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.

Radiation exposure of the radiologist's eye lens during CT-guided interventions.

PubMed

Heusch, Philipp; Kröpil, Patric; Buchbender, Christian; Aissa, Joel; Lanzman, Rotem S; Heusner, Till A; Ewen, Klaus; Antoch, Gerald; Fürst, Günther

2014-02-01

In the past decade the number of computed tomography (CT)-guided procedures performed by interventional radiologists have increased, leading to a significantly higher radiation exposure of the interventionalist's eye lens. Because of growing concern that there is a stochastic effect for the development of lens opacification, eye lens dose reduction for operators and patients should be of maximal interest. To determine the interventionalist's equivalent eye lens dose during CT-guided interventions and to relate the results to the maximum of the recommended equivalent dose limit. During 89 CT-guided interventions (e.g. biopsies, drainage procedures, etc.) measurements of eye lens' radiation doses were obtained from a dedicated dosimeter system for scattered radiation. The sensor of the personal dosimeter system was clipped onto the side of the lead glasses which was located nearest to the CT gantry. After the procedure, radiation dose (µSv), dose rate (µSv/min) and the total exposure time (s) were recorded. For all 89 interventions, the median total exposure lens dose was 3.3 µSv (range, 0.03-218.9 µSv) for a median exposure time of 26.2 s (range, 1.1-94.0 s). The median dose rate was 13.9 µSv/min (range, 1.1-335.5 µSv/min). Estimating 50-200 CT-guided interventions per year performed by one interventionalist, the median dose of the eye lens of the interventional radiologist does not exceed the maximum of the ICRP-recommended equivalent eye lens dose limit of 20 mSv per year.

The Effects of Dextromethorphan on Driving Performance and the Standardized Field Sobriety Test.

PubMed

Perry, Paul J; Fredriksen, Kristian; Chew, Stephanie; Ip, Eric J; Lopes, Ingrid; Doroudgar, Shadi; Thomas, Kelan

2015-09-01

Dextromethorphan (DXM) is abused most commonly among adolescents as a recreational drug to generate a dissociative experience. The objective of the study was to assess driving with and without DXM ingestion. The effects of one-time maximum daily doses of DXM 120 mg versus a guaifenesin 400 mg dose were compared among 40 healthy subjects using a crossover design. Subjects' ability to drive was assessed by their performance in a driving simulator (STISIM® Drive driving simulator software) and by conducting a standardized field sobriety test (SFST) administered 1-h postdrug administration. The one-time dose of DXM 120 mg did not demonstrate driving impairment on the STISIM® Drive driving simulator or increase SFST failures compared to guaifenesin 400 mg. Doses greater than the currently recommended maximum daily dose of 120 mg are necessary to perturb driving behavior. © 2015 American Academy of Forensic Sciences.

RADIATION DOSE ASSESSMENT FOR THE BIOTA OF TERRESTRIAL ECOSYSTEMS IN THE SHORELINE ZONE OF THE CHERNOBYL NUCLEAR POWER PLANT COOLING POND

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

Farfan, E.; Jannik, T.

2011-10-01

Radiation exposure of the biota in the shoreline area of the Chernobyl Nuclear Power Plant Cooling Pond was assessed to evaluate radiological consequences from the decommissioning of the Cooling Pond. The article addresses studies of radioactive contamination of the terrestrial faunal complex and radionuclide concentration ratios in bodies of small birds, small mammals, amphibians, and reptiles living in the area. The data were used to calculate doses to biota using the ERICA Tool software. Doses from {sup 90}Sr and {sup 137}Cs were calculated using the default parameters of the ERICA Tool and were shown to be consistent with biota dosesmore » calculated from the field data. However, the ERICA dose calculations for plutonium isotopes were much higher (2-5 times for small mammals and 10-14 times for birds) than the doses calculated using the experimental data. Currently, the total doses for the terrestrial biota do not exceed maximum recommended levels. However, if the Cooling Pond is allowed to drawdown naturally and the contaminants of the bottom sediments are exposed and enter the biological cycle, the calculated doses to biota may exceed the maximum recommended values. The study is important in establishing the current exposure conditions such that a baseline exists from which changes can be documented following the lowering of the reservoir water. Additionally, the study provided useful radioecological data on biota concentration ratios for some species that are poorly represented in the literature.« less

Proton Therapy Dose Characterization and Verification

DTIC Science & Technology

2016-10-01

than recommended as these patients are on a separate UPENN research study where dose maximum accepted was 6700 cGy. 15... Research Protection Office. 8.0 Data Handling and Record Keeping All patients must have a signed Informed Consent Form and an On - study (confirmation...this award. Phase 1 concentrated on designing and building a Multi-leaf collimator for use in proton therapy. Phase 2 focused on studying the

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

A retrospective analysis of rectal and bladder dose for gynecological brachytherapy treatments with GZP6 HDR afterloading system.

PubMed

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Makhdoumi, Yasha; Taheri, Mojtaba; Homaee Shandiz, Fatemeh; Zahed Anaraki, Siavash; Soleimani Meigooni, Ali

2012-01-01

The aim of this work is to evaluate rectal and bladder dose for the patients treated for gynecological cancers. The GZP6 high dose rate brachytherapy system has been recently introduced to a number of radiation therapy departments in Iran, for treatment of various tumor sites such as cervix and vagina. Our analysis was based on dose measurements for 40 insertions in 28 patients, treated by a GZP6 unit between June 2009 and November 2010. Treatments consisted of combined teletherapy and intracavitary brachytherapy. In vivo dosimetry was performed with TLD-400 chips and TLD-100 microcubes in the rectum and bladder. The average of maximum rectal and bladder dose values were found to be 7.62 Gy (range 1.72-18.55 Gy) and 5.17 Gy (range 0.72-15.85 Gy), respectively. It has been recommended by the ICRU that the maximum dose to the rectum and bladder in intracavitary treatment of vaginal or cervical cancer should be lower than 80% of the prescribed dose to point A in the Manchester system. In this study, of the total number of 40 insertions, maximum rectal dose in 29 insertions (72.5% of treatment sessions) and maximum bladder dose in 18 insertions (45% of treatments sessions) were higher than 80% of the prescribed dose to the point of dose prescription. In vivo dosimetry for patients undergoing treatment by GZP6 brachytherapy system can be used for evaluation of the quality of brachytherapy treatments by this system. This information could be used as a base for developing the strategy for treatment of patients treated with GZP6 system.

A retrospective analysis of rectal and bladder dose for gynecological brachytherapy treatments with GZP6 HDR afterloading system

PubMed Central

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Makhdoumi, Yasha; Taheri, Mojtaba; Homaee Shandiz, Fatemeh; Zahed Anaraki, Siavash; Soleimani Meigooni, Ali

2012-01-01

Aim The aim of this work is to evaluate rectal and bladder dose for the patients treated for gynecological cancers. Background The GZP6 high dose rate brachytherapy system has been recently introduced to a number of radiation therapy departments in Iran, for treatment of various tumor sites such as cervix and vagina. Materials and methods Our analysis was based on dose measurements for 40 insertions in 28 patients, treated by a GZP6 unit between June 2009 and November 2010. Treatments consisted of combined teletherapy and intracavitary brachytherapy. In vivo dosimetry was performed with TLD-400 chips and TLD-100 microcubes in the rectum and bladder. Results The average of maximum rectal and bladder dose values were found to be 7.62 Gy (range 1.72–18.55 Gy) and 5.17 Gy (range 0.72–15.85 Gy), respectively. It has been recommended by the ICRU that the maximum dose to the rectum and bladder in intracavitary treatment of vaginal or cervical cancer should be lower than 80% of the prescribed dose to point A in the Manchester system. In this study, of the total number of 40 insertions, maximum rectal dose in 29 insertions (72.5% of treatment sessions) and maximum bladder dose in 18 insertions (45% of treatments sessions) were higher than 80% of the prescribed dose to the point of dose prescription. Conclusion In vivo dosimetry for patients undergoing treatment by GZP6 brachytherapy system can be used for evaluation of the quality of brachytherapy treatments by this system. This information could be used as a base for developing the strategy for treatment of patients treated with GZP6 system. PMID:24377037

Regulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United Kingdom.

PubMed

Tobin, Claire L; Dobbin, Malcolm; McAvoy, Brian

2013-10-01

Analysis of the policy response by Australia's National Drugs and Poisons Schedule Committee (NDPSC) and comparison with recommendations by expert advisory committees in New Zealand and the United Kingdom. Analysis of public policy documents of relevant regulatory authorities was conducted. Data were extracted regarding changes to over-the-counter (OTC) codeine analgesic scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed. Expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine misuse and harm as small relative to total use and responded by restricting availability. Pharmacist supervision was required at the point-of-sale and pack sizes were reduced to short-term use. Comparison with recommendations by expert advisory committees in NZ and the UK suggests the NDPSC's actions in response to OTC codeine misuse were appropriate given the available evidence of misuse and harm, but highlights opportunities to utilise additional regulatory levers. Framing policy problems as matters of public health in the context of limited evidence may support decision makers to implement cautionary incremental policy change. © 2013 The Authors. ANZJPH © 2013 Public Health Association of Australia.

SU-F-T-18: The Importance of Immobilization Devices in Brachytherapy Treatments of Vaginal Cuff

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

Shojaei, M; Dumitru, N; Pella, S

2016-06-15

Purpose: High dose rate brachytherapy is a highly localized radiation therapy that has a very high dose gradient. Thus one of the most important parts of the treatment is the immobilization. The smallest movement of the patient or applicator can result in dose variation to the surrounding tissues as well as to the tumor to be treated. We will revise the ML Cylinder treatments and their localization challenges. Methods: A retrospective study of 25 patients with 5 treatments each looking into the applicator’s placement in regard to the organs at risk. Motion possibilities for each applicator intra and inter fractionationmore » with their dosimetric implications were covered and measured in regard with their dose variance. The localization immobilization devices used were assessed for the capability to prevent motion before and during the treatment delivery. Results: We focused on the 100% isodose on central axis and a 15 degree displacement due to possible rotation analyzing the dose variations to the bladder and rectum walls. The average dose variation for bladder was 15% of the accepted tolerance, with a minimum variance of 11.1% and a maximum one of 23.14% on the central axis. For the off axis measurements we found an average variation of 16.84% of the accepted tolerance, with a minimum variance of 11.47% and a maximum one of 27.69%. For the rectum we focused on the rectum wall closest to the 120% isodose line. The average dose variation was 19.4%, minimum 11.3% and a maximum of 34.02% from the accepted tolerance values Conclusion: Improved immobilization devices are recommended. For inter-fractionation, localization devices are recommended in place with consistent planning in regards with the initial fraction. Many of the present immobilization devices produced for external radiotherapy can be used to improve the localization of HDR applicators during transportation of the patient and during treatment.« less

Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats.

PubMed

Barbosa, Joana; Faria, Juliana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

2017-08-15

Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused attention by the medical community. Copyright © 2017 Elsevier B.V. All rights reserved.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

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

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

Output levels of commercially available portable compact disc players and the potential risk to hearing.

PubMed

Fligor, Brian J; Cox, L Clarke

2004-12-01

To measure the sound levels generated by the headphones of commercially available portable compact disc players and provide hearing healthcare providers with safety guidelines based on a theoretical noise dose model. Using a Knowles Electronics Manikin for Acoustical Research and a personal computer, output levels across volume control settings were recorded from headphones driven by a standard signal (white noise) and compared with output levels from music samples of eight different genres. Many commercially available models from different manufacturers were investigated. Several different styles of headphones (insert, supra-aural, vertical, and circumaural) were used to determine if style of headphone influenced output level. Free-field equivalent sound pressure levels measured at maximum volume control setting ranged from 91 dBA to 121 dBA. Output levels varied across manufacturers and style of headphone, although generally the smaller the headphone, the higher the sound level for a given volume control setting. Specifically, in one manufacturer, insert earphones increased output level 7-9 dB, relative to the output from stock headphones included in the purchase of the CD player. In a few headphone-CD player combinations, peak sound pressure levels exceeded 130 dB SPL. Based on measured sound pressure levels across systems and the noise dose model recommended by National Institute for Occupational Safety and Health for protecting the occupational worker, a maximum permissible noise dose would typically be reached within 1 hr of listening with the volume control set to 70% of maximum gain using supra-aural headphones. Using headphones that resulted in boosting the output level (e.g., insert earphones used in this study) would significantly decrease the maximum safe volume control setting; this effect was unpredictable from one manufacturer to another. In the interest of providing a straightforward recommendation that should protect the hearing of the majority of consumers, reasonable guidelines would include a recommendation to limit headphone use to 1 hr or less per day if using supra-aural style headphones at a gain control setting of 60% of maximum.

Locally Weighted Learning Methods for Predicting Dose-Dependent Toxicity with Application to the Human Maximum Recommended Daily Dose

DTIC Science & Technology

2012-09-10

Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, United States ABSTRACT: Toxicological ...species. Thus, it is more advantageous to predict the toxicological effects of a compound on humans directly from the human toxicological data of related...compounds. However, many popular quantitative structure−activity relationship ( QSAR ) methods that build a single global model by fitting all training

Reconstruction of Absorbed Doses to Fibroglandular Tissue of the Breast of Women undergoing Mammography (1960 to the Present)

PubMed Central

Thierry-Chef, Isabelle; Simon, Steven L.; Weinstock, Robert M.; Kwon, Deukwoo; Linet, Martha S.

2013-01-01

The assessment of potential benefits versus harms from mammographic examinations as described in the controversial breast cancer screening recommendations of the U.S. Preventive Task Force included limited consideration of absorbed dose to the fibroglandular tissue of the breast (glandular tissue dose), the tissue at risk for breast cancer. Epidemiological studies on cancer risks associated with diagnostic radiological examinations often lack accurate information on glandular tissue dose, and there is a clear need for better estimates of these doses. Our objective was to develop a quantitative summary of glandular tissue doses from mammography by considering sources of variation over time in key parameters including imaging protocols, x-ray target materials, voltage, filtration, incident air kerma, compressed breast thickness, and breast composition. We estimated the minimum, maximum, and mean values for glandular tissue dose for populations of exposed women within 5-year periods from 1960 to the present, with the minimum to maximum range likely including 90% to 95% of the entirety of the dose range from mammography in North America and Europe. Glandular tissue dose from a single view in mammography is presently about 2 mGy, about one-sixth the dose in the 1960s. The ratio of our estimates of maximum to minimum glandular tissue doses for average-size breasts was about 100 in the 1960s compared to a ratio of about 5 in recent years. Findings from our analysis provide quantitative information on glandular tissue doses from mammographic examinations which can be used in epidemiologic studies of breast cancer. PMID:21988547

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.

Pharmacometrics-based dose selection of levofloxacin as a treatment for postexposure inhalational anthrax in children.

PubMed

Li, Fang; Nandy, Partha; Chien, Shuchean; Noel, Gary J; Tornoe, Christoffer W

2010-01-01

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve efficacy comparable to that of adults.

Survey of patient knowledge related to acetaminophen recognition, dosing, and toxicity.

PubMed

Hornsby, Lori B; Whitley, Heather P; Hester, E Kelly; Thompson, Melissa; Donaldson, Amy

2010-01-01

To assess patient knowledge regarding acetaminophen dosing, toxicity, and recognition of acetaminophen-containing products. Descriptive, nonexperimental, cross-sectional study. Alabama, January 2007 to February 2008. 284 patients at four outpatient medical facilities. 12-item investigator-administered questionnaire. Degree of patient knowledge regarding acetaminophen safety, dosing recommendations, toxicity, alternative names and abbreviations, and products. Two-thirds of the 284 patients completing the survey reported current or recent use of pain, cold, or allergy medication. Of these, 25% reported knowing the active ingredient. Of patients, 46% and 13% knew that "acetaminophen" and "APAP," respectively, were synonymous with "Tylenol." Several patients (12%) believed that ingesting a harmful amount of acetaminophen was difficult or impossible. One-third of patients correctly identified the maximum daily dose, 10% reported a dose greater than 4 g, 25% were unsure of the dose, and 7% were unsure whether a maximum dose existed. One-half recognized liver damage as the primary toxicity. Results were similar between acetaminophen users and nonusers. Deficiencies were found in patient knowledge regarding acetaminophen recognition, dosing, and potential for toxicity. The development of effective educational initiatives is warranted to ensure patient awareness and limit the potential for acetaminophen overdose.

Comparative analysis of radioecological monitoring dosimeters

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

Sobolev, A.I.; Pol`skii, O.G.; Shanin, O.B.

1995-03-01

This paper describes comparative estimates of radiation doses measured by two types of thermoluminescence dosimeters and two types of background radiation radiometers. The dosimetry systems were tested by simultaneously recording background radiation and standard radiation sources at a radioactive waste storage facility. Statistical analysis of the measurement results is summarized. The maximum recorded exposure dose rate for the experiment was 19 microrads per hour. The DTK-2 dosimeter overestimated dose rates by 6 to 43% and the DTU-2 dosimeter underestimated dose rates by 7 to 21%. Both devices are recommended for radioecological monitoring in populated areas. 4 refs., 3 figs., 5more » tabs.« less

[Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen].

PubMed

Viguier, F; Roessle, C; Zerhouni, L; Rouleau, A; Benmelouka, C; Chevallier, A; Chast, F; Conort, O

2016-11-01

The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra-therapeutic doses of acetaminophen. This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

PubMed

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (<1.25 m²), 100 (1.25 ≤ 1.5 m²), and 120 mg (1.5 m²≥) per day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

Residues of acephate and its metabolite methamidophos in/on mango fruit (Mangifera indica L.).

PubMed

Mohapatra, Soudamini; Ahuja, A K; Deepa, M; Sharma, Debi

2011-01-01

Mango, the major fruit crop of India is affected by stone weevil, which can cause serious damage to the fruits. Acephate gives good control of mango stone weevil. Residues of acephate and its major metabolite, methamidophos were evaluated on mango fruits following repeated spray applications at the recommended dose (0.75 kg a.i. ha⁻¹) and double the recommended dose (1.5 kg a.i. ha⁻¹). Acephate residues mostly remained on the fruit peel which persisted up to 30 days. Movement of residues to the fruit pulp was detected after 1 day of application, increased to maximum of 0.14 and 0.26 mg kg⁻¹ after 3 days and reached to below detectable level (BDL) after 20 days. Methamidophos, a metabolite of acephate, was detected from 3rd day onwards in both peel and pulp and persisted up to 15 days. The residues (acephate + methamidophos) dissipated with the half-life of 5 days in peel and pulp. A safe pre-harvest interval of 30 days is recommended for consumption of mango fruits following treatment of acephate at the recommended dose of 0.75 kg a.i. ha⁻¹.

DOSIMETRIC CONSEQUENCES OF USING CONTRAST-ENHANCED COMPUTED TOMOGRAPHIC IMAGES FOR INTENSITY-MODULATED STEREOTACTIC BODY RADIOTHERAPY PLANNING.

PubMed

Yoshikawa, Hiroto; Roback, Donald M; Larue, Susan M; Nolan, Michael W

2015-01-01

Potential benefits of planning radiation therapy on a contrast-enhanced computed tomography scan (ceCT) should be weighed against the possibility that this practice may be associated with an inadvertent risk of overdosing nearby normal tissues. This study investigated the influence of ceCT on intensity-modulated stereotactic body radiotherapy (IM-SBRT) planning. Dogs with head and neck, pelvic, or appendicular tumors were included in this retrospective cross-sectional study. All IM-SBRT plans were constructed on a pre- or ceCT. Contours for tumor and organs at risk (OAR) were manually constructed and copied onto both CT's; IM-SBRT plans were calculated on each CT in a manner that resulted in equal radiation fluence. The maximum and mean doses for OAR, and minimum, maximum, and mean doses for targets were compared. Data were collected from 40 dogs per anatomic site (head and neck, pelvis, and limbs). The average dose difference between minimum, maximum, and mean doses as calculated on pre- and ceCT plans for the gross tumor volume was less than 1% for all anatomic sites. Similarly, the differences between mean and maximum doses for OAR were less than 1%. The difference in dose distribution between plans made on CTs with and without contrast enhancement was tolerable at all treatment sites. Therefore, although caution would be recommended when planning IM-SBRT for tumors near "reservoirs" for contrast media (such as the heart and urinary bladder), findings supported the use of ceCT with this dose calculation algorithm for both target delineation and IM-SBRT treatment planning. © 2015 American College of Veterinary Radiology.

Overdosing of benzodiazepines/Z-drugs and falls in older adults: Costs for the health system.

PubMed

Díaz-Gutiérrez, María José; Cengotitabengoa, Mónica Martínez; Bermúdez-Ampudia, Cristina; García, Sainza; López, Purificación; Martínez-Cengotitabengoa, Mayte; González-Pinto, Ana

2018-05-08

Benzodiazepines and Z drugs (BZD/Z drugs) are commonly used for the treatment of insomnia and anxiety in older adults for long periods of time. Given the physiological and metabolic characteristics of this group of patients, they are more prone to the adverse effects of these drugs which include falls. The recommendations for use of BZD/Z drugs include the need to adjust the dose and select those with a short half-life, to avoid adverse events, which as well as potentially affecting patient outcome, increase healthcare costs. In this study, we have evaluated the hospital-related costs associated with falls in older adults who use BZD/Z drugs at doses higher than recommended for this age group. We conducted a cross-sectional observational study assessing the BZD/Z drug prescriptions of older adults attending the emergency department after a fall. Cost analysis was performed for cases in which the prescriptions exceeded the maximum recommended dose for this age group. A total of 40.6% of the prescriptions recorded were higher than the defined daily dose in older adults (DDD olderadults ). Of the 57 patients who used BZD/Z drugs at higher-than-recommended doses, 53 experienced trauma and 33 required hospitalisation. The costs associated with emergency department services, tests performed and hospitalisation amounted to €1850/patient. Appropriate dosage of BZD/Z drugs in older adults could reduce both patient suffering and costs for the health system. Copyright © 2017. Published by Elsevier Inc.

Bolus-dependent dosimetric effect of positioning errors for tangential scalp radiotherapy with helical tomotherapy

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

Lobb, Eric, E-mail: eclobb2@gmail.com

2014-04-01

The dosimetric effect of errors in patient position is studied on-phantom as a function of simulated bolus thickness to assess the need for bolus utilization in scalp radiotherapy with tomotherapy. A treatment plan is generated on a cylindrical phantom, mimicking a radiotherapy technique for the scalp utilizing primarily tangential beamlets. A planning target volume with embedded scalplike clinical target volumes (CTVs) is planned to a uniform dose of 200 cGy. Translational errors in phantom position are introduced in 1-mm increments and dose is recomputed from the original sinogram. For each error the maximum dose, minimum dose, clinical target dose homogeneitymore » index (HI), and dose-volume histogram (DVH) are presented for simulated bolus thicknesses from 0 to 10 mm. Baseline HI values for all bolus thicknesses were in the 5.5 to 7.0 range, increasing to a maximum of 18.0 to 30.5 for the largest positioning errors when 0 to 2 mm of bolus is used. Utilizing 5 mm of bolus resulted in a maximum HI value of 9.5 for the largest positioning errors. Using 0 to 2 mm of bolus resulted in minimum and maximum dose values of 85% to 94% and 118% to 125% of the prescription dose, respectively. When using 5 mm of bolus these values were 98.5% and 109.5%. DVHs showed minimal changes in CTV dose coverage when using 5 mm of bolus, even for the largest positioning errors. CTV dose homogeneity becomes increasingly sensitive to errors in patient position as bolus thickness decreases when treating the scalp with primarily tangential beamlets. Performing a radial expansion of the scalp CTV into 5 mm of bolus material minimizes dosimetric sensitivity to errors in patient position as large as 5 mm and is therefore recommended.« less

[Gradation in the level of vitamin consumption: possible risk of excessive consumption].

