikhil I; Eroglu, Zeynep; Markowitz, Joseph; Thapa, Ram; Chen, Y Ann; Kudchadkar, Ragini; Weber, Jeffrey S

2016-01-01

Ipilimumab and peginterferon alfa-2b are established systemic treatment options for melanoma that have distinct mechanisms of action. Given the need for improved therapies for advanced melanoma, we conducted an open-label, single institution, phase Ib study to assess the safety and tolerability of using these two agents in combination. Study treatment consisted of ipilimumab given every 3 weeks, for a total of four infusions, concurrent with peginterferon alfa-2b administered subcutaneous weekly for a total of 12 weeks. This was followed by maintenance therapy with peginterferon alfa-2b administered subcutaneously weekly for up to 144 additional weeks. The study was designed as a two-stage dose escalation scheme with continuous dose-limiting toxicity monitoring during the induction phase. Thirty one patients received at least 1 dose of study treatment and 30 were assessable for efficacy endpoints. We found that ipilimumab at 3 mg/kg dosing with peginterfeon alfa-2b at 2 μg/kg/week was the maximum tolerated dose of this combination. The incidence of grade 3 drug-related adverse events (AEs) was 45.2%. There were no grade 4/5 AEs. The overall response rate was 40% by immune-related response criteria. Median progression-free survival was 5.9 months. The median overall survival was not reached with at a median follow-up of 35.8 months. We report that the combination of ipilimumab at 3 mg/kg dosing combined with peginterfeon alfa-2b at 2 μg/kg/week demonstrated an acceptable toxicity profile and a promising efficacy signal. Further study of this combination is warranted. ClinicalTrials.gov identifier: NCT01496807, Registered December 19th, 2011.

A comparison of quantum limited dose and noise equivalent dose

NASA Astrophysics Data System (ADS)

Job, Isaias D.; Boyce, Sarah J.; Petrillo, Michael J.; Zhou, Kungang

2016-03-01

Quantum-limited-dose (QLD) and noise-equivalent-dose (NED) are performance metrics often used interchangeably. Although the metrics are related, they are not equivalent unless the treatment of electronic noise is carefully considered. These metrics are increasingly important to properly characterize the low-dose performance of flat panel detectors (FPDs). A system can be said to be quantum-limited when the Signal-to-noise-ratio (SNR) is proportional to the square-root of x-ray exposure. Recent experiments utilizing three methods to determine the quantum-limited dose range yielded inconsistent results. To investigate the deviation in results, generalized analytical equations are developed to model the image processing and analysis of each method. We test the generalized expression for both radiographic and fluoroscopic detectors. The resulting analysis shows that total noise content of the images processed by each method are inherently different based on their readout scheme. Finally, it will be shown that the NED is equivalent to the instrumentation-noise-equivalent-exposure (INEE) and furthermore that the NED is derived from the quantum-noise-only method of determining QLD. Future investigations will measure quantum-limited performance of radiographic panels with a modified readout scheme to allow for noise improvements similar to measurements performed with fluoroscopic detectors.

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

PubMed Central

Manolis, E; Holford, N; Cheung, SYA; Friberg, LE; Ogungbenro, K; Posch, M; Yates, JWT; Berry, S; Thomas, N; Corriol‐Rohou, S; Bornkamp, B; Bretz, F; Hooker, AC; Van der Graaf, PH; Standing, JF; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-01-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. PMID:28722322

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

PubMed

Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Long-term outcome of accelerated partial breast irradiation using a multilumen balloon applicator in a patient with existing breast implants.

PubMed

Akhtari, Mani; Nitsch, Paige L; Bass, Barbara L; Teh, Bin S

2015-01-01

Accelerated partial breast irradiation is now an accepted component of breast-conserving therapy. However, data regarding long-term outcomes of patients treated with multilumen catheter systems who have existing breast implants are limited. We report the treatment and outcome of our patient who had existing bilateral silicone subpectoral implants at the time of presentation. Ultrasound-guided core needle biopsy of the right breast showed infiltrating mucinous carcinoma. Right breast lumpectomy revealed an 8 mm area of infiltrating ductal carcinoma with mucinous features and nuclear grade 1. A 4-5 cm Contura (Bard Biopsy Systems, Tempe, AZ) device was placed, and she was treated over the course of 5 days twice daily to a dose of 34 Gy using a high-dose-rate iridium-192 source. The planning target volume for evaluation was 73.9 cc. The percentage of the planning target volume for evaluation receiving 90%, 95%, and 100% of the prescribed dose was 99.9%, 99.3%, and 97.8%, respectively. The total implant volume was 234.5 cc and received a mean dose of 15.4 Gy and a maximum dose of 72.8 Gy. The percentage of implant volume receiving 50%, 75%, 100%, and 200% of the prescribed dose was 31.1%, 16.5%, 8.6%, 2.0%, and 0%, respectively. Maximum skin dose was 97% of the prescribed dose. With a followup of nearly 5 years, she continues to be cancer free with minimal late toxicities and good to excellent cosmetic outcome. Accelerated partial breast irradiation using a multilumen balloon applicator in patients with existing breast implants can safely be performed with excellent long-term cosmetic outcome. Further studies are needed to establish the absolute dosimetric tolerance of breast implants. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

SU-E-T-04: 3D Dose Based Patient Compensator QA Procedure for Proton Radiotherapy

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

Zou, W; Reyhan, M; Zhang, M

2015-06-15

Purpose: In proton double-scattering radiotherapy, compensators are the essential patient specific devices to contour the distal dose distribution to the tumor target. Traditional compensator QA is limited to checking the drilled surface profiles against the plan. In our work, a compensator QA process was established that assess the entire compensator including its internal structure for patient 3D dose verification. Methods: The fabricated patient compensators were CT scanned. Through mathematical image processing and geometric transformations, the CT images of the proton compensator were combined with the patient simulation CT images into a new series of CT images, in which the imagedmore » compensator is placed at the planned location along the corresponding beam line. The new CT images were input into the Eclipse treatment planning system. The original plan was calculated to the combined CT image series without the plan compensator. The newly computed patient 3D dose from the combined patientcompensator images was verified against the original plan dose. Test plans include the compensators with defects intentionally created inside the fabricated compensators. Results: The calculated 3D dose with the combined compensator and patient CT images reflects the impact of the fabricated compensator to the patient. For the test cases in which no defects were created, the dose distributions were in agreement between our method and the corresponding original plans. For the compensator with the defects, the purposely changed material and a purposely created internal defect were successfully detected while not possible with just the traditional compensator profiles detection methods. Conclusion: We present here a 3D dose verification process to qualify the fabricated proton double-scattering compensator. Such compensator detection process assesses the patient 3D impact of the fabricated compensator surface profile as well as the compensator internal material and structure changes. This research receives funding support from CURA Medical Technologies.« less

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.

PubMed

Choueiri, Toni K; Larkin, James; Oya, Mototsugu; Thistlethwaite, Fiona; Martignoni, Marcella; Nathan, Paul; Powles, Thomas; McDermott, David; Robbins, Paul B; Chism, David D; Cho, Daniel; Atkins, Michael B; Gordon, Michael S; Gupta, Sumati; Uemura, Hirotsugu; Tomita, Yoshihiko; Compagnoni, Anna; Fowst, Camilla; di Pietro, Alessandra; Rini, Brian I

2018-04-01

The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Pfizer and Merck. Copyright © 2018 Elsevier Ltd. All rights reserved.

Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media.

PubMed

Easton, Jane; Noble, Stuart; Perry, Caroline M

2003-01-01

Amoxicillin/clavulanic acid (Augmentin), Augmentin ES-600 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a beta-lactamase inhibitor). Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains. Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age approximately 2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age approximately 1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age approximately 1 year). The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L). Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial. Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC < or =2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent paediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

Radiocesium contamination and estimated internal exposure doses in edible wild plants in Kawauchi Village following the Fukushima nuclear disaster

PubMed Central

Tsuchiya, Rimi; Orita, Makiko; Fukushima, Yoshiko; Endo, Yuukou; Yamashita, Shunichi; Takamura, Noboru

2017-01-01

Kawauchi Village, in Fukushima Prefecture, is located within a 30-km radius of the nuclear disaster site of the Fukushima Daiichi Nuclear Power Plant (FDNPP). “Sansai” (edible wild plants) in this village have been evaluated by gamma spectrometry after the residents had returned to their homes, to determine the residents’ risk of internal exposure to artificial radionuclides due to consumption of these plants. The concentrations of radiocesium (cesium-134 and cesium-137) were measured in all 364 samples collected in spring 2015. Overall, 34 (9.3%) samples exceeded the regulatory limit of 100 Bq/kg established by Japanese guidelines, 80 (22.0%) samples registered between 100 Bq/kg and 20 Bq/kg, and 250 (68.7%) registered below 20 Bq/kg (the detection limit). The internal effective doses from edible wild plants were sufficiently low (less than 1 mSv/y), at 3.5±1.2 μSv/y for males and 3.2±0.9 μSv/y for females (2.7±1.5 μSv/y for children and 3.7±0.7 μSv/y for adults in 2015). Thus, the potential internal exposure doses due to consumption of these edible wild plants were below the applicable radiological standard limits for foods. However, high radiocesium levels were confirmed in specific species, such as Eleutherococcus sciadophylloides (“Koshiabura”) and Osmunda japonica (Asian royal fern, “Zenmai”). Consequently, a need still might exist for long-term follow-up such as environmental monitoring, physical and mental support to avoid unnecessary radiation exposure and to remove anxiety about adverse health effects due to radiation. The customs of residents, especially the “satoyama” (countryside) culture of ingesting “sansai,” also require consideration in the further reconstruction of areas such as Kawauchi Village that were affected by the nuclear disaster. PMID:29240794

Radiocesium contamination and estimated internal exposure doses in edible wild plants in Kawauchi Village following the Fukushima nuclear disaster.

PubMed

Tsuchiya, Rimi; Taira, Yasuyuki; Orita, Makiko; Fukushima, Yoshiko; Endo, Yuukou; Yamashita, Shunichi; Takamura, Noboru

2017-01-01

Kawauchi Village, in Fukushima Prefecture, is located within a 30-km radius of the nuclear disaster site of the Fukushima Daiichi Nuclear Power Plant (FDNPP). "Sansai" (edible wild plants) in this village have been evaluated by gamma spectrometry after the residents had returned to their homes, to determine the residents' risk of internal exposure to artificial radionuclides due to consumption of these plants. The concentrations of radiocesium (cesium-134 and cesium-137) were measured in all 364 samples collected in spring 2015. Overall, 34 (9.3%) samples exceeded the regulatory limit of 100 Bq/kg established by Japanese guidelines, 80 (22.0%) samples registered between 100 Bq/kg and 20 Bq/kg, and 250 (68.7%) registered below 20 Bq/kg (the detection limit). The internal effective doses from edible wild plants were sufficiently low (less than 1 mSv/y), at 3.5±1.2 μSv/y for males and 3.2±0.9 μSv/y for females (2.7±1.5 μSv/y for children and 3.7±0.7 μSv/y for adults in 2015). Thus, the potential internal exposure doses due to consumption of these edible wild plants were below the applicable radiological standard limits for foods. However, high radiocesium levels were confirmed in specific species, such as Eleutherococcus sciadophylloides ("Koshiabura") and Osmunda japonica (Asian royal fern, "Zenmai"). Consequently, a need still might exist for long-term follow-up such as environmental monitoring, physical and mental support to avoid unnecessary radiation exposure and to remove anxiety about adverse health effects due to radiation. The customs of residents, especially the "satoyama" (countryside) culture of ingesting "sansai," also require consideration in the further reconstruction of areas such as Kawauchi Village that were affected by the nuclear disaster.

Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls.

PubMed

Bandla, Aishwarya; Sundar, Raghav; Liao, Lun-De; Sze Hui Tan, Stacey; Lee, Soo-Chin; Thakor, Nitish V; Wilder-Smith, Einar P V

2016-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and no effective treatment has been established so far. The mechanisms of CIPN damage are unclear, but are directly dose-related. We had earlier demonstrated, in rats, the influence of hypothermia in reducing nerve blood flow. Here, we hypothesize that continuous flow limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects. In 15 healthy human subjects, hypothermia was administered as continuous flow cooling, unilaterally, via a thermoregulator setup covering the digits up to the elbow/knee, along with continuous skin temperature monitoring. Thermoregulator coolant temperatures between 25 °C and 20 °C were tested for tolerability, based on a carefully designed temperature regulation protocol, and maintained for three hours mimicking the duration of chemotherapy. Tolerability was evaluated using various safety and tolerability scores to monitor the subjects. At the end of the cooling session the healthy subjects presented without significant adverse effects, the main being brief mild skin erythema and transient numbness. Coolant temperatures as low as 22 °C were well tolerated continuously over three hours. Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use 22 °C thermoregulator temperature to investigate hypothermia in preventing CIPN in breast cancer patients receiving adjuvant weekly paclitaxel. This pilot study may contribute to alleviating chemotherapy dose limitation due to CIPN and increase the likelihood of success of chemotherapy.

Dose audit for patients undergoing two common radiography examinations with digital radiology systems.

PubMed

İnal, Tolga; Ataç, Gökçe

2014-01-01

We aimed to determine the radiation doses delivered to patients undergoing general examinations using computed or digital radiography systems in Turkey. Radiographs of 20 patients undergoing posteroanterior chest X-ray and of 20 patients undergoing anteroposterior kidney-ureter-bladder radiography were evaluated in five X-ray rooms at four local hospitals in the Ankara region. Currently, almost all radiology departments in Turkey have switched from conventional radiography systems to computed radiography or digital radiography systems. Patient dose was measured for both systems. The results were compared with published diagnostic reference levels (DRLs) from the European Union and International Atomic Energy Agency. The average entrance surface doses (ESDs) for chest examinations exceeded established international DRLs at two of the X-ray rooms in a hospital with computed radiography. All of the other ESD measurements were approximately equal to or below the DRLs for both examinations in all of the remaining hospitals. Improper adjustment of the exposure parameters, uncalibrated automatic exposure control systems, and failure of the technologists to choose exposure parameters properly were problems we noticed during the study. This study is an initial attempt at establishing local DRL values for digital radiography systems, and will provide a benchmark so that the authorities can establish reference dose levels for diagnostic radiology in Turkey.

Probabilistic framework for the estimation of the adult and child toxicokinetic intraspecies uncertainty factors.

PubMed

Pelekis, Michael; Nicolich, Mark J; Gauthier, Joseph S

2003-12-01

Human health risk assessments use point values to develop risk estimates and thus impart a deterministic character to risk, which, by definition, is a probability phenomenon. The risk estimates are calculated based on individuals and then, using uncertainty factors (UFs), are extrapolated to the population that is characterized by variability. Regulatory agencies have recommended the quantification of the impact of variability in risk assessments through the application of probabilistic methods. In the present study, a framework that deals with the quantitative analysis of uncertainty (U) and variability (V) in target tissue dose in the population was developed by applying probabilistic analysis to physiologically-based toxicokinetic models. The mechanistic parameters that determine kinetics were described with probability density functions (PDFs). Since each PDF depicts the frequency of occurrence of all expected values of each parameter in the population, the combined effects of multiple sources of U/V were accounted for in the estimated distribution of tissue dose in the population, and a unified (adult and child) intraspecies toxicokinetic uncertainty factor UFH-TK was determined. The results show that the proposed framework accounts effectively for U/V in population toxicokinetics. The ratio of the 95th percentile to the 50th percentile of the annual average concentration of the chemical at the target tissue organ (i.e., the UFH-TK) varies with age. The ratio is equivalent to a unified intraspecies toxicokinetic UF, and it is one of the UFs by which the NOAEL can be divided to obtain the RfC/RfD. The 10-fold intraspecies UF is intended to account for uncertainty and variability in toxicokinetics (3.2x) and toxicodynamics (3.2x). This article deals exclusively with toxicokinetic component of UF. The framework provides an alternative to the default methodology and is advantageous in that the evaluation of toxicokinetic variability is based on the distribution of the effective target tissue dose, rather than applied dose. It allows for the replacement of the default adult and children intraspecies UF with toxicokinetic data-derived values and provides accurate chemical-specific estimates for their magnitude. It shows that proper application of probability and toxicokinetic theories can reduce uncertainties when establishing exposure limits for specific compounds and provide better assurance that established limits are adequately protective. It contributes to the development of a probabilistic noncancer risk assessment framework and will ultimately lead to the unification of cancer and noncancer risk assessment methodologies.

TIME COURSE AND DOSE RESPONSE ASSESSMENT OF CHOLINESTERASE (CHE) INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL, METHOMYL, METHIOCARB, OXAMYL, OR PROPOXUR.

EPA Science Inventory

To compare the toxicity of 5 N-methyl carbamates, the time course and dose response profiles for ChE inhibition were established for each. For the time course comparison, adult male Long Evans rats (n=5 dose group) were dosed orally with either carbaryl (CB; 30 mg/kg in corn oi...

SU-E-T-310: Micro-Dosimetry Study of the Radiation Dose Enhancement at the Gold-Tissue Interface for Nanoparticle-Aided Radiation Therapy.

PubMed

Paudel, N; Shvydka, D; Parsai, E

2012-06-01

Gold nanoparticles (AuNP) have been proposed to be utilized for local dose enhancement in radiation therapy. Due to a very sharp spatial fall-off of the effect, the dosimetry associated with such an approach is difficult to implement in a direct measurement. This study is aimed at establishing a micro-dosimetry technique for experimental verification of dose enhancement in the vicinity of gold-tissue interface. The spatial distribution of the dose enhancement near the gold-tissue interface is modeled with Monte Carlo (MC) package MCNP5 in a 1-dimentional approach of a thin gold slab placed in an ICRU-4 component tissue phantom. The model is replicating the experiment, where the dose enhancement due to gold foils having thicknesses of 1, 10, and 100μm and areas of 12.5×25mm 2 are placed at a short distance from clinical HDR brachytherapy (Ir-192) source. The measurements are carried out with a thin-film CdTe-based photodetector, having thickness <10μm, allowing for high spatial resolution at progressively increasing distances from the foil. Our MC simulation results indicate that for Ir-192 energy spectrum the dose enhancement region extends over ∼1 mm distance from the foil, changing from several hundred at the interface to just a few percent. The trend in the measured dose enhancement closely follows the results obtained from MC simulations. AuNP's have been established as promising candidates for dose enhancement in nanoparticle-aided radiation therapy, particularly, in the energy range relevant to brachytherapy applications. Most researchers study the dose enhancement with MC simulations, or experimental approaches involving biological systems, where achievable dose enhancements are difficult to quantify. Successful development of micro-dosimetry approaches will pave a way for direct assessment of the dose in experiments on biological models, shedding some light on apparent discrepancy between physical dose enhancement and biological effect established in studies of AuNP-aided radiation therapy. No conflict of interest. © 2012 American Association of Physicists in Medicine.

Evaluation and comparison of absorbed dose for electron beams by LiF and diamond dosimeters

NASA Astrophysics Data System (ADS)

Mosia, G. J.; Chamberlain, A. C.

2007-09-01

The absorbed dose response of LiF and diamond thermoluminescent dosimeters (TLDs), calibrated in 60Co γ-rays, has been determined using the MCNP4B Monte Carlo code system in mono-energetic megavoltage electron beams from 5 to 20 MeV. Evaluation of the dose responses was done against the dose responses of published works by other investigators. Dose responses of both dosimeters were compared to establish if any relation exists between them. The dosimeters were irradiated in a water phantom with the centre of their top surfaces (0.32×0.32 cm 2), placed at dmax perpendicular to the radiation beam on the central axis. For LiF TLD, dose responses ranged from 0.945±0.017 to 0.997±0.011. For the diamond TLD, the dose response ranged from 0.940±0.017 to 1.018±0.011. To correct for dose responses by both dosimeters, energy correction factors were generated from dose response results of both TLDs. For LiF TLD, these correction factors ranged from 1.003 up to 1.058 and for diamond TLD the factors ranged from 0.982 up to 1.064. The results show that diamond TLDs can be used in the place of the well-established LiF TLDs and that Monte Carlo code systems can be used in dose determinations for radiotherapy treatment planning.

A single institution study of radiation dose received from CT imaging: A comparison to Malaysian NDRL

NASA Astrophysics Data System (ADS)

Osman, N. D.; Shamsuri, S. B. M.; Tan, Y. W.; Razali, M. A. S. M.; Isa, S. M.

2017-05-01

Advancement of CT technology has led to an increase in CT scanning as it improves the diagnosis. However, it is important to assess health risk of patients associated with ionising radiation received from CT. This study evaluated current dose distributions at Advanced Medical and Dental Institute (AMDI), Malaysia and was used to establish Local Diagnostic Reference Level (LDRL). Dose indicators such as CT Dose Index (CTDIvol and CTDIw) and Dose-Length Product (DLP) were gathered for all routine CT examinations performed at the Imaging Unit, AMDI from January 2015 to June 2016. The first and third quartile values for each dose indicator were determined. A total of 364 CT studies were performed during that period with the highest number of cases being Thorax-Abdomen-Pelvis (TAP) study (57% of total study). The CTDIw ranged between 2.0 mGy to 23.4 mGy per procedure. DLP values were ranged between 94 mGy.cm to 1687 mGy.cm. The local dose data was compared with the national DRL to monitor the current CT practice at AMDI and LDRL will be established from the calculated third quartile values of dose distribution. From the results, some of the local dose values exceeded the Malaysian and further evaluation is important to ensure the dose optimisation for patients.

10 CFR 835.206 - Limits for the embryo/fetus.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Limits for the embryo/fetus. 835.206 Section 835.206... Exposure § 835.206 Limits for the embryo/fetus. (a) The equivalent dose limit for the embryo/fetus from the... provided in § 835.206(a) shall be avoided. (c) If the equivalent dose to the embryo/fetus is determined to...

10 CFR 835.206 - Limits for the embryo/fetus.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Limits for the embryo/fetus. 835.206 Section 835.206... Exposure § 835.206 Limits for the embryo/fetus. (a) The equivalent dose limit for the embryo/fetus from the... provided in § 835.206(a) shall be avoided. (c) If the equivalent dose to the embryo/fetus is determined to...

10 CFR 835.206 - Limits for the embryo/fetus.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Limits for the embryo/fetus. 835.206 Section 835.206... Exposure § 835.206 Limits for the embryo/fetus. (a) The equivalent dose limit for the embryo/fetus from the... provided in § 835.206(a) shall be avoided. (c) If the equivalent dose to the embryo/fetus is determined to...

10 CFR 835.206 - Limits for the embryo/fetus.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Limits for the embryo/fetus. 835.206 Section 835.206... Exposure § 835.206 Limits for the embryo/fetus. (a) The equivalent dose limit for the embryo/fetus from the... provided in § 835.206(a) shall be avoided. (c) If the equivalent dose to the embryo/fetus is determined to...

10 CFR 835.206 - Limits for the embryo/fetus.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Limits for the embryo/fetus. 835.206 Section 835.206... Exposure § 835.206 Limits for the embryo/fetus. (a) The equivalent dose limit for the embryo/fetus from the... provided in § 835.206(a) shall be avoided. (c) If the equivalent dose to the embryo/fetus is determined to...

Pharmacokinetics and tissue elimination of flunixin in veal calves.

PubMed

Kissell, Lindsey W; Brinson, Patrick D; Gehring, Ronette; Tell, Lisa A; Wetzlich, Scott E; Baynes, Ronald E; Riviere, Jim E; Smith, Geof W

2016-06-01

OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves. ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old. PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose. CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.

The use of human hair as biodosimeter.

PubMed

Tepe Çam, S; Polat, M; Seyhan, N

2014-12-01

The potential use of human hair samples as biologic dosimeter was investigated by electron spin resonance (ESR) spectroscopy. The hair samples were obtained from female volunteers and classified according to the color, age and whether they are natural or dyed. Natural black, brown, red, blonde and dyed black hair samples were irradiated at low doses (5-50Gy) and high doses (75-750Gy) by gamma source giving the dose rate of 0.25Gy/s in The Sarayköy Establishment of Turkish Atomic Energy Authority. While the peak heights and g-values (2.0021-2.0023) determined from recorded spectra of hair were color dependent, the peak-to-peak line widths were varied according to natural or dyed hair (ΔHpp: 0.522-0.744mT). In all samples, the linear dose-response curves at low doses saturated after ~300Gy. In black hair samples taken from different individuals, differences in the structure of the spectrum and signal intensities were not observed. The EPR signal intensities of samples stored at room temperature for 22 days fell to their half-values in 44h in black hair, 41h in blonde and brown hairs, 35h in dyed black hair and in 17h in red hair. The activation energies of samples annealed at high temperatures for different periods of time were correlated well with those obtained in the literature. In conclusion, hair samples can be used as a biological dosimeter considering the limitations showed in this study. Copyright © 2014 Elsevier Ltd. All rights reserved.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PubMed

Wang-Gillam, Andrea; Arnold, Susanne M; Bukowski, Ronald M; Rothenberg, Mace L; Cooper, Wendy; Wang, Kenneth K; Gauthier, Eric; Lockhart, A Craig

2012-02-01

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

PubMed

Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-07-15

Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. © 2015 American Cancer Society.

Semaglutide, a Once-Weekly Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral Contraceptive, Ethinylestradiol/Levonorgestrel

PubMed Central

Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

2015-01-01

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80–1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0–24 h) for semaglutide steady-state/semaglutide-free; 1.11 (1.06–1.15). AUC0–24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15–1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (–1.1 ± 0.6%) and weight (–4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel. PMID:25475122

Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.

PubMed

Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

2015-05-01

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Dose received by occupationally exposed workers at a nuclear medicine department

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

Avila, O.; Sanchez-Uribe, N. A.; Rodriguez-Laguna, A.

2012-10-23

Personal Dose Equivalent (PDE) values were determined for occupational exposed workers (OEW) at the Nuclear Medicine Department (NMD) of 'Instituto Nacional de Cancerologia' (INCan), Mexico, using TLD-100 thermoluminescent dosemeters. OEW at NMD, INCan make use of radiopharmaceuticals for diagnosis and treatment of diseases. Radionuclides associated to a pharmaceutical compound used at this Department are {sup 131}I, {sup 18}F, {sup 68}Ga, {sup 99m}Tc, {sup 111}In and {sup 11}C with main gamma emission energies between 140 and 511 keV. Dosemeter calibration was performed at the metrology department of 'Instituto Nacional de Investigaciones Nucleares' (ININ), Mexico. Every occupational worker used dark containers withmore » three dosimeters which were replaced monthly for a total of 5 periods. Additionally, control dosemeters were also placed at a site free of radioactive sources in order to determine the background radiation. Results were adjusted to find PDE/day and estimating annual PDE values in the range between 2 mSv (background) and 9 mSv. The mean annual value is 3.51 mSv and the standard deviation SD is 0.78 mSv. Four of the 16 OEW received annual doses higher than the average +1 SD (4.29 mSv). Results depend on OEW daily activities and were consistent for each OEW for the 5 studied periods as well as with PDE values reported by the firm that performs the monthly service. All obtained values are well within the established annual OEW dose limit stated in the {sup R}eglamento General de Seguridad Radiologica{sup ,} Mexico (50 mSv), as well as within the lower limit recommended by the 'International Commission on Radiation Protection' (ICRP), report no.60 (20 mSv). These results verify the adequate compliance of the NMD at INCan, Mexico with the norms given by the national regulatory commission.« less

Is there a place for quantitative risk assessment?

PubMed

Hall, Eric J

2009-06-01

The use of ionising radiations is so well established, especially in the practice of medicine, that it is impossible to imagine contemporary life without them. At the same time, ionising radiations are a known and proven human carcinogen. Exposure to radiation in some contexts elicits fear and alarm (nuclear power for example) while in other situations, until recently at least, it was accepted with alacrity (diagnostic x-rays for example). This non-uniform reaction to the potential hazards of radiation highlights the importance of quantitative risk estimates, which are necessary to help put things into perspective. Three areas will be discussed where quantitative risk estimates are needed and where uncertainties and limitations are a problem. First, the question of diagnostic x-rays. CT usage over the past quarter of a century has increased about 12 fold in the UK and more than 20 fold in the US. In both countries, more than 90% of the collective population dose from diagnostic x-rays comes from the few high dose procedures, such as interventional radiology, CT scans, lumbar spine x-rays and barium enemas. These all involve doses close to the lower limit at which there are credible epidemiological data for an excess cancer incidence. This is a critical question; what is the lowest dose at which there is good evidence of an elevated cancer incidence? Without low dose risk estimates the risk-benefit ratio of diagnostic procedures cannot be assessed. Second, the use of new techniques in radiation oncology. IMRT is widely used to obtain a more conformal dose distribution, particularly in children. It results in a larger total body dose, due to an increased number of monitor units and to the application of more radiation fields. The Linacs used today were not designed for IMRT and are based on leakage standards that were decided decades ago. It will be difficult and costly to reduce leakage from treatment machines, and a necessary first step is to refine the available radiation risks at the fractionated high doses characteristic of radiotherapy. The dose response for carcinogenesis is known for single doses up to about 2 Sv from the A-bomb data, but the shape at higher fractionated doses is uncertain. Third, the proliferation of proton facilities. The improved dose distribution made possible by charged particle beams has created great interest and led to the design and building of many expensive proton centres. However, due to technical problems, most facilities use passive scattering, rather than spot scanning, to spread the pencil beam to cover realistic target volumes. This process, together with the methods used of final collimation, results in substantial total body doses of neutrons. The relative biological effectiveness of these neutrons is not well known, and the risk estimates are therefore uncertain. Unless and until the risks are known with more certainty, it is difficult to know how much effort and cost should be directed towards reducing, or eliminating, the neutron doses. These three examples, where uncertainties in quantitative risk estimates result in important practical problems, will be discussed.

Current situations and discussions in Japan in relation to the new occupational equivalent dose limit for the lens of the eye.

PubMed

Yokoyama, Sumi; Hamada, Nobuyuki; Hayashida, Toshiyuki; Tsujimura, Norio; Tatsuzaki, Hideo; Kurosawa, Tadahiro; Nabatame, Kuniaki; Ohguchi, Hiroyuki; Ohno, Kazuko; Yamauchi-Kawaura, Chiyo; Iimoto, Takeshi; Ichiji, Takeshi; Hotta, Yutaka; Iwai, Satoshi; Akahane, Keiichi

2017-09-25

Since the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens of the eye in 2011, there have been extensive discussions in various countries. This paper reviews the current situation in radiation protection of the ocular lens and the discussions on the potential impact of the new lens dose limit in Japan. Topics include historical changes to the lens dose limit, the current situation with occupational lens exposures (e.g., in medical workers, nuclear workers, and Fukushima nuclear power plant workers) and measurements, and the current status of biological studies and epidemiological studies on radiation cataracts. Our focus is on the situation in Japan, but we believe such information sharing will be useful in many other countries.

SU-E-T-769: T-Test Based Prior Error Estimate and Stopping Criterion for Monte Carlo Dose Calculation in Proton Therapy

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

Hong, X; Gao, H; Schuemann, J

2015-06-15

Purpose: The Monte Carlo (MC) method is a gold standard for dose calculation in radiotherapy. However, it is not a priori clear how many particles need to be simulated to achieve a given dose accuracy. Prior error estimate and stopping criterion are not well established for MC. This work aims to fill this gap. Methods: Due to the statistical nature of MC, our approach is based on one-sample t-test. We design the prior error estimate method based on the t-test, and then use this t-test based error estimate for developing a simulation stopping criterion. The three major components are asmore » follows.First, the source particles are randomized in energy, space and angle, so that the dose deposition from a particle to the voxel is independent and identically distributed (i.i.d.).Second, a sample under consideration in the t-test is the mean value of dose deposition to the voxel by sufficiently large number of source particles. Then according to central limit theorem, the sample as the mean value of i.i.d. variables is normally distributed with the expectation equal to the true deposited dose.Third, the t-test is performed with the null hypothesis that the difference between sample expectation (the same as true deposited dose) and on-the-fly calculated mean sample dose from MC is larger than a given error threshold, in addition to which users have the freedom to specify confidence probability and region of interest in the t-test based stopping criterion. Results: The method is validated for proton dose calculation. The difference between the MC Result based on the t-test prior error estimate and the statistical Result by repeating numerous MC simulations is within 1%. Conclusion: The t-test based prior error estimate and stopping criterion are developed for MC and validated for proton dose calculation. Xiang Hong and Hao Gao were partially supported by the NSFC (#11405105), the 973 Program (#2015CB856000) and the Shanghai Pujiang Talent Program (#14PJ1404500)« less

Low doses of glyphosate enhance growth, CO2 assimilation, stomatal conductance and transpiration in sugarcane and eucalyptus

USDA-ARS?s Scientific Manuscript database

Sublethal doses of herbicides can enhance plant growth and stimulate other process, an effect known as hormesis. The magnitude of hormesis is dependent on the plant species, the herbicide and its dose, plant development stage, and environmental parameters. Glyphosate hormesis is well established, bu...

The Dose-Effect Relationship in Psychodynamic Psychotherapy with People with Intellectual Disabilities

ERIC Educational Resources Information Center

Beail, Nigel; Kellett, Stephen; Newman, David W.; Warden, Sharon

2007-01-01

Background: Although there is an established body of evidence attesting to the dose-effect relationship in psychotherapy with non-disabled adults, the issue as to whether such a relationship exists for persons with intellectual disabilities has not been previously examined. Dose-effect essentially concerns the amount of psychotherapy required to…

COMPARISON OF ORGAN DOSES IN HUMAN PHANTOMS: VARIATIONS DUE TO BODY SIZE AND POSTURE.

PubMed

Feng, Xu; Xiang-Hong, Jia; Qian, Liu; Xue-Jun, Yu; Zhan-Chun, Pan; Chun-Xin, Yang

2017-04-20

Organ dose calculations performed using human phantoms can provide estimates of astronauts' health risks due to cosmic radiation. However, the characteristics of such phantoms strongly affect the estimation precision. To investigate organ dose variations with body size and posture in human phantoms, a non-uniform rational B-spline boundary surfaces model was constructed based on cryosection images. This model was used to establish four phantoms with different body size and posture parameters, whose organs parameters were changed simultaneously and which were voxelised with 4 × 4 × 4 mm3 resolution. Then, using Monte Carlo transport code, the organ doses caused by ≤500 MeV isotropic incident protons were calculated. The dose variations due to body size differences within a certain range were negligible, and the doses received in crouching and standing-up postures were similar. Therefore, a standard Chinese phantom could be established, and posture changes cannot effectively protect astronauts during solar particle events. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

National Emission Standards for Hazardous Air Pollutants - Radionuclide Emissions, Calendar Year 2010

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

NSTec Ecological and Environmental Monitoring

2011-06-30

The U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office operates the Nevada National Security Site (NNSS, formerly the Nevada Test Site) and North Las Vegas Facility (NLVF). From 1951 through 1992, the NNSS was the continental testing location for U.S. nuclear weapons. The release of radionuclides from NNSS activities has been monitored since the initiation of atmospheric testing. Limitation to underground detonations after 1962 greatly reduced radiation exposure to the public surrounding the NNSS. After nuclear testing ended in 1992, NNSS radiation monitoring focused on detecting airborne radionuclides from historically contaminated soils. These radionuclides are derived frommore » re-suspension of soil (primarily by wind) and emission of tritium-contaminated soil moisture through evapotranspiration. Low amounts of tritium are also emitted to air at the NLVF, an NNSS support complex in North Las Vegas. To protect the public from harmful levels of man-made radiation, the Clean Air Act, National Emission Standards for Hazardous Air Pollutants (NESHAP) (Title 40 Code of Federal Regulations [CFR] Part 61 Subpart H) (CFR, 2010a) limits the release of radioactivity from a U.S. Department of Energy (DOE) facility to that which would cause 10 millirem per year (mrem/yr) effective dose equivalent to any member of the public. This limit does not include radiation unrelated to NNSS activities. Unrelated doses could come from naturally occurring radioactive elements, from sources such as medically or commercially used radionuclides, or from sources outside of the United States, such as those from the damaged Fukushima nuclear power plant in Japan. Because this report is intended to discuss radioactive air emissions during calendar year 2010, data on radionuclides in air from the 2011 Fukushima nuclear power plant releases are not presented but will be included in the report for calendar year 2011. The NNSS demonstrates compliance with the NESHAP limit by using environmental measurements of radionuclide air concentrations at critical receptor locations (U.S. Environmental Protection Agency [EPA] and DOE, 1995). This method was approved by the EPA for use on the NNSS in 2001(EPA, 2001a) and has been the sole method used since 2005. Six locations on the NNSS have been established to act as critical receptor locations to demonstrate compliance with the NESHAP limit. These locations are actually pseudo-critical receptor stations, because no member of the public actually resides at these onsite locations. Compliance is demonstrated if the measured annual average concentration is less than the NESHAP Concentration Levels (CLs) for Environmental Compliance listed in 40 CFR 61, Appendix E, Table 2 (CFR, 2010a). For multiple radionuclides, compliance is demonstrated when the sum of the fractions (determined by dividing each radionuclide's concentration by its CL and then adding the fractions together) is less than 1.0. In 2010, the potential dose from radiological emissions to air, resulting from both current and past NNSS activities, at onsite compliance monitoring stations was well below the 10 mrem/yr dose limit. Air sampling data collected at all air monitoring stations had average concentrations of radioactivity that were a fraction of the CL values. Concentrations ranged from less than 1 percent to a maximum of 17 percent of the allowed NESHAP limit. Because the nearest member of the public resides about 20 kilometers from potential release points on the NNSS, dose to the public would be only a small fraction of that measured on the NNSS. The potential dose to the public from NLVF emissions was also very low at 0.000032 mrem/yr, more than 300,000 times lower than the 10 mrem/yr limit.« less

Construction of dose response calibration curves for dicentrics and micronuclei for X radiation in a Serbian population.