PubMed

Kodentsova, V M

2014-01-01

The ratio between the levels of consumption of certain vitamins and minerals [recommended daily allowance for labelling purposes < maximum supplement levels < tolerable upper intake level (UL) < safe level (limit) of consumption < or = therapeutic dose has been characterized. Vitamin A and beta-carotene maximum supplement levels coincides with UL, and recommended daily allowance for these micronutrients coincides with the maximal level of consumption through dietary supplements and/or multivitamins. Except for vitamin A and beta-carotene recommended daily allowance for other vitamins adopted in Russia are considerably lower than the upper safe level of consumption. For vitamin A and beta-carotene there is a potential risk for excess consumption. According to the literature data (meta-analysis) prolonged intake of high doses of antioxidant vitamins (above the RDA) both alone and in combination with two other vitamins or vitamin C [> 800 microg (R.E.) of vitamin A, > 9.6 mg of beta-carotene, > 15 mg (T.E.) of vitamin E] do not possess preventive effects and may be harmful with unwanted consequences to health, especially in well-nourished populations, persons having risk of lung cancer (smokers, workers exposed to asbestos), in certain conditions (in the atmosphere with high oxygen content, hyperoxia, oxygen therapy). Proposed mechanisms of such action may be due to the manifestation of prooxidant action when taken in high doses, shifting balance with other important natural antioxidants, their displacement (substitution), interference with the natural defense mechanisms. Athletes are the population group that requires attention as used antioxidant vitamins A, C, E, both individually and in combination in extremely high doses. In summary, it should be noted that intake of physiological doses which are equivalent to the needs of the human organism, as well as diet inclusion of fortified foods not only pose no threat to health, but will bring undoubted benefits, filling the existing lack of vitamins in the ration.

Organ dose measurement using Optically Stimulated Luminescence Detector (OSLD) during CT examination

NASA Astrophysics Data System (ADS)

Yusuf, Muhammad; Alothmany, Nazeeh; Abdulrahman Kinsara, Abdulraheem

2017-10-01

This study provides detailed information regarding the imaging doses to patient radiosensitive organs from a kilovoltage computed tomography (CT) scan procedure using OSLD. The study reports discrepancies between the measured dose and the calculated dose from the ImPACT scan, as well as a comparison with the dose from a chest X-ray radiography procedure. OSLDs were inserted in several organs, including the brain, eyes, thyroid, lung, heart, spinal cord, breast, spleen, stomach, liver and ovaries, of the RANDO phantom. Standard clinical scanning protocols were used for each individual site, including the brain, thyroid, lung, breast, stomach, liver and ovaries. The measured absorbed doses were then compared with the simulated dose obtained from the ImPACT scan. Additionally, the equivalent doses for each organ were calculated and compared with the dose from a chest X-ray radiography procedure. Absorbed organ doses measured by OSLD in the RANDO phantom of up to 17 mGy depend on the organ scanned and the scanning protocols used. A maximum 9.82% difference was observed between the target organ dose measured by OSLD and the results from the ImPACT scan. The maximum equivalent organ dose measured during this experiment was equal to 99.899 times the equivalent dose from a chest X-ray radiography procedure. The discrepancies between the measured dose with the OSLD and the calculated dose from the ImPACT scan were within 10%. This report recommends the use of OSLD for measuring the absorbed organ dose during CT examination.

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.

Radon survey and soil gamma doses in primary schools of Batman, Turkey.

PubMed

Damla, Nevzat; Aldemir, Kamuran

2014-06-01

A survey was conducted to evaluate levels of indoor radon and gamma doses in 42 primary schools located in Batman, southeastern Anatolia, Turkey. Indoor radon measurements were carried out using CR-39 solid-state nuclear track detector-based radon dosimeters. The overall mean annual (222)Rn activity in the surveyed area was found to be 49 Bq m(-3) (equivalent to an annual effective dose of 0.25 mSv). However, in one of the districts (Besiri) the maximum radon value turned out to be 307 Bq m(-3). The estimated annual effective doses are less than the recommended action level (3-10 mSv). It is found that the radon concentration decreases with increasing floor number. The concentrations of natural and artificial radioisotopes were determined using gamma-ray spectroscopy for soil samples collected in close vicinity of the studied schools. The mean gamma activity concentrations in the soil samples were 31, 25, 329 and 12 Bq kg(-1) for (226)Ra, (232)Th, (40)K and (137)Cs, respectively. The radiological parameters such as the absorbed dose rate in air and the annual effective dose equivalent were calculated. These radiological parameters were evaluated and compared with the internationally recommended values.

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Safe Handling of Radioactive Materials. Recommendations of the National Committee on Radiation Protection. Handbook 92.

ERIC Educational Resources Information Center

National Bureau of Standards (DOC), Washington, DC.

This handbook is designed to help users of radioactive materials to handle the radioactive material without exposing themselves or others to radiation doses in excess of maximum permissible limits. The discussion of radiation levels is in terms of readings from dosimeters and survey instruments. Safety in the handling of radioactive materials in…

SU-E-T-578: On Definition of Minimum and Maximum Dose for Target Volume

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

Gong, Y; Yu, J; Xiao, Y

Purpose: This study aims to investigate the impact of different minimum and maximum dose definitions in radiotherapy treatment plan quality evaluation criteria by using tumor control probability (TCP) models. Methods: Dosimetric criteria used in RTOG 1308 protocol are used in the investigation. RTOG 1308 is a phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC. The prescription dose for planning target volume (PTV) is 70Gy. Maximum dose (Dmax) should not exceed 84Gy and minimum dose (Dmin) should not go below 59.5Gy in order for the plan to be “per protocol” (satisfactory).A mathematicalmore » model that simulates the characteristics of PTV dose volume histogram (DVH) curve with normalized volume is built. The Dmax and Dmin are noted as percentage volumes Dη% and D(100-δ)%, with η and d ranging from 0 to 3.5. The model includes three straight line sections and goes through four points: D95%= 70Gy, Dη%= 84Gy, D(100-δ)%= 59.5 Gy, and D100%= 0Gy. For each set of η and δ, the TCP value is calculated using the inhomogeneously irradiated tumor logistic model with D50= 74.5Gy and γ50=3.52. Results: TCP varies within 0.9% with η; and δ values between 0 and 1. With η and η varies between 0 and 2, TCP change was up to 2.4%. With η and δ variations from 0 to 3.5, maximum of 8.3% TCP difference is seen. Conclusion: When defined maximum and minimum volume varied more than 2%, significant TCP variations were seen. It is recommended less than 2% volume used in definition of Dmax or Dmin for target dosimetric evaluation criteria. This project was supported by NIH grants U10CA180868, U10CA180822, U24CA180803, U24CA12014 and PA CURE Grant.« less

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

PubMed

Bruera, Gemma; Massacese, Silvia; Galvano, Antonio; Mas, Antonella Dal; Guadagni, Stefano; Calvisi, Giuseppe; Ciacco, Eugenio; Russo, Antonio; Ricevuto, Enrico

2018-04-17

Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m 2 /d and 80 mg/m 2 , respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

Direct plan comparison of RapidArc and CyberKnife for spine stereotactic body radiation therapy

NASA Astrophysics Data System (ADS)

Choi, Young Eun; Kwak, Jungwon; Song, Si Yeol; Choi, Eun Kyung; Ahn, Seung Do; Cho, Byungchul

2015-07-01

We compared the treatment planning performance of RapidArc (RA) vs. CyberKnife (CK) for spinal stereotactic body radiation therapy (SBRT). Ten patients with spinal lesions who had been treated with CK were re-planned with RA, which consisted of two complete arcs. Computed tomography (CT) and volumetric dose data of CK, generated using the Multiplan (Accuray) treatment planning system (TPS) and the Ray-trace algorithm, were imported to Varian Eclipse TPS in Dicom format, and the data were compared with the RA plan by using an analytical anisotropic algorithm (AAA) dose calculation. The optimized dose priorities for both the CK and the RA plans were similar for all patients. The highest priority was to provide enough dose coverage to the planned target volume (PTV) while limiting the maximum dose to the spinal cord. Plan quality was evaluated with respect to PTV coverage, conformity index (CI), high-dose spillage, intermediate-dose spillage (R50% and D2cm), and maximum dose to the spinal cord, which are criteria recommended by the RTOG 0631 spine and 0915 lung SBRT protocols. The mean CI' SD values of the PTV were 1.11' 0.03 and 1.17' 0.10 for RA and CK ( p = 0.02), respectively. On average, the maximum dose delivered to the spinal cord in CK plans was approximately 11.6% higher than that in RA plans, and this difference was statistically significant ( p < 0.001). High-dose spillages were 0.86% and 2.26% for RA and CK ( p = 0.203), respectively. Intermediate-dose spillage characterized by D2cm was lower for RA than for CK; however, R50% was not statistically different. Even though both systems can create highly conformal volumetric dose distributions, the current study shows that RA demonstrates lower high- and intermediate-dose spillages than CK. Therefore, RA plans for spinal SBRT may be superior to CK plans.

Patient perception and knowledge of acetaminophen in a large family medicine service.

PubMed

Herndon, Christopher M; Dankenbring, Dawn M

2014-06-01

The use of acetaminophen is currently under increased scrutiny by the US Food and Drug Administration (FDA) due to the risk of intentional and more concerning, unintentional overdose-related hepatotoxicity. Acetaminophen is responsible for an estimated 48% of all acute liver failure diagnoses. The purpose of this study is to evaluate patient perception and knowledge of the safe use and potential toxicity of acetaminophen-containing products. The authors conducted a descriptive, 2-week study using a convenience sample from a large family medicine clinic waiting room. Survey questions assessed ability to identify acetaminophen, knowledge of the current recommended maximum daily dose, respondent acetaminophen use patterns, common adverse effects associated with acetaminophen, and respondent self-reported alcohol consumption. Acetaminophen safety information was provided to all persons regardless of participation in the study. Of the 102 patients who chose to participate, 79% recognized acetaminophen as a synonym of Tylenol, whereas only 9% identified APAP as a frequently used abbreviation. One third of respondents thought acetaminophen was synonymous with ibuprofen and naproxen. Approximately one fourth of patients correctly identified the then maximum recommended daily acetaminophen dose of 4 g. Seventy-eight percent of patients correctly identified hepatotoxicity as the most common serious adverse effect. We conclude that patient deficiencies in knowledge of acetaminophen recognition, dosing, and toxicity warrant public education by health professionals at all levels of interaction. Current initiatives are promising; however, further efforts are required.

[Measurements of vancomycin concentrations in the blood - a method of personalization the antibiotic therapy in patients with chronic kidney disease].

PubMed

Pondel, Joanna; Krajewski, Piotr; Królikowska, Natalia; Tobiasz, Aleksandra; Augustyniak-Bartosik, Hanna; Hurkacz, Magdalena

2017-04-21

Therapeutic Drug Monitoring is a recognized method of personalizing treatment, having particular application in patients with chronic kidney disease who have frequent infections, requiring administration of vancomycin. International guidelines indicate the need to adjust the dose of the drug to the state of renal function. The recommended therapeutic ranges of minimum and maximum levels should be achieved in order to increase the effectiveness and safety of treatment. The aim of this study was to evaluate the usefulness of measuring the concentration of vancomycin in patients with chronic kidney disease due to bacterial infection. The study included 96 adult patients with chronic kidney disease of varying severity treated with vancomycin Patients were divided into 3 groups: treated by haemodialysis (hd), after renal transplantations (ktx), do not require renal replacement therapy (nef). In subjects were examined the minimum and maximum concentrations of vancomycin in steady-state and were compared with recommended therapeutic ranges. Statistically significant decrease of inflammatory markers was observed only in patients treated with dialysis. In the other groups not significant changes in values of inflammatory parameters were confirmed. Trough concentrations of vancomycin marked in patients were consistent with the recommendation of EUCAST, but exceeded the value recommended by the manufacturers of the drug. Considering absolute values of the minimum concentrations, only about 50% of patients achieved the therapeutic range (58% for recommendation EUCAST and 36% for the manufacturer's instructions). Peak concentration values indicated in dialyzed patients were below the prescribed range of 20-50 mg/l and averaged 17.7 mg / l. In the other subgroups they were correct. The rating of the absolute values of the peak concentrations of vancomycin also showed that only 46% (64% in the ktx, 30% - hd and 53% - nef) was within the recommended range, while 50% were classified as concentrations of sub-therapeutic (36% in the ktx, 42% of the nef group and 65% in hd). Vancomycin concentrations measured in patients with chronic kidney disease, both minimum and maximum, were not fully comply with the recommended therapeutic ranges, despite the use of doses determined based on a calculation of glomerular filtration rate. This points to the need for particularly careful monitoring of therapy and analysis of antibiotic concentrations to improve the effectiveness and reduce the incidence of undesirable consequences of treatment.

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

Lafata, K; Ren, L; Wu, Q

Purpose: To develop a data-mining methodology based on quantum clustering and machine learning to predict expected dosimetric endpoints for lung SBRT applications based on patient-specific anatomic features. Methods: Ninety-three patients who received lung SBRT at our clinic from 2011–2013 were retrospectively identified. Planning information was acquired for each patient, from which various features were extracted using in-house semi-automatic software. Anatomic features included tumor-to-OAR distances, tumor location, total-lung-volume, GTV and ITV. Dosimetric endpoints were adopted from RTOG-0195 recommendations, and consisted of various OAR-specific partial-volume doses and maximum point-doses. First, PCA analysis and unsupervised quantum-clustering was used to explore the feature-space tomore » identify potentially strong classifiers. Secondly, a multi-class logistic regression algorithm was developed and trained to predict dose-volume endpoints based on patient-specific anatomic features. Classes were defined by discretizing the dose-volume data, and the feature-space was zero-mean normalized. Fitting parameters were determined by minimizing a regularized cost function, and optimization was performed via gradient descent. As a pilot study, the model was tested on two esophageal dosimetric planning endpoints (maximum point-dose, dose-to-5cc), and its generalizability was evaluated with leave-one-out cross-validation. Results: Quantum-Clustering demonstrated a strong separation of feature-space at 15Gy across the first-and-second Principle Components of the data when the dosimetric endpoints were retrospectively identified. Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. The largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating an intuitively strong correlation between this feature and both endpoints. Conclusion: This pilot study shows that it is feasible to predict dose-volume endpoints based on patient-specific anatomic features. The developed methodology can potentially help to identify patients at risk for higher OAR doses, thus improving the efficiency of treatment planning. R01-184173.« less

First evaluation of the serum level of anti-hepatitis B surface antigen after vaccination in Libya.

PubMed

Madour, A; Alkout, A; Vanin, S

2013-12-01

The hepatitis B virus (HBV) vaccination schedule in Libya follows international recommendations (1st dose at birth, 2nd after 1 month and 3rd after 6 months). This research aimed to evaluate the long-term protection of the HBV immunization programme in Tripoli and to determine the best age to administer booster doses. Serum levels of hepatitis B surface antigen were determined in 277 randomly selected children aged 1-12 years. The response to HBV vaccine in 1-3-year-olds was 93.2%, but this declined with age and at 7-9 years after initial vaccination only 53.1% of children had protective titres (> or = 10 mIU/mL). No significant differences between males and females in antibody persistence or response to vaccine were observed. We recommend continuing the HBV vaccination programme and that a booster dose be given to 6-year-old children to ensure maximum protection during the period of school entry and beyond.

Dosimetry of Strontium eye applicator: Comparison of Monte Carlo calculations and radiochromic film measurements

NASA Astrophysics Data System (ADS)

Laoues, M.; Khelifi, R.; Moussa, A. S.

2015-01-01

Strontium-90 eye applicators are a beta-ray emitter with a relatively high-energy (maximum energy about 2.28 MeV and average energy about 0.9 MeV). These applicators come in different shapes and dimensions; they are used for the treatment of eye diseases. Whenever, radiation is used in treatment, dosimetry is essential. However, knowledge of the exact dose distribution is a critical decision-making to the outcome of the treatment. The main aim of our study is to simulate the dosimetry of the SIA.20 eye applicator with Monte Carlo GATE 6.1 platform and to compare the calculated results with those measured with EBT2 films. This means that GATE and EBT2 were used to quantify the surface and depths dose- rate, the relative dose profile and the dosimetric parameters in according to international recommendations. Calculated and measured results are in good agreement and they are consistent with the ICRU and NCS recommendations.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

PubMed

Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-06

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer.

An analysis of collegiate band directors' exposure to sound pressure levels

NASA Astrophysics Data System (ADS)

Roebuck, Nikole Moore

Noise-induced hearing loss (NIHL) is a significant but unfortunate common occupational hazard. The purpose of the current study was to measure the magnitude of sound pressure levels generated within a collegiate band room and determine if those sound pressure levels are of a magnitude that exceeds the policy standards and recommendations of the Occupational Safety and Health Administration (OSHA), and the National Institute of Occupational Safety and Health (NIOSH). In addition, reverberation times were measured and analyzed in order to determine the appropriateness of acoustical conditions for the band rehearsal environment. Sound pressure measurements were taken from the rehearsal of seven collegiate marching bands. Single sample t test were conducted to compare the sound pressure levels of all bands to the noise exposure standards of OSHA and NIOSH. Multiple regression analysis were conducted and analyzed in order to determine the effect of the band room's conditions on the sound pressure levels and reverberation times. Time weighted averages (TWA), noise percentage doses, and peak levels were also collected. The mean Leq for all band directors was 90.5 dBA. The total accumulated noise percentage dose for all band directors was 77.6% of the maximum allowable daily noise dose under the OSHA standard. The total calculated TWA for all band directors was 88.2% of the maximum allowable daily noise dose under the OSHA standard. The total accumulated noise percentage dose for all band directors was 152.1% of the maximum allowable daily noise dose under the NIOSH standards, and the total calculated TWA for all band directors was 93dBA of the maximum allowable daily noise dose under the NIOSH standard. Multiple regression analysis revealed that the room volume, the level of acoustical treatment and the mean room reverberation time predicted 80% of the variance in sound pressure levels in this study.

Patients' knowledge about paracetamol (acetaminophen): a study in a French hospital emergency department.

PubMed

Boudjemai, Y; Mbida, P; Potinet-Pagliaroli, V; Géffard, F; Leboucher, G; Brazier, J-L; Allenet, B; Charpiat, B

2013-07-01

Paracetamol is the most widely used analgesic and antipyretic drug. In France, little is known concerning patients' knowledge and beliefs about paracetamol. To determine how much outpatients attending an emergency department know about paracetamol. A semi-structured questionnaire was applied to patients consulting for non-severe medical or traumatic conditions. Thirty-three (45%) of 73 participating patients knew that paracetamol was the active ingredient of the medication they used to reduce pain and/or fever. Three patients thought 2g was the maximum recommended single dose; 25% thought that a delay between two doses ≤ 3 hours was recommended and 15% thought the maximum daily dose was > 4 g. While 8% cited liver toxicity as a side effect, 38% did not believe an excessive dose could be fatal. Two patients correctly answered all questions and five gave no correct answer. Outpatients attending an emergency department (ED) have poor knowledge about paracetamol. This situation is disturbing and our results may serve as an eye opener to healthcare professionals. They emphasize the need for research programs with the following objectives: a) to determine the actual content of the message delivered by healthcare professionals; b) to study conditions under which this message is issued; c) to analyze how patients understand key messages and what their behavioral response is. In ED patients, the level of knowledge about paracetamol is insufficient to ensure its safe use in ambulatory care. Further studies are needed to determine the causes and to permit better patient education. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Absolute dose determination in high-energy electron beams: Comparison of IAEA dosimetry protocols

PubMed Central

Sathiyan, S.; Ravikumar, M.

2008-01-01

In this study, absorbed doses were measured and compared for high-energy electrons (6, 9, 12, 16, and 20 MeV) using International Atomic Energy Agency (IAEA), Technical Reports Series No. 277 (TRS), TRS 381, and TRS 398 dosimetry protocols. Absolute dose measurements were carried out using FC65-G Farmer chamber and Nordic Association of Clinical Physicists (NACP) parallel plate chamber with DOSE1 electrometer in WP1-D water phantom for reference field size of 15 × 15 cm2 at 100 cm source-to-surface distance. The results show that the difference between TRS 398 and TRS 381 was about 0.24% to 1.3% depending upon the energy, and the maximum difference between TRS 398 and TRS 277 was 1.5%. The use of cylindrical chamber in electron beam gives the maximum dose difference between the TRS 398 and TRS 277 in the order of 1.4% for energies above 10 MeV (R50 > 4 g/cm2). It was observed that the accuracy of dose estimation was better with the protocols based on the water calibration procedures, as no conversion quantities are involved for conversion of dose from air to water. The cross-calibration procedure of parallel plate chamber with high-energy electron beams is recommended as it avoids pwall correction factor entering into the determination of kQ,Qo. PMID:19893700

Effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 on the left ventricular pressure-volume relationship in the halothane-anesthetized dogs.

PubMed

Honda, Atsushi; Nakamura, Yuji; Ohara, Hiroshi; Cao, Xin; Nomura, Hiroaki; Katagi, Jun; Wada, Takeshi; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Sugiyama, Atsushi

2016-03-15

Cardiac effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 were assessed in the halothane-anesthetized dogs under the monitoring of left ventricular pressure-volume relationship, which were compared with those of clinically recommended doses of dopamine, dobutamine and milrinone (n=4-5 for each treatment). ONO-AE1-329 was intravenously administered in doses of 0.3, 1 and 3 ng/kg/min for 10 min with a pause of 20 min. Dopamine in a dose of 3 µg/kg/min for 10 min, dobutamine in a dose of 1 µg/kg/min for 10 min and milrinone in a dose of 5 µg/kg/min for 10 min followed by 0.5 µg/kg/min for 10 min were intravenously administered. Low dose of ONO-AE1-329 increased the stroke volume. Middle dose of ONO-AE1-329 increased the cardiac output, left ventricular end-diastolic volume, ejection fraction, maximum upstroke/downstroke velocities of the left ventricular pressure and external work, but decreased the end-systolic pressure and internal work besides the change by the low dose. High dose of ONO-AE1-329 increased the heart rate and maximum elastance, but decreased the end-systolic volume besides the changes by the middle dose. Dopamine, dobutamine and milrinone exerted essentially similar cardiac effects to ONO-AE1-329, but they did not significantly change the end-diastolic volume, end-systolic volume, stroke volume, ejection fraction, end-systolic pressure, maximum elastance, external work or internal work. Thus, EP4-receptor stimulation by ONO-AE1-329 may have potential to better promote the passive ventricular filling than the conventional cardiotonic drugs, which could become a candidate of novel therapeutic strategy for the treatment of heart failure with preserved ejection fraction. Copyright © 2016 Elsevier B.V. All rights reserved.

[Effectiveness of thalidomide for erythema nodosum leprosum (ENL): retrospective study of 20 Japanese cases in National Sanatrium Oku-Komyoen].

PubMed

Matsuki, Takanobu; Okano, Yoshiko; Aoki, Yoshinori; Ishida, Yutaka; Hatano, Kentaro; Kumano, Kimiko

2014-12-01

Thalidomide is a TNF-alpha inhibitor and has been administrated for erythema nodosum leprosum (ENL, Type II leprosy reaction) which is one of leprosy reactions and can cause serious illness to patients oflepromatous pole among the immune spectrum. Twenty live cases (at May, 2011) were identified to whom thalidomide had been administrated since 1978 for their ENL reactions. Data were collected from their clinical records in order to evaluate the usage and effectiveness of thalidomide in National Sanatorium Oku-Komyoen, Okayama, Setouchi-city, Japan. Individual data includes bacillary index (BI), total dose, average daily dose, maximum daily dose, minimum daily dose, methods of thalidomide administration and change of symptoms of ENL. Results: No adverse effect was found among 20 cases. Average daily dose of 20 cases was 19 mg. Regarding to the maximum daily dose, in 3 cases (15%) more than 100 mg, in 3 cases (15%) 50 mg, and in 14 cases (70%) less than 40 mg was administrated. Dose was gradually tapered in most cases. From clinical records, thalidomide was found effective for ENL in 19 cases and clinicians concerned were trying to adjust the proper dose of the drug carefully depending on the current symptoms, because there was no guideline of thalidomide administration for ENL. This data suggests that even less than 50-100 mg as the initial daily dose was still effective, though 50-100 mg daily dose is recommended in the current guideline of Japan (2011) and more dose had been administrated in USA and India.

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

Iwai, P; Lins, L Nadler

Purpose: There is a lack of studies with significant cohort data about patients using pacemaker (PM), implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device undergoing radiotherapy. There is no literature comparing the cumulative doses delivered to those cardiac implanted electronic devices (CIED) calculated by different algorithms neither studies comparing doses with heterogeneity correction or not. The aim of this study was to evaluate the influence of the algorithms Pencil Beam Convolution (PBC), Analytical Anisotropic Algorithm (AAA) and Acuros XB (AXB) as well as heterogeneity correction on risk categorization of patients. Methods: A retrospective analysis of 19 3DCRT ormore » IMRT plans of 17 patients was conducted, calculating the dose delivered to CIED using three different calculation algorithms. Doses were evaluated with and without heterogeneity correction for comparison. Risk categorization of the patients was based on their CIED dependency and cumulative dose in the devices. Results: Total estimated doses at CIED calculated by AAA or AXB were higher than those calculated by PBC in 56% of the cases. In average, the doses at CIED calculated by AAA and AXB were higher than those calculated by PBC (29% and 4% higher, respectively). The maximum difference of doses calculated by each algorithm was about 1 Gy, either using heterogeneity correction or not. Values of maximum dose calculated with heterogeneity correction showed that dose at CIED was at least equal or higher in 84% of the cases with PBC, 77% with AAA and 67% with AXB than dose obtained with no heterogeneity correction. Conclusion: The dose calculation algorithm and heterogeneity correction did not change the risk categorization. Since higher estimated doses delivered to CIED do not compromise treatment precautions to be taken, it’s recommend that the most sophisticated algorithm available should be used to predict dose at the CIED using heterogeneity correction.« less

Evaluation of the in vivo genotoxicity of Allura Red AC (Food Red No. 40).

PubMed

Honma, Masamitsu

2015-10-01

Allura Red AC (Food Red No. 40) is a red azo dye that is used for food coloring in beverage and confectionary products. However, its genotoxic properties remain controversial. To clarify the in vivo genotoxicity, we treated mice with Allura Red AC and investigated the induction of DNA damage (liver, glandular stomach), clastogenicity/anuegenicity (bone marrow), and mutagenicity (liver, glandular stomach) using Comet assays, micronucleus tests, and transgenic gene mutation assays, respectively. All studies were conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guideline. Although Allura Red AC was administered up to the maximum doses recommended by the OECD guideline, no genotoxic effect was observed in any of the genotoxic endpoints. These data clearly show no evidence of in vivo genotoxic potential of Allura Red AC administered up to the maximum doses in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

MPC and ALI: their basis and their comparison

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

Kennedy, W.E. Jr.; Watson, E.C.

Radiation protection regulations in the United States have evolved from the recommendations of the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP). In 1959, the ICRP issued Publication 2 which contained specific recommendations on dose rate limits, permissible body burdens, metabolic data for radionuclides, and maximum permissible concentrations (MPC) in air or water. Over the next 20 years, new information became available concerning the effects of radiation, the uptake and retention of radionuclides, and the radioactive decay schemes of parent radionuclides. To include this newer information, the ICRP issued Publication 30 inmore » 1978 to supersede Publication 2. One of the secondary limits defined in Publication 30 is the annual limit of intake (ALI). Radionuclide specific ALI values are intended to replace MPC values in determining whether or not ambient air and water concentrations are sufficiently low to maintain the dose to workers within accepted dose rate limits. In this paper, we discuss the derivation of MPC and ALI values, compare inhalation committed dose equivalent factors derived from ICRP Publications 2 and 30, and discuss the practical implications of using either MPC or ALI in determining compliance with occupational exposure limits. 6 references.« less

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship.

PubMed

Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V S; Greer, Jacqueline M; Wright, John J; Smith, B Douglas; Pratz, Keith W; Rudek, Michelle A

2018-04-27

Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer.

PubMed

Marshall, John; Shapiro, Geoffrey I; Uttenreuther-Fischer, Martina; Ould-Kaci, Mahmoud; Stopfer, Peter; Gordon, Michael S

2013-02-01

To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. The MTD was determined from dose-limiting toxicities in the first cycle. Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.

PubMed

Postel-Vinay, Sophie; Collette, Laurence; Paoletti, Xavier; Rizzo, Elisa; Massard, Christophe; Olmos, David; Fowst, Camilla; Levy, Bernard; Mancini, Pierre; Lacombe, Denis; Ivy, Percy; Seymour, Lesley; Le Tourneau, Christophe; Siu, Lillian L; Kaye, Stan B; Verweij, Jaap; Soria, Jean-Charles

2014-08-01

Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI. Copyright © 2014 Elsevier Ltd. All rights reserved.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

PubMed Central

2013-01-01

Background Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Methods Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Results Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0–t were dose proportional for the 6–12 mg/m2 doses. Conclusion The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. Trial registration The study was registered with ClinicalTrials.gov as NCT01755390. PMID:24099585

Recommendations of the Spanish brachytherapy group (GEB) of Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for high-dose rate (HDR) non melanoma skin cancer brachytherapy.

PubMed

Rodríguez, S; Arenas, M; Gutierrez, C; Richart, J; Perez-Calatayud, J; Celada, F; Santos, M; Rovirosa, A

2018-04-01

Clinical indications of brachytherapy in non-melanoma skin cancers, description of applicators and dosimetry recommendations are described based on the literature review, clinical practice and experience of Spanish Group of Brachytherapy and Spanish Society of Medical Physics reported in the XIV Annual Consensus Meeting on Non Melanoma Skin Cancer Brachytherapy held in Benidorm, Alicante (Spain) on October 21st, 2016. All the recommendations for which consensus was achieved are highlighted in blue. Regular and small surfaces may be treated with Leipzig, Valencia, flap applicators or electronic brachytherapy (EBT). For irregular surfaces, customized molds or interstitial implants should be employed. The dose is prescribed at a maximum depth of 3-4 mm of the clinical target volume/planning target volume (CTV/PTV) in all cases except in flaps or molds in which 5 mm is appropriate. Interstitial brachytherapy should be used for CTV/PTV >5 mm. Different total doses and fraction sizes are used with very similar clinical and toxicity results. Hypofractionation is very useful twice or 3 times a week, being comfortable for patients and practical for Radiotherapy Departments. In interstitial brachytherapy 2 fractions twice a day are applied.

Effect of Antacids and Ranitidine on the Single-Dose Pharmacokinetics of Fosamprenavir

PubMed Central

Ford, Susan L.; Wire, Mary B.; Lou, Yu; Baker, Katherine L.; Stein, Daniel S.

2005-01-01

Single doses of MAALOX TC and ranitidine were administered separately with 1,400 mg of fosamprenavir (FPV). MAALOX TC decreased the area under the concentration-time curve from 0 to 24 h (AUC0-24) for plasma amprenavir (APV) by 18% and the maximum concentration of drug in serum (Cmax) by 35%; the plasma APV concentration at 12 h (C12) increased by 14%. Ranitidine at 300 mg decreased the AUC0-24 for plasma APV by 30% and Cmax by 51%; C12 was unchanged. FPV may be coadministered with antacids without concern and without separation in dosing; however, caution is recommended when FPV is coadministered with histamine2- receptor antagonists or proton pump inhibitors. PMID:15616339

Evaluation of the optimal combinations of modulation factor and pitch for Helical TomoTherapy plans made with TomoEdge using Pareto optimal fronts.

PubMed

De Kerf, Geert; Van Gestel, Dirk; Mommaerts, Lobke; Van den Weyngaert, Danielle; Verellen, Dirk

2015-09-17

Modulation factor (MF) and pitch have an impact on Helical TomoTherapy (HT) plan quality and HT users mostly use vendor-recommended settings. This study analyses the effect of these two parameters on both plan quality and treatment time for plans made with TomoEdge planning software by using the concept of Pareto optimal fronts. More than 450 plans with different combinations of pitch [0.10-0.50] and MF [1.2-3.0] were produced. These HT plans, with a field width (FW) of 5 cm, were created for five head and neck patients and homogeneity index, conformity index, dose-near-maximum (D2), and dose-near-minimum (D98) were analysed for the planning target volumes, as well as the mean dose and D2 for most critical organs at risk. For every dose metric the median value will be plotted against treatment time. A Pareto-like method is used in the analysis which will show how pitch and MF influence both treatment time and plan quality. For small pitches (≤0.20), MF does not influence treatment time. The contrary is true for larger pitches (≥0.25) as lowering MF will both decrease treatment time and plan quality until maximum gantry speed is reached. At this moment, treatment time is saturated and only plan quality will further decrease. The Pareto front analysis showed optimal combinations of pitch [0.23-0.45] and MF > 2.0 for a FW of 5 cm. Outside this range, plans will become less optimal. As the vendor-recommended settings fall within this range, the use of these settings is validated.

Gross alpha and beta activity and annual committed effective dose due to natural radionuclides in some water spinach (ipomoea aquatica Forssk) samples in Ho Chi Minh City, Vietnam.

PubMed

Le, Hao Cong; Nguyen, Thang Van; Huynh, Thu Nguyen Phong; Huynh, Phuong Truc

2017-07-01

The results of gross alpha and beta radioactivity measurement in water spinach samples from some districts in Ho Chi Minh City, Vietnam are presented in this paper. The measurements were performed using a low-background proportional counters LB4200 manufactured by Canberra Company, Inc. Mean concentrations of gross alpha and beta activity were found to be 1.50 ± 0.38 Bq kg -1 to 84.25 ± 8.67 Bq kg -1 . In order to keep the recommended dose level, a recommended maximum intake of water spinach was proposed to be 6 kg fresh per year. The total annual committed effective dose due to natural radionuclides in water spinach samples was then found in range from 0.07 mSv y -1 to 0.82 mSv y -1 . The dose from 26.32% of samples exceeds the exemption mean dose criterion of 0.3 mSv y -1 but complies with the upper dose principle of 1 mSv y -1 provided in UNSCEAR 2008 report. The estimated soil-to-plant transfer factors for gross alpha and beta for water spinach samples were also presented. Copyright © 2016 Elsevier Ltd. All rights reserved.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.

PubMed

Murthy, Rashmi; Borges, Virginia F; Conlin, Alison; Chaves, Jorge; Chamberlain, Marc; Gray, Todd; Vo, Alex; Hamilton, Erika

2018-05-24

Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases. In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m 2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192. Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab. Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794). Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer

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

Shinoto, Makoto, E-mail: shinoto@saga-himat.jp; Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka

Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m{sup 2} under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions undermore » the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m{sup 2}. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m{sup 2}) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.« less

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

PubMed

Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

2012-04-01

Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers

PubMed Central

Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-01

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step‐and‐shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose <45 Gy to spinal cord and <50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5±2.2 Gy and 36.7±14.0 Gy), without significant changes on the other OARs. A marked difference (−15.9±1.9 Gy and −10.1±5.7 Gy) was obtained at the expense of a small difference (−1.3%±0.9%) from initial PTV195% coverage (96.6%±0.9%). Similar difference (−15.7±2.2 Gy and −10.2±6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (−0.3%±0.3% from the initial 98.3%±0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer. PACS number: 87.55.D PMID:24423836

Tanning facility use: are we exceeding Food and Drug Administration limits?

PubMed

Hornung, Robin L; Magee, Kristin H; Lee, Willie J; Hansen, Lori A; Hsieh, Yi-Ching

2003-10-01

The US Food and Drug Administration (FDA) recommends exposure limits for tanning bed use. Tanning patrons may not be following these recommendations and may be overexposed to damaging ultraviolet radiation (UV). This study was conducted to assess tanning patrons' adherence to FDA-recommended exposure limits and to measure the amount of UVA and UVB radiation emitted by tanning beds. A community-based survey was administered during routine state inspections of North Carolina tanning facilities (n = 50). At each facility, patron records were randomly selected (n = 483) for a survey of exposure records, and UVA and UVB outputs were measured for each tanning bed. The recommended limits were exceeded by 95% of patrons, and 33% of patrons began tanning at the maximum doses recommended for maintenance tanning. Average tanning bed output was 192.1 W/m(2) UVA and 0.35 W/m(2) erythemally weighted UVB. Interventions for tanning bed operators and patrons are needed to increase compliance with federally recommended exposure limits.

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.

Suvorexant: a promising, novel treatment for insomnia

PubMed Central

Lee-Iannotti, Joyce K; Parish, James M

2016-01-01

Suvorexant a novel, orexin receptor antagonist was recently approved by the US Food and Drug Administration for the treatment of sleep onset and sleep maintenance insomnia in August 2014. Multiple animal and human studies support the efficacy, safety, and tolerability of suvorexant for patients of various profiles. Current recommendations advocate for a starting dose of 10 mg and a maximum dose of 20 mg, with cautious use in women, obese patients, and patients taking other CYP3A4 inhibitors. More head-to-head studies comparing suvorexant to other sedative-hypnotic therapies are needed to further delineate which patients will benefit the most from this medication over others. PMID:26955275

Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study.

PubMed

Auger, R Robert; Goodman, Scott H; Silber, Michael H; Krahn, Lois E; Pankratz, V Shane; Slocumb, Nancy L

2005-06-01

To ascertain complications associated with high-dose stimulant therapy in patients with narcolepsy or idiopathic hypersomnia. Case-control, retrospective chart review. Sleep center in an academic hospital. 116 patients with narcolepsy or idiopathic hypersomnia were individually matched by sex, diagnosis, age of onset, and duration of follow-up from both onset and diagnosis. Members of the high-dose group (n = 58) had received at least 1 stimulant at a dosage > or = 120% of the maximum recommended by the American Academy of Sleep Medicine Standards of Practice Committee. The standard-dose control group (n = 58) had received stimulants at a dosage < or = 100% of the American Academy of Sleep Medicine guidelines. N/A. The prevalence of psychosis (odds ratio = 12.0 [1.6-92.0]), alcohol or polysubstance misuse (odds ratio = 4.3 [1.2-15.2]), and psychiatric hospitalization (odds ratio = 3.2 [1.1-10.0]) was significantly increased in the high-dose group. More high-dose patients also experienced tachyarrhythmias (odds ratio = 3.3 [0.92-12.1] and anorexia or weight loss (odds ratio = 11.0 [1.4-85.2]). The frequency of physician-diagnosed depression, drug-seeking and suicide-related behaviors, hypertension, and cardiovascular disease did not differ significantly between the groups. This study demonstrated a significantly higher occurrence of psychosis, substance misuse, and psychiatric hospitalizations in patients using high-dose stimulants compared to those using standard doses. Tachyarrhythmias and anorexia or weight loss were also more common in this group as compared with controls. Clinicians should be very cautious in prescribing dosages that exceed maximum guidelines.

Dyshidrotic eczema associated with the use of IVIg

PubMed Central

Kotan, Dilcan; Erdem, Teoman; Acar, Bilgehan Atilgan; Boluk, Ayhan

2013-01-01

Intravenous immunoglobulin (IVIg) treatment is highly effective for autoimmune diseases including myasthenia gravis. Recovery is observed at approximately. 75% of myasthenia gravis patients through IVIg treatment. As a result of many clinical studies, the recommended dose is determined as 0.4 g/kg for 5 days (maximum total dose at 2 g/kg body weight). If an additional immunomodulatory treatment is not administered, IVIg maintenance treatment is needed mostly. However, some side effects may inhibit long-term treatment. For this reason, it is important to know the effect profile well and when the treatment should be discontinued. A female myasthenia gravis patient case is presented here, where dyshidrotic eczema has occurred after the second dose of  intravenous Ig medication and whose treatment is despite further IVIg therapy. PMID:23417935

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations

PubMed Central

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100–400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations. PMID:28182625

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations.

PubMed

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100-400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations.

Characterizing the marker-dye correction for Gafchromic(®) EBT2 film: a comparison of three analysis methods.

PubMed

McCaw, Travis J; Micka, John A; Dewerd, Larry A

2011-10-01

Gafchromic(®) EBT2 film has a yellow marker dye incorporated into the active layer of the film that can be used to correct the film response for small variations in thickness. This work characterizes the effect of the marker-dye correction on the uniformity and uncertainty of dose measurements with EBT2 film. The effect of variations in time postexposure on the uniformity of EBT2 is also investigated. EBT2 films were used to measure the flatness of a (60)Co field to provide a high-spatial resolution evaluation of the film uniformity. As a reference, the flatness of the (60)Co field was also measured with Kodak EDR2 films. The EBT2 films were digitized with a flatbed document scanner 24, 48, and 72 h postexposure, and the images were analyzed using three methods: (1) the manufacturer-recommended marker-dye correction, (2) an in-house marker-dye correction, and (3) a net optical density (OD) measurement in the red color channel. The field flatness was calculated from orthogonal profiles through the center of the field using each analysis method, and the results were compared with the EDR2 measurements. Uncertainty was propagated through a dose calculation for each analysis method. The change in the measured field flatness for increasing times postexposure was also determined. Both marker-dye correction methods improved the field flatness measured with EBT2 film relative to the net OD method, with a maximum improvement of 1% using the manufacturer-recommended correction. However, the manufacturer-recommended correction also resulted in a dose uncertainty an order of magnitude greater than the other two methods. The in-house marker-dye correction lowered the dose uncertainty relative to the net OD method. The measured field flatness did not exhibit any unidirectional change with increasing time postexposure and showed a maximum change of 0.3%. The marker dye in EBT2 can be used to improve the response uniformity of the film. Depending on the film analysis method used, however, application of a marker-dye correction can improve or degrade the dose uncertainty relative to the net OD method. The uniformity of EBT2 was found to be independent of the time postexposure.

Dose estimates for the local inhabitants from 210Po ingestion via dietary sources at a proposed uranium mining site in India.

PubMed

Giri, Soma; Jha, V N; Singh, Gurdeep; Tripathi, R M

2012-07-01

To study the distribution of (210)Po activity in food in Bagjata in East Singhbhum, India. (210)Po were analyzed in the food samples of plant origin such as cereals, pulses, fruits, vegetables and food of animal origin such fish, chicken, egg, etc., in and around Bagjata uranium mining area as a part of baseline study after acid digestion. The intake and ingestion dose of the radionuclide was estimated. The general range of (210)Po activity in all the dietary components ranged widely from <0.2-36 Bqkg(-1)(fresh). In the food of plant origin, the minimum activity of (210)Po was estimated in vegetables while maximum in pulses. In food of animal origin, the observed minimum activity of (210)Po was in eggs and the maximum observed was in chicken samples. The intake of (210)Po considering all dietary components was found to be 464 Bq.Y(-1) while the ingestion dose was calculated to be 557 μSv.Y(-1), respectively. The estimated doses are reflecting the natural background dose via the route of ingestion, which is much below the 1 mSv limit set in the International Commission on Radiological Protection (ICRP) recommendations. The study confirms that current levels of (210)Po do not pose a significant radiological risk to the local inhabitants.

Methamphetamine and Amphetamine Isomer Concentrations in Human Urine Following Controlled Vicks VapoInhaler Administration

PubMed Central

Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; Flegel, Ron; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

2014-01-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography–mass spectrometry (GC–MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC–MS method with >99% purity of R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC–MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0–1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT® II Plus, KIMS® II and DRI® had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT® II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. PMID:25217541

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

The US Food and Drug Administration's perspective on the new antidepressant vortioxetine.

PubMed

Zhang, Jing; Mathis, Mitchell V; Sellers, Jenn W; Kordzakhia, George; Jackson, Andre J; Dow, Antonia; Yang, Peiling; Fossom, Linda; Zhu, Hao; Patel, Hiren; Unger, Ellis F; Temple, Robert J

2015-01-01

This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs. © Copyright 2015 Physicians Postgraduate Press, Inc.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

PubMed

Ettienne, Earl B; Chapman, Edwin; Maneno, Mary; Ofoegbu, Adaku; Wilson, Bradford; Settles-Reaves, Beverlyn; Clarke, Melissa; Dunston, Georgia; Rosenblatt, Kevin

2017-12-01

Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency.

PubMed

Clark, N P

2008-01-01

Superior bioavailability and simple weight-based dosing have made low-molecular-weight heparins (LMWH) the preferred agents for treatment and prevention of venous thromboembolism (VTE) for most indications. Despite improved pharmacokinetics, there remain populations where appropriate LMWH dose intensity and frequency are open to question. Obese patients have a lower proportion of lean body mass as a percentage of total body weight. As a result, LMWH dosing based on total body weight could cause supra-therapeutic anticoagulation. Elderly patients also have less lean body mass in addition to a higher incidence of age-related renal disease and increased risk of bleeding. Renal insufficiency presents a risk of LMWH accumulation as well as increased risk of bleeding. Among LMWH products, only dalteparin labeling recommends a maximum dose. Prospective data call into question the validity of this dose limitation. Additionally, because obese patients are already at higher risk of VTE recurrence, they may be particularly sensitive to subtherapeutic anticoagulation. Prospective data evaluating LMWH use in elderly patients have been limited to in-patient treatment. Few recommendations can be made in this population other than close monitoring. Renal insufficiency is a risk for bleeding during LMWH use. Available evidence supports the potential for enoxaparin accumulation, but not tinzaparin. Enoxaparin dose adjustment, either empiric or based on anti-Xa monitoring, has insufficient data to support widespread implementation. Unfractionated heparin is not reliant on renal elimination and is a sensible option for VTE treatment in patients with a creatinine clearance<30 ml/min.