PubMed

Pajic, J; Rakic, B; Jovicic, D; Milovanovic, A

2014-10-01

Biological dosimetry using chromosome damage biomarkers is a valuable dose assessment method in cases of radiation overexposure with or without physical dosimetry data. In order to estimate dose by biodosimetry, any biological dosimetry service have to have its own dose response calibration curve. This paper reveals the results obtained after irradiation of blood samples from fourteen healthy male and female volunteers in order to establish biodosimetry in Serbia and produce dose response calibration curves for dicentrics and micronuclei. Taking into account pooled data from all the donors, the resultant fitted curve for dicentrics is: Ydic=0.0009 (±0.0003)+0.0421 (±0.0042)×D+0.0602 (±0.0022)×D(2); and for micronuclei: Ymn=0.0104 (±0.0015)+0.0824 (±0.0050)×D+0.0189 (±0.0017)×D(2). Following establishment of the dose response curve, a validation experiment was carried out with four blood samples. Applied and estimated doses were in good agreement. On this basis, the results reported here give us confidence to apply both calibration curves for future biological dosimetry requirements in Serbia. Copyright © 2014 Elsevier B.V. All rights reserved.

Methodology using a portable X-ray fluorescence device for on-site and rapid evaluation of heavy-atom contamination in wounds: a model study for application to plutonium contamination.

PubMed

Yoshii, Hiroshi; Yanagihara, Kouta; Imaseki, Hitoshi; Hamano, Tsuyoshi; Yamanishi, Hirokuni; Inagaki, Masayo; Sakai, Yasuhiro; Sugiura, Nobuyuki; Kurihara, Osamu; Sakai, Kazuo

2014-01-01

Workers decommissioning the Fukushima-Daiichi nuclear power plant damaged from the Great East Japan Earthquake and resulting tsunami are at risk of injury with possible contamination from radioactive heavy atoms including actinides, such as plutonium. We propose a new methodology for on-site and rapid evaluation of heavy-atom contamination in wounds using a portable X-ray fluorescence (XRF) device. In the present study, stable lead was used as the model contaminant substitute for radioactive heavy atoms. First, the wound model was developed by placing a liquid blood phantom on an epoxy resin wound phantom contaminated with lead. Next, the correlation between the concentration of contaminant and the XRF peak intensity was formulated considering the thickness of blood exiting the wound. Methods to determine the minimum detection limit (MDL) of contaminants at any maximal equivalent dose to the wound by XRF measurement were also established. For example, in this system, at a maximal equivalent dose of 16.5 mSv to the wound and blood thickness of 0.5 mm, the MDL value for lead was 1.2 ppm (3.1 nmol). The radioactivity of 239Pu corresponding to 3.1 nmol is 1.7 kBq, which is lower than the radioactivity of 239Pu contaminating puncture wounds in previous severe accidents. In conclusion, the established methodology could be beneficial for future development of a method to evaluate plutonium contamination in wounds. Highlights: Methodology for evaluation of heavy-atom contamination in a wound was established. A portable X-ray fluorescence device enables on-site, rapid and direct evaluation. This method is expected to be used for evaluation of plutonium contamination in wounds.

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

PubMed Central

Madsen, Daniel Elenius; Nichols, Timothy C.; Merricks, Elizabeth P.; Waters, Emily K.; Wiinberg, Bo

2017-01-01

Introduction Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material. Aim Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples. Methods A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent. Results With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX. Conclusion A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established. PMID:28384182

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

Kofler, J.

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

The magnetofection method: using magnetic force to enhance gene delivery.

PubMed

Plank, Christian; Schillinger, Ulrike; Scherer, Franz; Bergemann, Christian; Rémy, Jean-Serge; Krötz, Florian; Anton, Martina; Lausier, Jim; Rosenecker, Joseph

2003-05-01

In order to enhance and target gene delivery we have previously established a novel method, termed magnetofection, which uses magnetic force acting on gene vectors that are associated with magnetic particles. Here we review the benefits, the mechanism and the potential of the method with regard to overcoming physical limitations to gene delivery. Magnetic particle chemistry and physics are discussed, followed by a detailed presentation of vector formulation and optimization work. While magnetofection does not necessarily improve the overall performance of any given standard gene transfer method in vitro, its major potential lies in the extraordinarily rapid and efficient transfection at low vector doses and the possibility of remotely controlled vector targeting in vivo.

Quality correction factors of composite IMRT beam deliveries: Theoretical considerations

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

Bouchard, Hugo

2012-11-15

Purpose: In the scope of intensity modulated radiation therapy (IMRT) dosimetry using ionization chambers, quality correction factors of plan-class-specific reference (PCSR) fields are theoretically investigated. The symmetry of the problem is studied to provide recommendable criteria for composite beam deliveries where correction factors are minimal and also to establish a theoretical limit for PCSR delivery k{sub Q} factors. Methods: The concept of virtual symmetric collapsed (VSC) beam, being associated to a given modulated composite delivery, is defined in the scope of this investigation. Under symmetrical measurement conditions, any composite delivery has the property of having a k{sub Q} factor identicalmore » to its associated VSC beam. Using this concept of VSC, a fundamental property of IMRT k{sub Q} factors is demonstrated in the form of a theorem. The sensitivity to the conditions required by the theorem is thoroughly examined. Results: The theorem states that if a composite modulated beam delivery produces a uniform dose distribution in a volume V{sub cyl} which is symmetric with the cylindrical delivery and all beams fulfills two conditions in V{sub cyl}: (1) the dose modulation function is unchanged along the beam axis, and (2) the dose gradient in the beam direction is constant for a given lateral position; then its associated VSC beam produces no lateral dose gradient in V{sub cyl}, no matter what beam modulation or gantry angles are being used. The examination of the conditions required by the theorem lead to the following results. The effect of the depth-dose gradient not being perfectly constant with depth on the VSC beam lateral dose gradient is found negligible. The effect of the dose modulation function being degraded with depth on the VSC beam lateral dose gradient is found to be only related to scatter and beam hardening, as the theorem holds also for diverging beams. Conclusions: The use of the symmetry of the problem in the present paper leads to a valuable theorem showing that k{sub Q} factors of composite IMRT beam deliveries are close to unity under specific conditions. The theoretical limit k{sub Q{sub p{sub c{sub s{sub r,Q{sub m{sub s{sub r}{sup f{sub p}{sub c}{sub s}{sub r},f{sub m}{sub s}{sub r}}}}}}}}}=1 is determined based on the property of PCSR deliveries to provide a uniform dose in the target volume. The present approach explains recent experimental observations and proposes ideal conditions for IMRT reference dosimetry. The result of this study could potentially serve as a theoretical basis for reference dosimetry of composite IMRT beam deliveries or for routine IMRT quality assurance.« less

Re-evaluation of the regulation of omeprazole in racehorses: An evidence-based approach.

PubMed

Viljanto, M; Hillyer, L; Hincks, P; Pearce, C; Paine, S W

2018-06-01

Medication control and doping control have been established in horse racing to ensure the integrity of the sport and the welfare of the horses. This ensures that horses do not compete under the influence of any drugs, including omeprazole, a therapeutic medication used to treat equine gastric ulcer syndrome. In this study, pharmacokinetic data were produced in equine plasma and urine following an oral administration of 4 mg/kg of generic buffered formulation of omeprazole to six Thoroughbred horses in five daily doses to determine an appropriate screening limit and detection time in equine plasma and to assess whether the current detection time of 72 hr in equine urine would be applicable when an alternative omeprazole product is administered. C max of 436-2,432 ng/ml and AUC 0-tau of 1,476-4,371 ng hr ml -1 were obtained for plasma and indicated, in conjunction with other published oral omeprazole studies, that an appropriate plasma screening limit would be 500 pg/ml with a detection time of 48 hr. Urine analysis showed that omeprazole could be detected for up to 25 hr above the previously established urine screening limit of 500 pg/ml and thus indicated that the detection time advice could be potentially reduced from 72 to 48 hr to allow more comprehensive treatment of gastric lesions. © 2018 John Wiley & Sons Ltd.

Nuclear emulsion measurements of the astronauts' radiation exposure on the Apollo-Soyuz mission

NASA Technical Reports Server (NTRS)

Schaefer, H. J.; Sullivan, J. J.

1976-01-01

On the Apollo-Soyuz mission each astronaut carried one passive dosimeter containing nuclear photographic emulsions, plastic foils, TLD chips, and neutron-activation foils for recording radiation exposure. This report is limited to the presentation of data retrieved from nuclear emulsions. Protons, most of them trapped particles encountered in numerous passes through the South Atlantic Anomaly, contributed by far the largest share to the mission dose. Their linear energy transfer (LET) spectrum was established from track and grain counts in a G.5 emulsion which is used for medium and high energies, and from ender counts in a K.2 emulsion which is used for low energies. The total mission fluence of protons was found to be equivalent to a unidirectional beam of 448,500 square centimeters. The broad spectrum was broken down into small LET intervals, which allowed for the computation of absorbed doses and dose equivalents. The totals are 51 millirad and 74 millirem. Counts of disintegration stars in K.2 emulsion are incomplete at present. While a total of 467 stars were identified, counting their prong numbers is still in progress. It was concluded that the Apollo-Soyuz astronauts' radiation exposure as such did not contain anything out of the ordinary that would seem to require special attention.

Epidemiology and etiology of meningioma

PubMed Central

Wrensch, Margaret; Claus, Elizabeth B.

2010-01-01

Although most meningiomas are encapsulated and benign tumors with limited numbers of genetic aberrations, their intracranial location often leads to serious and potentially lethal consequences. They are the most frequently diagnosed primary brain tumor accounting for 33.8% of all primary brain and central nervous system tumors reported in the United States between 2002 and 2006. Inherited susceptibility to meningioma is suggested both by family history and candidate gene studies in DNA repair genes. People with certain mutations in the neurofibromatosis gene (NF2) have a very substantial increased risk for meningioma. High dose ionizing radiation exposure is an established risk factor for meningioma, and lower doses may also increase risk, but which types and doses are controversial or understudied. Because women are twice as likely as men to develop meningiomas and these tumors harbor hormone receptors, an etiologic role for hormones (both endogenous and exogenous) has been hypothesized. The extent to which immunologic factors influence meningioma etiology has been largely unexplored. Growing emphasis on brain tumor research coupled with the advent of new genetic and molecular epidemiologic tools in genetic and molecular epidemiology promise hope for advancing knowledge about the causes of intra-cranial meningioma. In this review, we highlight current knowledge about meningioma epidemiology and etiology and suggest future research directions. PMID:20821343

Low-dose γ-radiation inhibits IL-1β-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling

PubMed Central

Hong, Eun-Hee; Song, Jie-Young; Lee, Su-Jae; Park, In-Chul; Um, Hong-Duck; Park, Jong Kuk; Lee, Kee-Ho; Nam, Seon Young; Hwang, Sang-Gu

2014-01-01

Although low-dose radiation (LDR) regulates a wide range of biological processes, limited information is available on the effects of LDR on the chondrocyte phenotype. Here, we found that LDR, at doses of 0.5–2 centiGray (cGy), inhibited interleukin (IL)-1β-induced chondrocyte destruction without causing side effects, such as cell death and senescence. IL-1β treatment induced an increase in the expression of α-, β-, and γ-catenin proteins in chondrocytes via Akt signaling, thereby promoting dedifferentiation through catenin-dependent suppression of Sox-9 transcription factor expression and induction of inflammation through activation of the NF-κB pathway. Notably, LDR blocked cartilage disorders by inhibiting IL-1β-induced catenin signaling and subsequent catenin-dependent suppression of the Sox-9 pathway and activation of the NF-κB pathway, without directly altering catenin expression. LDR also inhibited chondrocyte destruction through the catenin pathway induced by epidermal growth factor, phorbol 12-myristate 13-acetate, and retinoic acid. Collectively, these results identify the molecular mechanisms by which LDR suppresses pathophysiological processes and establish LDR as a potentially valuable therapeutic tool for patients with cytokine- or soluble factors-mediated cartilage disorders. PMID:24604706

General Anaesthesia Protocols for Patients Undergoing Electroconvulsive Therapy

PubMed Central

Narayanan, Aravind; Lal, Chandar; Al-Sinawi, Hamed

2017-01-01

Objectives This study aimed to review general anaesthesia protocols for patients undergoing electroconvulsive therapy (ECT) at a tertiary care hospital in Oman, particularly with regards to clinical profile, potential drug interactions and patient outcomes. Methods This retrospective study took place at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. The electronic medical records of patients undergoing ECT at SQUH between January 2010 and December 2014 were reviewed for demographic characteristics and therapy details. Results A total of 504 modified ECT sessions were performed on 57 patients during the study period. All of the patients underwent a uniform general anaesthetic regimen consisting of propofol and succinylcholine; however, they received different doses between sessions, as determined by the treating anaesthesiologist. Variations in drug doses between sessions in the same patient could not be attributed to any particular factor. Self-limiting tachycardia and hypertension were periprocedural complications noted among all patients. One patient developed aspiration pneumonitis (1.8%). Conclusion All patients undergoing ECT received a general anaesthetic regimen including propofol and succinylcholine. However, the interplay of anaesthetic drugs with ECT efficacy could not be established due to a lack of comprehensive data, particularly with respect to seizure duration. In addition, the impact of concurrent antipsychotic therapy on anaesthetic dose and subsequent complications could not be determined. PMID:28417028

In vitro assessment on the impact of soil arsenic in the eight rice varieties of West Bengal, India.

PubMed

Bhattacharya, Piyal; Samal, Alok C; Majumdar, Jayjit; Banerjee, Satabdi; Santra, Subhas C

2013-11-15

Rice is an efficient accumulator of arsenic and thus irrigation with arsenic-contaminated groundwater and soil may induce human health hazard via water-soil-plant-human pathway. A greenhouse pot experiment was conducted on three high yielding, one hybrid and four local rice varieties to investigate the uptake, distribution and phytotoxicity of arsenic in rice plant. 5, 10, 20, 30 and 40 mg kg(-1) dry weights arsenic dosing was applied in pot soil and the results were compared with the control samples. All the studied high yielding and hybrid varieties (Ratna, IET 4094, IR 50 and Gangakaveri) were found to be higher accumulator of arsenic as compared to all but one local rice variety, Kerala Sundari. In these five rice varieties accumulation of arsenic in grain exceeded the WHO permissible limit (1.0 mg kg(-1)) at 20 mg kg(-1) arsenic dosing. Irrespective of variety, arsenic accumulation in different parts of rice plant was found to increase with increasing arsenic doses, but not at the same rate. A consistent negative correlation was established between soil arsenic and chlorophyll contents while carbohydrate accumulation depicted consistent positive correlation with increasing arsenic toxicity in rice plant. Copyright © 2012 Elsevier B.V. All rights reserved.

Sterilization of allograft bone: is 25 kGy the gold standard for gamma irradiation?

PubMed

Nguyen, Huynh; Morgan, David A F; Forwood, Mark R

2007-01-01

For several decades, a dose of 25 kGy of gamma irradiation has been recommended for terminal sterilization of medical products, including bone allografts. Practically, the application of a given gamma dose varies from tissue bank to tissue bank. While many banks use 25 kGy, some have adopted a higher dose, while some choose lower doses, and others do not use irradiation for terminal sterilization. A revolution in quality control in the tissue banking industry has occurred in line with development of quality assurance standards. These have resulted in significant reductions in the risk of contamination by microorganisms of final graft products. In light of these developments, there is sufficient rationale to re-establish a new standard dose, sufficient enough to sterilize allograft bone, while minimizing the adverse effects of gamma radiation on tissue properties. Using valid modifications, several authors have applied ISO standards to establish a radiation dose for bone allografts that is specific to systems employed in bone banking. These standards, and their verification, suggest that the actual dose could be significantly reduced from 25 kGy, while maintaining a valid sterility assurance level (SAL) of 10(-6). The current paper reviews the methods that have been used to develop radiation doses for terminal sterilization of medical products, and the current trend for selection of a specific dose for tissue banks.

76 FR 17617 - Changes to Treatments for Citrus Fruit From Australia

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-30

... from Australia into the United States. We also proposed to establish an approved irradiation dose for... Manual to include the new treatment schedules for sweet cherries and the revised irradiation dose for...

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

Mayo, Charles, E-mail: charles.mayo@umassmemorial.or; Yorke, Ellen; Merchant, Thomas E.

Publications relating brainstem radiation toxicity to quantitative dose and dose-volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60-64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose-volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumesmore » of the brainstem (1-10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions <=2 Gy; however, the risk appears to increase markedly at doses >64 Gy.« less

Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability.

PubMed

Childs, Scott L; Kandi, Praveen; Lingireddy, Sreenivas Reddy

2013-08-05

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.

Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study.

PubMed

Traversa, Giuseppe; Spila-Alegiani, Stefania; Bianchi, Clara; Ciofi degli Atti, Marta; Frova, Luisa; Massari, Marco; Raschetti, Roberto; Salmaso, Stefania; Scalia Tomba, Gianpaolo

2011-01-26

The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999-2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1-23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0-1, 0-7, and 0-14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0-7 and 0-14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age.

Factors associated with quality of life in patients with severe asthma: the impact of pharmacotherapy

PubMed Central

Souza, Daiane Silva; Noblat, Lúcia de Araújo Costa Beisl; Santos, Pablo de Moura

2015-01-01

ABSTRACT OBJECTIVE: To identify, characterize, and quantify associations of various factors with quality of life (QoL) in patients with asthma, according to the pharmacotherapy employed. METHODS: This was a cross-sectional study involving 49 patients (≥ 18 years of age) with severe uncontrolled or refractory asthma treated at a specialized outpatient clinic of the Brazilian Unified Health Care System, regularly using high doses of inhaled corticosteroids (ICs) or other medications, and presenting comorbidities. At a single time point, QoL was assessed with the Asthma Quality of Life Questionnaire (AQLQ). The overall AQLQ score and those of its domains were correlated with demographic variables (gender and age); Asthma Control Questionnaire score; pharmacotherapy (initial IC dose, inhaler devices, and polytherapy); and comorbidities. RESULTS: Better AQLQ scores were associated with asthma control-overall (OR = 0.38; 95% CI: 0.004-0.341; p < 0.001), "symptoms" domain (OR = 0.086; 95% CI: 0.016-0.476; p = 0.001), and "emotional function" domain (OR = 0.086; 95% CI: 0.016-0.476; p = 0.001)-and with IC dose ≤ 800 µg-"activity limitation" domain (OR = 0.249; 95% CI: 0.070-0.885; p = 0.029). Worse AQLQ scores were associated with polytherapy-"activity limitation" domain (OR = 3.651; 95% CI: 1.061-12.561; p = 0.036)-and number of comorbidities ≤ 5-"environmental stimuli" domain (OR = 5.042; 95% CI: 1.316-19.317; p = 0.015). CONCLUSIONS: Our results, the importance of this issue, and the lack of studies taking pharmacotherapy into consideration warrant longitudinal studies to establish a causal relationship between the identified factors and QoL in asthma patients. PMID:26785957

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

PubMed

Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

2015-06-01

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC.

PubMed

Figueroa, Isabel; Leipold, Doug; Leong, Steve; Zheng, Bing; Triguero-Carrasco, Montserrat; Fourie-O'Donohue, Aimee; Kozak, Katherine R; Xu, Keyang; Schutten, Melissa; Wang, Hong; Polson, Andrew G; Kamath, Amrita V

2018-05-14

For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

Evaluation of military field-water quality: Volume 6, Infectious organisms of military concern associated with nonconsumptive exposure: Assessment of health risks and recommendations for establishing related standards

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

Cooper, R.C.; Olivieri, A.W.; Danielson, R.E.

1986-02-01

This study is an assessment of the risk of illness due to exposure to water-related (i.e., water-based, water-washed) infectious organisms. The organisms under consideration are Aeromonas spp., Leptospira spp., Pseudomonas spp., Staphylococcus spp., non-cholerae Vibrio spp., Acanthamoeba spp., Balantidium coli, Naegleria spp., Ascaris lumbricoides, Dracunculus medinesis, Schistosoma spp., and the agents responsible for cercarial dermatitis (i.e., Trichobilharzia, Gigantobilharzia, and Austrobilharzia). Evaluation of the risk to disease associated with the above pathogens requires information in specific areas such as dose response, concentration of agents in the environment, and environmental persistence. The existing body of knowledge concerning these agents ranges from speculationmore » to established fact. Unfortunately, areas of information critical to risk assessment are frequently unavailable. Because of this lack of data, the risk assessment presented is semiquantitative and limited to the presentation of an environmental classification scheme. 14 refs., 2 figs., 57 tabs.« less

Use of Osmotic Pumps to Establish the Pharmacokinetic-Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors.

PubMed

Wiley, Michael R; Durham, Timothy B; Adams, Lisa A; Chambers, Mark G; Lin, Chaohua; Liu, Chin; Marimuthu, Jothirajah; Mitchell, Peter G; Mudra, Daniel R; Swearingen, Craig A; Toth, James L; Weller, Jennifer M; Thirunavukkarasu, Kannan

2016-06-23

The development of reliable relationships between in vivo target engagement, pharmacodynamic activity, and efficacy in chronic disease models is beneficial for enabling hypothesis-driven drug discovery and facilitating the development of patient-focused candidate selection criteria. Toward those ends, osmotic infusion pumps can be useful for overcoming limitations in the PK properties of proof-of-concept (POC) compounds to accelerate the development of such relationships. In this report, we describe the application of this strategy to the development of hydantoin-derived aggrecanase inhibitors (eg, 3) for the treatment of osteoarthiritis (OA). Potent, selective inhibitors were efficacious in both chemical and surgical models of OA when exposures were sustained in excess of 10 times the plasma IC50. The use of these data for establishing patient-focused candidate selection criteria is exemplified with the characterization of compound 8, which is projected to sustain the desired level of target engagement at a dose of 45 mg qd.

The Chernobyl accident — an epidemiological perspective

PubMed Central

Cardis, E.; Hatch, M.

2011-01-01

Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer – particularly the risk of thyroid tumours from exposure to iodine isotopes - that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well-documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer endpoints. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers (“liquidators”) have provided evidence of increased risks of leukaemia and other hematological malignancies and of cataracts, and suggestions of an increase in risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation. PMID:21396807

The Chernobyl accident--an epidemiological perspective.

PubMed

Cardis, E; Hatch, M

2011-05-01

Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to the exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer-particularly the risk of thyroid tumours from exposure to iodine isotopes-that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with the risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer end points. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers ('liquidators') have provided evidence of increased risks of leukaemia and other haematological malignancies and of cataracts, and suggestions of an increase in the risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including the establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation. Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Prescribing and up-titration in recently hospitalized heart failure patients attending a disease management program.

PubMed

Carroll, Robert; Mudge, Alison; Suna, Jessica; Denaro, Charles; Atherton, John

2016-08-01

Heart failure (HF) medications improve clinical outcomes, with optimal doses defined in clinical trials. Patient, provider and system barriers may limit achievement of optimal doses in real life settings, although disease management programs (HF-DMPs) can facilitate up-titration. Secondary analysis of a prospective cohort of 216 participants recently hospitalized with systolic HF, attending 5 HF-DMPs in Queensland, Australia. Medication history at baseline (6weeks after discharge) and 6months provided data to describe prescription rates, dosage and optimal titration of HF medications, and associations with patient and system factors were explored. At baseline, 94% were on an angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB), 94% on a beta-blocker (BB) and 42% on a mineralocorticoid receptor antagonist (MRA). The proportion of participants on optimal doses of ACEI/ARB increased from 38% (baseline) to 52% (6months, p=0.001) and on optimal BB dose from 23% to 49% (p<0.001). Significant barriers to ACEI/ARB up-titration were body mass index (BMI)<25, female gender, polypharmacy, previously diagnosed HF, and tertiary hospital. Significant barriers for BB up-titration were BMI<25, previously diagnosed HF and non-cardiologist care. Effective up-titration in HF DMPs is influenced by patient, disease and service factors. Better understanding of barriers to effective up-titration in women, normal weight, and established HF patients may help provide targeted strategies for improving outcomes in these groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

75 FR 46901 - Changes to Treatments for Sweet Cherries from Australia and Irradiation Dose for Mediterranean...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-04

...] Changes to Treatments for Sweet Cherries from Australia and Irradiation Dose for Mediterranean Fruit Fly... into the United States. We are also adding to the treatment manual a new approved irradiation dose for... imported from Australia into the United States.\\3\\ We also proposed to establish an approved irradiation...

An organ-based approach to dose calculation in the assessment of dose-dependent biological effects of ionising radiation in Arabidopsis thaliana.

PubMed

Biermans, Geert; Horemans, Nele; Vanhoudt, Nathalie; Vandenhove, Hildegarde; Saenen, Eline; Van Hees, May; Wannijn, Jean; Vives i Batlle, Jordi; Cuypers, Ann

2014-07-01

There is a need for a better understanding of biological effects of radiation exposure in non-human biota. Correct description of these effects requires a more detailed model of dosimetry than that available in current risk assessment tools, particularly for plants. In this paper, we propose a simple model for dose calculations in roots and shoots of Arabidopsis thaliana seedlings exposed to radionuclides in a hydroponic exposure setup. This model is used to compare absorbed doses for three radionuclides, (241)Am (α-radiation), (90)Sr (β-radiation) and (133)Ba (γ radiation). Using established dosimetric calculation methods, dose conversion coefficient values were determined for each organ separately based on uptake data from the different plant organs. These calculations were then compared to the DCC values obtained with the ERICA tool under equivalent geometry assumptions. When comparing with our new method, the ERICA tool appears to overestimate internal doses and underestimate external doses in the roots for all three radionuclides, though each to a different extent. These observations might help to refine dose-response relationships. The DCC values for (90)Sr in roots are shown to deviate the most. A dose-effect curve for (90)Sr β-radiation has been established on biomass and photosynthesis endpoints, but no significant dose-dependent effects are observed. This indicates the need for use of endpoints at the molecular and physiological scale. Copyright © 2013 Elsevier Ltd. All rights reserved.

SU-G-TeP3-09: Proton Minibeam Radiation Therapy Increases Normal Tissue Resistance

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

Prezado, Y; Gonzalez-Infantes, W; Juchaux, M

Purpose: The dose tolerances of normal tissues continue being the main limitation in radiotherapy. To overcome it, we recently proposed a novel concept: proton minibeam radiation therapy (pMBRT) [1]. It allies the physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams (minibeam radiation therapy) [2]. The dose distributions are such that the tumor receives a homogeneous dose distribution, while normal tissues benefit from the spatial fractionation of the dose. The objective of our work was to implement this promising technique at a clinical center (Proton therapy center in Orsay) in order tomore » evaluate the potential gain in tissue sparing. Methods: Dose distributions were measured by means of gafchromic films and a PTW microdiamond detector (60019). Once the dosimetry was established, the whole brain of 7 weeks old male Fischer 344 rats was irradiated. Half of the animals received conventional seamless proton irradiation (25 Gy in one fraction). The other rats were irradiated with pMBRT (58 Gy peak dose in one fraction). The average dose deposited in the same targeted volume was in both cases 25 Gy. Results: The first complete set of dosimetric data in such small proton field sizes was obtained [3]. Rats treated with conventional proton irradiation exhibited severe moist desquamation and permanent epilation afterwards. The minibeam group, on the other hand, exhibited no skin damage and no clinical symptoms. MRI imaging and histological analysis are planned at 6 months after irradiation. Conclusion: Our preliminary results indicate that pMBRT leads to an increase in tissue resistance. This can open the door to an efficient treatment of very radioresistant tumours. [1] Prezado et al. Med. Phys. 40, 031712, 1–8 (2013).[2] Prezado et al., Rad. Research. 184, 314-21 (2015). [3] Peucelle et al., Med. Phys. 42 7108-13 (2015).« less

Design and dosimetric characteristics of a new endocavitary contact radiotherapy system using an electronic brachytherapy source.

PubMed

Richardson, Susan; Garcia-Ramirez, Jose; Lu, Wei; Myerson, Robert J; Parikh, Parag

2012-11-01

To present design aspects and acceptance tests performed for clinical implementation of electronic brachytherapy treatment of early stage rectal adenocarcinoma. A dosimetric comparison is made between the historically used Philips RT-50 unit and the newly developed Axxent(®) Model S700 electronic brachytherapy source manufactured by Xoft (iCad, Inc.). Two proctoscope cones were manufactured by ElectroSurgical Instruments (ESI). Two custom surface applicators were manufactured by Xoft and were designed to fit and interlock with the proctoscope cones from ESI. Dose rates, half value layers (HVL), and percentage depth dose (PDD) measurements were made with the Xoft system and compared to historical RT-50 data. A description of the patient treatment approach and exposure rates during the procedure is also provided. The electronic brachytherapy system has a lower surface dose rate than the RT-50. The dose rate to water on the surface from the Xoft system is approximately 2.1 Gy∕min while the RT-50 is 10-12 Gy∕min. However, treatment times with Xoft are still reasonable. The HVLs and PDDs between the two systems were comparable resulting in similar doses to the target and to regions beyond the target. The exposure rate levels around a patient treatment were acceptable. The standard uncertainty in the dose rate to water on the surface is approximately ±5.2%. The Philips RT-50 unit is an out-of-date radiotherapy machine that is no longer manufactured with limited replacement parts. The use of a custom-designed proctoscope and Xoft surface applicators allows delivery of a well-established treatment with the ease of a modern radiotherapy device. While the dose rate is lower with the use of Xoft, the treatment times are still reasonable. Additionally, personnel may stand farther away from the Xoft radiation source, thus potentially reducing radiation exposure to the operator and other personnel.

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

PubMed

Hahn, Roberta Zilles; Antunes, Marina Venzon; Verza, Simone Gasparin; Perassolo, Magda Susana; Suyenaga, Edna Sayuri; Schwartsmann, Gilberto; Linden, Rafael

2018-06-22

Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.

PubMed

Bedard, Philippe L; Tabernero, Josep; Janku, Filip; Wainberg, Zev A; Paz-Ares, Luis; Vansteenkiste, Johan; Van Cutsem, Eric; Pérez-García, José; Stathis, Anastasios; Britten, Carolyn D; Le, Ngocdiep; Carter, Kirsten; Demanse, David; Csonka, Denes; Peters, Malte; Zubel, Angela; Nauwelaerts, Heidi; Sessa, Cristiana

2015-02-15

MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. ©2014 American Association for Cancer Research.

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.

PubMed

Bendell, J; O'Reilly, E M; Middleton, M R; Chau, I; Hochster, H; Fielding, A; Burke, W; Burris, H

2015-04-01

Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. NCT00515866. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Dose audit for patients undergoing two common radiography examinations with digital radiology systems

PubMed Central

İnal, Tolga; Ataç, Gökçe

2014-01-01

PURPOSE We aimed to determine the radiation doses delivered to patients undergoing general examinations using computed or digital radiography systems in Turkey. MATERIALS AND METHODS Radiographs of 20 patients undergoing posteroanterior chest X-ray and of 20 patients undergoing anteroposterior kidney-ureter-bladder radiography were evaluated in five X-ray rooms at four local hospitals in the Ankara region. Currently, almost all radiology departments in Turkey have switched from conventional radiography systems to computed radiography or digital radiography systems. Patient dose was measured for both systems. The results were compared with published diagnostic reference levels (DRLs) from the European Union and International Atomic Energy Agency. RESULTS The average entrance surface doses (ESDs) for chest examinations exceeded established international DRLs at two of the X-ray rooms in a hospital with computed radiography. All of the other ESD measurements were approximately equal to or below the DRLs for both examinations in all of the remaining hospitals. Improper adjustment of the exposure parameters, uncalibrated automatic exposure control systems, and failure of the technologists to choose exposure parameters properly were problems we noticed during the study. CONCLUSION This study is an initial attempt at establishing local DRL values for digital radiography systems, and will provide a benchmark so that the authorities can establish reference dose levels for diagnostic radiology in Turkey. PMID:24317331

Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for use as a dietary supplement and in functional foods.

PubMed

Ribnicky, David M; Poulev, Alexander; O'Neal, Joseph; Wnorowski, Gary; Malek, Dolores E; Jäger, Ralf; Raskin, Ilya

2004-04-01

TARRALIN is an ethanolic extract of Artemisia dracunculus (Russian tarragon), a common medicinal and culinary herb with centuries of use. Artemisia dracunculus is a close relative of the French or cooking tarragon and contains components common to many herbs that are routinely consumed without reported adverse effects. Since safety information of Artemisia dracunculus and its extract is limited to historical use, TARRALIN was examined in a series of toxicological studies. Complete Ames analysis did not reveal any mutagenic activity either with or without metabolic activation. TARRALIN was tested in an acute limit test at 5000 mg/kg with no signs of toxicity noted. In a 14 day repeated dose oral toxicity study, rats appeared to well tolerate 1000 mg/kg/day. Subsequently, TARRALIN was tested in an oral subchronic 90-day toxicity study (rat) at doses of 10, 100 and 1000 mg/kg/day. No noteworthy signs of toxicity were noted in feeding or body weight, functional observational battery or motor activity. Gross necropsy and clinical chemistry did not reveal any effects on organ mass or blood chemistry and microscopic examinations found no lesions associated with treatment. Therefore, TARRALIN appears to be safe and non-toxic in these studies and a no-observed adverse effect level in rats is established at 1000 mg/kg/day.

Acute and Cumulative Effects of Unmodified 50-nm Nano-ZnO on Mice.

PubMed

Kong, Tao; Zhang, Shu-Hui; Zhang, Ji-Liang; Hao, Xue-Qin; Yang, Fan; Zhang, Cai; Yang, Zi-Jun; Zhang, Meng-Yu; Wang, Jie

2018-01-02

Nanometer zinc oxide (nano-ZnO) is widely used in diverse industrial and agricultural fields. Due to the extensive contact humans have with these particles, it is crucial to understand the potential effects that nano-ZnO have on human health. Currently, information related to the toxicity and mechanisms of nano-ZnO is limited. The aim of the present study was to investigate acute and cumulative toxic effects of 50-nm unmodified ZnO in mice. This investigation will seek to establish median lethal dose (LD50), a cumulative coefficient, and target organs. The acute and cumulative toxicity was investigated by Karber's method and via a dose-increasing method, respectively. During the experiment, clinical signs, mortality, body weights, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. The LD50 was 5177-mg/kg·bw; the 95% confidence limits for the LD50 were 5116-5238-mg/kg·bw. It could be concluded that the liver, kidney, lung, and gastrointestinal tract were target organs for the 50-nm nano-ZnO acute oral treatment. The cumulative coefficient (K) was 1.9 which indicated that the cumulative toxicity was apparent. The results also indicated that the liver, kidney, lung, and pancrea were target organs for 50-nm nano-ZnO cumulative oral exposure and might be target organs for subchronic and chronic toxicity of oral administered 50-nm ZnO.

Benchmark dose for cadmium exposure and elevated N-acetyl-β-D-glucosaminidase: a meta-analysis.

PubMed

Liu, CuiXia; Li, YuBiao; Zhu, ChunShui; Dong, ZhaoMin; Zhang, Kun; Zhao, YanBin; Xu, YiLu

2016-10-01

Cadmium (Cd) is a well-known nephrotoxic contaminant, and N-acetyl-β-D-glucosaminidase (NAG) is considered to be an early and sensitive marker of tubular dysfunction. The link between Cd exposure and NAG level enables us to derive the benchmark dose (BMD) of Cd. Although several reports have already documented urinary Cd (UCd)-NAG relationships and BMD estimations, high heterogeneities arise due to the sub-populations (age, gender, and ethnicity) and BMD methodologies being employed. To clarify the influences that these variables exert, firstly, a random effect meta-analysis was performed in this study to correlate the UCd and NAG based on 92 datasets collected from 30 publications. Later, this established correlation (Ln(NAG) = 0.51 × Ln(UCd) + 0.83) was applied to derive the UCd BMD 5 of 1.76 μg/g creatinine and 95 % lower confidence limit of BMD 5 (BMDL 5 ) of 1.67 μg/g creatinine. While the regressions for different age groups and genders differed slightly, it is age and not gender that significantly affects BMD estimations. Ethnic differences may require further investigation given that limited data is currently available. Based on a comprehensive and systematic literature review, this study is a new attempt to quantify the UCd-NAG link and estimate BMD.

Kilovoltage Imaging of Implanted Fiducials to Monitor Intrafraction Motion With Abdominal Compression During Stereotactic Body Radiation Therapy for Gastrointestinal Tumors.

PubMed

Yorke, Ellen; Xiong, Ying; Han, Qian; Zhang, Pengpeng; Mageras, Gikas; Lovelock, Michael; Pham, Hai; Xiong, Jian-Ping; Goodman, Karyn A

2016-07-01

To assess intrafraction respiratory motion using a commercial kilovoltage imaging system for abdominal tumor patients with implanted fiducials and breathing constrained by pneumatic compression during stereotactic body radiation therapy (SBRT). A pneumatic compression belt limited respiratory motion in 19 patients with radiopaque fiducials in or near their tumor during SBRT for abdominal tumors. Kilovoltage images were acquired at 5- to 6-second intervals during treatment using a commercial system. Intrafractional fiducial displacements were measured using in-house software. The dosimetric effect of the observed displacements was calculated for 3 sessions for each patient. Intrafraction displacement patterns varied between patients and between individual treatment sessions. Averaged over 19 patients, 73 sessions, 7.6% of craniocaudal displacements exceeded 0.5 cm, and 1.2% exceeded 0.75 cm. The calculated single-session dose to 95% of gross tumor volume differed from planned by an average of -1.2% (range, -11.1% to 4.8%) but only for 4 patients was the total 3-session calculated dose to 95% of gross tumor volume more than 3% different from planned. Our pneumatic compression limited intrafractional abdominal target motion, maintained target position established at setup, and was moderately effective in preserving coverage. Commercially available intrafractional imaging is useful for surveillance but can be made more effective and reliable. Copyright © 2015 Elsevier Inc. All rights reserved.