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma1

PubMed Central

Quinn, Jennifer A.; Reardon, David A.; Friedman, Allan H.; Rich, Jeremy N.; Sampson, John H.; Vredenburgh, James; Gururangan, Sridharan; Provenzale, James M.; Walker, Amy; Schweitzer, Holly; Bigner, Darell D.; Tourt-Uhlig, Sandra; Herndon, James E.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah; Ziegler, Karen; Bohlin, Cindy; Lentz, Christy; Friedman, Henry S.

2004-01-01

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs. PMID:15134629

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

PubMed

Saber, Haleh; Del Valle, Pedro; Ricks, Tiffany K; Leighton, John K

2017-11-01

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe. Published by Elsevier Inc.

Evaluation of lens dose from anterior electron beams: comparison of Pinnacle and Gafchromic EBT3 film.

PubMed

Sonier, Marcus; Wronski, Matt; Yeboah, Collins

2015-03-08

Lens dose is a concern during the treatment of facial lesions with anterior electron beams. Lead shielding is routinely employed to reduce lens dose and minimize late complications. The purpose of this work is twofold: 1) to measure dose pro-files under large-area lead shielding at the lens depth for clinical electron energies via film dosimetry; and 2) to assess the accuracy of the Pinnacle treatment planning system in calculating doses under lead shields. First, to simulate the clinical geometry, EBT3 film and 4 cm wide lead shields were incorporated into a Solid Water phantom. With the lead shield inside the phantom, the film was positioned at a depth of 0.7 cm below the lead, while a variable thickness of solid water, simulating bolus, was placed on top. This geometry was reproduced in Pinnacle to calculate dose profiles using the pencil beam electron algorithm. The measured and calculated dose profiles were normalized to the central-axis dose maximum in a homogeneous phantom with no lead shielding. The resulting measured profiles, functions of bolus thickness and incident electron energy, can be used to estimate the lens dose under various clinical scenarios. These profiles showed a minimum lead margin of 0.5 cm beyond the lens boundary is required to shield the lens to ≤ 10% of the dose maximum. Comparisons with Pinnacle showed a consistent overestimation of dose under the lead shield with discrepancies of ~ 25% occur-ring near the shield edge. This discrepancy was found to increase with electron energy and bolus thickness and decrease with distance from the lead edge. Thus, the Pinnacle electron algorithm is not recommended for estimating lens dose in this situation. The film measurements, however, allow for a reasonable estimate of lens dose from electron beams and for clinicians to assess the lead margin required to reduce the lens dose to an acceptable level.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Dissipation kinetics and safety evaluation of tebuconazole and trifloxystrobin in tea under tropical field conditions.

PubMed

Paramasivam, Mariappan; Deepa, Manthirachalam; Selvi, Chellamuthu; Chandrasekaran, Subramanian

2017-12-01

Dissipation kinetics of tebuconazole, trifloxystrobin and its acid metabolite residues were studied in tea under tropical field conditions using GC-MS (SIM). The average recoveries ranged from 80.7% to 105.8%, with a RSD of <9.3%. Dissipation rate for both doses applied followed first-order kinetics, with half-lives in green leaves in the range of 2.8-3.3 and 2.9-3.3 days; ranges in processed tea were 2.7-3.6 days for trifloxystrobin and 3.0-3.1 days for tebuconazole. The trifloxystrobin residues were not transferred into the tea infusion during the infusion process; tebuconazole did transfer, in the range of 14.3-18.9%. As the theoretical maximum residue contributions on tea from initial deposits were found to be less than the maximum permissible intake values, at the recommended application dose a withdrawal period of 23 days before consumption should be applied to reduce risk.

Dissipation of Flonicamid in Honeysuckle and Its Transfer during Brewing Process.

PubMed

Wang, Yujie; Xue, Jian; Jin, Hongyu; Ma, Shuangcheng

2017-05-01

The dissipation of flonicamid in Honeysuckle and transfer pattern from Honeysuckle to its tea infusion were investigated. Flonicamid was applied on Honeysuckle crop at two dosages, 60 g of active gradient per hectare (g a.i. hm -2 ) and 180 g a.i. hm -2 (recommended and triple the recommended) in Fenqiu, Henan Province in 2015 and 2016. Gas Chromatography-Electron Capture Detector (GC-ECD) detection methods were developed for the analysis of flonicamid residues in honeysuckles and its infusion. The recoveries in both honeysuckles and its infusion ranged from 81.5 to 101.7% with relative standard deviations (RSDs) of 3.2-9.1%. The dissipations of flonicamid in Honeysuckle were found to follow the first order kinetics with half-life ranging between 2.8 and 3.2 d. After recommended dose pesticide application, contents of flonicamid residues were lower than theoretical maximum residue limit (tMRL). Flonicamid residues can easily transfer from Honeysuckle to its tea infusion and transfer rates of flonicamid decrease with the brewing temperature reduction or the brewing times increase. These results are helpful to establish maximum residue limit and develop guidance on the appropriate and secure use of flonicamid in Honeysuckle.

Methods and procedures for: A randomized double-blind study investigating dose-dependent longitudinal effects of vitamin D supplementation on bone health.

PubMed

Burt, Lauren A; Gaudet, Sharon; Kan, Michelle; Rose, Marianne S; Billington, Emma O; Boyd, Steven K; Hanley, David A

2018-04-01

The optimum dose of vitamin D and corresponding serum 25-hydroxyvitamin D (25OHD) concentration for bone health is still debated and some health practitioners are recommending doses well above the Canada/USA recommended Dietary Reference Intake (DRI). We designed a three-year randomized double-blind clinical trial investigating whether there are dose-dependent effects of vitamin D supplementation above the Dietary Reference Intake (DRI) on bone health. The primary aims of this study are to assess, whether supplementation of vitamin D 3 increases 1) volumetric bone mineral density measured by high-resolution peripheral quantitative computed tomography (HR-pQCT); 2) bone strength assessed by finite element analysis, and 3) areal bone mineral density by dual X-ray absorptiometry (DXA). Secondary aims are to understand whether vitamin D 3 supplementation improves parameters of bone microarchitecture, balance, physical function and quality of life. Participants are men and women aged 55-70 years, with women at least 5-years post-menopause. The intervention is daily vitamin D 3 supplementation doses of 400, 4000 or 10,000 IU. Participants not achieving adequate dietary calcium intake are provided with calcium supplementation, up to a maximum supplemental dose of 600 mg elemental calcium per day. Results from this three-year study will provide evidence whether daily vitamin D 3 supplementation with adequate calcium intake can affect bone density, bone microarchitecture and bone strength in men and women. Furthermore, the safety of high dose daily vitamin D 3 supplementation will be explored. Copyright © 2018 Elsevier Inc. All rights reserved.

Providing solid angle formalism for skyshine calculations.

PubMed

Gossman, Michael S; Pahikkala, A Jussi; Rising, Mary B; McGinley, Patton H

2010-08-17

We detail, derive and correct the technical use of the solid angle variable identified in formal guidance that relates skyshine calculations to dose-equivalent rate. We further recommend it for use with all National Council on Radiation Protection and Measurements (NCRP), Institute of Physics and Engineering in Medicine (IPEM) and similar reports documented. In general, for beams of identical width which have different resulting areas, within ± 1.0 % maximum deviation the analytical pyramidal solution is 1.27 times greater than a misapplied analytical conical solution through all field sizes up to 40 × 40 cm². Therefore, we recommend determining the exact results with the analytical pyramidal solution for square beams and the analytical conical solution for circular beams.

Occurrence of 222Rn in irrigation water from Wadi Al-Rummah Qassim province, Saudi Arabia

NASA Astrophysics Data System (ADS)

El-Taher, Atef; Alashrah, Saleh

2015-08-01

Naturally accruing radioactive materials in the environment have received attention since they may be present in high level and pose risk to human health. The present work deals with measuring of 222Rn in irrigation water samples from Wadi Al-Rummah, Qassim province, in central of Saudi Arabia. 222Rn concentrations were measured by RAD7. It was found that the concentration of 222Rn ranged from 2.1 ± 1.2 to 7.2 ± 1.5 BqL-1. These values are below 11.1 BqL-1 the maximum contamination level recommended from the U.S. Environmental Protection Agency. The calculated annual effective dose (AED) ranging from 7.5 to 26.1 µSv/y. It was evident that the total annual effective dose resulting from radon in irrigation groundwater in Wadi Al-Rummah in Qassim area were significantly lower than the recommended limit 1 mSv/y for the public.

Occurrence of {sup 222}Rn in irrigation water from Wadi Al-Rummah Qassim province, Saudi Arabia

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

El-Taher, Atef; Alashrah, Saleh

Naturally accruing radioactive materials in the environment have received attention since they may be present in high level and pose risk to human health. The present work deals with measuring of {sup 222}Rn in irrigation water samples from Wadi Al-Rummah, Qassim province, in central of Saudi Arabia. {sup 222}Rn concentrations were measured by RAD7. It was found that the concentration of {sup 222}Rn ranged from 2.1 ± 1.2 to 7.2 ± 1.5 BqL{sup −1}. These values are below 11.1 BqL{sup −1} the maximum contamination level recommended from the U.S. Environmental Protection Agency. The calculated annual effective dose (AED) ranging frommore » 7.5 to 26.1 µSv/y. It was evident that the total annual effective dose resulting from radon in irrigation groundwater in Wadi Al-Rummah in Qassim area were significantly lower than the recommended limit 1 mSv/y for the public.« less

A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

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

Tada, Takuhito, E-mail: tada@msic.med.osaka-cu.ac.jp; Department of Radiology, Izumi Municipal Hospital, Izumi; Chiba, Yasutaka

2012-05-01

Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m{sup 2}) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m{sup 2}). Total doses were 54 Gy in 36 fractions, 60 Gymore » in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade {>=}4 esophagitis and neutropenic fever and Grade {>=}3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.« less

Clinical implementation of MOSFET detectors for dosimetry in electron beams.

PubMed

Bloemen-van Gurp, Esther J; Minken, Andre W H; Mijnheer, Ben J; Dehing-Oberye, Cary J G; Lambin, Philippe

2006-09-01

To determine the factors converting the reading of a MOSFET detector placed on the patient's skin without additional build-up to the dose at the depth of dose maximum (D(max)) and investigate their feasibility for in vivo dose measurements in electron beams. Factors were determined to relate the reading of a MOSFET detector to D(max) for 4 - 15 MeV electron beams in reference conditions. The influence of variation in field size, SSD, angle and field shape on the MOSFET reading, obtained without additional build-up, was evaluated using 4, 8 and 15 MeV beams and compared to ionisation chamber data at the depth of dose maximum (z(max)). Patient entrance in vivo measurements included 40 patients, mostly treated for breast tumours. The MOSFET reading, converted to D(max), was compared to the dose prescribed at this depth. The factors to convert MOSFET reading to D(max) vary between 1.33 and 1.20 for the 4 and 15 MeV beams, respectively. The SSD correction factor is approximately 8% for a change in SSD from 95 to 100 cm, and 2% for each 5-cm increment above 100 cm SSD. A correction for fields having sides smaller than 6 cm and for irregular field shape is also recommended. For fields up to 20 x 20 cm(2) and for oblique incidence up to 45 degrees, a correction is not necessary. Patient measurements demonstrated deviations from the prescribed dose with a mean difference of -0.7% and a standard deviation of 2.9%. Performing dose measurements with MOSFET detectors placed on the patient's skin without additional build-up is a well suited technique for routine dose verification in electron beams, when applying the appropriate conversion and correction factors.

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

PubMed Central

2010-01-01

Background YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. Methods This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. Results Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. Conclusions The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. Trial registration ClinicalTrials.gov unique identifier: NCT00633490 PMID:20923544

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.

Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

PubMed

Mato, Anthony R; Thompson, Meghan; Allan, John N; Brander, Danielle M; Pagel, John M; Ujjani, Chaitra S; Hill, Brian T; Lamanna, Nicole; Lansigan, Frederick; Jacobs, Ryan; Shadman, Mazyar; Skarbnik, Alan P; Pu, Jeffrey J; Barr, Paul M; Sehgal, Alison R; Cheson, Bruce D; Zent, Clive S; Tuncer, Hande H; Schuster, Stephen J; Pickens, Peter V; Shah, Nirav N; Goy, Andre; Winter, Allison M; Garcia, Christine; Kennard, Kaitlin; Isaac, Krista; Dorsey, Colleen; Gashonia, Lisa M; Singavi, Arun K; Roeker, Lindsey E; Zelenetz, Andrew; Williams, Annalynn; Howlett, Christina; Weissbrot, Hanna; Ali, Naveed; Khajavian, Sirin; Sitlinger, Andrea; Tranchito, Eve; Rhodes, Joanna; Felsenfeld, Joshua; Bailey, Neil; Patel, Bhavisha; Burns, Timothy F; Yacur, Melissa; Malhotra, Mansi; Svoboda, Jakub; Furman, Richard R; Nabhan, Chadi

2018-06-07

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients , the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study. Copyright © 2018, Ferrata Storti Foundation.

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

PubMed

de la Peña, Amparo; Cui, Xuewei; Geiser, Jeanne; Loghin, Corina

2017-11-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Application of a prospective model for calculating worker exposure due to the air pathway for operations in a laboratory.

PubMed

Grimbergen, T W M; Wiegman, M M

2007-01-01

In order to arrive at recommendations for guidelines on maximum allowable quantities of radioactive material in laboratories, a proposed mathematical model was used for the calculation of transfer fractions for the air pathway. A set of incident scenarios was defined, including spilling, leakage and failure of the fume hood. For these 'common incidents', dose constraints of 1 mSv and 0.1 mSv are proposed in case the operations are being performed in a controlled area and supervised area, respectively. In addition, a dose constraint of 1 microSv is proposed for each operation under regular working conditions. Combining these dose constraints and the transfer fractions calculated with the proposed model, maximum allowable quantities were calculated for different laboratory operations and situations. Provided that the calculated transfer fractions can be experimentally validated and the dose constraints are acceptable, it can be concluded from the results that the dose constraint for incidents is the most restrictive one. For non-volatile materials this approach leads to quantities much larger than commonly accepted. In those cases, the results of the calculations in this study suggest that limitation of the quantity of radioactive material, which can be handled safely, should be based on other considerations than the inhalation risks. Examples of such considerations might be the level of external exposure, uncontrolled spread of radioactive material by surface contamination, emissions in the environment and severe accidents like fire.

Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

PubMed Central

Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.

2016-01-01

Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

Phase I study of adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioloalveolar cell lung carcinoma: ECOG 6597.

PubMed

Keedy, Vicki; Wang, Wei; Schiller, Joan; Chada, Sunil; Slovis, Bonnie; Coffee, Keith; Worrell, John; Thet, Lyn A; Johnson, David H; Carbone, David P

2008-09-01

This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC). Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 x 10(9) viral particles (vp) per dose and escalated to a maximum of 2 x 10(12) vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes. Twenty-five patients were treated at doses between 2 x 10(9) and 2 x 10(12) vp. At 2 x 10(12) vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 x 10(11) vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration. Ad-p53 can be administered safely by BAL at 5 x 10(11) vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.

A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

PubMed

Venugopal, B; Awada, A; Evans, T R J; Dueland, S; Hendlisz, A; Rasch, W; Hernes, K; Hagen, S; Aamdal, S

2015-10-01

CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

Comparative dosimetric evaluation of nanotargeted (188)Re-(DXR)-liposome for internal radiotherapy.

PubMed

Chang, Chih-Hsien; Stabin, Michael G; Chang, Ya-Jen; Chen, Liang-Cheng; Chen, Min-Hua; Chang, Tsui-Jung; Lee, Te-Wei; Ting, Gann

2008-12-01

A dosimetric analysis was performed to evaluate nanoliposomes as carriers of radionuclides ((188)Re-liposomes) and radiochemotherapeutic drugs [(188)Re-doxorubicin (DXR)-liposomes] in internal radiotherapy for colon carcinoma, as evaluated in mice. Pharmacokinetic data for (188)Re-N, N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA), (188)Re-liposome, and (188)Re-DXR-liposome were obtained for the estimation of absorbed doses in tumors and normal organs. Two colon carcinoma mouse models were employed: subcutaneous growing solid tumor and malignant ascites pervading tumor models. Radiation-dose estimates for normal tissues and tumors were calculated by using the OLINDA/EXM program. An evaluation of a recommended maximum administered activity (MAA) for the nanotargeted drugs was also made. Mean absorbed doses derived from (188)Re-liposome and (188)Re-DXR-liposome in normal tissues were generally similar to those from (188)Re-BMEDA in intraperitoneal and intravenous administration. Tissue-absorbed dose in the liver was 0.24-0.40 and 0.17-0.26 (mGy/MBq) and in red marrow was 0.033-0.050 and 0.038-0.046 (mGy/MBq), respectively, for (188)Re-liposome and (188)Re-DXR-liposome. Tumor-absorbed doses for the nanotargeted (188)Re-liposome and (188)Re-DXR-liposome were higher than those of (188)Re-BMEDA for both routes of administration (4-26-fold). Dose to red marrow defined the recommended MAA. Our results suggest that radionuclide and chemoradiotherapeutic passive targeting delivery, using nanoliposomes as the carrier, is feasible and promising in systemic-targeted radionuclide therapy.

Natural and anthropogenic radionuclides in rocks and beach sands from Ezine region (Canakkale), Western Anatolia, Turkey.

PubMed

Orgün, Y; Altinsoy, N; Sahin, S Y; Güngör, Y; Gültekin, A H; Karahan, G; Karacik, Z

2007-06-01

This paper represents the first reports on the natural and anthropogenic radionuclides in Kestanbol granitic pluton and surrounding rocks, and coastal region of the Ezine town. To assess the radiological hazard of the natural radioactivity, the radium equivalent activity, the absorbed dose rate and the external hazard index were calculated, and in situ gamma dose rates were measured. The high-activity concentrations were measured in the pluton and sands, which was originated mainly from the pluton, due to the presence of zircon, allanite, monazite, thorite, uranothorite and apatite. The average activity concentrations of (238)U, (232)Th and (40)K are 174.78, 204.69 and 1171.95 Bq kg(-1) for pluton, and 290.36, 532.04 and 1160.75 Bq kg(-1) for sands, respectively. (137)Cs in Ezine region ranged from 0-6.57 Bq kg(-1). The average absorbed dose rate for the granitic and sand samples were calculated to be 251.6 and 527.92 nGy h(-1), respectively. The maximum contribution to the total absorbed gamma dose rate in air was due to the (232)Th (52.3% for pluton and 67.1% for sands). The Raeq activities of the pluton and sands are higher than the recommended maximum value of 370 Bq kg(-1) criterion limit of Raeq activity for building materials.

Eye lens dosimetry in anesthesiology: a prospective study.

PubMed

Vaes, Bart; Van Keer, Karel; Struelens, Lara; Schoonjans, Werner; Nijs, Ivo; Vandevenne, Jan; Van Poucke, Sven

2017-04-01

The eye lens is one of the most sensitive organs for radiation injury and exposure might lead to radiation induced cataract. Eye lens dosimetry in anesthesiology has been published in few clinical trials and an active debate about the causality of radiation induced cataract is still ongoing. Recently, the International Commission on Radiological Protection (ICRP) recommended a reduction in the annual dose limit for occupational exposure for the lens of the eye from 150 to 20 mSv, averaged over a period of 5 years, with the dose in a single year not exceeding 50 mSv. This prospective study investigated eye lens dosimetry in anesthesiology practice during a routine year of professional activity. The radiation exposure measured represented the exposure in a normal working schedule of a random anesthesiologist during 1 month and this cumulative eye lens dose was extrapolated to 1 year. Next, eye lens doses were measured in anesthesiology during neuro-embolisation procedures, radiofrequency ablations or vertebroplasty/kyphoplasty procedures. The eye lens doses are measured in terms of the dose equivalent H p (3) with the Eye-D dosimeter (Radcard, Poland) close to the right eye (on the temple). In 16 anesthesiologists, the estimated annual eye lens doses range from a minimum of 0.4 mSv to a maximum of 3.5 mSv with an average dose of 1.33 mSv. Next, eye lens doses were measured for nine neuro-embolisation procedures, ten radiofrequency ablations and six vertebroplasty/kyphoplasty procedures. Average eye lens doses of 77 ± 76 µSv for neuro-embolisations, 38 ± 34 µSv for cardiac ablations and 40 ± 44 µSv for vertebro-/kyphoplasty procedures were recorded. The maximum doses were respectively 264, 97 and 122 µSv. This study demonstrated that the estimated annual eye lens dose is well below the revised ICRP's limit of 20 mSv/year. However, we demonstrated high maximum and average doses during neuro-embolisation, cardiac ablation and vertebro-/kyphoplasty procedures. With radiation induced cataract being explained as a possible stochastic effect, without a threshold dose, anesthesiologists who regularly work in a radiological environment should remain vigilant and maintain radiation safety standards at all times. This includes adequately protective equipment (protection shields, apron, thyroid shield and leaded eye wear), keeping distance, routine monitoring and appropriate education.

Current knowledge on radon risk: implications for practical radiation protection? radon workshop, 1/2 December 2015, Bonn, BMUB (Bundesministerium für Umwelt, Naturschutz, Bau und Reaktorsicherheit; Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety).

PubMed

Müller, Wolfgang-Ulrich; Giussani, Augusto; Rühm, Werner; Lecomte, Jean-Francois; Harrison, John; Kreuzer, Michaela; Sobotzki, Christina; Breckow, Joachim

2016-08-01

ICRP suggested a strategy based on the distinction between a protection approach for dwellings and one for workplaces in the previous recommendations on radon. Now, the Commission recommends an integrated approach for the protection against radon exposure in all buildings irrespective of their purpose and the status of their occupants. The strategy of protection in buildings, implemented through a national action plan, is based on the application of the optimisation principle below a derived reference level in concentration (maximum 300 Bq m(-3)). A problem, however, arises that due to new epidemiological findings and application of dosimetric models, ICRP 115 (Ann ICRP 40, 2010) presents nominal probability coefficients for radon exposure that are approximately by a factor of 2 larger than in the former recommendations of ICRP 65 (Ann ICRP 23, 1993). On the basis of the so-called epidemiological approach and the dosimetric approach, the doubling of risk per unit exposure is represented by a doubling of the dose coefficients, while the risk coefficient of ICRP 103 (2007) remains unchanged. Thus, an identical given radon exposure situation with the new dose coefficients would result in a doubling of dose compared with the former values. This is of serious conceptual implications. A possible solution of this problem was presented during the workshop.

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.