EMP Attachment 3 DOE-SC PNNL Site Dose Assessment Guidance

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

Snyder, Sandra F.

2011-12-21

This Dose Assessment Guidance (DAG) describes methods to use to determine the Maximally-Exposed Individual (MEI) location and to estimate dose impact to that individual under the U.S. Department of Energy Office of Science (DOE-SC) Pacific Northwest National Laboratory (PNNL) Site Environmental Monitoring Plan (EMP). This guidance applies to public dose from radioactive material releases to the air from PNNL Site operations. This document is an attachment to the Pacific Northwest National Laboratory (PNNL) Environmental Monitoring Plan (EMP) and describes dose assessment guidance for radiological air emissions. The impact of radiological air emissions from the U.S. Department of Energy Office ofmore » Science (DOE-SC) PNNL Site is indicated by dose estimates to a maximally exposed member of the public, referred to as the maximally exposed individual (MEI). Reporting requirements associated with dose to members of the public from radiological air emissions are in 40 CFR Part 61.94, WAC 246-247-080, and DOE Order 458.1. The DOE Order and state standards for dose from radioactive air emissions are consistent with U.S. Environmental Protection Agency (EPA) dose standards in 40 CFR 61.92 (i.e., 10 mrem/yr to a MEI). Despite the fact that the current Contract Requirements Document (CRD) for the DOE-SC PNNL Site operations does not include the requirement to meet DOE CRD 458.1, paragraph 2.b, public dose limits, the DOE dose limits would be met when EPA limits are met.« less

Dose planning management of patients undergoing salvage whole brain radiation therapy after radiosurgery

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

Saw, Cheng B., E-mail: cheng.saw@aol.com; Battin, Frank; McKeague, Janice

2016-01-01

Dose or treatment planning management is necessary for the re-irradiation of intracranial relapses after focal irradiation, radiosurgery, or stereotactic radiotherapy. The current clinical guidelines for metastatic brain tumors are the use of focal irradiation if the patient presents with 4 lesions or less. Salvage treatments with the use of whole brain radiation therapy (WBRT) can then be used to limit disease progression if there is an intracranial relapse. However, salvage WBRT poses a number of challenges in dose planning to limit disease progression and preserve neurocognitive function. This work presents the dose planning management that addresses a method of delineatingmore » previously treated volumes, dose level matching, and the dose delivery techniques for WBRT.« less

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

Thompson, Reid F.; Zhai, Huifang; Both, Stefan

Purpose: Uncontrolled local growth is the cause of death in ∼30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk. Methods: The authors compared DS, PBS, andmore » IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test. Results: Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6–53.8 and 34.9–52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning. Conclusions: Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.« less

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

PubMed

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

2017-05-07

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

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

NASA Astrophysics Data System (ADS)

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

2017-05-01

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

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

PubMed

Musuamba, F T; Manolis, E; Holford, N; Cheung, Sya; Friberg, L E; Ogungbenro, K; Posch, M; Yates, Jwt; Berry, S; Thomas, N; Corriol-Rohou, S; Bornkamp, B; Bretz, F; Hooker, A C; Van der Graaf, P H; Standing, J F; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-07-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. © 2017 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

NSR&D Program Fiscal Year 2015 Funded Research Stochastic Modeling of Radioactive Material Releases Final Report

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

Andrus, Jason P.; Pope, Chad; Toston, Mary

2016-12-01

Nonreactor nuclear facilities operating under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose distribution associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. Users can also specify custom distributions through a user defined distribution option. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA, developed using the MATLAB coding framework, has a graphical user interface and can be installed on both Windows and Mac computers. SODA is a standalone software application and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC; rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The SODA development project was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

NSR&D Program Fiscal Year 2015 Funded Research Stochastic Modeling of Radioactive Material Releases Final Report

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

Andrus, Jason P.; Pope, Chad; Toston, Mary

Nonreactor nuclear facilities operating under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose distribution associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. Users can also specify custom distributions through a user defined distribution option. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA, developed using the MATLAB coding framework, has a graphical user interface and can be installed on both Windows and Mac computers. SODA is a standalone software application and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC; rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The SODA development project was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

Dose reduction of scattered photons from concrete walls lined with lead: Implications for improvement in design of megavoltage radiation therapy facility mazes.

PubMed

Al-Affan, I A M; Hugtenburg, R P; Bari, D S; Al-Saleh, W M; Piliero, M; Evans, S; Al-Hasan, M; Al-Zughul, B; Al-Kharouf, S; Ghaith, A

2015-02-01

This study explores the possibility of using lead to cover part of the radiation therapy facility maze walls in order to absorb low energy photons and reduce the total dose at the maze entrance of radiation therapy rooms. Experiments and Monte Carlo simulations were utilized to establish the possibility of using high-Z materials to cover the concrete walls of the maze in order to reduce the dose of the scattered photons at the maze entrance. The dose of the backscattered photons from a concrete wall was measured for various scattering angles. The dose was also calculated by the FLUKA and EGSnrc Monte Carlo codes. The FLUKA code was also used to simulate an existing radiotherapy room to study the effect of multiple scattering when adding lead to cover the concrete walls of the maze. Monoenergetic photons were used to represent the main components of the x ray spectrum up to 10 MV. It was observed that when the concrete wall was covered with just 2 mm of lead, the measured dose rate at all backscattering angles was reduced by 20% for photons of energy comparable to Co-60 emissions and 70% for Cs-137 emissions. The simulations with FLUKA and EGS showed that the reduction in the dose was potentially even higher when lead was added. One explanation for the reduction is the increased absorption of backscattered photons due to the photoelectric interaction in lead. The results also showed that adding 2 mm lead to the concrete walls and floor of the maze reduced the dose at the maze entrance by up to 90%. This novel proposal of covering part or the entire maze walls with a few millimeters of lead would have a direct implication for the design of radiation therapy facilities and would assist in upgrading the design of some mazes, especially those in facilities with limited space where the maze length cannot be extended to sufficiently reduce the dose. © 2015 American Association of Physicists in Medicine.

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

PubMed

Chiuccariello, Lina; Cooke, Robert G; Miler, Laura; Levitan, Robert D; Baker, Glen B; Kish, Stephen J; Kolla, Nathan J; Rusjan, Pablo M; Houle, Sylvain; Wilson, Alan A; Meyer, Jeffrey H

2015-08-27

Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets. © The Author 2015. Published by Oxford University Press on behalf of the American Association for Public Opinion Research.

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

PubMed Central

Chiuccariello, Lina; Cooke, Robert G; Miler, Laura; Levitan, Robert D; Baker, Glen B; Kish, Stephen J; Kolla, Nathan J; Rusjan, Pablo M; Houle, Sylvain; Wilson, Alan A

2016-01-01

Background: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer’s, and Parkinson’s Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. Methods: Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. Results: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean ‘a’: 88.62±2.38%, mean ‘b’: 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01]. Conclusions: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets. PMID:26316187

Dose reduction of scattered photons from concrete walls lined with lead: Implications for improvement in design of megavoltage radiation therapy facility mazes

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

Al-Affan, I. A. M., E-mail: info@medphys-environment.co.uk; Hugtenburg, R. P.; Piliero, M.

Purpose: This study explores the possibility of using lead to cover part of the radiation therapy facility maze walls in order to absorb low energy photons and reduce the total dose at the maze entrance of radiation therapy rooms. Methods: Experiments and Monte Carlo simulations were utilized to establish the possibility of using high-Z materials to cover the concrete walls of the maze in order to reduce the dose of the scattered photons at the maze entrance. The dose of the backscattered photons from a concrete wall was measured for various scattering angles. The dose was also calculated by themore » FLUKA and EGSnrc Monte Carlo codes. The FLUKA code was also used to simulate an existing radiotherapy room to study the effect of multiple scattering when adding lead to cover the concrete walls of the maze. Monoenergetic photons were used to represent the main components of the x ray spectrum up to 10 MV. Results: It was observed that when the concrete wall was covered with just 2 mm of lead, the measured dose rate at all backscattering angles was reduced by 20% for photons of energy comparable to Co-60 emissions and 70% for Cs-137 emissions. The simulations with FLUKA and EGS showed that the reduction in the dose was potentially even higher when lead was added. One explanation for the reduction is the increased absorption of backscattered photons due to the photoelectric interaction in lead. The results also showed that adding 2 mm lead to the concrete walls and floor of the maze reduced the dose at the maze entrance by up to 90%. Conclusions: This novel proposal of covering part or the entire maze walls with a few millimeters of lead would have a direct implication for the design of radiation therapy facilities and would assist in upgrading the design of some mazes, especially those in facilities with limited space where the maze length cannot be extended to sufficiently reduce the dose.« less

Beyond dose assessment: using risk with full disclosure of uncertainty in public and scientific communication.

PubMed

Hoffman, F Owen; Kocher, David C; Apostoaei, A Iulian

2011-11-01

Evaluations of radiation exposures of workers and the public traditionally focus on assessments of radiation dose, especially annual dose, without explicitly evaluating the health risk associated with those exposures, principally the risk of radiation-induced cancer. When dose is the endpoint of an assessment, opportunities to communicate the significance of exposures are limited to comparisons with dose criteria in regulations, doses due to natural background or medical x-rays, and doses above which a statistically significant increase of disease has been observed in epidemiologic studies. Risk assessment generally addresses the chance (probability) that specific diseases might be induced by past, present, or future exposure. The risk of cancer per unit dose will vary depending on gender, age, exposure type (acute or chronic), and radiation type. It is not uncommon to find that two individuals with the same effective dose will have substantially different risks. Risk assessment has shown, for example, that: (a) medical exposures to computed tomography scans have become a leading source of future risk to the general population, and that the risk would be increased above recently published estimates if the incidence of skin cancer and the increased risk from exposure to x-rays compared with high-energy photons were taken into account; (b) indoor radon is a significant contributor to the baseline risk of lung cancer, particularly among people who have never smoked; and (c) members of the public who were exposed in childhood to I in fallout from atmospheric nuclear weapons tests and were diagnosed with thyroid cancer later in life would frequently meet criteria established for federal compensation of cancers experienced by energy workers and military participants at atmospheric weapons tests. Risk estimation also enables comparisons of impacts of exposures to radiation and chemical carcinogens and other hazards to life and health. Communication of risk with uncertainty is essential for reaching informed consent, whether communicating to a larger community debating the tradeoffs of risks and benefits of an action that involves radiation exposure or communicating at the level of a physician and patient.

Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine

PubMed Central

Micek, Mark A.; Blanco, Ana Judith; Beck, Ingrid A.; Dross, Sandra; Matunha, Laurinda; Montoya, Pablo; Seidel, Kristy; Gantt, Soren; Matediane, Eduardo; Jamisse, Lilia; Gloyd, Stephen; Frenkel, Lisa M.

2011-01-01

Background In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection. Methods We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time. Results Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P =.006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P =.001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P =.017, compared with established in utero infection). Conclusions The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals. PMID:20384494

Online dose reconstruction for tracked volumetric arc therapy: Real-time implementation and offline quality assurance for prostate SBRT.

PubMed

Kamerling, Cornelis Ph; Fast, Martin F; Ziegenhein, Peter; Menten, Martin J; Nill, Simeon; Oelfke, Uwe

2017-11-01

Firstly, this study provides a real-time implementation of online dose reconstruction for tracked volumetric arc therapy (VMAT). Secondly, this study describes a novel offline quality assurance tool, based on commercial dose calculation algorithms. Online dose reconstruction for VMAT is a computationally challenging task in terms of computer memory usage and calculation speed. To potentially reduce the amount of memory used, we analyzed the impact of beam angle sampling for dose calculation on the accuracy of the dose distribution. To establish the performance of the method, we planned two single-arc VMAT prostate stereotactic body radiation therapy cases for delivery with dynamic MLC tracking. For quality assurance of our online dose reconstruction method we have also developed a stand-alone offline dose reconstruction tool, which utilizes the RayStation treatment planning system to calculate dose. For the online reconstructed dose distributions of the tracked deliveries, we could establish strong resemblance for 72 and 36 beam co-planar equidistant beam samples with less than 1.2% deviation for the assessed dose-volume indicators (clinical target volume D98 and D2, and rectum D2). We could achieve average runtimes of 28-31 ms per reported MLC aperture for both dose computation and accumulation, meeting our real-time requirement. To cross-validate the offline tool, we have compared the planned dose to the offline reconstructed dose for static deliveries and found excellent agreement (3%/3 mm global gamma passing rates of 99.8%-100%). Being able to reconstruct dose during delivery enables online quality assurance and online replanning strategies for VMAT. The offline quality assurance tool provides the means to validate novel online dose reconstruction applications using a commercial dose calculation engine. © 2017 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

SU-C-201-03: Ionization Chamber Collection Efficiency in Pulsed Radiation Fields of High Pulse Dose

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

Gotz, M; Karsch, L; Pawelke, J

Purpose: To investigate the reduction of collection efficiency of ionization chambers (IC) by volume recombination and its correction in pulsed fields of very high pulse dose. Methods: Measurements of the collection efficiency of a plane-parallel advanced Markus IC (PTW 34045, 1mm electrode spacing, 300V nominal voltage) were obtained for collection voltages of 100V and 300V by irradiation with a pulsed electron beam (20MeV) of varied pulse dose up to approximately 600mGy (0.8nC liberated charge). A reference measurement was performed with a Faraday cup behind the chamber. It was calibrated for the liberated charge in the IC by a linear fitmore » of IC measurement to reference measurement at low pulse doses. The results were compared to the commonly used two voltage approximation (TVA) and to established theories for volume recombination, with and without considering a fraction of free electrons. In addition, an equation system describing the charge transport and reactions in the chamber was solved numerically. Results: At 100V collection voltage and moderate pulse doses the established theories accurately predict the observed collection efficiency, but at extreme pulse doses a fraction of free electrons needs to be considered. At 300V the observed collection efficiency deviates distinctly from that predicted by any of the established theories, even at low pulse doses. However, the numeric solution of the equation system is able to reproduce the measured collection efficiency across the entire dose range of both voltages with a single set of parameters. Conclusion: At high electric fields (3000V/cm here) the existing theoretical descriptions of collection efficiency, including the TVA, are inadequate to predict pulse dose dependency. Even at low pulse doses they might underestimate collection efficiency. The presented, more accurate numeric solution, which considers additional effects like electric shielding by the charges, might provide a valuable tool for future investigations. This project was funded by the German ministry of research and education (BMBF) under grant number: 03Z1N511 and by the state of Saxony under grant number: B 209.« less

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents

PubMed Central

Simon, Nicholas W.; Moghaddam, Bita

2016-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3 mg/kg) improving inhibition, and high dose (3 mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. PMID:27431940

TU-D-201-05: Validation of Treatment Planning Dose Calculations: Experience Working with MPPG 5.a

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

Xue, J; Park, J; Kim, L

2016-06-15

Purpose: Newly published medical physics practice guideline (MPPG 5.a.) has set the minimum requirements for commissioning and QA of treatment planning dose calculations. We present our experience in the validation of a commercial treatment planning system based on MPPG 5.a. Methods: In addition to tests traditionally performed to commission a model-based dose calculation algorithm, extensive tests were carried out at short and extended SSDs, various depths, oblique gantry angles and off-axis conditions to verify the robustness and limitations of a dose calculation algorithm. A comparison between measured and calculated dose was performed based on validation tests and evaluation criteria recommendedmore » by MPPG 5.a. An ion chamber was used for the measurement of dose at points of interest, and diodes were used for photon IMRT/VMAT validations. Dose profiles were measured with a three-dimensional scanning system and calculated in the TPS using a virtual water phantom. Results: Calculated and measured absolute dose profiles were compared at each specified SSD and depth for open fields. The disagreement is easily identifiable with the difference curve. Subtle discrepancy has revealed the limitation of the measurement, e.g., a spike at the high dose region and an asymmetrical penumbra observed on the tests with an oblique MLC beam. The excellent results we had (> 98% pass rate on 3%/3mm gamma index) on the end-to-end tests for both IMRT and VMAT are attributed to the quality beam data and the good understanding of the modeling. The limitation of the model and the uncertainty of measurement were considered when comparing the results. Conclusion: The extensive tests recommended by the MPPG encourage us to understand the accuracy and limitations of a dose algorithm as well as the uncertainty of measurement. Our experience has shown how the suggested tests can be performed effectively to validate dose calculation models.« less

Status of NCRP Scientific Committee 1-23 Commentary on Guidance on Radiation Dose Limits for the Lens of the Eye.

PubMed

Dauer, Lawrence T; Ainsbury, Elizabeth A; Dynlacht, Joseph; Hoel, David; Klein, Barbara E K; Mayer, Don; Prescott, Christina R; Thornton, Raymond H; Vano, Eliseo; Woloschak, Gayle E; Flannery, Cynthia M; Goldstein, Lee E; Hamada, Nobuyuki; Tran, Phung K; Grissom, Michael P; Blakely, Eleanor A

2016-02-01

Previous National Council on Radiation Protection and Measurements (NCRP) publications have addressed the issues of risk and dose limitation in radiation protection and included guidance on specific organs and the lens of the eye. NCRP decided to prepare an updated commentary intended to enhance the previous recommendations provided in earlier reports. The NCRP Scientific Committee 1-23 (SC 1-23) is charged with preparing a commentary that will evaluate recent studies on the radiation dose response for the development of cataracts and also consider the type and severity of the cataracts as well as the dose rate; provide guidance on whether existing dose limits to the lens of the eye should be changed in the United States; and suggest research needs regarding radiation effects on and dose limits to the lens of the eye. A status of the ongoing work of SC 1-23 was presented at the Annual Meeting, "Changing Regulations and Radiation Guidance: What Does the Future Hold?" The following represents a synopsis of a few main points in the current draft commentary. It is likely that several changes will be forthcoming as SC 1-23 responds to subject matter expert review and develops a final document, expected by mid 2016.

Liposomal encapsulation enhances and prolongs the anti-inflammatory effects of water-soluble dexamethasone phosphate in experimental adjuvant arthritis

PubMed Central

2010-01-01

Introduction The objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes. Methods Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry. Results Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug. Conclusions This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P. PMID:20642832

The impact on CT dose of the variability in tube current modulation technology: a theoretical investigation

NASA Astrophysics Data System (ADS)

Li, Xiang; Segars, W. Paul; Samei, Ehsan

2014-08-01

Body CT scans are routinely performed using tube-current-modulation (TCM) technology. There is notable variability across CT manufacturers in terms of how TCM technology is implemented. Some manufacturers aim to provide uniform image noise across body regions and patient sizes, whereas others aim to provide lower noise for smaller patients. The purpose of this study was to conduct a theoretical investigation to understand how manufacturer-dependent TCM scheme affects organ dose, and to develop a generic approach for assessing organ dose across TCM schemes. The adult reference female extended cardiac-torso (XCAT) phantom was used for this study. A ray-tracing method was developed to calculate the attenuation of the phantom for a given projection angle based on phantom anatomy, CT system geometry, x-ray energy spectrum, and bowtie filter filtration. The tube current (mA) for a given projection angle was then calculated as a log-linear function of the attenuation along that projection. The slope of this function, termed modulation control strength, α, was varied from 0 to 1 to emulate the variability in TCM technology. Using a validated Monte Carlo program, organ dose was simulated for five α values (α = 0, 0.25, 0.5, 0.75, and 1) in the absence and presence of a realistic system mA limit. Organ dose was further normalized by volume-weighted CT dose index (CTDIvol) to obtain conversion factors (h factors) that are relatively independent of system specifics and scan parameters. For both chest and abdomen-pelvis scans and for 24 radiosensitive organs, organ dose conversion factors varied with α, following second-order polynomial equations. This result suggested the need for α-specific organ dose conversion factors (i.e., conversion factors specific to the modulation scheme used). On the other hand, across the full range of α values, organ dose in a TCM scan could be derived from the conversion factors established for a fixed-mA scan (hFIXED). This was possible by multiplying hFIXED by a revised definition of CTDIvol that accounts for two factors: (a) the tube currents at the location of an organ and (b) the variation in organ volume along the longitudinal direction. This α-generic approach represents an approximation. The error associated with this approximation was evaluated using the α-specific organ dose (i.e., the organ dose obtained by using α-specific mA profiles as inputs into the Monte Carlo simulation) as the reference standard. When the mA profiles were constrained by a realistic system limit, this α-generic approach had errors of less than ~20% for the full range of α values. This was the case for 24 radiosensitive organs in both chest and abdomen-pelvis CT scans with the exception of thyroid in the chest scan and bladder in the abdomen-pelvis scan. For these two organs, the errors were less than ~40%. The results of this theoretical study suggested that knowing the mA modulation profile and the fixed-mA conversion factors, organ dose may be estimated for a TCM scan independent of the specific modulation scheme applied.

WE-AB-201-00: Treatment Planning System Commissioning and QA

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

NONE

Treatment planning systems (TPS) are a cornerstone of modern radiation therapy. Errors in their commissioning or use can have a devastating impact on many patients. To support safe and high quality care, medical physicists must conduct efficient and proper commissioning, good clinical integration, and ongoing quality assurance (QA) of the TPS. AAPM Task Group 53 and related publications have served as seminal benchmarks for TPS commissioning and QA over the past two decades. Over the same time, continuing innovations have made the TPS even more complex and more central to the clinical process. Medical goals are now expressed in termsmore » of the dose and margins around organs and tissues that are delineated from multiple imaging modalities (CT, MR and PET); and even temporally resolved (i.e., 4D) imaging. This information is passed on to optimization algorithms to establish accelerator movements that are programmed directly for IMRT, VMAT and stereotactic treatments. These advances have made commissioning and QA of the TPS much more challenging. This education session reviews up-to-date experience and guidance on this subject; including the recently published AAPM Medical Physics Practice Guideline (MPPG) #5 “Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams”. Treatment Planning System Commissioning and QA: Challenges and Opportunities (Greg Salomons) This session will provide some key background and review publications describing prominent incidents relating to TPS commissioning and QA. Traditional approaches have been hardware and feature oriented. They aim to establish a functional configuration and establish specifications for regular testing of features (like dose calculation) to assure stable operation and detect failures. With the advent of more complex systems, more patient-specific testing has also been adopted. A number of actual TPS defects will be presented along with heuristics for identifying similar defects in the future. Finally, the Gamma test has become a popular metric for reporting TPS Commissioning and QA results. It simplifies complex testing into a numerical index, but noisy data and casual application can make it misleading. A brief review of the issues around the use of the Gamma test will be presented. TPS commissioning and QA: A process orientation and application of control charts (Michael Sharpe) A framework for commissioning a treatment planning system will be presented, focusing on preparations, practical aspects of configuration, priorities, specifications, and establishing performance. The complexity of the modern TPS make modular testing of features inadequate, and modern QA tools can provide “too much information” about the performance of techniques like IMRT and VMAT. We have adopted a process orientation and quality tools, like control charts, for ongoing TPS QA and assessment of patient-specific tests. The trending nature of these tools reveals the overall performance of the TPS system, and quantifies the variations that arise from individual plans, discrete calculations, and experimentation based on discrete measurements. Examples demonstrating application of these tools to TPS QA will be presented. TPS commissioning and QA: Incorporating the entire planning process (Sasa Mutic) The TPS and its features do not perform in isolation. Instead, the features and modules are key components in a complex process that begins with CT Simulation and extends to treatment delivery, along with image guidance and verification. Most importantly, the TPS is used by people working in a multi-disciplinary environment. It is very difficult to predict the outcomes of human interactions with software. Therefore, an interdisciplinary approach to training, commissioning and QA will be presented, along with an approach to the physics chart check and end-to-end testing as a tool for TPS QA. The role of standardization and automation in QA will also be discussed. The recommendations of MPPG #5 and practical implementation strategies (Jennifer Smilowitz) The recently published recommendations from Task Group No. 244, Medical Physics Practice Guideline on Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams will be presented. The recommendations focus on the validation of commissioning data and dose calculations. Tolerance values for non-IMRT beam configurations are summarized based on established criteria and data collected by the IROC. More stringent evaluation criteria for IMRT dose calculations are suggested to test the limitations of the TPS dose algorithms for advanced delivery conditions. The MPPG encourages users to create a suite of validation tests for dose calculation for various conditions for static photon beams, heterogeneities, IMRT/VMAT and electron beams. This test suite is intended to be used for subsequent testing, including TPS software upgrades. In the past, the recommendations of some reports have not been widely implemented due to practical limitations. Implementation strategies, tools and processes developed by multiple centers for efficient and “do-able” MPPG # 5 testing will be presented, as well as a discussion on the overall validation experience. Learning Objectives: Identify some of the key documents relevant for TPS commissioning and QA Understand strategies for testing TPS software Gain a practical knowledge of the Gamma test criteria Increase familiarity with the process of commissioning a TPS Learn about the use of Control Charts for TPS QA Review the role of the TPS in the overall planning process Increase awareness of the link between TPS QA and chart checking Gain an increased appreciation for the importance of interdisciplinary communication Understand the new recommendations from MPPG #5 on TPS Dose Algorithm Commissioning and QC/QA Learn practical implementation processes and tools for MPPG #5 validation recommendations.« less

WE-AB-201-03: TPS Commissioning and QA: Incorporating the Entire Planning Process

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

Mutic, S.

Treatment planning systems (TPS) are a cornerstone of modern radiation therapy. Errors in their commissioning or use can have a devastating impact on many patients. To support safe and high quality care, medical physicists must conduct efficient and proper commissioning, good clinical integration, and ongoing quality assurance (QA) of the TPS. AAPM Task Group 53 and related publications have served as seminal benchmarks for TPS commissioning and QA over the past two decades. Over the same time, continuing innovations have made the TPS even more complex and more central to the clinical process. Medical goals are now expressed in termsmore » of the dose and margins around organs and tissues that are delineated from multiple imaging modalities (CT, MR and PET); and even temporally resolved (i.e., 4D) imaging. This information is passed on to optimization algorithms to establish accelerator movements that are programmed directly for IMRT, VMAT and stereotactic treatments. These advances have made commissioning and QA of the TPS much more challenging. This education session reviews up-to-date experience and guidance on this subject; including the recently published AAPM Medical Physics Practice Guideline (MPPG) #5 “Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams”. Treatment Planning System Commissioning and QA: Challenges and Opportunities (Greg Salomons) This session will provide some key background and review publications describing prominent incidents relating to TPS commissioning and QA. Traditional approaches have been hardware and feature oriented. They aim to establish a functional configuration and establish specifications for regular testing of features (like dose calculation) to assure stable operation and detect failures. With the advent of more complex systems, more patient-specific testing has also been adopted. A number of actual TPS defects will be presented along with heuristics for identifying similar defects in the future. Finally, the Gamma test has become a popular metric for reporting TPS Commissioning and QA results. It simplifies complex testing into a numerical index, but noisy data and casual application can make it misleading. A brief review of the issues around the use of the Gamma test will be presented. TPS commissioning and QA: A process orientation and application of control charts (Michael Sharpe) A framework for commissioning a treatment planning system will be presented, focusing on preparations, practical aspects of configuration, priorities, specifications, and establishing performance. The complexity of the modern TPS make modular testing of features inadequate, and modern QA tools can provide “too much information” about the performance of techniques like IMRT and VMAT. We have adopted a process orientation and quality tools, like control charts, for ongoing TPS QA and assessment of patient-specific tests. The trending nature of these tools reveals the overall performance of the TPS system, and quantifies the variations that arise from individual plans, discrete calculations, and experimentation based on discrete measurements. Examples demonstrating application of these tools to TPS QA will be presented. TPS commissioning and QA: Incorporating the entire planning process (Sasa Mutic) The TPS and its features do not perform in isolation. Instead, the features and modules are key components in a complex process that begins with CT Simulation and extends to treatment delivery, along with image guidance and verification. Most importantly, the TPS is used by people working in a multi-disciplinary environment. It is very difficult to predict the outcomes of human interactions with software. Therefore, an interdisciplinary approach to training, commissioning and QA will be presented, along with an approach to the physics chart check and end-to-end testing as a tool for TPS QA. The role of standardization and automation in QA will also be discussed. The recommendations of MPPG #5 and practical implementation strategies (Jennifer Smilowitz) The recently published recommendations from Task Group No. 244, Medical Physics Practice Guideline on Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams will be presented. The recommendations focus on the validation of commissioning data and dose calculations. Tolerance values for non-IMRT beam configurations are summarized based on established criteria and data collected by the IROC. More stringent evaluation criteria for IMRT dose calculations are suggested to test the limitations of the TPS dose algorithms for advanced delivery conditions. The MPPG encourages users to create a suite of validation tests for dose calculation for various conditions for static photon beams, heterogeneities, IMRT/VMAT and electron beams. This test suite is intended to be used for subsequent testing, including TPS software upgrades. In the past, the recommendations of some reports have not been widely implemented due to practical limitations. Implementation strategies, tools and processes developed by multiple centers for efficient and “do-able” MPPG #5 testing will be presented, as well as a discussion on the overall validation experience. Learning Objectives: Identify some of the key documents relevant for TPS commissioning and QA Understand strategies for testing TPS software Gain a practical knowledge of the Gamma test criteria Increase familiarity with the process of commissioning a TPS Learn about the use of Control Charts for TPS QA Review the role of the TPS in the overall planning process Increase awareness of the link between TPS QA and chart checking Gain an increased appreciation for the importance of interdisciplinary communication Understand the new recommendations from MPPG #5 on TPS Dose Algorithm Commissioning and QC/QA Learn practical implementation processes and tools for MPPG #5 validation recommendations.« less

WE-AB-201-04: The Recommendations of MPPG #5 and Practical Implementation Strategies

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

Smilowitz, J.

Treatment planning systems (TPS) are a cornerstone of modern radiation therapy. Errors in their commissioning or use can have a devastating impact on many patients. To support safe and high quality care, medical physicists must conduct efficient and proper commissioning, good clinical integration, and ongoing quality assurance (QA) of the TPS. AAPM Task Group 53 and related publications have served as seminal benchmarks for TPS commissioning and QA over the past two decades. Over the same time, continuing innovations have made the TPS even more complex and more central to the clinical process. Medical goals are now expressed in termsmore » of the dose and margins around organs and tissues that are delineated from multiple imaging modalities (CT, MR and PET); and even temporally resolved (i.e., 4D) imaging. This information is passed on to optimization algorithms to establish accelerator movements that are programmed directly for IMRT, VMAT and stereotactic treatments. These advances have made commissioning and QA of the TPS much more challenging. This education session reviews up-to-date experience and guidance on this subject; including the recently published AAPM Medical Physics Practice Guideline (MPPG) #5 “Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams”. Treatment Planning System Commissioning and QA: Challenges and Opportunities (Greg Salomons) This session will provide some key background and review publications describing prominent incidents relating to TPS commissioning and QA. Traditional approaches have been hardware and feature oriented. They aim to establish a functional configuration and establish specifications for regular testing of features (like dose calculation) to assure stable operation and detect failures. With the advent of more complex systems, more patient-specific testing has also been adopted. A number of actual TPS defects will be presented along with heuristics for identifying similar defects in the future. Finally, the Gamma test has become a popular metric for reporting TPS Commissioning and QA results. It simplifies complex testing into a numerical index, but noisy data and casual application can make it misleading. A brief review of the issues around the use of the Gamma test will be presented. TPS commissioning and QA: A process orientation and application of control charts (Michael Sharpe) A framework for commissioning a treatment planning system will be presented, focusing on preparations, practical aspects of configuration, priorities, specifications, and establishing performance. The complexity of the modern TPS make modular testing of features inadequate, and modern QA tools can provide “too much information” about the performance of techniques like IMRT and VMAT. We have adopted a process orientation and quality tools, like control charts, for ongoing TPS QA and assessment of patient-specific tests. The trending nature of these tools reveals the overall performance of the TPS system, and quantifies the variations that arise from individual plans, discrete calculations, and experimentation based on discrete measurements. Examples demonstrating application of these tools to TPS QA will be presented. TPS commissioning and QA: Incorporating the entire planning process (Sasa Mutic) The TPS and its features do not perform in isolation. Instead, the features and modules are key components in a complex process that begins with CT Simulation and extends to treatment delivery, along with image guidance and verification. Most importantly, the TPS is used by people working in a multi-disciplinary environment. It is very difficult to predict the outcomes of human interactions with software. Therefore, an interdisciplinary approach to training, commissioning and QA will be presented, along with an approach to the physics chart check and end-to-end testing as a tool for TPS QA. The role of standardization and automation in QA will also be discussed. The recommendations of MPPG #5 and practical implementation strategies (Jennifer Smilowitz) The recently published recommendations from Task Group No. 244, Medical Physics Practice Guideline on Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams will be presented. The recommendations focus on the validation of commissioning data and dose calculations. Tolerance values for non-IMRT beam configurations are summarized based on established criteria and data collected by the IROC. More stringent evaluation criteria for IMRT dose calculations are suggested to test the limitations of the TPS dose algorithms for advanced delivery conditions. The MPPG encourages users to create a suite of validation tests for dose calculation for various conditions for static photon beams, heterogeneities, IMRT/VMAT and electron beams. This test suite is intended to be used for subsequent testing, including TPS software upgrades. In the past, the recommendations of some reports have not been widely implemented due to practical limitations. Implementation strategies, tools and processes developed by multiple centers for efficient and “do-able” MPPG #5 testing will be presented, as well as a discussion on the overall validation experience. Learning Objectives: Identify some of the key documents relevant for TPS commissioning and QA Understand strategies for testing TPS software Gain a practical knowledge of the Gamma test criteria Increase familiarity with the process of commissioning a TPS Learn about the use of Control Charts for TPS QA Review the role of the TPS in the overall planning process Increase awareness of the link between TPS QA and chart checking Gain an increased appreciation for the importance of interdisciplinary communication Understand the new recommendations from MPPG #5 on TPS Dose Algorithm Commissioning and QC/QA Learn practical implementation processes and tools for MPPG #5 validation recommendations.« less

WE-AB-201-01: Treatment Planning System Commissioning and QA: Challenges and Opportunities

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

Salomons, G.

Treatment planning systems (TPS) are a cornerstone of modern radiation therapy. Errors in their commissioning or use can have a devastating impact on many patients. To support safe and high quality care, medical physicists must conduct efficient and proper commissioning, good clinical integration, and ongoing quality assurance (QA) of the TPS. AAPM Task Group 53 and related publications have served as seminal benchmarks for TPS commissioning and QA over the past two decades. Over the same time, continuing innovations have made the TPS even more complex and more central to the clinical process. Medical goals are now expressed in termsmore » of the dose and margins around organs and tissues that are delineated from multiple imaging modalities (CT, MR and PET); and even temporally resolved (i.e., 4D) imaging. This information is passed on to optimization algorithms to establish accelerator movements that are programmed directly for IMRT, VMAT and stereotactic treatments. These advances have made commissioning and QA of the TPS much more challenging. This education session reviews up-to-date experience and guidance on this subject; including the recently published AAPM Medical Physics Practice Guideline (MPPG) #5 “Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams”. Treatment Planning System Commissioning and QA: Challenges and Opportunities (Greg Salomons) This session will provide some key background and review publications describing prominent incidents relating to TPS commissioning and QA. Traditional approaches have been hardware and feature oriented. They aim to establish a functional configuration and establish specifications for regular testing of features (like dose calculation) to assure stable operation and detect failures. With the advent of more complex systems, more patient-specific testing has also been adopted. A number of actual TPS defects will be presented along with heuristics for identifying similar defects in the future. Finally, the Gamma test has become a popular metric for reporting TPS Commissioning and QA results. It simplifies complex testing into a numerical index, but noisy data and casual application can make it misleading. A brief review of the issues around the use of the Gamma test will be presented. TPS commissioning and QA: A process orientation and application of control charts (Michael Sharpe) A framework for commissioning a treatment planning system will be presented, focusing on preparations, practical aspects of configuration, priorities, specifications, and establishing performance. The complexity of the modern TPS make modular testing of features inadequate, and modern QA tools can provide “too much information” about the performance of techniques like IMRT and VMAT. We have adopted a process orientation and quality tools, like control charts, for ongoing TPS QA and assessment of patient-specific tests. The trending nature of these tools reveals the overall performance of the TPS system, and quantifies the variations that arise from individual plans, discrete calculations, and experimentation based on discrete measurements. Examples demonstrating application of these tools to TPS QA will be presented. TPS commissioning and QA: Incorporating the entire planning process (Sasa Mutic) The TPS and its features do not perform in isolation. Instead, the features and modules are key components in a complex process that begins with CT Simulation and extends to treatment delivery, along with image guidance and verification. Most importantly, the TPS is used by people working in a multi-disciplinary environment. It is very difficult to predict the outcomes of human interactions with software. Therefore, an interdisciplinary approach to training, commissioning and QA will be presented, along with an approach to the physics chart check and end-to-end testing as a tool for TPS QA. The role of standardization and automation in QA will also be discussed. The recommendations of MPPG #5 and practical implementation strategies (Jennifer Smilowitz) The recently published recommendations from Task Group No. 244, Medical Physics Practice Guideline on Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams will be presented. The recommendations focus on the validation of commissioning data and dose calculations. Tolerance values for non-IMRT beam configurations are summarized based on established criteria and data collected by the IROC. More stringent evaluation criteria for IMRT dose calculations are suggested to test the limitations of the TPS dose algorithms for advanced delivery conditions. The MPPG encourages users to create a suite of validation tests for dose calculation for various conditions for static photon beams, heterogeneities, IMRT/VMAT and electron beams. This test suite is intended to be used for subsequent testing, including TPS software upgrades. In the past, the recommendations of some reports have not been widely implemented due to practical limitations. Implementation strategies, tools and processes developed by multiple centers for efficient and “do-able” MPPG #5 testing will be presented, as well as a discussion on the overall validation experience. Learning Objectives: Identify some of the key documents relevant for TPS commissioning and QA Understand strategies for testing TPS software Gain a practical knowledge of the Gamma test criteria Increase familiarity with the process of commissioning a TPS Learn about the use of Control Charts for TPS QA Review the role of the TPS in the overall planning process Increase awareness of the link between TPS QA and chart checking Gain an increased appreciation for the importance of interdisciplinary communication Understand the new recommendations from MPPG #5 on TPS Dose Algorithm Commissioning and QC/QA Learn practical implementation processes and tools for MPPG #5 validation recommendations.« less

WE-AB-201-02: TPS Commissioning and QA: A Process Orientation and Application of Control Charts

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

Sharpe, M.