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas

PubMed Central

Kilburn, Lindsay B.; Kocak, Mehmet; Schaedeli Stark, Franziska; Meneses-Lorente, Georgina; Brownstein, Carrie; Hussain, Sazzad; Chintagumpala, Murali; Thompson, Patrick A.; Gururangan, Sri; Banerjee, Anuradha; Paulino, Arnold C.; Kun, Larry; Boyett, James M.; Blaney, Susan M.

2013-01-01

Background We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas. Methods Children 3–21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m2, given twice daily, with subsequent cohorts enrolled at 650 mg/m2 and 850 mg/m2 using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles. Results Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data. Conclusions Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m2, administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030). PMID:23592571

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

PubMed Central

Loghin, Corina; Haber, Harry; Beasley, Charles M; Kothare, Prajakti A; Kauffman, Lynnette; April, John; Jin, Ling; Allen, Albert J; Mitchell, Malcolm I

2013-01-01

Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. PMID:22803597

Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.

PubMed

Takeoka, Hiroaki; Yamada, Kazuhiko; Azuma, Koichi; Zaizen, Yoshiaki; Yamashita, Fumie; Yoshida, Tsukasa; Naito, Yoshiko; Okayama, Yusuke; Miyamoto, Maki; Hoshino, Tomoaki

2014-05-01

The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.

Leaded eyeglasses substantially reduce radiation exposure of the surgeon's eyes during acquisition of typical fluoroscopic views of the hip and pelvis.

PubMed

Burns, Sean; Thornton, Raymond; Dauer, Lawrence T; Quinn, Brian; Miodownik, Daniel; Hak, David J

2013-07-17

Despite recommendations to do so, few orthopaedists wear leaded glasses when performing operative fluoroscopy. Radiation exposure to the ocular lens causes cataracts, and regulatory limits for maximum annual occupational exposure to the eye continue to be revised downward. Using anthropomorphic patient and surgeon phantoms, radiation dose at the surgeon phantom's lens was measured with and without leaded glasses during fluoroscopic acquisition of sixteen common pelvic and hip views. The magnitude of lens dose reduction from leaded glasses was calculated by dividing the unprotected dose by the dose measured behind leaded glasses. On average, the use of leaded glasses reduced radiation to the surgeon phantom's eye by tenfold, a 90% reduction in dose. However, there was widespread variation in the amount of radiation that reached the phantom surgeon's eye among the various radiographic projections we studied. Without leaded glasses, the dose measured at the surgeon's lens varied more than 250-fold among these sixteen different views. In addition to protecting the surgeon's eye from the deleterious effects of radiation, the use of leaded glasses could permit an orthopaedist to perform fluoroscopic views on up to ten times more patients before reaching the annual dose limit of 20 mSv of radiation to the eye recommended by the International Commission on Radiological Protection. Personal safety and adherence to limits of occupational radiation exposure should compel orthopaedists to wear leaded glasses for fluoroscopic procedures if other protective barriers are not in use. Leaded glasses are a powerful tool for reducing the orthopaedic surgeon's lens exposure to radiation during acquisition of common intraoperative fluoroscopic views.

Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

PubMed

Suzuki, Misaki; Tse, Susanna; Hirai, Midori; Kurebayashi, Yoichi

2017-05-09

Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese

PubMed Central

SUZUKI, MISAKI; TSE, SUSANNA; HIRAI, MIDORI; KUREBAYASHI, YOICHI

2016-01-01

Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population. PMID:28490712

The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens.

PubMed

Haeseker, Michiel; Stolk, Leo; Nieman, Fred; Hoebe, Christian; Neef, Cees; Bruggeman, Cathrien; Verbon, Annelies

2013-01-01

The aim of this study was to determine the ciprofloxacin serum concentrations in hospitalized patients and to determine which percentage reached the efficacy target of AUC : MIC > 125. Additionally, the influence of demographic anthropomorphic and clinical parameters on the pharmacokinetics and pharmacodynamics of ciprofloxacin were investigated. In serum of 80 hospitalized patients ciprofloxacin concentrations were measured with reverse phase high performance liquid chromatography with fluorescence detection. The ciprofloxacin dose was 400-1200 mg day(-1) i.v. in two or three doses depending on renal function and causative bacteria. Pharmacokinetic parameters were calculated with maximum a posteriori Bayesian estimation (MW\\PHARM 3.60). A two compartment open model was used. Mean (± SD) age was 66 (± 17) years, the mean clearance corrected for bodyweight was 0.24 l h(-1) kg(-1) and the mean AUC was 49 mg l(-1) h. Ciprofloxacin clearance and thus AUC were associated with both age and serum creatinine. Of all patients, 21% and 75% of the patients, did not reach the proposed ciprofloxacin AUC : MIC > 125 target with MICs of 0.25 and 0.5 mg l(-1), respectively. A computer simulated increase in the daily dose from 800 mg to 1200 mg, decreased these percentages to 1% and 37%, respectively. A substantial proportion of the hospitalized patients did not reach the target ciprofloxacin AUC : MIC and are suboptimally dosed with recommended doses. Taking into account the increasing resistance to ciprofloxacin worldwide, a ciprofloxacin dose of 1200 mg i.v. daily in patients with normal renal function is necessary to reach the targeted AUC : MIC > 125. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Radiation dose produced by patients during radiopharmaceutical incorporation in nuclear medicine diagnostic procedures.

PubMed

Morán, V; Prieto, E; García-García, B; Barbés, B; Ribelles, M J; Richter, J Á; Martí-Climent, J M

2016-01-01

The aim of this study was to assess the dose received by members of the public due to close contact with patients undergoing nuclear medicine procedures during radiopharmaceutical incorporation, and comparing it with the emitted radiation dose when the test was complete, in order to establish recommendations. A prospective study was conducted on 194 patients. H*(10) dose rates were measured at 0.1, 0.5, and 1.0m after the radiopharmaceutical administration, before the image acquisition, and at the end of the nuclear medicine procedure. Effective dose for different close contact scenarios were calculated, according to 95th percentile value (bone scans) and the maximum value (remaining tests). During the radiopharmaceutical incorporation, a person who stays with another injected patient in the same waiting room may receive up to 0.59 mSv. If the patient had a medical appointment, or went to a restaurant or a coffee shop, members of the public could receive 23, 43, and 22 μSv, respectively. After finishing the procedure, these doses are reduced by a factor 3. In most of the studies, the use of private instead of public transport may reduce the dose by more than a factor 6. It is recommended to increase the distance between the patients during the radiopharmaceutical incorporation and to distribute them according to the diagnostic procedure. Patients should be encouraged to use private instead of public transport. Depending on the number of nuclear medicine outpatients per year attended by a physician, it could be necessary to apply restrictions. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

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

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

PubMed Central

Flaherty, Keith T.; Puzanov, Igor; Kim, Kevin B.; Ribas, Antoni; McArthur, Grant A.; Sosman, Jeffrey A.; O'Dwyer, Peter J.; Lee, Richard J.; Grippo, Joseph F.; Nolop, Keith; Chapman, Paul B.

2013-01-01

Background The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) PMID:20818844

Annual limits on intake (ALI) values in ICRP 61 and 10 CFR Part 20 (1991)

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

Zhu, M.; Kearfott, K.J.

The newest major revision of Nuclear Regulatory Commission`s 10 CFR Part 20 (1991) incorporates the new dose methodology system, revised limits, and improved internal dose computations presented in International Commission on Radiation Protection (ICRP) Publication 30 (1979). A year before the issue of this revised 10 CFR Part 20, the ICRP dispatched Publication 61 (1990). This new ICRP report employed different dose limits, in addition to incorporating more recent biological information and variations in physiological and different tissue weighing factors for various organs. An investigation of the numerical differences in the Annual Limit on Intake (ALI) reported in this moremore » recent international regulations and those of the new regulations was thus undertaken. Overall means, medians, modes, maximum, minimum, and ranges of the percent changes are almost identical for ingestion and inhalation, although the percent difference between 10 CFR and ICRP Publication 61 showed minor differences for individual radionuclides. Approximately 334 of 1,351 radionuclides for inhalation and 173 of 771 radionuclides for ingestion have much less restrictive ALIs in the new ICRP recommendations than in the old, with some of those limits increased by at least a factor of two. Approximately 51% of the radionuclides for ingestion intake and 48% of radionuclides for inhalation intake showed changes of greater than 25%. The radionuclides observed to have much less restrictive ALIs are primarily the radionuclides of thorium, mercury, plutonium, uranium, and americium which have short effective clearance rates. While many countries have already applied the ICRP 61 recommendations to their radiation protection standards, using the ICRP 30 recommendation in the United States does not match the international standards even when the values of the ALIs are adjusted for differences in dose limits.« less

Radiation exposure of contrast-enhanced spectral mammography compared with full-field digital mammography.

PubMed

Jeukens, Cécile R L P N; Lalji, Ulrich C; Meijer, Eduard; Bakija, Betina; Theunissen, Robin; Wildberger, Joachim E; Lobbes, Marc B I

2014-10-01

Contrast-enhanced spectral mammography (CESM) shows promising initial results but comes at the cost of increased dose as compared with full-field digital mammography (FFDM). We aimed to quantitatively assess the dose increase of CESM in comparison with FFDM. Radiation exposure-related data (such as kilovoltage, compressed breast thickness, glandularity, entrance skin air kerma (ESAK), and average glandular dose (AGD) were retrieved for 47 CESM and 715 FFDM patients. All examinations were performed on 1 mammography unit. Radiation dose values reported by the unit were validated by phantom measurements. Descriptive statistics of the patient data were generated using a statistical software package. Dose values reported by the mammography unit were in good qualitative agreement with those of phantom measurements. Mean ESAK was 10.5 mGy for a CESM exposure and 7.46 mGy for an FFDM exposure. Mean AGD for a CESM exposure was 2.80 mGy and 1.55 mGy for an FFDM exposure. Compared with our institutional FFDM, the AGD of a single CESM exposure is increased by 1.25 mGy (+81%), whereas ESAK is increased by 3.07 mGy (+41%). Dose values of both techniques meet the recommendations for maximum dose in mammography.

Analysis of the criteria used by the International Commission on Radiological Protection to justify the setting of numerical protection level values.

PubMed

2006-01-01

This report compiles the various numerical protection level values published by the International Commission on Radiological Protection (ICRP) since its 1990 Recommendations (Publication 60). Several terms are used to denominate the protection levels: individual dose limit, 'maximum' individual dose, dose constraint, exemption level, exclusion level, action level, or intervention level. The reasons provided by the Commission for selecting the associated numerical values is quoted as far as available. In some cases the rationale is not totally explicit in the original ICRP report concerned; in such cases the Task Group that prepared the present report have proposed their own interpretation. Originally, this report was prepared by a Task Group at CEPN, a French research and development center, in behalf of IRSN, a French public expert body engaged in radiological protection and nuclear safety. It is published here with kind permission by CEPN and IRSN.

Pediatric dosimetry for intrapleural lung injections of 32P chromic phosphate

NASA Astrophysics Data System (ADS)

Konijnenberg, Mark W.; Olch, Arthur

2010-10-01

Intracavitary injections of 32P chromic phosphate are used in the therapy of pleuropulmonary blastoma and pulmonary sarcomas in children. The lung dose, however, has never been calculated despite the potential risk of lung toxicity from treatment. In this work the dosimetry has been calculated in target tissue and lung for pediatric phantoms. Pleural cavities were modeled in the Monte Carlo code MCNP within the pediatric MIRD phantoms. Both the depth-dose curves in the pleural lining and into the lung as well as 3D dose distributions were calculated for either homogeneous or inhomogeneous 32P activity distributions. Dose-volume histograms for the lung tissue and isodose graphs were generated. The results for the 2D depth-dose curve to the pleural lining and tumor around the pleural cavity correspond well with the point kernel model-based recommendations. With a 2 mm thick pleural lining, one-third of the lung parenchyma volume gets a dose more than 30 Gy (V30) for 340 MBq 32P in a 10 year old. This is close to lung tolerance. Younger children will receive a larger dose to the lung when the lung density remains equal to the adult value; the V30 relative lung volume for a 5 year old is 35% at an activity of 256 MBq and for a 1 year old 165 MBq yields a V30 of 43%. At higher densities of the lung tissue V30 stays below 32%. All activities yield a therapeutic dose of at least 225 Gy in the pleural lining. With a more normal pleural lining thickness (0.5 mm instead of 2 mm) the injected activities will have to be reduced by a factor 5 to obtain tolerable lung doses in pediatric patients. Previous dosimetry recommendations for the adult apply well down to lung surface areas of 400 cm2. Monte Carlo dosimetry quantitates the three-dimensional dose distribution, providing a better insight into the maximum tolerable activity for this therapy.

Pharmacokinetic interaction of enrofloxacin/trimethoprim combination following single-dose intraperitoneal and oral administration in rats.

PubMed

Choi, Myung-Jin; Yohannes, Sileshi Belew; Lee, Seung-Jin; Damte, Dereje; Kim, Jong-Choon; Suh, Joo-Won; Park, Seung-Chun

2014-03-01

The pharmacokinetic interaction of enrofloxacin and trimethoprim was evaluated after single-dose intraperitoneal or oral co-administration in rats. Plasma concentrations of the two drugs were determined by high-performance liquid chromatography. Following intraperitoneal combination, a significant (P < 0.05) increase in mean values of plasma half-life (t 1/2) and maximum plasma concentration (C max) was observed for enrofloxacin and trimethoprim, respectively. There was a significant (P < 0.05) increase in mean values of area under the plasma drug concentration versus time from time zero to infinity (AUC0-∞) and C max between combined oral doses (10, 30 and 100 mg/kg) of both antibacterial drugs. Also, after oral conjugation a significant difference in mean values of MRT0-∞ was observed between lower (10 mg/kg) and higher (100 mg/kg) doses of both drugs. A significant increase in pharmacokinetic parameters of both drugs in combined intraperitoneal and oral doses indicated pharmacokinetic interaction of enrofloxacin and trimethoprim. Further study is recommended in other species of animals.

Methamphetamine and amphetamine isomer concentrations in human urine following controlled Vicks VapoInhaler administration.

PubMed

Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; Flegel, Ron; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

2014-10-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography-mass spectrometry (GC-MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC-MS method with >99% purity of R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC-MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0-1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤ 4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT(®) II Plus, KIMS(®) II and DRI(®) had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT(®) II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers.

PubMed

Kropeit, D; Johnson, M; Cawello, W; Rudd, G D; Horstmann, R

2015-11-01

To determine whether lacosamide prolongs the corrected QT interval (QTc). In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of lens dose from anterior electron beams: comparison of Pinnacle and Gafchromic EBT3 film

PubMed Central

Wronski, Matt; Yeboah, Collins

2015-01-01

Lens dose is a concern during the treatment of facial lesions with anterior electron beams. Lead shielding is routinely employed to reduce lens dose and minimize late complications. The purpose of this work is twofold: 1) to measure dose profiles under large‐area lead shielding at the lens depth for clinical electron energies via film dosimetry; and 2) to assess the accuracy of the Pinnacle treatment planning system in calculating doses under lead shields. First, to simulate the clinical geometry, EBT3 film and 4 cm wide lead shields were incorporated into a Solid Water phantom. With the lead shield inside the phantom, the film was positioned at a depth of 0.7 cm below the lead, while a variable thickness of solid water, simulating bolus, was placed on top. This geometry was reproduced in Pinnacle to calculate dose profiles using the pencil beam electron algorithm. The measured and calculated dose profiles were normalized to the central‐axis dose maximum in a homogeneous phantom with no lead shielding. The resulting measured profiles, functions of bolus thickness and incident electron energy, can be used to estimate the lens dose under various clinical scenarios. These profiles showed a minimum lead margin of 0.5 cm beyond the lens boundary is required to shield the lens to ≤10% of the dose maximum. Comparisons with Pinnacle showed a consistent overestimation of dose under the lead shield with discrepancies of ∼25% occurring near the shield edge. This discrepancy was found to increase with electron energy and bolus thickness and decrease with distance from the lead edge. Thus, the Pinnacle electron algorithm is not recommended for estimating lens dose in this situation. The film measurements, however, allow for a reasonable estimate of lens dose from electron beams and for clinicians to assess the lead margin required to reduce the lens dose to an acceptable level. PACS number(s): 87.53.Bn, 87.53.Kn, 87.55.‐x, 87.55.D‐ PMID:27074448

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-03-08

In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Persistence of two neem formulations on peach leaves and fruit: effect of the distribution.

PubMed

Sarais, Giorgia; Angioni, Alberto; Lai, Francesco; Cabras, Paolo; Caboni, Pierluigi

2009-03-25

Persistence of azadirachtins (A+B) and of the other limonoids (nimbin, salannin, deacetylnimbin, and deacetylsalannin) on peach leaves and fruits was studied using a commercial formulation (form. C) compared with an experimental formulation (form. E) prepared with coformulations allowed in organic culture. Field experiments were carried out using three concentrations: 1x, 5x, and 10x the dose recommended by the manufacturer. The EU maximum residue level (MRL) in fruits and vegetables for azadirachtin A is 1 mg/kg with a preharvest interval (PHI) of 3 days. At the recommended dose, azadirachtin A residue on fruits was not detectable (LOQ < 0.8 microg/kg). After field treatment at the 5x concentration, azadirachtoids were found with 22% in the epicuticular waxes and the remaining 78% on the fruit surface. No residues were found in the fruit pulp. The experimental formulation (E) produced lower residues on leaves and fruit compared with the commercial formulation (C), although formulation E showed greater stability. This is probably due to the amount of the active ingredients that diffuse into the epicuticular wax layer thus enhancing photostability of azadirachtoids.

Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

PubMed Central

Infante, Jeffrey; Janku, Filip; Jones, Suzanne; Nguyen, Ly M.; Burris, Howard; Naing, Aung; Bauer, Todd M.; Piha-Paul, Sarina; Johnson, Faye M.; Kurzrock, Razelle; Golden, Lisa; Hynes, Scott; Lin, Ji; Lin, Aimee Bence; Bendell, Johanna

2016-01-01

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC. PMID:27044938

Interplay effect on a 6-MV flattening-filter-free linear accelerator with high dose rate and fast multi-leaf collimator motion treating breast and lung phantoms.

PubMed

Netherton, Tucker; Li, Yuting; Nitsch, Paige; Shaitelman, Simona; Balter, Peter; Gao, Song; Klopp, Ann; Muruganandham, Manickam; Court, Laurence

2018-06-01

Using a new linear accelerator with high dose rate (800 MU/min), fast MLC motions (5.0 cm/s), fast gantry rotation (15 s/rotation), and 1 cm wide MLCs, we aimed to quantify the effects of complexity, arc number, and fractionation on interplay for breast and lung treatments under target motion. To study lung interplay, eight VMAT plans (1-6 arcs) and four-nine-field sliding-window IMRT plans varying in complexity were created. For the breast plans, four-four-field sliding-window IMRT plans were created. Using the Halcyon 1.0 linear accelerator, each plan was delivered five times each under sinusoidal breathing motion to a phantom with 20 implanted MOSFET detectors; MOSFET dose (cGy), delivery time, and MU/cGy values were recorded. Maximum and mean dose deviations were calculated from MOSFET data. The number of MOSFETs with at least 19 of 20 detectors agreeing with their expected dose within 5% per fraction was calculated across 10 6 iterations to model dose deviation as function of fraction number for all plan variants. To put interplay plans into clinical context, additional IMRT and VMAT plans were created and delivered for the sites of head and neck, prostate, whole brain, breast, pelvis, and lung. Average modulation and interplay effect were compared to those from conventional linear accelerators, as reported from previous studies. The mean beam modulation for plans created for the Halcyon 1.0 linear accelerator was 2.9 MU/cGy (two- to four-field IMRT breast plans), 6.2 MU/cGy (at least five-field IMRT), and 3.6 MU/cGy (four-arc VMAT). To achieve treatment plan objectives, Halcyon 1.0 VMAT plans require more arcs and modulation than VMAT on conventional linear accelerators. Maximum and mean dose deviations increased with increasing plan complexity under tumor motion for breast and lung treatments. Concerning VMAT plans under motion, maximum, and mean dose deviations were higher for one arc than for two arcs regardless of plan complexity. For plan variants with maximum dose deviations greater than 3.7%, dose deviation as a function of fraction number was protracted. For treatments on the Halcyon 1.0 linear accelerator, the convergence of dose deviation with fraction number happened more slowly than reported for conventional linear accelerators. However, if plan complexity is reduced for IMRT and if tumor motion is less than ~10-mm, interplay is greatly reduced. To minimize dose deviations across multiple fractions for dynamic targets, we recommend limiting treatment plan complexity and avoiding one-arc VMAT on the Halcyon 1.0 linear accelerator when interplay is a concern. © 2018 American Association of Physicists in Medicine.

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Phase I study of stereotactic body radiation therapy for centrally located stage IA non-small cell lung cancer (JROSG10-1).

PubMed

Kimura, Tomoki; Nagata, Yasushi; Harada, Hideyuki; Hayashi, Shinya; Matsuo, Yukinori; Takanaka, Tsuyoshi; Kokubo, Masaki; Takayama, Kenji; Onishi, Hiroshi; Hirakawa, Koichi; Shioyama, Yoshiyuki; Ehara, Takeshi

2017-10-01

To investigate the maximum tolerated dose (MTD) and recommended dose (RD) of stereotactic body radiation therapy (SBRT) for centrally located stage IA non-small cell lung cancer (NSCLC). Five dose levels, ranging from of 52 to 68 Gy in eight fractions, were determined; the treatment protocol began at 60 Gy (level 3). Each dose level included 10 patients. Levels 1-2 were indicated if more than four patients exhibited dose-limiting toxicity (DLT), which was defined as an occurrence of a grade 3 (or worse) adverse effect within 12 months after SBRT initiation. MTD was defined as the lowest dose level at which more than four patients exhibited DLT. Ten patients were enrolled in the level 3 study. One patient was considered unsuitable because of severe emphysema. Therefore, nine patients were evaluated and no patient exhibited DLT. The level 3 results indicated that we should proceed to level 4 (64 Gy). However, due to the difficulty involved in meeting the dose constraints, further dose escalation was not feasible and the MTD was found to be 60 Gy. The RD of SBRT for centrally located stage IA NSCLC was 60 Gy in eight fractions.

Public member dose assessment of Bushehr Nuclear Power Plant under normal operation by modeling the fallout from stack using the HYSPLIT atmospheric dispersion model.

PubMed

Zali, A; Shamsaei Zafarghandi, M; Feghhi, S A; Taherian, A M

2017-05-01

In this work, public dose resulting from fission products released from Bushehr Nuclear Power Plant (BNPP) under normal operation is assessed. Due to the long range transport of radionuclides in this work (80 km) and considering terrain and meteorological data, HYbrid Single-Particle Lagrangian Integrated Trajectory (HYsplit) model, which uses three dimensional long-range numerical models, has been employed to calculate atmospheric dispersion. Annual effective dose calculation is carried out for inhalation, ingestion, and external exposure pathways in 16directions and within 80 km around the site for representative person. The results showed the maximum dose of inhalation and external exposure for adults is 3.8 × 10 -8 Sv/y in the SE direction and distance of 600 m from the BNPP site which is less than ICRP 103 recommended dose limit (1 mSv). Children and infants' doses are higher in comparison with adults, although they are less than 1 mSv. Ingestion dose percentage in the total dose is less than 0.1%. The results of this study underestimate the Final Safety Analysis Report ofBNPP-1 (FSAR)data. Copyright © 2017 Elsevier Ltd. All rights reserved.

Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

PubMed

Thompson, Gary A; Solomon, Gail; Albrecht, Helmut H; Reitberg, Donald P; Guenin, Eric

2016-07-01

This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Dosimetric distribution of the surroundings of different dental crowns and implants during LINAC photon irradiation

NASA Astrophysics Data System (ADS)

Chang, Kwo-Ping; Lin, Wei-Ting; Shiau, An-Cheng; Chie, Yu-Huang

2014-11-01

In radiotherapy of the head and neck, metal dentures or implants will increase the risk of complications such as mucositis and osteoradionecrosis. The aim of this study is to explore the back scatter effect of commercially available dental metal alloys on the mucosa and bone under 6 MV LINAC irradiation. The Monte Carlo method has been employed to calculate the dose distribution in the heterogeneous media of the designed oral phantom based on the oral cavity geometry. Backscatter dose increases up to a maximum of 53%, and is primarily dependent on the physical density and electron density of the metal crown alloy. Ceramic metal crowns have been quantified to increase backscatter dose up to 10% on mucosa. Ceramic serves as an inherent shield of mucosa. The backscatter dose will be greater for a small field size if the tumor is located at a deeper region. Titanium implants will increase the backscatter dose by 13% to bone but will not affect the mucosa. QC-20 (polystyrene resin) is recommended as a shield material (3 mm) to eliminate the backscatter dose on mucosa due to the high density metals.

Intra-arterial 4-hydroxyanisole chemotherapy for locally recurrent malignant melanoma: a re-appraisal.

PubMed

Belcher, H J; Nizam, M; O'Neill, T J

1992-04-01

Ten female patients with recurrent cutaneous malignant melanoma (MM) confined to the lower limb were treated with 4-hydroxyanisole (4HA) infused intra-arterially. 10 g of 4HA was infused twice per day up to a maximum dose of 80 g. 4HA infusion caused significant alterations in liver function which precluded completion of the treatment regimen in all but two patients. No tumour regression was observed in any patient. We cannot recommend this technique for managing patients with recurrent cutaneous MM.

Measurement of doses to the extremities of nuclear medicine staff

NASA Astrophysics Data System (ADS)

Shousha, Hany A.; Farag, Hamed; Hassan, Ramadan A.

2010-01-01

Medical uses of ionizing radiation now represent>95% of all man-made radiation exposure, and is the largest single radiation source after natural background radiation. Therefore, it is important to quantify the amount of radiation received by occupational individuals to optimize the working conditions for staff, and further, to compare doses in different departments to ensure compatibility with the recommended standards. For some groups working with unsealed sources in nuclear medicine units, the hands are more heavily exposed to ionizing radiation than the rest of the body. A personal dosimetry service runs extensively in Egypt. But doses to extremities have not been measured to a wide extent. The purpose of this study was to investigate the equivalent radiation doses to the fingers for five different nuclear medicine staff occupational groups for which heavy irradiation of the hands was suspected. Finger doses were measured for (1) nuclear medicine physicians, (2) technologists, (3) nurses and (4) physicists. The fifth group contains three technicians handling 131I, while the others handled 99mTc. Each staff member working with the radioactive material wore two thermoluminescent dosimeters (TLDs) during the whole testing period, which lasted from 1 to 4 weeks. Staff performed their work on a regular basis throughout the month, and mean annual doses were calculated for these groups. Results showed that the mean equivalent doses to the fingers of technologist, nurse and physicist groups were 30.24±14.5, 30.37±17.5 and 16.3±7.7 μSv/GBq, respectively. Equivalent doses for the physicians could not be calculated per unit of activity because they did not handle the radiopharmaceuticals directly. Their doses were reported in millisieverts (mSv) that accumulated in one week. Similarly, the dose to the fingers of individuals in Group 5 was estimated to be 126.13±38.2 μSv/GBq. The maximum average finger dose, in this study, was noted in the technologists who handled therapeutic 131I (2.5 mSv). In conclusion, the maximum expected annual dose to extremities is less than the annual limit (500 mSv/y).

[Comparative toxicity of photosensitizers in varying destruction].

PubMed

Sinitsina, O O; Zholdakova, Z I; Poliakova, E E; Golovach, E N; Sycheva, L P; Beliaeva, N N; Kuznetsova, N A

2007-01-01

The toxicity of the photosensitizers proflavine acetate (PA) versus methylene blue (MB) was evaluated during their varying destruction. Under the influence of visible light, a partial (25%) transformation of the photosensitizers was shown to be attended by their enhanced toxicity and 100% destruction of the parent substances caused a reduction in their hazard. PA and its phototransformation products mainly affect the antiperoxide protection system and the structural and functional states of the liver, kidney, and duodenum. The maximum noneffective dose is 0.002 mg/kg. The possibility of using PA for water disinfection depends on the ratio of safe and effective concentrations. A partial (25%) MB destruction products cause mutagenic effects; the permissible dose of the mutagen is 0.00025 mg/kg. MB is not recommended for disinfection of all types of waters.

Hypothyroidism as a Consequence of Intensity-Modulated Radiotherapy With Concurrent Taxane-Based Chemotherapy for Locally Advanced Head-and-Neck Cancer

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

Diaz, Roberto; Jaboin, Jerry J.; Morales-Paliza, Manuel

Purpose: To conduct a retrospective review of 168 consecutively treated locally advanced head-and-neck cancer (LAHNC) patients treated with intensity-modulated radiotherapy (IMRT)/chemotherapy, to determine the rate and risk factors for developing hypothyroidism. Methods and Materials: Intensity-modulated radiotherapy was delivered in 33 daily fractions to 69.3 Gy to gross disease and 56.1 Gy to clinically normal cervical nodes. Dose-volume histograms (DVHs) of IMRT plans were used to determine radiation dose to thyroid and were compared with DVHs using conventional three-dimensional radiotherapy (3D-RT) in 10 of these same patients randomly selected for replanning and with DVHs of 16 patients in whom the thyroidmore » was intentionally avoided during IMRT. Weekly paclitaxel (30 mg/m{sup 2}) and carboplatin area under the curve-1 were given concurrently with IMRT. Results: Sixty-one of 128 evaluable patients (47.7%) developed hypothyroidism after a median of 1.08 years after IMRT (range, 2.4 months to 3.9 years). Age and volume of irradiated thyroid were associated with hypothyroidism development after IMRT. Compared with 3D-RT, IMRT with no thyroid dose constraints resulted in significantly higher minimum, maximum, and median dose (p < 0.0001) and percentage thyroid volume receiving 10, 20, and 60 Gy (p < 0.05). Compared with 3D-RT, IMRT with thyroid dose constraints resulted in lower median dose and percentage thyroid volume receiving 30, 40, and 50 Gy (p < 0.005) but higher minimum and maximum dose (p < 0.005). Conclusions: If not protected, IMRT for LAHNC can result in higher radiation to the thyroid than with conventional 3D-RT. Techniques to reduce dose and volume of radiation to thyroid tissue with IMRT are achievable and recommended.« less

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

SU-F-T-537: Prone Breast Accelerated Partial Breast Irradiation Using Non-Coplanar Volumetric Arc Therapy

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

Beninati, G; Barbiere, J; Godfrey, L

2016-06-15

Purpose: To demonstrate that Volumetric Modulated Arc Therapy (VMAT) can be an alternative technique to Brachytherapy Accelerated Partial Breast Irradiation (APBI) for treating large breasted women. The non-coplanar VMAT technique uses a commercially available couch and a small number of angles. This technique with the patient in the prone position can reduce high skin and critical structure doses in large breasted women, which are usually associated with Brachytherapy APBI. Methods: Philips Pinnacle treatment planning system with Smart Arc was used to plan a left sided laterally located excision cavity on a standard prone breast patient setup. Three thirty-degree arcs enteredmore » from the lateral side at respective couch angles of 345, 0, and 15 degrees. A fourth thirty degree arc beam entered from the medial side at a couch angle of 0 degrees. The arcs were selected to avoid critical structures as much as possible. A test run was then performed to verify that the beams did not collide with the patient nor support structures. NSABP B-39/RTOG 0413 protocol guidelines were used for dose prescription, normal tissue, and target definition. Results: Dose Volume Histogram analysis indicated that all parameters were equal or better than RTOG recommendations. Of particular note regarding the plan quality:1.(a) For a prescribed dose of 3850cGy the PTV-EVAL target volume receiving 100 percent of the dose(V100) was 93; protocol recommendation is V90 > 90 percent. (b) Maximum dose was 110 percent versus the allowed 120 percent .2. Uninvolved percentage of normal breast V100 and V50 were 17 and 47 versus allowed 35 and 60 percent respectively.3. For the skin, V100 was 5.7cc and the max dose to 0.1 cc was 4190cGy. Conclusion: Prone Breast non-coplanar VMAT APBI can achieve better skin cosmesis and lower critical structure doses than Brachytherapy APBI.« less

Dosimetry of intracavitary placements for uterine and cervical carcinoma: results of orthogonal film, TLD, and CT-assisted techniques.

PubMed

Kapp, K S; Stuecklschweiger, G F; Kapp, D S; Hackl, A G

1992-07-01

A total of 720 192Ir high-dose-rate (HDR) applications in 331 patients with gynecological tumors were analyzed to evaluate the dose to normal tissues from brachytherapy. Based on the calculations of bladder base, bladder neck, and rectal doses derived from orthogonal films the planned tumor dose or fractionation was altered in 20.4% of intracavitary placements (ICP) for cervix carcinoma and 9.2% of ICP for treatment of the vaginal vault. In 13.8% of intracervical and 8.1% of intravaginal treatments calculated doses to both the bladder and rectum were greater than or equal to 140% of the initially planned dose fraction. Doses at the bladder base were significantly higher than at the bladder neck (p less than 0.001). In 17.5% of ICP the dose to the bladder base was at least twice as high as to the bladder neck. The ratio of bladder base dose to the bladder neck was 1.5 (+/- 1.19 SD) for intracervical and 1.46 (+/- 1.14 SD) for intravaginal applications. The comparison of calculated doses from orthogonal films with in-vivo readings showed a good correlation of rectal doses with a correlation coefficient factor of 0.9556. CT-assisted dosimetry, however, revealed that the maximum doses to bladder and rectum were generally higher than those obtained from films with ratios of 1-1.7 (average: 1.44) for the bladder neck, 1-5.4 (average: 2.42) for the bladder base, and 1.1-2.7 (average: 1.37) for the rectum. When doses to the specified reference points of bladder neck and rectum from orthogonal film dosimetry were compared with the corresponding points on CT scans, similar values were obtained for both methods with a maximum deviation of +/- 10%. Despite the determination of multiple reference points our study revealed that this information was inadequate to predict doses to the entire rectum and bladder. If conventional methods are used for dosimetry it is recommended that doses to the bladder base should be routinely calculated, since single point measurements at the bladder neck seriously underestimate the dose to the bladder. Also the rectal dose should be determined at several points over the length of the implant due to the wide range of anatomic variations possible.

Comparison of 2D and 3D Imaging and Treatment Planning for Postoperative Vaginal Apex High-Dose Rate Brachytherapy for Endometrial Cancer

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

Russo, James K.; Armeson, Kent E.; Richardson, Susan, E-mail: srichardson@radonc.wustl.edu

2012-05-01

Purpose: To evaluate bladder and rectal doses using two-dimensional (2D) and 3D treatment planning for vaginal cuff high-dose rate (HDR) in endometrial cancer. Methods and Materials: Ninety-one consecutive patients treated between 2000 and 2007 were evaluated. Seventy-one and 20 patients underwent 2D and 3D planning, respectively. Each patient received six fractions prescribed at 0.5 cm to the superior 3 cm of the vagina. International Commission on Radiation Units and Measurements (ICRU) doses were calculated for 2D patients. Maximum and 2-cc doses were calculated for 3D patients. Organ doses were normalized to prescription dose. Results: Bladder maximum doses were 178% ofmore » ICRU doses (p < 0.0001). Two-cubic centimeter doses were no different than ICRU doses (p = 0.22). Two-cubic centimeter doses were 59% of maximum doses (p < 0.0001). Rectal maximum doses were 137% of ICRU doses (p < 0.0001). Two-cubic centimeter doses were 87% of ICRU doses (p < 0.0001). Two-cubic centimeter doses were 64% of maximum doses (p < 0.0001). Using the first 1, 2, 3, 4 or 5 fractions, we predicted the final bladder dose to within 10% for 44%, 59%, 83%, 82%, and 89% of patients by using the ICRU dose, and for 45%, 55%, 80%, 85%, and 85% of patients by using the maximum dose, and for 37%, 68%, 79%, 79%, and 84% of patients by using the 2-cc dose. Using the first 1, 2, 3, 4 or 5 fractions, we predicted the final rectal dose to within 10% for 100%, 100%, 100%, 100%, and 100% of patients by using the ICRU dose, and for 60%, 65%, 70%, 75%, and 75% of patients by using the maximum dose, and for 68%, 95%, 84%, 84%, and 84% of patients by using the 2-cc dose. Conclusions: Doses to organs at risk vary depending on the calculation method. In some cases, final dose accuracy appears to plateau after the third fraction, indicating that simulation and planning may not be necessary in all fractions. A clinically relevant level of accuracy should be determined and further research conducted to address this issue.« less

Range and trend of expected toxicity level (ETL) in standard A + B designs: a report from the Children's Oncology Group.

PubMed

Chen, Zhengjia; Krailo, Mark D; Sun, Junfeng; Azen, Stanley P

2009-03-01

The traditional algorithm-based 3+3 designs are most widely used for their practical simplicity in phase I clinical trials. At early stage, a common belief was that the expected toxicity level (ETL) at the maximum tolerated dose (MTD) should be 33% [Storer, B. Design and analysis of phase I clinical trials. Biometrics 1989;45;925-937, Gorden, N., Willson, J. Using toxicity grades in the design and analysis of cancer phase I clinical trials. Statistics in Medicine 1992; 11: 2063-2075, Mick, R. Phase I Clinical Trial Design. In Schilsky, R., Milano, G., Ratain, M., eds. Principles of Antineoplastic Drug Development and Pharmacology New York, NY: Marcel Dekker, 1996; 29-36]. Recently, Kang and Ahn [Kang, S., Ahn, C. The expected toxicity rate at the maximum tolerated dose in the standard phase I cancer clinical trial design. Drug Information Journal 2001; 35:1189-1199, Kang, S., Ahn, C. An investigation of the traditional algorithm-based designs for phase I cancer clinical trials. Drug Information Journal 2002; 36:865-873] found that the ETL is between 17% and 21% and He et al [He, W., Liu, J., Binkowitz, B., Quan, H. A model-based approach in the estimation of the maximum tolerated dose in phase I cancer clinical trials. Statistics in Medicine 2006; 25(12):2027-42] further reported that the ETL ranges from 19% to 24%. However they only investigated designs where the number of dose levels was at most 20. It has practical significance in designing and conducting phase I clinical trial to definitely assess the full range and trend of ETL by all possible number of tested dose levels in traditional algorithm-based A+B designs, especially 3+3 designs. In this simulation study, we originally find that the ETL decreases monotonically from about 30% to 0% as the number of dose levels increase from 3 to infinity, which will correct the inaccuracy in the common belief among phase I trial investigators. To help better design and conduct phase I trials, we create a table as a reference for the association between ETL and number of dose levels considered in a design when the exact shape of the dose-toxicity relationship is not well understood. We conclude that the number of specified dose levels is an important factor affecting substantially the ETL at MTD and recommend that fewer than 20 dose levels be designated.

Estimates of internal-dose equivalent from inhalation and ingestion of selected radionuclides

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

Dunning, D.E.

1982-01-01

This report presents internal radiation dose conversion factors for radionuclides of interest in environmental assessments of nuclear fuel cycles. This volume provides an updated summary of estimates of committed dose equivalent for radionuclides considered in three previous Oak Ridge National Laboratory (ORNL) reports. Intakes by inhalation and ingestion are considered. The International Commission on Radiological Protection (ICRP) Task Group Lung Model has been used to simulate the deposition and retention of particulate matter in the respiratory tract. Results corresponding to activity median aerodynamic diameters (AMAD) of 0.3, 1.0, and 5.0 ..mu..m are given. The gastorintestinal (GI) tract has been representedmore » by a four-segment catenary model with exponential transfer of radioactivity from one segment to the next. Retention of radionuclides in systemic organs is characterized by linear combinations of decaying exponential functions, recommended in ICRP Publication 30. The first-year annual dose rate, maximum annual dose rate, and fifty-year dose commitment per microcurie intake of each radionuclide is given for selected target organs and the effective dose equivalent. These estimates include contributions from specified source organs plus the systemic activity residing in the rest of the body; cross irradiation due to penetrating radiations has been incorporated into these estimates. 15 references.« less

Can we achieve a radionuclide radiation dose equal to or less than that of 99mTc-hydroxymethane diphosphonate bone scintigraphy with a low-dose 18F-sodium fluoride time-of-flight PET of diagnostic quality?

PubMed

Ohnona, Jessica; Michaud, Laure; Balogova, Sona; Paycha, Frédéric; Nataf, Valérie; Chauchat, Paul; Talbot, Jean-Noël; Kerrou, Khaldoun

2013-05-01

18F-Sodium fluoride is a bone tracer with a high signal-to-noise ratio, but its dosimetry is higher than that of 99mTc-labeled phosphonates at the recommended activities. The study's purpose was to determine whether the reduction by half of F-sodium fluoride-injected activity, mimicked by a short-timed reconstruction image, simulating a total dose less than or equal to that of 99mTc-hydroxymethane diphosphonate scintigraphy, had an impact on the accuracy of PET semiquantitative measurements and image quality. Whole-body time-of-flight 18F-sodium fluoride PET/computed tomography (CT) images were acquired prospectively from 40 adult patients for detection of bone metastases. 18F-Sodium fluoride was administered according to the European Association of Nuclear Medicine (EANM) and Society of Nuclear Medicine (SNM) practice guidelines. From the acquired 1 min/bed position list-mode data, 30-s reconstructions were extracted. Measurements of maximum standard uptake value were recorded with a region of interest applied to the same location on the 1-min and 30-s images, which were displayed side by side, and were analyzed using Bland-Altman plots. A masked reading was performed by two senior nuclear medicine physicians who counted the foci of visually increased uptake. Bland-Altman plots showed an excellent agreement between the maximum standard uptake value measurements of the 60- and 30-s images. The paired Wilcoxon test results between the corresponding 60- and 30-s images read by masked readers A and B were not significant (P=0.15 and 0.19, respectively). Reducing acquisition duration by half or injecting half of the activity recommended by the EANM and SNM practice guidelines can lead to 18F-sodium fluoride time-of-flight PET images of diagnostic quality, achieving a radiation dose less than or equal to that of 99mTc-labeled phosphonates.

Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis: I. Reproductive and Developmental Toxicity Studies.

PubMed

Ciaravino, Vic; Coronado, Dina; Lanphear, Cheryl; Hoberman, Alan; Chanda, Sanjay

2016-09-01

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively. © The Author(s) 2016.

Oral penicillin prescribing for children in the UK: a comparison with BNF for Children age-band recommendations

PubMed Central

Saxena, Sonia; Ismael, Zareen; Murray, Macey L; Barker, Charlotte; Wong, Ian CK; Sharland, Mike; Long, Paul F

2014-01-01

Background The British National Formulary for Children (BNFC) recommends dosing oral penicillins according to age-bands, weight-bands, or weight-based calculations. Because of the rising prevalence of childhood obesity, age-band-based prescribing could lead to subtherapeutic dosing. Aim To investigate actual oral penicillin prescribing by GPs in the UK with reference to the current BNFC age-band recommendations. Design and setting Descriptive analysis of UK prescriptions in the 2010 IMS Disease-Analyzer database (IMS-DA). Method A detailed database analysis was undertaken of oral penicillin prescriptions for 0–18 year olds from the 2010 IMS-DA. The prescription analysis included all available data on formulation, strength (mg), prescription quantity unit, package size, prescribed quantity, and volume. Results Considering amoxicillin alone, no infants (aged <1 year) were prescribed the BNFC 2011 edition recommended unit dose (62.5 mg), while the majority received double the dose (125 mg); among children aged 1–5 years, 96% were prescribed the recommended unit dose (125 mg), but 40% of 6–12 year olds and 70% of 12–18 year olds were prescribed unit doses below the BNFC recommendations. For otitis media, only those children aged <1 year received the recommended dose of amoxicillin (40–90 mg/kg/day). Similar variations in dosing across age-bands were observed for phenoxymethylpenicillin and flucloxacillin. Conclusion There is wide variation in the dosing of penicillins for children in UK primary care, with very few children being prescribed the current national recommended doses. There is an urgent need to review dosing guidelines, in relation to the weights of children today. PMID:24686886

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...

Overview of extended release tacrolimus in solid organ transplantation

PubMed Central

Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

2016-01-01

Tacrolimus (Prograf©, Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf©, Astagraf XL©) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient’s due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher. PMID:27011912

Overview of extended release tacrolimus in solid organ transplantation.

PubMed

Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

2016-03-24

Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.