Treatment planning systems (TPS) are a cornerstone of modern radiation therapy. Errors in their commissioning or use can have a devastating impact on many patients. To support safe and high quality care, medical physicists must conduct efficient and proper commissioning, good clinical integration, and ongoing quality assurance (QA) of the TPS. AAPM Task Group 53 and related publications have served as seminal benchmarks for TPS commissioning and QA over the past two decades. Over the same time, continuing innovations have made the TPS even more complex and more central to the clinical process. Medical goals are now expressed in termsmore » of the dose and margins around organs and tissues that are delineated from multiple imaging modalities (CT, MR and PET); and even temporally resolved (i.e., 4D) imaging. This information is passed on to optimization algorithms to establish accelerator movements that are programmed directly for IMRT, VMAT and stereotactic treatments. These advances have made commissioning and QA of the TPS much more challenging. This education session reviews up-to-date experience and guidance on this subject; including the recently published AAPM Medical Physics Practice Guideline (MPPG) #5 “Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams”. Treatment Planning System Commissioning and QA: Challenges and Opportunities (Greg Salomons) This session will provide some key background and review publications describing prominent incidents relating to TPS commissioning and QA. Traditional approaches have been hardware and feature oriented. They aim to establish a functional configuration and establish specifications for regular testing of features (like dose calculation) to assure stable operation and detect failures. With the advent of more complex systems, more patient-specific testing has also been adopted. A number of actual TPS defects will be presented along with heuristics for identifying similar defects in the future. Finally, the Gamma test has become a popular metric for reporting TPS Commissioning and QA results. It simplifies complex testing into a numerical index, but noisy data and casual application can make it misleading. A brief review of the issues around the use of the Gamma test will be presented. TPS commissioning and QA: A process orientation and application of control charts (Michael Sharpe) A framework for commissioning a treatment planning system will be presented, focusing on preparations, practical aspects of configuration, priorities, specifications, and establishing performance. The complexity of the modern TPS make modular testing of features inadequate, and modern QA tools can provide “too much information” about the performance of techniques like IMRT and VMAT. We have adopted a process orientation and quality tools, like control charts, for ongoing TPS QA and assessment of patient-specific tests. The trending nature of these tools reveals the overall performance of the TPS system, and quantifies the variations that arise from individual plans, discrete calculations, and experimentation based on discrete measurements. Examples demonstrating application of these tools to TPS QA will be presented. TPS commissioning and QA: Incorporating the entire planning process (Sasa Mutic) The TPS and its features do not perform in isolation. Instead, the features and modules are key components in a complex process that begins with CT Simulation and extends to treatment delivery, along with image guidance and verification. Most importantly, the TPS is used by people working in a multi-disciplinary environment. It is very difficult to predict the outcomes of human interactions with software. Therefore, an interdisciplinary approach to training, commissioning and QA will be presented, along with an approach to the physics chart check and end-to-end testing as a tool for TPS QA. The role of standardization and automation in QA will also be discussed. The recommendations of MPPG #5 and practical implementation strategies (Jennifer Smilowitz) The recently published recommendations from Task Group No. 244, Medical Physics Practice Guideline on Commissioning and QA of Treatment Planning Dose Calculations: Megavoltage Photon and Electron Beams will be presented. The recommendations focus on the validation of commissioning data and dose calculations. Tolerance values for non-IMRT beam configurations are summarized based on established criteria and data collected by the IROC. More stringent evaluation criteria for IMRT dose calculations are suggested to test the limitations of the TPS dose algorithms for advanced delivery conditions. The MPPG encourages users to create a suite of validation tests for dose calculation for various conditions for static photon beams, heterogeneities, IMRT/VMAT and electron beams. This test suite is intended to be used for subsequent testing, including TPS software upgrades. In the past, the recommendations of some reports have not been widely implemented due to practical limitations. Implementation strategies, tools and processes developed by multiple centers for efficient and “do-able” MPPG #5 testing will be presented, as well as a discussion on the overall validation experience. Learning Objectives: Identify some of the key documents relevant for TPS commissioning and QA Understand strategies for testing TPS software Gain a practical knowledge of the Gamma test criteria Increase familiarity with the process of commissioning a TPS Learn about the use of Control Charts for TPS QA Review the role of the TPS in the overall planning process Increase awareness of the link between TPS QA and chart checking Gain an increased appreciation for the importance of interdisciplinary communication Understand the new recommendations from MPPG #5 on TPS Dose Algorithm Commissioning and QC/QA Learn practical implementation processes and tools for MPPG #5 validation recommendations.« less

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

PubMed

Cohen, Ezra E W; Davis, Darren W; Karrison, Theodore G; Seiwert, Tanguy Y; Wong, Stuart J; Nattam, Sreenivasa; Kozloff, Mark F; Clark, Joseph I; Yan, Duen-Hwa; Liu, Wen; Pierce, Carolyn; Dancey, Janet E; Stenson, Kerstin; Blair, Elizabeth; Dekker, Allison; Vokes, Everett E

2009-03-01

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Limitations of current dosimetry for intracavitary accelerated partial breast irradiation with high dose rate iridium-192 and electronic brachytherapy sources

NASA Astrophysics Data System (ADS)

Raffi, Julie A.

Intracavitary accelerated partial breast irradiation (APBI) is a method of treating early stage breast cancer using a high dose rate (HDR) brachytherapy source positioned within the lumpectomy cavity. An expandable applicator stretches the surrounding tissue into a roughly spherical or elliptical shape and the dose is prescribed to 1 cm beyond the edge of the cavity. Currently, dosimetry for these treatments is most often performed using the American Association of Physicists in Medicine Task Group No. 43 (TG-43) formalism. The TG-43 dose-rate equation determines the dose delivered to a homogeneous water medium by scaling the measured source strength with standardized parameters that describe the radial and angular features of the dose distribution. Since TG-43 parameters for each source model are measured or calculated in a homogeneous water medium, the dosimetric effects of the patient's dimensions and composition are not accounted for. Therefore, the accuracy of TG-43 calculations for intracavitary APBI is limited by the presence of inhomogeneities in and around the target volume. Specifically, the breast is smaller than the phantoms used to determine TG-43 parameters and is surrounded by air, ribs, and lung tissue. Also, the composition of the breast tissue itself can affect the dose distribution. This dissertation is focused on investigating the limitations of TG-43 dosimetry for intracavitary APBI for two HDR brachytherapy sources: the VariSource TM VS2000 192Ir source and the AxxentRTM miniature x-ray source. The dose for various conditions was determined using thermoluminescent dosimeters (TLDs) and Monte Carlo (MC) calculations. Accurate measurements and calculations were achieved through the implementation of new measurement and simulation techniques and a novel breast phantom was developed to enable anthropomorphic phantom measurements. Measured and calculated doses for phantom and patient geometries were compared with TG-43 calculated doses to illustrate the limitations of TG-43 dosimetry for intracavitary APBI. TG-43 dose calculations overestimate the dose for regions approaching the lung and breast surface and underestimate the dose for regions in and beyond less-attenuating media such as lung tissue, and for lower energies, breast tissue as well.

Ionizing radiation fluxes and dose measurements during the Kosmos 1887 satellite flight.

PubMed

Charvat, J; Spurny, F; Kopecka, B; Votockova, I

1990-01-01

The results of dosimetric experiments performed during the flight of Kosmos 1887 biosatellite are presented. Two kinds of measurements were performed on the external surface of the satellite. First, the fluences and spectra of low energy charged particles were established. It was found that most of the particles registered by means of solid state nuclear track detectors are helium nuclei. Tracks of oxygen nuclei and some heavier charged particles were also observed. Thermoluminescent detectors were used to establish absorbed doses in open space on the satellite's surface and behind thin shielding. It was found that these doses were rather high; nevertheless, their decrease with shielding thickness is very rapid. Dosimetric and other consequences of the results obtained are analyzed and discussed.

Vocal Dose Measures: Quantifying Accumulated Vibration Exposure in Vocal Fold Tissues

PubMed Central

Titze, Ingo R.; Švec, Jan G.; Popolo, Peter S.

2011-01-01

To measure the exposure to self-induced tissue vibration in speech, three vocal doses were defined and described: distance dose, which accumulates the distance that tissue particles of the vocal folds travel in an oscillatory trajectory; energy dissipation dose, which accumulates the total amount of heat dissipated over a unit volume of vocal fold tissues; and time dose, which accumulates the total phonation time. These doses were compared to a previously used vocal dose measure, the vocal loading index, which accumulates the number of vibration cycles of the vocal folds. Empirical rules for viscosity and vocal fold deformation were used to calculate all the doses from the fundamental frequency (F0) and sound pressure level (SPL) values of speech. Six participants were asked to read in normal, monotone, and exaggerated speech and the doses associated with these vocalizations were calculated. The results showed that large F0 and SPL variations in speech affected the dose measures, suggesting that accumulation of phonation time alone is insufficient. The vibration exposure of the vocal folds in normal speech was related to the industrial limits for hand-transmitted vibration, in which the safe distance dose was derived to be about 500 m. This limit was found rather low for vocalization; it was related to a comparable time dose of about 17 min of continuous vocalization, or about 35 min of continuous reading with normal breathing and unvoiced segments. The voicing pauses in normal speech and dialogue effectively prolong the safe time dose. The derived safety limits for vocalization will likely require refinement based on a more detailed knowledge of the differences in hand and vocal fold tissue morphology and their response to vibrational stress, and on the effect of recovery of the vocal fold tissue during voicing pauses. PMID:12959470

Vocal dose measures: quantifying accumulated vibration exposure in vocal fold tissues.

PubMed

Titze, Ingo R; Svec, Jan G; Popolo, Peter S

2003-08-01

To measure the exposure to self-induced tissue vibration in speech, three vocal doses were defined and described: distance dose, which accumulates the distance that tissue particles of the vocal folds travel in an oscillatory trajectory; energy dissipation dose, which accumulates the total amount of heat dissipated over a unit volume of vocal fold tissues; and time dose, which accumulates the total phonation time. These doses were compared to a previously used vocal dose measure, the vocal loading index, which accumulates the number of vibration cycles of the vocal folds. Empirical rules for viscosity and vocal fold deformation were used to calculate all the doses from the fundamental frequency (F0) and sound pressure level (SPL) values of speech. Six participants were asked to read in normal, monotone, and exaggerated speech and the doses associated with these vocalizations were calculated. The results showed that large F0 and SPL variations in speech affected the dose measures, suggesting that accumulation of phonation time alone is insufficient. The vibration exposure of the vocal folds in normal speech was related to the industrial limits for hand-transmitted vibration, in which the safe distance dose was derived to be about 500 m. This limit was found rather low for vocalization; it was related to a comparable time dose of about 17 min of continuous vocalization, or about 35 min of continuous reading with normal breathing and unvoiced segments. The voicing pauses in normal speech and dialogue effectively prolong the safe time dose. The derived safety limits for vocalization will likely require refinement based on a more detailed knowledge of the differences in hand and vocal fold tissue morphology and their response to vibrational stress, and on the effect of recovery of the vocal fold tissue during voicing pauses.

Low Dose Risk, Decisions, and Risk Communication

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

Flynn, James

The overall research objective was to establish new levels of information about how people, groups, and communities respond to low dose radiation exposure. This is basic research into the social psychology of individual, group, and community responses to radiation exposures. The results of this research are directed to improving risk communication and public participation in management of environmental problems resulting from low dose radiation.

Interferometer-Based Calorimetric Measurements of Absorbed Dose to Water in External Beam Radiotherapy

NASA Astrophysics Data System (ADS)

Flores-Martinez, Everardo

Calorimetry is often used to establish high-energy photon absorbed dose to water (ADW) primary standards as calorimetry is a direct measurement of the energy imparted to the water by ionizing radiation. Current calorimeters use thermistors to establish national standards but there is the possibility of systematic errors in these instruments because thermistors overheat due to their low heat capacity. For this reason, there has been renewed interest in using alternative temperature measurement techniques, especially those that do not require a mechanical probe. Interferometer-based thermometry is a technique that exploits the temperature dependence of the refractive index of water and can be used as an alternative method for temperature measurement in radiation calorimetry. A distinctive advantage of the use of interferometry for radiation calorimetry is the capability of obtaining 2D or 3D temperature/dose distributions. Compared to thermistor-based measurements, the use of interferometer-based ADW measurements has been limited by the low measurement resolution. Optimized setups with higher accuracy and precision are necessary to perform measurements at clinically relevant dose rates. A calorimeter for thermistor-based ADW measurements was developed. The instrument was used to measure thermal drifts and noise were measured using the instrument in a water phantom. Residual thermal drifts were accounted for by using a three-step measurement protocol. Additionally, the instrument was used to measure ADW from a 6MV photon beam from a medical linear accelerator. A Michelson-type interferometer was built, characterized, and placed inside the calorimeter with the water phantom at the reference arm. Interferometer and phantom temperature fluctuations were minimized by means of the passive thermal control provide by the calorimeter enclosure, leading to increased fringe pattern stability. The interferometer characterization included phase shift measurements induced by displacing a piezoelectric transducer. Measurements were compared with calculations to estimate the accuracy of the technique. The interferometer-based system was used to measure ADW in a water-filled glass phantom, irradiated with a 6MV photon beam. The estimated Type-A, (k = 1) uncertainty in the associated doses was about 0.3Gy, which is an order of magnitude lower than previously published interferometer-based ADW measurements. Additionally a comparative analysis was performed with the thermistor-based measurements, results for both techniques agreed within the uncertainty. This work presents the first absolute ADW measurements performed using interferometry in the dose range of linac-based radiotherapy and represents a significant step towards standards-level measurements using this technique.

EPR/PTFE dosimetry for test reactor environments

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

Vehar, D.W.; Griffin, P.J.; Quirk, T.J.

2011-07-01

The use of Electron Paramagnetic Resonance (EPR) spectroscopy with materials such as alanine is well established as a technique for measurement of ionizing radiation absorbed dose in photon and electron fields such as Co-60, high-energy bremsstrahlung and electron-beam fields [1]. In fact, EPR/Alanine dosimetry has become a routine transfer standard for national standards bodies such as NIST and NPL. In 1992 the Radiation Metrology Laboratory (RML) at Sandia National Laboratories implemented EPR/Alanine capabilities for use in routine and calibration activities at its Co-60 and pulsed-power facilities. At that time it also investigated the usefulness of the system for measurement ofmore » absorbed dose in the mixed neutron/photon environments of reactors such as the Sandia Pulsed Reactor and the Annular Core Research Reactor used for hardness testing of electronics. The RML concluded that the neutron response of alanine was a sufficiently high fraction of the overall dosimeter response that the resulting uncertainties in the photon dose would be unacceptably large for silicon-device testing. However, it also suggested that non-hydrogenous materials such as polytetrafluoroethylene (PTFE) would exhibit smaller neutron response and might be useful in mixed environments. Preliminary research with PTFE in photon environments indicated considerable promise, but further development was not pursued at that time. Because of renewed interest in absorbed dose measurements that could better define the individual contributions of photon and neutron components to the overall dose delivered to a test object, the RML has re-initiated the development of an EPR/PTFE dosimetry system. This effort consists of three stages: 1) Identification of PTFE materials that may be suitable for dosimetry applications. It was speculated that the inconsistency of EPR signatures in the earlier samples may have been due to variability in PTFE manufacturing processes. 2) Characterization of dosimetry in photon-only environments. This is necessary to establish requirements for sample preparation, operating parameters and limitations for use in well-defined and predictable environments prior to deployment in the less well-defined mixed environments of test reactors. 3) Characterization of the EPR responses obtained with PTFE in mixed neutron/photon fields. This includes evaluation of the neutron and photon contributions to response, determination of applicable of neutron fluence and photon dose ranges. This paper presents a summary of the research, a description of the EPR/PTFE dosimetry system, and recommendations for preparation and fielding of the dosimetry in photon and mixed neutron/photon environments. (authors)« less

Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance

PubMed Central

2013-01-01

Background Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. Results The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Conclusions Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics. PMID:23800340

Evaluation of Aged Garlic Extract Neuroprotective Effect in a Focal Model of Cerebral Ischemia

NASA Astrophysics Data System (ADS)

Aguilera, Penélope; Maldonado, Perla D.; Ortiz-Plata, Alma; Barrera, Diana; Chánez-Cárdenas, María Elena

2008-02-01

The oxidant species generated in cerebral ischemia have been implicated as important mediators of neuronal injury through damage to lipids, DNA, and proteins. Since ischemia as well as reperfusion insults generate oxidative stress, the administration of antioxidants may limit oxidative damage and ameliorate disease progression. The present work shows the transitory neuroprotective effect of the aged garlic extract (AGE) administration (a proposed antioxidant compound) in a middle cerebral artery occlusion (MCAO) model in rats and established its therapeutic window. To determine the optimal time of administration, animal received AGE (1.2 mL/kg) intraperitoneally 30 min before onset of reperfusion (-0.5 R), at the beginning of reperfusion (0R), or 1 h after onset of reperfusion (1R). Additional doses were administrated after 1, 2, or 3 h after onset of reperfusion. To establish the therapeutic window of AGE, the infarct area was determined for each treatment after different times of reperfusion. Results show that the administration of AGE at the onset of reperfusion reduced the infarct area by 70% (evaluated after 2 h reperfusion). The therapeutic window of AGE was determined. Repeated doses did not extend the temporal window of protection. A significant reduction in the nitrotyrosine level was observed in the brain tissue subjected to MCAO after AGE treatment at the onset of reperfusion. Data in the present work show that AGE exerts a transitory neuroprotective effect in response to ischemia/reperfusion-induced neuronal injury.

[EFFECTS OF GREEN TEA ON THE NUTRITIONAL STATUS OF THE EXERCISE].