SU-E-J-53: Dosimetric Evaluation at Volumetric Modulated Arc Therapy for Treatment of Prostate Cancer Using Single Or Double Arcs

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

Silva, D; Salmon, H; Pavan, G

2014-06-01

Purpose: Evaluate and compare retrospective prostate treatment plan using Volumetric Modulated Arc Therapy (RapidArc™ - Varian) technique with single or double arcs at COI Group. Methods: Ten patients with present prostate and seminal vesicle neoplasia were replanned as a target treatment volume and a prescribed dose of 78 Gy. A baseline planning, using single arc, was developed for each case reaching for the best result on PTV, in order to minimize the dose on organs at risk (OAR). Maintaining the same optimization objectives used on baseline plan, two copies for optimizing single and double arcs, have been developed. The plansmore » were performed with 10 MV photon beam energy on Eclipse software, version 11.0, making use of Trilogy linear accelerator with Millenium HD120 multileaf collimator. Comparisons on PTV have been performed, such as: maximum, minimum and mean dose, gradient dose, as well as the quantity of monitor units, treatment time and homogeneity and conformity index. OARs constrains dose have been evaluated, comparing both optimizations. Results: Regarding PTV coverage, the difference of the minimum, maximum and mean dose were 1.28%, 0.7% and 0.2% respectively higher for single arc. When analyzed the index of homogeneity found a difference of 0.99% higher when compared with double arcs. However homogeneity index was 0.97% lower on average by using single arc. The doses on the OARs, in both cases, were in compliance to the recommended limits RTOG 0415. With the use of single arc, the quantity of monitor units was 10,1% lower, as well as the Beam-On time, 41,78%, when comparing double arcs, respectively. Conclusion: Concerning the optimization of patients with present prostate and seminal vesicle neoplasia, the use of single arc reaches similar objectives, when compared to double arcs, in order to decrease the treatment time and the quantity of monitor units.« less

SU-C-16A-05: OAR Dose Tolerance Recommendations for Prostate and Cervical HDR Brachytherapy: Dose Versus Volume Metrics

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

Geneser, S; Cunha, J; Pouliot, J

Purpose: HDR brachytherapy consensus dose tolerance recommendations for organs at risk (OARs) remain widely debated. Prospective trials reporting metrics must be sufficiently data-dense to assess adverse affects and identify optimally predictive tolerances. We explore the tradeoffs between reporting dose-metrics versus volume-metrics and the potential impact on trial outcome analysis and tolerance recommendations. Methods: We analyzed 26 prostate patients receiving 15 Gy HDR single-fraction brachytherapy boost to 45 Gy external beam radiation therapy and 28 cervical patients receiving 28 Gy HDR brachytherapy monotherapy in 4 fractions using 2 implants. For each OAR structure, a robust linear regression fit was performed formore » the dose-metrics as a function of the volume-metrics. The plan quality information provided by recommended dose-metric and volume-metric values were compared. Results: For prostate rectal dose, D2cc and V75 lie close to the regression line, indicating they are similarly informative. Two outliers for prostate urethral dose are substantially different from the remaining cohort in terms of D0.1cc and V75, but not D1cc, suggesting the choice of reporting dose metric is essential. For prostate bladder and cervical bladder, rectum, and bowel, dose outliers are more apparent via V75 than recommended dose-metrics. This suggests that for prostate bladder dose and all cervical OAR doses, the recommended volume-metrics may be better predictors of clinical outcome than dose-metrics. Conclusion: For plan acceptance criteria, dose and volume-metrics are reciprocally equivalent. However, reporting dosemetrics or volume-metrics alone provides substantially different information. Our results suggest that volume-metrics may be more sensitive to differences in planned dose, and if one metric must be chosen, volumemetrics are preferable. However, reporting discrete DVH points severely limits the ability to identify planning tolerances most predictive of adverse effects. Thus, we recommend that full OAR DVH reporting be required for future prospective trials.« less

Avoiding OHSS: Controlled Ovarian Low-Dose Stimulation in Women with PCOS.

PubMed

Fischer, D; Reisenbüchler, C; Rösner, S; Haussmann, J; Wimberger, P; Goeckenjan, M

2016-06-01

The polycystic ovary syndrome is a common endocrine disorder which influences outcome and potential risks involved with controlled ovarian stimulation for artificial reproductive techniques (ART). Concrete practical recommendations for the dosage of gonadotropins, the preferred protocol and preventive methods to avoid ovarian hyperstimulation syndrome (OHSS) are lacking. We present retrospective data of 235 individually calculated gonadotropin low-dose stimulations for ART in a single center from 2012 to 2014. Clinical data and outcome parameter of patients diagnosed with PCOS according to Rotterdam criteria (n = 39) were compared with patients without PCOS (n = 196). The starting dose of gonadotropins was individually calculated depending on patients' age, BMI, ovarian reserve, ovarian response in previous cycles, and diagnostic criteria of PCOS. Mean age and duration of infertility did not differ between the groups, whereas mean BMI (p = 0.007) and AMH (p < 0.001) were higher in the PCOS-group. A lower mean FSH-starting and maximum dose was administered to women with PCOS (p < 0.001). The biochemical pregnancy rate of 42.4 % and the clinical pregnancy rate of 32.2 % for PCOS-patients did not differ from those of the control group (42.2 % and 34.4 % respectively). Neither mild, nor moderate or severe manifestation of OHSS occurred significantly more often in patients with PCOS. Our study supports the use of a calculated low-dose FSH-stimulation strategy in ART for patients with PCOS. Further randomized clinical trials should confirm this strategy and lead to define individual risk factors for OHSS, which can be used for recommendation of safer ART-techniques like in vitro maturation.

Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients.

PubMed

Dubinsky, Marla C; Phan, Becky L; Singh, Namita; Rabizadeh, Shervin; Mould, Diane R

2017-01-01

Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego). Dosing was blinded to PK data. Dashboard-based assessments were conducted on de-identified clinical, laboratory, and PK data. Bayesian algorithms were used to forecast individualized troughs and determine optimal dosing to maintain target trough concentrations (3 μg/mL). Dashboard forecasted dosing post-week 14 was compared to actual administered dose and frequency and SOC. Using week 14 clinical data only, the dashboard recommended either a dose or an interval change (<0.5 mg/kg or <1 week difference) in 43/50 patients; only 44% recommended to have SOC dosing. When IFX14 concentration and ADA status were added to clinical data, dose and/or interval changes based on actual dosing were recommended in 48/50 (96%) patients; SOC dosing was recommended in only 11/50 (22%). Dashboard recommended SOC IFX dosing in a minority of patients. Dashboards will be an important tool to individualize IFX dosing to improve treatment durability.

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

PubMed

Bahleda, Rastislav; Grilley-Olson, Juneko E; Govindan, Ramaswamy; Barlesi, Fabrice; Greillier, Laurent; Perol, Maurice; Ray-Coquard, Isabelle; Strumberg, Dirk; Schultheis, Beate; Dy, Grace K; Zalcman, Gérard; Weiss, Glen J; Walter, Annette O; Kornacker, Martin; Rajagopalan, Prabhu; Henderson, David; Nogai, Hendrik; Ocker, Matthias; Soria, Jean-Charles

2017-06-06

To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma.

PubMed

Hu, Wei; Wang, Wei; Yang, Peinong; Zhou, Chao; Yang, Weifang; Wu, Bo; Lu, Hongsheng; Yang, Haihua

2015-01-01

Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patients with NPC. Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated.

Acute and repeated dose (28 days) oral safety studies of an alkoxyglycerol extract from shark liver oil in rats.

PubMed

Anadón, Arturo; Martínez, Maria A; Ares, Irma; Ramos, Eva; Señoráns, Francisco J; Reglero, Guillermo; Torres, Carlos

2010-02-10

Shark liver oil has been used for over 50 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkoxyglycerols. Despite its popularity, there is little published toxicology data on alkoxyglycerols. The toxicity of a supercritical fluid extract of shark liver oil (AKG-1 extract) has been evaluated in acute and repeated dose (28 days) oral toxicity studies in rats at doses of 200 and 100 times the maximum recommended dose by supplement manufacturers in humans, respectively. The AKG-1 extract administered in a single oral gavage dose of 2000 mg kg(-1) of body weight resulted in no adverse events or mortality. The AKG-1 extract administered as a daily dose of 1000 mg kg(-1) of body weight for 28 days by gavage resulted in no adverse effects or mortality. For both studies, no abnormal clinical signs, behavioral changes, body weight changes, or change in food and water consumption occurred. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. It is concluded that the AKG-1 extract is well tolerated in rats at an acute dose of 2000 mg kg(-1) and at a subchronic (28 days) dose of 1000 mg kg(-1).

Maximum dose rate is a determinant of hypothyroidism after 131I therapy of Graves' disease but the total thyroid absorbed dose is not.

PubMed

Krohn, Thomas; Hänscheid, Heribert; Müller, Berthold; Behrendt, Florian F; Heinzel, Alexander; Mottaghy, Felix M; Verburg, Frederik A

2014-11-01

The determinants of successful (131)I therapy of Graves' disease (GD) are unclear. To relate dosimetry parameters to outcome of therapy to identify significant determinants eu- and/or hypothyroidism after (131)I therapy in patients with GD. A retrospective study in which 206 Patients with GD treated in University Hospital between November 1999 and January 2011. All received (131)I therapy aiming at a total absorbed dose to the thyroid of 250 Gy based on pre-therapeutic dosimetry. Post-therapy dosimetric thyroid measurements were performed twice daily until discharge. From these measurements, thyroid (131)I half-life, the total thyroid absorbed dose, and the maximum dose rate after (131)I administration were calculated. In all, 48.5% of patients were hypothyroid and 28.6% of patients were euthyroid after (131)I therapy. In univariate analysis, nonhyperthyroid and hyperthyroid patients only differed by sex. A lower thyroid mass, a higher activity per gram thyroid tissue, a shorter effective thyroidal (131)I half-life, and a higher maximum dose rate, but not the total thyroid absorbed dose, were significantly associated with hypothyroidism. In multivariate analysis, the maximum dose rate remained the only significant determinant of hypothyroidism (P < .001). Maximum dose rates of 2.2 Gy/h and higher were associated with a 100% hypothyroidism rate. Not the total thyroid absorbed dose, but the maximum dose rate is a determinant of successfully achieving hypothyroidism in Graves' disease. Dosimetric concepts aiming at a specific total thyroid absorbed dose will therefore require reconsideration if our data are confirmed prospectively.

Antipsychotic medication and length of stay at a psychiatric maximum-security unit in Norway (1987-2000).

PubMed

Renkel, Sabine; Rasmussen, Kirsten

2006-01-01

The aim of this study was to evaluate psychopharmacological treatment and the length of stay (LOS) of patients with schizophrenia in a maximum-security psychiatric unit. Data were collected from the hospital files of 82 consecutively admitted patients with schizophrenia who were both admitted and discharged between the years 1987 and 2000. Psychotropic medication and LOS at the time of discharge were registered. Ninety-five per cent of the patients received antipsychotic medication. Zuclopenthixol was the most frequent medication, given to 43% of the patients. Antipsychotic polypharmacy was found in 20% of the cases. Twenty-seven per cent of the patients were medicated with doses above the recommended therapeutic dose range. During the study period, there was no change in the administration and number of psychotropics, but there was an increase in the dosage of antipsychotics. However, LOS was unchanged during the same time. This supports other findings, which suggest that there is no clinical benefit of higher antipsychotic dosage. It is suggested that an optimized medication practice could yield beneficiary effects, not only for schizophrenic symptoms, but also for violence in schizophrenic patients.

Experimental determination of the effective point of measurement of cylindrical ionization chambers for high-energy photon and electron beams.

PubMed

Huang, Yanxiao; Willomitzer, Christian; Zakaria, Golam Abu; Hartmann, Guenther H

2010-01-01

Measurements of depth-dose curves in water phantom using a cylindrical ionization chamber require that its effective point of measurement is located at the measuring depth. Recommendations for the position of the effective point of measurement with respect to the central axis valid for high-energy electron and photon beams are given in dosimetry protocols. According to these protocols, the use of a constant shift P(eff) is currently recommended. However, this is still based on a very limited set of experimental results. It is therefore expected that an improved knowledge of the exact position of the effective point of measurement will further improve the accuracy of dosimetry. Recent publications have revealed that the position of the effective point of measurement is indeed varying with beam energy, field size and also with chamber geometry. The aim of this study is to investigate whether the shift of P(eff) can be taken to be constant and independent from the beam energy. An experimental determination of the effective point of measurement is presented based on a comparison between cylindrical chambers and a plane-parallel chamber using conventional dosimetry equipment. For electron beams, the determination is based on the comparison of halfvalue depth R(50) between the cylindrical chamber of interest and a well guarded plane-parallel Roos chamber. For photon beams, the depth of dose maximum, d(max), the depth of 80% dose, d(80), and the dose parameter PDD(10) were used. It was again found that the effective point of measurement for both, electron and photon beams Dosimetry, depends on the beam energy. The deviation from a constant value remains very small for photons, whereas significant deviations were found for electrons. It is therefore concluded that use of a single upstream shift value from the centre of the cylindrical chamber as recommended in current dosimetry protocols is adequate for photons, however inadequate for accurate electron beam dosimetry.

A product of independent beta probabilities dose escalation design for dual-agent phase I trials.

PubMed

Mander, Adrian P; Sweeting, Michael J

2015-04-15

Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

The effectiveness of reducing the daily dose of finasteride in men with benign prostatic hyperplasia

PubMed Central

Sullivan, Michael J; Geller, Jack

2002-01-01

Background Finasteride, a 5 alpha reductase inhibitor, is an established treatment for benign prostatic hyperplasia. The recommended dosage is 5 mg a day, however case reports have show effectiveness with lower doses. The objective of the current study was to determine in men with benign prostatic hyperplasia, previously treated for at least one year with finasteride 5 mg daily, if they will maintain subjective and objective improvements in urinary obstruction when treated with 2.5 mg of finasteride daily for one year. Methods In an open label, prospective study, 40 men with benign prostatic hyperplasia, previously treated for at least one year with 5 mg of finasteride, took 2.5 mg of finasteride daily for one year. Measurements included AUA symptom score, maximum flow rate, voided volume and PSA. Results There were no significant changes in maximum flow rate, voided volume, or AUA symptom score after one year of finasteride 2.5 mg daily therapy. PSA increased significantly, p < .01, after one year of finasteride 2.5 mg daily, 2.0 +1.4 ng/ml, when compared to finasteride 5 mg daily, 1.4+ 1.0 ng/ml. Conclusions The daily dose of finasteride can be reduced to 2.5 mg daily without significant effect on subjective and objective measures of urinary obstruction. Although statistically significant increases in PSA are noted when reducing the daily finasteride dose from 5 mg to 2.5 mg, the clinical significance of a mean .6 ng/ml increase in PSA is questionable. PMID:11818031

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review

PubMed Central

Kurz, A; Farlow, M; Lefèvre, G

2009-01-01

Background: Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer’s disease (AD) (including the USA, Latin America, Europe and Asia). Objectives: To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. Results: The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). Conclusion: The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment. PMID:19392927

Healthcare provider compliance with the 2013 ACC/AHA Adult Cholesterol Guideline recommendation for high-intensity dose statins for patients with coronary artery disease.

PubMed

Housholder-Hughes, Susan D; Martin, Melanie M; McFarland, Marilyn R; Creech, Constance J; Shea, Michael J

Atherosclerotic cardiovascular disease is the foremost cause of death for U.S. adults. The 2013 ACC/AHA Adult Cholesterol Guidelines recommend high-intensity dose statins for individuals with coronary artery disease (CAD). To determine healthcare provider compliance with the Cholesterol Guideline recommendation specific to high-intensity dose statins for patients with CAD. A retrospective chart review was conducted to determine compliance rate. A questionnaire was developed to evaluate healthcare provider beliefs, attitudes, and self-confidence toward this recommendation. Of the 473 patients with CAD, 67% were prescribed a high-intensity dose statin. Patients with non-ST segment myocardial infarction and ST segment myocardial infarction were more likely to be prescribed a high-intensity dose statin versus a moderate or low-intensity dose. Healthcare providers strongly agreed with this guideline recommendation. There exists a dichotomy between intention to prescribe and actual prescribing behaviors of high-intensity dose statin for patients with CAD. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-G-BRB-06: Commissioning and Evaluation of EPID-Based in Vivo Dosimetry Software Using a Tissue-Maximum Ratio Approach

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

Held, M; Cheung, J; Morin, O

Purpose: To commission and evaluate an in vivo EPID-based transit dosimetry software (EPIgray, DOSIsoft, Cachan, France) using simple fields and TG119-based IMRT treatment plans. Methods: EPIgray was commissioned on a Truebeam based on finite tissue-maximum ratio (fTMR) measurements with solid water blocks of thicknesses between 0 and 37 cm. Field sizes varied from 2×2 to 20×20 cm{sup 2}. Subsequently, treatment plans of single and opposed beams with field sizes between 4×4 and 15×15 cm{sup 2} as well as IMRT plans were measured to evaluate the dose reconstruction accuracy. Single field dose predictions were made for anterior-posterior and lateral beams. IMRTmore » plans were created based on TG119 recommendations. The reconstructed dose was compared to the planned dose for selected points at isocenter and away from isocenter. Results: For single square fields, the dose in EPIgray was reconstructed within 3% accuracy at isocenter relative to the planned dose. Similarly, the relative deviation of the total dose was accurately reconstructed within 3% for all IMRT plans with points placed inside a high dose region near the isocenter. Predictions became less accurate than 5% when the evaluation point was outside the majority of IMRT beam segments. Additionally, points 5 cm or more away from the isocenter or within an avoidance structure were predicted less reliably. Conclusion: EPIgray formalism accuracy is adequate for an efficient error detection system. It provides immediate intra-fractional feedback on the delivery of treatment plans without affecting the treatment beam. Besides the EPID, no additional hardware is required, which makes it accessible to all clinics. The software evaluates point dose measurements to verify treatment plan delivery and patient positioning within 5% accuracy, depending on the placement of evaluation points. EPIgray is not intended to replace patient-specific quality assurance but should be utilized as an additional layer of safety for continuous patient treatment verification. This research is supported by DOSIsoft.« less

A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer.

PubMed

Center, Brian; Petty, William Jeffrey; Ayala, Diandra; Hinson, William H; Lovato, James; Capellari, James; Oaks, Timothy; Miller, Antonius A; Blackstock, Arthur William

2010-01-01

Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Growth, yield and tuber quality of Solanum tuberosum L. under supplemental ultraviolet-B radiation at different NPK levels.

PubMed

Singh, S; Kumari, R; Agrawal, M; Agrawal, S B

2011-05-01

In many areas, decreases in the stratospheric ozone layer have resulted in an increase in ultraviolet-B (UV-B, 280-315 nm) radiation reaching the Earth's surface. The present study was conducted to evaluate the interactive effects of supplemental UV-B (sUV-B) and mineral nutrients on a tuber crop, potato (Solanum tuberosum L. var Kufri Badshah), under natural field conditions in a dry tropical environment. The nutrient treatments were the recommended dose of NPK (F(o)), 1.5 times the recommended dose of NPK (F(1)), 1.5 times the recommended dose of N (F(2)) and 1.5 times the recommended dose of K (F(3)). The response of potato plants to sUV-B varied with nutrient treatment and concentration. sUV-B adversely affected growth, yield and quality of tubers, causing an increase in reducing sugars in the tubers and thus reducing the economic value. Growth and fresh weight of tubers was maximal with sUV-B at 1.5 times recommended NPK, but the dry weight of tubers were highest with the recommended NPK dose. Reducing sugar content was lower in potato plants treated with sUV-B and the recommended NPK than with sUV-B and 1.5 times the recommended NPK. This study thus clearly shows that growing potato with 1.5 times the recommended NPK or 1.5 times the recommended dose of N/K does not alleviate the sUV-B induced changes in yield and quality of tubers compared to the recommended NPK dose. © 2010 German Botanical Society and The Royal Botanical Society of the Netherlands.

MicroCT imaging dose to mouse organs using a validated Monte Carlo model of the small animal radiation research platform (SARRP)

NASA Astrophysics Data System (ADS)

Johnstone, Christopher Daniel; Bazalova-Carter, Magdalena

2018-06-01

The goal of this work was to establish imaging dose to mouse organs with a validated Monte Carlo (MC) model of the image-guided Small Animal Radiation Research Platform (SARRP) and to investigate the effect of scatter from the internal walls on animal therapy dose determination. A MC model of the SARRP was built in the BEAMnrc code and validated with a series of homogeneous and heterogeneous phantom measurements. A segmented microCT scan of a mouse was used in DOSXYZnrc to determine mouse organ microCT imaging doses to 15–35 g mice for the SARRP pancake (mouse lying on couch) and standard (mouse standing on couch) imaging geometries for 40–80 kVp tube voltages. Imaging dose for off-center positioning shifts and maintaining image noise across tube voltages were also calculated. Half-value layer (HVL) measurements for the 220 kVp therapy beam in the presence of the SARRP shielding cabinet were modeled in BEAMnrc and compared to the 100 cm source-to-detector distance (SDD) in the scatter free, narrow-beam geometry recommended by the American Association of Physicists in Medicine Task Group 61 (AAPM TG-61). For a 60 kVp, 0.8 mA, and 60 s scan protocol, maximum mean organ imaging doses to boney and non-boney structures were 10.5 cGy and 3.5 cGy, respectively, for an average size 20 g mouse. Current-exposure combinations above 323, 203, 147, 116, and 95 mAs for 40–80 kVp tube voltages, respectively, will increase body doses above 10 cGy. MicroCT mean body dose was 18% lower in pancake compared to standard imaging geometry. An 11% difference in measured HVL at a 50 cm SDD was found compared to MC simulated HVL for the AAPM TG-61 recommended scatter free geometry at a 100 cm SDD. This change in HVL resulted in a 0.5% change in absorbed dose to water calculations for the treatment beam.

Recommended Guidelines for Use of Intravitreal Aflibercept With a Treat-and-Extend Regimen for the Management of Neovascular Age-Related Macular Degeneration in the Asia-Pacific Region: Report From a Consensus Panel.

PubMed

Koh, Adrian; Lanzetta, Paolo; Lee, Won Ki; Lai, Chi-Chun; Chan, Wai-Man; Yang, Chung-May; Cheung, Chui Ming Gemmy

2017-01-01

To summarize recommendations for the use of intravitreal aflibercept with a treat-and-extend regimen to manage neovascular age-related macular degeneration (nAMD) in the Asia-Pacific region. Although anti-vascular endothelial growth factor therapies have improved the quality of life of patients with nAMD, a leading cause of blindness and visual impairment, the high treatment frequency recommended by current guidelines places a significant burden on patients and healthcare providers. Recommended guidelines from a consensus panel. An expert panel formed a consensus on recommendations for use of intravitreal aflibercept as treatment of nAMD in the Asia-Pacific region. After 3 initial monthly doses, treatment interval could be extended by 4-week increments, to a maximum of 12 weeks, in patients with inactive disease. Conversely, in active disease, treatment intervals should be shortened, by 4 weeks, or to 4 weeks in cases of severe recurrence. Treatment could be ceased in patients with stable disease activity after 12 months of treatment at 12-week intervals, as a means to prevent over treatent and lifelong injections. These recommendations could potentially minimize the number of treatments while maintaining efficacy and improve compliance by reducing the number of clinic visits compared with existing recommendations. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Chemoprophylaxis of infective endocarditis.

PubMed

Finch, R

1990-01-01

Infective endocarditis is a serious disease with a continuing mortality of approximately 20%. Risk factors include a variety of congenital and acquired heart diseases. Infection follows an episode of bacteraemia which is most commonly due to oral bacteria, notably streptococci. Less commonly bacteraemia may arise from surgical procedures or diseases of the gastrointestinal and genitourinary tracts or from sepsis at other body sites, including intravenous drug abuse. Several societies and associations have published recommendations for the prevention of bacteraemia in those at risk from endocarditis through the use of perioperative antibiotic chemoprophylaxis. The recommendations are targetted at patients with defined cardiovascular lesions undergoing dental and other procedures known to predictably produce bacteraemia. The major recommendations for standard risk patients undergoing dental procedures without general anaesthesia is high-dose oral penicillin or amoxycillin. Alternative agents include erythromycin and clindamycin. For those requiring general anaesthesia, parenteral regimens are generally recommended although the British Society for Antimicrobial Chemotherapy permits an oral amoxycillin regimen 4 hours preoperatively. For specified gastrointestinal and genitourinary procedures a 2-drug regimen of ampicillin/amoxycillin (or vancomycin for penicillin-allergic patients) plus an aminoglycoside is generally recommended. The emphasis has been to simplify the earlier regimens without compromising the antimicrobial protection with a view to encouraging maximum compliance. The latter continues to be a problem where drug recommendations are either complex or include multiple drug or dosage recommendations. The emphasis on maintaining good dental health is endorsed by all authorities.