PubMed

Albert Pérez, Enrique José; Reig García-Galbis, Manuel

2015-10-01

assessing the magnitude of the effects of green tea in subjects that do exercise. a search was been carried out with key words "green tea" AND "exercise" in four documentary databases: Pubmed, EBSCOHOST, OvidSP and Proquest. adult age of the sample (18-65 years, based on WHO), and the consumption of a quantified amount of green tea or substitutes, along with doing physical exercise measurable in intensity, in clinical tests published between January 2010 and December 2014, whose source were indexed scientific journals. 260 articles were analyzed, of which 13 items were selected. 69% are studies with a designed workout, and 92% have included an exercise test to assess parameters. 77% fluctuate between 20-40 years and sample size between 9 and 36 subjects. 69% are long length. GTE has been the most used substitute (38%). 92% of studies have obtained some improvement and 92% of them, were significantly statistic. Interpretation of results: little homogeneity has been found in results in the analysis of results expression. Sample size is limited. There is a wide range of GTE substitutes and diversity of doses and exercise done. It cannot be possible to establish a dose, dosage and physical activity recommended. green tea gives us a wide variety of benefits in combination with physical exercise. There is a little evidence about quality. It cannot be possible to establish specific recommendations for obtaining benefits. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates.

PubMed

Hansard, Matthew J; Smith, Lance A; Jackson, Michael J; Cheetham, Sharon C; Jenner, Peter

2004-01-01

Long-term treatment of Parkinson's disease (PD) with levodopa (L-dopa) induces dyskinesia that, once established, is provoked by each dose of L-dopa or a dopamine (DA) agonist. In contrast, monoamine reuptake inhibitors may reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates without provoking established involuntary movements. We now examine whether the potent monoamine reuptake blocker BTS 74 398 induces established dyskinesia in MPTP-treated common marmosets primed previously with L-dopa and whether co-administration of BTS 74 398 with L-dopa potentiates motor behaviour and dyskinesia induced by acute L-dopa treatment. Administration of BTS 74 398 (2.5, 5.0, or 10.0 mg/kg, p.o.) in MPTP-treated common marmosets increased locomotor activity and reduced motor disability in a dose-related manner but did not provoke involuntary movements. BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia. Similarly, concomitant administration of BTS 74 398 (5.0 mg/kg p.o.) with a submaximal L-dopa dose (12.5 mg/kg p.o.) did not potentiate the motor response produced by L-dopa alone and there was no alteration in the dyskinesia provoked by L-dopa challenge. BTS 74 398 reverses motor abnormalities in MPTP-treated marmosets without evoking established dyskinesia but no additive improvement occurs when administered in combination with L-dopa. The lack of synergy with L-dopa may suggest different sites of drug action. Copyright 2003 Movement Disorder Society

A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.

PubMed

Hong, David S; Kurzrock, Razelle; Supko, Jeffrey G; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J; Ferguson, Deborah A; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I; Dezube, Bruce J

2012-06-15

Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2-related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. ©2012 AACR.

A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

PubMed Central

Hong, David S.; Kurzrock, Razelle; Supko, Jeffrey G.; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J.; Ferguson, Deborah A.; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I.; Dezube, Bruce J.

2015-01-01

Purpose Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. PMID:22634319

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

PubMed Central

Deming, Dustin A.; Cavalcante, Ludmila L.; Lubner, Sam J.; Mulkerin, Daniel L.; LoConte, Noelle K.; Eickhoff, Jens C.; Kolesar, Jill M.; Fioravanti, Suzanne; Greten, Tim F.; Compton, Kathryn; Doyle, Austin G.; Wilding, George; Duffy, Austin; Liu, Glenn

2015-01-01

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes. PMID:26666244

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.

PubMed

Deming, Dustin A; Cavalcante, Ludmila L; Lubner, Sam J; Mulkerin, Daniel L; LoConte, Noelle K; Eickhoff, Jens C; Kolesar, Jill M; Fioravanti, Suzanne; Greten, Tim F; Compton, Kathryn; Doyle, Austin G; Wilding, George; Duffy, Austin; Liu, Glenn

2016-04-01

KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Towards real-time photon Monte Carlo dose calculation in the cloud

NASA Astrophysics Data System (ADS)

Ziegenhein, Peter; Kozin, Igor N.; Kamerling, Cornelis Ph; Oelfke, Uwe

2017-06-01

Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.

Towards real-time photon Monte Carlo dose calculation in the cloud.

PubMed

Ziegenhein, Peter; Kozin, Igor N; Kamerling, Cornelis Ph; Oelfke, Uwe

2017-06-07

Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.

Evaluation of Spirulina platensis extract as natural antivirus against foot and mouth disease virus strains (A, O, SAT2)

PubMed Central

Daoud, Hind M.; Soliman, Eman M.

2015-01-01

Aim: This work was aimed to document the antiviral activates of Spirulina platensis extract against foot and mouth disease virus (FMDV) different types to evaluate its replication in Baby Hamster Kidney (BHK) cell culture and in baby mice. Materials and Methods: Cytotoxicity assay studied for S. platensis extract on BHK cells to determine the non-toxic dose. The non-toxic dose of Spirulina extract was mixed with each type of FMDV (A, O, SAT2). Then 10-fold dilutions from each mixture were done. FMDV titer for each type of treated FMDV was calculated to evaluate the antiviral activity of the Spirulina extract against FMDV. Furthermore, old baby Swiss mice were inoculated with 0.1 ml intraperitonially from the mixture of FMDV different types and different concentration of Spirulina extracts. After 48 h post inoculation, all the baby mice examined to evaluate the antiviral action of Spirulina extract. Results: The result showed that the non-toxic doses of S. platensis (50 ug/ml) revealed 35.7%, 28.5%, and 31% reductions in FMDV titers Type O, A, and SAT2 on BHK cells, respectively. The same non-toxic dose gave 50% of the inhibitory concentration in baby mice without cytotoxic effect. Conclusion: This study confirmed the biological activity of the ethanol extract of S. platensis against FMDV Types O, A, and SAT2. From the results, S. platensis could be useful as antiviral lead to limitation of infection among animals during outbreaks but further studies need to evaluate the S. platensis on experimental or natural infected farm animals to establish the effective dose side affected period of treatment of S. platensis. PMID:27047027

Evaluation of Spirulina platensis extract as natural antivirus against foot and mouth disease virus strains (A, O, SAT2).

PubMed

Daoud, Hind M; Soliman, Eman M

2015-10-01

This work was aimed to document the antiviral activates of Spirulina platensis extract against foot and mouth disease virus (FMDV) different types to evaluate its replication in Baby Hamster Kidney (BHK) cell culture and in baby mice. Cytotoxicity assay studied for S. platensis extract on BHK cells to determine the non-toxic dose. The non-toxic dose of Spirulina extract was mixed with each type of FMDV (A, O, SAT2). Then 10-fold dilutions from each mixture were done. FMDV titer for each type of treated FMDV was calculated to evaluate the antiviral activity of the Spirulina extract against FMDV. Furthermore, old baby Swiss mice were inoculated with 0.1 ml intraperitonially from the mixture of FMDV different types and different concentration of Spirulina extracts. After 48 h post inoculation, all the baby mice examined to evaluate the antiviral action of Spirulina extract. The result showed that the non-toxic doses of S. platensis (50 ug/ml) revealed 35.7%, 28.5%, and 31% reductions in FMDV titers Type O, A, and SAT2 on BHK cells, respectively. The same non-toxic dose gave 50% of the inhibitory concentration in baby mice without cytotoxic effect. This study confirmed the biological activity of the ethanol extract of S. platensis against FMDV Types O, A, and SAT2. From the results, S. platensis could be useful as antiviral lead to limitation of infection among animals during outbreaks but further studies need to evaluate the S. platensis on experimental or natural infected farm animals to establish the effective dose side affected period of treatment of S. platensis.

Fundamental limits of image registration performance: Effects of image noise and resolution in CT-guided interventions.

PubMed

Ketcha, M D; de Silva, T; Han, R; Uneri, A; Goerres, J; Jacobson, M; Vogt, S; Kleinszig, G; Siewerdsen, J H

2017-02-11

In image-guided procedures, image acquisition is often performed primarily for the task of geometrically registering information from another image dataset, rather than detection / visualization of a particular feature. While the ability to detect a particular feature in an image has been studied extensively with respect to image quality characteristics (noise, resolution) and is an ongoing, active area of research, comparatively little has been accomplished to relate such image quality characteristics to registration performance. To establish such a framework, we derived Cramer-Rao lower bounds (CRLB) for registration accuracy, revealing the underlying dependencies on image variance and gradient strength. The CRLB was analyzed as a function of image quality factors (in particular, dose) for various similarity metrics and compared to registration accuracy using CT images of an anthropomorphic head phantom at various simulated dose levels. Performance was evaluated in terms of root mean square error (RMSE) of the registration parameters. Analysis of the CRLB shows two primary dependencies: 1) noise variance (related to dose); and 2) sum of squared image gradients (related to spatial resolution and image content). Comparison of the measured RMSE to the CRLB showed that the best registration method, RMSE achieved the CRLB to within an efficiency factor of 0.21, and optimal estimators followed the predicted inverse proportionality between registration performance and radiation dose. Analysis of the CRLB for image registration is an important step toward understanding and evaluating an intraoperative imaging system with respect to a registration task. While the CRLB is optimistic in absolute performance, it reveals a basis for relating the performance of registration estimators as a function of noise content and may be used to guide acquisition parameter selection (e.g., dose) for purposes of intraoperative registration.

A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.

PubMed

Dy, Grace K; Bruzek, Laura M; Croghan, Gary A; Mandrekar, Sumithra; Erlichman, Charles; Peethambaram, Prema; Pitot, Henry C; Hanson, Lorelei J; Reid, Joel M; Furth, Alfred; Cheng, Shinta; Martell, Robert E; Kaufmann, Scott H; Adjei, Alex A

2005-03-01

This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

Activity concentrations of (137)Caesium and (210)Polonium in seafood from fishing regions of New Zealand and the dose assessment for seafood consumers.

PubMed

Pearson, Andrew J; Gaw, Sally; Hermanspahn, Nikolaus; Glover, Chris N

2016-01-01

A study was undertaken to determine activity concentrations for (134)Caesium, (137)Caesium and (210)Polonium in New Zealand seafood, and establish if activity concentrations varied with respect to species/ecological niche and coastal region. Thirty seafood samples were obtained from six fishing regions of New Zealand along with a further six samples of two commercially important species (hoki and arrow squid) with well-defined fisheries. (134)Caesium was not detected in any sample. (137)Caesium was detected in 47% of samples, predominantly in pelagic fish species, with most activities at a trace level. Detections of (137)Caesium were evenly distributed across all regions. Activity concentrations were consistent with those expected from the oceanic inventory representing residual fallout from global nuclear testing. (210)Polonium was detected above the minimum detectable concentration in 33 (92%) of the analysed samples. Molluscs displayed significantly elevated activity concentrations relative to all other species groups. No significant regional variation in activity concentrations were determined. Two dose assessment models for high seafood consumers were undertaken. Dose contribution from (137)Caesium was minimal and far below the dose exemption limit of 1 mSv/year. Exposure to (210)Polonium was significant in high seafood consumers at 0.44-0.77 mSv/year (5th-95th percentile). (137)Caesium is concluded to be a valuable sentinel radionuclide for monitoring anthropogenic releases, such as global fallout and reactor releases, in the marine environment. (210)Polonium is of importance as a natural radionuclide sentinel due to its high contribution to dietary committed dose in seafood consumers. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

TU-D-209-04: How Useful Are Indirect Dose Metrics for Estimating Peak Skin Dose in Interventional Cardiology?

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

Jones, A; Pasciak, A

Purpose: The purpose of this study was to determine if a relationship between indirect dose metrics and PSD could be established for fluoroscopically-guided interventional cardiology procedures. Methods: PSD were measured directly using XR-RV3 radiochromic film for 94 consecutive fluoroscopically guided interventional cardiology procedures performed at two sites. Procedures were both diagnostic and therapeutic in nature. Radiation dose structured reports (RDSR) were collected for each procedure and used to calculate indirect estimates of PSD which were compared to the measured PSD. Reference air kerma (Ka,r) was also compared to the measured PSD. Pearson’s correlation coefficient was calculated for each metric andmore » metrics were compared to measured PSD using a two-tailed t-test. Data were log transformed prior to statistical analysis. Results: Both Ka,r and the calculated PSD were closely correlated with measured PSD at each sites (Ka,r: 0.92 and 0.86, indirect PSD: 0.91 and 0.88). At one site, neither Ka,r nor indirect PSD was significantly different from the measured PSD (p = 0.22 and p=0.054, respectively), while at the second site both Ka,r and indirect PSD were significantly higher than measured PSD (p<0.0001 and p<0.0001, respectively). In almost all cases, both Ka,r and indirect PSD overestimated the true PSD. Conclusions: The use of a range of gantry angles and table positions, along with variation in procedural imaging requirements, limits the utility of indirect dose metrics for predicting PSD for interventional cardiology procedures. A. Kyle Jones and Alexander S. Pasciak are owners of Fluoroscopic Safety, LLC.« less

Establishment of Cry9C susceptibility baselines for European corn borer and southwestern corn borer (Lepidoptera: Crambidae).

PubMed

Reed, J P; Halliday, W R

2001-04-01

In 1997 and 1998, Cry9C susceptibility baselines were established for field-collected populations of European corn borer, Osrinia nubilalis (Hubner), and southwestern corn borer, Diatraea grandiosella Dyar. Bioassay of neonate European corn borer larvae of 16 colonies collected from the midwestern United States indicated LC50 values ranging from 13.2 to 65.1 ng of Cry9C protein per square centimeter. Neonate European corn borer LC50 values ranged from 46.5 to 214 ng/cm2. Neonate larvae of three colonies of southwestern corn borer collected from the southern and southwestern United States exhibited LC50 values from 16.9 to 39.9 ng of Cry9C protein per square centimeter. Southwestern corn borer neonate LC90 confidence limit values ranged from 40.3 to 157 ng of Cry9C protein per centimeter. The most sensitive southwestern corn borer colony was collected from the Mississippi delta exhibiting an LC50 value of 22.6 ng of Cry9C per cm2 and also displayed the widest LC0 confidence limits of 40.3-94.8 ng of Cry9C per cm2. Geographic baseline susceptibility data establishes the natural genetic variation and provides the foundation for future testing of insect populations exposed to increased use of Bacillus thuringiensis-based crops. Insect resistance management and stewardship of Cry9C will rely upon baseline data for the validation of discriminating dose assays for European corn borer and southwestern corn borer.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

PubMed

Atkins, Michael B; Plimack, Elizabeth R; Puzanov, Igor; Fishman, Mayer N; McDermott, David F; Cho, Daniel C; Vaishampayan, Ulka; George, Saby; Olencki, Thomas E; Tarazi, Jamal C; Rosbrook, Brad; Fernandez, Kathrine C; Lechuga, Mariajose; Choueiri, Toni K

2018-03-01

Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Pfizer Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Determination of cocaine and benzoylecgonine in guinea pig's hair after a single dose administration by LC-MS/MS.

PubMed

Sun, Qi-ran; Xiang, Ping; Yan, Hui; Shen, Min

2008-12-01

A sensitive LC-MS/MS method to determine cocaine and its major metabolite benzoylecgonine in guinea pig' s hair has been established. About 20 mg of decontaminated hair sample was hydrolyzed with 0. 1 mol x L(-1) HCl at 50 degrees C overnight, in the presence of cocaine-d3 and benzoylecgonine-d8 used as internal standards, and then extracted with dichlormethane. The analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Positive electrospray ionization (ESI +) and multiple reactions monitoring (MRM) mode were used. The limit of detection (LOD) for cocaine and benzoylecgonine was 1 pg x mg(-1). The calibration curves of extracted standards were linear over the range from 5 pg x mg(-1) to 250 pg x mg(-1) (r2 > or = 0.9997). The method was validated and applied to the analysis of guinea pig's hair after a single dose administration of cocaine hydrochloride. Cocaine and benzoylecgonine were not only detected, but also quantified in guinea pigs hair.

Incidental irradiation of mediastinal and hilar lymph node stations during 3D-conformal radiotherapy for non-small cell lung cancer.

PubMed

Kepka, Lucyna; Bujko, Krzysztof; Zolciak-Siwinska, Agnieszka; Garmol, Dariusz

2008-01-01

To estimate the doses of incidental irradiation in particular lymph node stations (LNS) in different extents of elective nodal irradiation (ENI) in 3D-conformal radiotherapy (3D-CRT) for non-small cell lung cancer (NSCLC). METHODS; Doses of radiotherapy were estimated for particular LNS delineated according to the recommendations of the University of Michigan in 220 patients treated using 3D-CRT with different (extended, limited and omitted) extents of ENI. Minimum doses and volumes of LNS receiving 40 Gy or more (V40) were compared for omitted vs. limited+ extended ENI and limited vs. extended ENI. For omission of the ENI the minimum doses and V40 for particular LNS were significantly lower than for patients treated with ENI. For the limited ENI group, the minimum doses for LNS 5, 6 lower parts of 3A and 3P (not included in the elective area) did not differ significantly from doses given to respective LNS for extended ENI group. When the V40 values for extended and limited ENI were compared, no significant differences were seen for any LNS, except for group 1/2R, 1/2L. Incidental irradiation of untreated LNS seems play a part in case of limited ENI, but not in cases without ENI. For subclinical disease the delineation of uninvolved LNS 5, 6, and lower parts of 3A, 3P may be not necessary, because these stations receive the substantial part of irradiation incidentally, if LNS 4R, 4L, 7, and ipsilateral hilum are included in the elective area while this is not case for stations 1 and 2.

CROSS-SPECIES DOSE EXTRAPOLATION FOR DIESEL EMISSIONS

EPA Science Inventory

Models for cross-species (rat to human) dose extrapolation of diesel emission were evaluated for purposes of establishing guidelines for human exposure to diesel emissions (DE) based on DE toxicological data obtained in rats. Ideally, a model for this extrapolation would provide...

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

PubMed

Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O; Kumar, A K Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly E; Savic, Radojka M

2017-12-16

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

10 CFR 20.1208 - Dose equivalent to an embryo/fetus.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Dose equivalent to an embryo/fetus. 20.1208 Section 20.1208 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1208 Dose equivalent to an embryo/fetus. (a) The licensee shall ensure that the dose...

10 CFR 20.1208 - Dose equivalent to an embryo/fetus.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Dose equivalent to an embryo/fetus. 20.1208 Section 20.1208 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1208 Dose equivalent to an embryo/fetus. (a) The licensee shall ensure that the dose...

10 CFR 20.1208 - Dose equivalent to an embryo/fetus.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Dose equivalent to an embryo/fetus. 20.1208 Section 20.1208 Energy NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Occupational Dose Limits § 20.1208 Dose equivalent to an embryo/fetus. (a) The licensee shall ensure that the dose...