[Estimation of Maximum Entrance Skin Dose during Cerebral Angiography].

PubMed

Kawauchi, Satoru; Moritake, Takashi; Hayakawa, Mikito; Hamada, Yusuke; Sakuma, Hideyuki; Yoda, Shogo; Satoh, Masayuki; Sun, Lue; Koguchi, Yasuhiro; Akahane, Keiichi; Chida, Koichi; Matsumaru, Yuji

2015-09-01

Using radio-photoluminescence glass dosimeter, we measured the entrance skin dose (ESD) in 46 cases and analyzed the correlations between maximum ESD and angiographic parameters [total fluoroscopic time (TFT); number of digital subtraction angiography (DSA) frames, air kerma at the interventional reference point (AK), and dose-area product (DAP)] to estimate the maximum ESD in real time. Mean (± standard deviation) maximum ESD, dose of the right lens, and dose of the left lens were 431.2 ± 135.8 mGy, 33.6 ± 15.5 mGy, and 58.5 ± 35.0 mGy, respectively. Correlation coefficients (r) between maximum ESD and TFT, number of DSA frames, AK, and DAP were r=0.379 (P<0.01), r=0.702 (P<0.001), r=0.825 (P<0.001), and r=0.709 (P<0.001), respectively. AK was identified as the most useful parameter for real-time prediction of maximum ESD. This study should contribute to the development of new diagnostic reference levels in our country.

Decrease in varicella incidence after implementation of the 2-dose recommendation for varicella vaccine in New Hampshire.

PubMed

Daly, Elizabeth R; Anderson, Ludmila; Dreisig, John; Dionne-Odom, Jodie

2013-09-01

Varicella is a common infectious disease, for which 2-dose vaccination was recommended in 2006. Varicella case and vaccination data in New Hampshire were analyzed to assess impact of this recommendation on disease incidence and clinical characteristics. Varicella incidence decreased after the 2-dose recommendation, with greatest reductions in ages 5-19 years. Continued vaccination efforts should further reduce disease.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. Daiichi Sankyo Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

PubMed

Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Radiation exposure to the eye lens of orthopaedic surgeons during various orthopaedic procedures.

PubMed

Romanova, K; Vassileva, J; Alyakov, M

2015-07-01

The aim of the present study was to assess the radiation dose to the eye lens of orthopaedic surgeons during various orthopaedic procedures and to make efforts to ensure that radiation protection is optimised. The study was performed for Fractura femoris and Fractura cruris procedures performed in orthopaedic operating theatres, as well as for fractures of wrist, ankle and hand/shoulder performed in the emergency trauma room. The highest mean value of the eye lens dose of 47.2 μSv and higher mean fluoroscopy time of 3 min, as well as the corresponding highest maximum values of 77.1 μSv and 5.0 min were observed for the Fractura femoris procedure performed with the Biplanar 500e fluoroscopy systems. At a normal workload, the estimated mean annual dose values do not exceed the annual occupational dose limit for the lens of eye, but at a heavy workload in the department, this dose limit could be achieved or exceeded. The use of protective lead glasses is recommended as they could reduce the radiation exposure of the lens of the eye. The phantom measurements demonstrated that the use of half-dose mode could additionally reduce dose to the operator's eye lens. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Efficacy of intravenous phenobarbital treatment for status epilepticus].

PubMed

Muramoto, Emiko; Mizobuchi, Masahiro; Sumi, Yoshihiro; Sako, Kazuya; Nihira, Atsuko; Takeuchi, Akiko; Nakamura, Hirohiko

2013-08-01

Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. The initial doses of IV-PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV-PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose.

CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.

PubMed

Seto, Takashi; Kiura, Katsuyuki; Nishio, Makoto; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yamamoto, Nobuyuki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Takeuchi, Kengo; Shimada, Tadashi; Tanaka, Tomohiro; Tamura, Tomohide

2013-06-01

Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. Chugai Pharmaceutical Co, Ltd. Copyright © 2013 Elsevier Ltd. All rights reserved.

From AAA to Acuros XB-clinical implications of selecting either Acuros XB dose-to-water or dose-to-medium.

PubMed

Zifodya, Jackson M; Challens, Cameron H C; Hsieh, Wen-Long

2016-06-01

When implementing Acuros XB (AXB) as a substitute for anisotropic analytic algorithm (AAA) in the Eclipse Treatment Planning System, one is faced with a dilemma of reporting either dose to medium, AXB-Dm or dose to water, AXB-Dw. To assist with decision making on selecting either AXB-Dm or AXB-Dw for dose reporting, a retrospective study of treated patients for head & neck (H&N), prostate, breast and lung is presented. Ten patients, previously treated using AAA plans, were selected for each site and re-planned with AXB-Dm and AXB-Dw. Re-planning was done with fixed monitor units (MU) as well as non-fixed MUs. Dose volume histograms (DVH) of targets and organs at risk (OAR), were analyzed in conjunction with ICRU-83 recommended dose reporting metrics. Additionally, comparisons of plan homogeneity indices (HI) and MUs were done to further highlight the differences between the algorithms. Results showed that, on average AAA overestimated dose to the target volume and OARs by less than 2.0 %. Comparisons between AXB-Dw and AXB-Dm, for all sites, also showed overall dose differences to be small (<1.5 %). However, in non-water biological media, dose differences between AXB-Dw and AXB-Dm, as large as 4.6 % were observed. AXB-Dw also tended to have unexpectedly high 3D maximum dose values (>135 % of prescription dose) for target volumes with high density materials. Homogeneity indices showed that AAA planning and optimization templates would need to be adjusted only for the H&N and Lung sites. MU comparison showed insignificant differences between AXB-Dw relative to AAA and between AXB-Dw relative to AXB-Dm. However AXB-Dm MUs relative to AAA, showed an average difference of about 1.3 % signifying an underdosage by AAA. In conclusion, when dose is reported as AXB-Dw, the effect that high density structures in the PTV has on the dose distribution should be carefully considered. As the results show overall small dose differences between the algorithms, when transitioning from AAA to AXB, no significant change to existing prescription protocols is expected. As most of the clinical experience is dose-to-water based and calibration protocols and clinical trials are also dose-to-water based and there still exists uncertainties in converting CT number to medium, selecting AXB-Dw is strongly recommended.

The new World Health Organization recommendation on the 2-dose measles vaccine schedule and the way forward in African Region

PubMed Central

Biellik, Robin Julian; Davis, Robert

2017-01-01

The new W.H.O. recommendation, which drops the coverage criterion for adoption of the 2-dose measles vaccine schedule, makes some African countries eligible for the 2-dose schedule which were previously ineligible. We look at the implications of the new recommendation for Ethiopia and Nigeria, the two largest African countries which are eligible under the new recommendation. PMID:29296149

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study

PubMed Central

Goldman, Stewart; Yamada, Tohru; Beattie, Craig W.; Bressler, Linda; Pacini, Michael; Pollack, Ian F.; Fisher, Paul Graham; Packer, Roger J.; Dunkel, Ira J.; Dhall, Girish; Wu, Shengjie; Onar, Arzu; Boyett, James M.; Fouladi, Maryam

2016-01-01

Background p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. Methods Children aged 3–21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. Results Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. Conclusions This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose. PMID:27022131

Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service

PubMed Central

Nutescu, Edith A.; Drozda, Katarzyna; Bress, Adam P.; Galanter, William L.; Stevenson, James; Stamos, Thomas D.; Desai, Ankit A.; Duarte, Julio D.; Gordeuk, Victor; Peace, David; Kadkol, ShriHari S.; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A.; Garcia, Joe G.N.; Cavallari, Larisa H.

2013-01-01

Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. PMID:23864527

Concentration dependence of biotransformation in fish liver S9: Optimizing substrate concentrations to estimate hepatic clearance for bioaccumulation assessment.

PubMed

Lo, Justin C; Allard, Gayatri N; Otton, S Victoria; Campbell, David A; Gobas, Frank A P C

2015-12-01

In vitro bioassays to estimate biotransformation rate constants of contaminants in fish are currently being investigated to improve bioaccumulation assessments of hydrophobic contaminants. The present study investigates the relationship between chemical substrate concentration and in vitro biotransformation rate of 4 environmental contaminants (9-methylanthracene, pyrene, chrysene, and benzo[a]pyrene) in rainbow trout (Oncorhynchus mykiss) liver S9 fractions and methods to determine maximum first-order biotransformation rate constants. Substrate depletion experiments using a series of initial substrate concentrations showed that in vitro biotransformation rates exhibit strong concentration dependence, consistent with a Michaelis-Menten kinetic model. The results indicate that depletion rate constants measured at initial substrate concentrations of 1 μM (a current convention) could underestimate the in vitro biotransformation potential and may cause bioconcentration factors to be overestimated if in vitro biotransformation rates are used to assess bioconcentration factors in fish. Depletion rate constants measured using thin-film sorbent dosing experiments were not statistically different from the maximum depletion rate constants derived using a series of solvent delivery-based depletion experiments for 3 of the 4 test chemicals. Multiple solvent delivery-based depletion experiments at a range of initial concentrations are recommended for determining the concentration dependence of in vitro biotransformation rates in fish liver fractions, whereas a single sorbent phase dosing experiment may be able to provide reasonable approximations of maximum depletion rates of very hydrophobic substances. © 2015 SETAC.

SU-F-T-613: Multi-Lesion Cranial SRS VMAT Plan Quality

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

Ballangrud, A; Kuo, L; Happersett, L

Purpose: Cranial SRS VMAT plans must have steep dose gradient around each target to reduce dose to normal brain. This study reports on the correlation between gradient index (GI=V50%/V100%), target size and target dose heterogeneity index (HI=PTV Dmax/prescription dose) for multi-lesion cranial SRS VMAT plans. Methods: VMAT plans for 10 cranial cases with 3 to 6 lesions (total 39 lesions) generated in Varian Eclipse V11.0.47 with a fine-tuned AAA beam model and 0.125 cm dose grid were analyzed. One or two iso centers were used depending on the spatial distribution of lesions. Two to nine coplanar and non-coplanar arcs weremore » used per isocenter. Conformity index (CI= V100%/VPTV), HI, and GI were determined for each lesion. Dose to critical structures were recorded. Results: Lesion size ranged from 0.05–11.00 cm3. HI ranged from 1.2–1.4, CI ranged from 1.0–2.8 and GI from 3.1–8.4. Maximum dose to brainstem, chiasm, lenses, optic nerves and eyes ranged from 120–1946 cGy, 47–463 cGy, 9–121 cGy, 14–512 cGy, and 17–294 cGy, respectively. Brain minus PTV (Brain-PTV) V7Gy was in the range 1.1–6.5%, and Brain-PTV Dmean was in the range 94–324 cGy. Conclusion: This work shows that a GI < 5 can be achieved for lesions > 0.4cc. For smaller lesions, GI increases rapidly. GI is lower when HI is increased. Based on this study, recommend HI is 1.4, and recommended GI is for volumes <0.1cc GI<9, 0.1–0.4cc GI<6, 0.4–0.1.0cc GI<5, and for volumes >1.0cc GI<4. CI is < 1.3 for all lesions except for targets < 0.1cc. Cranial SRS VMAT plans must be optimized to lower the GI to reduce the dose to normal brain tissue.« less

Using the time-to-event continual reassessment method in the presence of partial orders

PubMed Central

Wages, Nolan A.; Conaway, Mark R.; O'Quigley, John

2012-01-01

The time-to-event continual reassessment method (TITE-CRM) was proposed to handle the problem of long trial duration in Phase 1 trials as a result of late-onset toxicities. Here, we implement the TITE-CRM in dose–finding trials of combinations of agents. When studying multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. Therefore, the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. A CRM design for partially ordered trials (PO-CRM) was recently proposed. Simulation studies show that extending the TITE-CRM to the partial order setting produces results similar to those of the PO-CRM in terms of maximum tolerated dose recommendation yet reduces the duration of the trial. PMID:22806898

Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment.

PubMed Central

Albero, R.; Cerdan, A.; Sanchez Franco, F.

1987-01-01

Hypothyroidism from iodide transport deficiency is a rare disease, especially when found in two affected siblings. Treatment with high doses of iodide has been recommended, but no long term results have been reported. Two siblings with congenital hypothyroidism due to total failure to transport iodide have been followed up during twelve and a half years of treatment with oral potassium iodide. Iodine doses varied between 10.3 and 22 mg/day, and serum total iodine concentrations between 100 and 210 micrograms/dl. Total triiodothyronine (T3), thyroxine (T4) and free T4 were in the normal range during the time of study. Basal thyroid stimulating hormones (TSH) and maximum TSH response to thyrotrophin releasing hormone (TRH) were also in the range of normal values. These data along with clinical findings confirmed the potential usefulness of iodine in hypothyroidism due to complete iodide transport defect. PMID:3451231

A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

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

Drappatz, Jan; Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Wong, Eric T.

2009-01-01

Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-threemore » patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m{sup 2}/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m{sup 2}/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered.« less

Yellow Fever Vaccine Booster Doses: Recommendations of the Advisory Committee on Immunization Practices, 2015.

PubMed

Staples, J Erin; Bocchini, Joseph A; Rubin, Lorry; Fischer, Marc

2015-06-19

On February 26, 2015, the Advisory Committee on Immunization Practices (ACIP) voted that a single primary dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers. ACIP also approved recommendations for at-risk laboratory personnel and certain travelers to receive additional doses of yellow fever vaccine (Box). The ACIP Japanese Encephalitis and Yellow Fever Vaccines Workgroup evaluated published and unpublished data on yellow fever vaccine immunogenicity and safety. The evidence for benefits and risks associated with yellow fever vaccine booster doses was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. This report summarizes the evidence considered by ACIP and provides the updated recommendations for yellow fever vaccine booster doses.

Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials.

PubMed

Paoletti, X; Ezzalfani, M; Le Tourneau, C

2015-09-01

More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose. We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents. The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions. Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials. © 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.

Risk assessment of free hydroquinone derived from Arctostaphylos Uva-ursi folium herbal preparations.

PubMed

de Arriba, Susana Garcia; Naser, Belal; Nolte, Klaus-Ulrich

2013-01-01

Uva-ursi folium (bearberry leaf) has been traditionally used to treat symptoms of lower urinary tract infections. The most representative constituent of this herbal drug is arbutin that is rapidly absorbed in the small intestine and undergoes hepatic conjugation to form hydroquinone (HQ) conjugates. As free HQ is crucial for the safety of the herbal preparation, we reviewed published and unpublished experimental and human studies to clarify some outdated assumptions and to support the safety of therapeutic daily doses of Uva-ursi folium extract. Specifically, data on pharmacokinetics and the human exposure of arbutin and HQ were reviewed. A therapeutic recommended human daily dose of bearberry leaf extract (420 mg hydroquinone derivatives calculated as anhydrous arbutin) liberates free HQ in urine at a maximum exposure level of 11 µg/kg body weight (bw)/d. By means of an experimental no observed effect level value, a permitted daily exposure dose below which there is a negligible risk to human health was estimated for free HQ (100 µg/kg bw/d). Dietary sources of arbutin/HQ that are regularly consumed long term by humans generate comparable free HQ exposure levels. There is no direct evidence, regarding human data, supporting the fact that free HQ causes convulsion, hepatotoxicity, nephrotoxicity, or promotion of tumors in humans. Free HQ had no activity promoting pancreatic, bladder, stomach, or liver carcinogenesis. In conclusion, under the recommended use conditions Uva-ursi folium is a safe therapeutic option for treating lower urinary tract infections.

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.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

PubMed

Alvarez, Edwin A; Wolfson, Aaron H; Pearson, J Matt; Crisp, Meredith P; Mendez, Luis E; Lambrou, Nicholas C; Lucci, Joseph A

2009-05-01

This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

PubMed

Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

2005-04-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity modulated and volumetric modulated arc radiotherapy

PubMed Central

Crowe, Scott B; Kairn, Tanya; Middlebrook, Nigel; Hill, Brendan; Christie, David R H; Knight, Richard T; Kenny, John; Langton, Christian M; Trapp, Jamie V

2013-01-01

Introduction This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across five centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity modulated radiotherapy (IMRT) and 47 treated with volumetric modulated arc therapy (VMAT). Methods Treatment plan quality was evaluated in terms of target dose homogeneity and organs at risk (OAR), through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each OAR. Statistical significance was evaluated using two-tailed Welch's T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. Results The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the OAR: with increased compliance with recommended OAR dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. Conclusions This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT. PMID:26229621

Factors associated with higher oxytocin requirements in labor.

PubMed

Frey, Heather A; Tuuli, Methodius G; England, Sarah K; Roehl, Kimberly A; Odibo, Anthony O; Macones, George A; Cahill, Alison G

2015-09-01

To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation. A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20 mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20 mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression. Maximum oxytocin doses >20 mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20 mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000 g, intrapartum fever, administration of magnesium, and induction of labor. Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.

Environmental Problems Associated with Decommissioning of Chernobyl Power Plant Cooling Pond

NASA Astrophysics Data System (ADS)

Foley, T. Q.; Oskolkov, B. Y.; Bondarkov, M. D.; Gashchak, S. P.; Maksymenko, A. M.; Maksymenko, V. M.; Martynenko, V. I.; Jannik, G. T.; Farfan, E. B.; Marra, J. C.

2009-12-01

Decommissioning of nuclear power plants and other nuclear fuel cycle facilities associated with residual radioactive contamination is a fairly pressing issue. Significant problems may result from decommissioning of cooling ponds. The Chernobyl Nuclear Power Plant (ChNPP) Cooling Pond is one of the largest self-contained bodies of water in the Chernobyl Region and Ukrainian Polesye with a water surface area of 22.9 km2. The major hydrological feature of the ChNPP Cooling Pond is that its water level is 6-7 m higher than the water level in the Pripyat River and water losses due to seepage and evaporation are replenished by pumping water from the Pripyat River. In 1986, the accident at the ChNPP #4 Reactor Unit significantly contaminated the ChNPP Cooling Pond. According to the 2001 data, the total radionuclide inventory in the ChNPP Cooling Pond bottom deposits was as follows: 16.28 ± 2.59 TBq for 137Cs; 2.4 ± 0.48 TBq for 90Sr, and 0.00518 ± 0.00148 TBq for 239+240Pu. Since ChNPP is being decommissioned, the ChNPP Cooling Pond of such a large size will no longer be needed and cost effective to maintain. However, shutdown of the water feed to the Pond would expose the contaminated bottom deposits and change the hydrological features of the area, destabilizing the radiological and environmental situation in the entire region in 2007 - 2008, in order to assess potential consequences of draining the ChNPP Cooling Pond, the authors conducted preliminary radio-ecological studies of its shoreline ecosystems. The radioactive contamination of the ChNPP Cooling Pond shoreline is fairly variable and ranges from 75 to 7,500 kBq/m2. Three areas with different contamination levels were selected to sample soils, vegetation, small mammals, birds, amphibians, and reptilians in order to measure their 137Cs and 90Sr content. Using the ERICA software, their dose exposures were estimated. For the 2008 conditions, the estimated dose rates were found to be as follows: amphibians - 11.4 µGy/hr; birds - 6.3 µGy/hr; mammals - 15.1 µGy/hr; reptilians - 10.3 µGy/hr, with the recommended maximum allowable limit of 40 µGy/hr. The conservative risk coefficient ranged from 0.51 for birds to 1.82 for amphibians. In spite of a high contamination level of the shoreline areas, the current total doses received by the animals do not reach the recommended maximum allowable doses. However, drainage of the ChNPP Cooling Pond is likely to increase the dose rates as follows: amphibians - 94.5, birds - 95.2, mammals - 284.0, reptilians - 847.0 µGy/hr, which will significantly exceed the maximum allowable values. These predictions are conservative and prior to making the final decision on the fate of the ChNPP Cooling Pond, a detailed radio-ecological assessment of its drainage will have to be performed.

A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints.

PubMed

Slob, Wout

2017-04-01

A general theory on effect size for continuous data predicts a relationship between maximum response and within-group variation of biological parameters, which is empirically confirmed by results from dose-response analyses of 27 different biological parameters. The theory shows how effect sizes observed in distinct biological parameters can be compared and provides a basis for a generic definition of small, intermediate and large effects. While the theory is useful for experimental science in general, it has specific consequences for risk assessment: it solves the current debate on the appropriate metric for the Benchmark response in continuous data. The theory shows that scaling the BMR expressed as a percent change in means to the maximum response (in the way specified) automatically takes "natural variability" into account. Thus, the theory supports the underlying rationale of the BMR 1 SD. For various reasons, it is, however, recommended to use a BMR in terms of a percent change that is scaled to maximum response and/or within group variation (averaged over studies), as a single harmonized approach.

[Rivastigmine as treatment for patients with mild to moderately severe Alzheimer disease under normal clinical practice conditions. The ENTERPRISE study].

PubMed

Cruz Jentoft, A J; Hernández, B

2014-01-01

Alzheimer disease (AD) causes progressive cognitive decline leading to loss of independence for activities of daily living; rivastigmine is one of the drugs used for symptomatic management. To assess the therapeutic use of different pharmaceutical forms of rivastigmine in patients with AD in normal clinical practice. Cross-sectional, observational, multi-centre study conducted on patients with mild to moderate AD treated with rivastigmine in Spanish outpatient clinics specialising in Geriatrics, Psychiatry, and Neurology. Data regarding use of oral (OR) and transdermal (TDR) rivastigmine, compliance (degree of adherence), and caregiver satisfaction with treatment were evaluated. In total, 2252 patients with a mean age of 77.2 years were included; 60.2% were women. AD was moderate to moderately severe in 58.4%. Rivastigmine treatment was started orally in 54.4% of the patients and transdermally in 45.6%; 35.6% of those who started treatment by the OR route switched to TDR. A single dose adjustment was sufficient for 77.5% of patients on TDR treatment vs 11.8% of patients receiving OR treatment. More patients on TDR treatment (80.8% vs. 57.1% on OR treatment) reached the maximum therapeutic dose of rivastigmine and did so in a shorter period of time (51.6 vs 205.8 days). Compliance rates (60.5% vs 47.2%) and caregivers' satisfaction with treatment (89.4% vs 81.9%) were also higher for TDR. In normal clinical practice, using the TDR route of administration improves dose titration and drug compliance, allowing more patients to reach the maximum recommended dose of rivastigmine in a shorter time period. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

PubMed

Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H

2013-11-01

To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.

Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD.

PubMed

Brown, J T; Abdel-Rahman, S M; van Haandel, L; Gaedigk, A; Lin, Y S; Leeder, J S

2016-06-01

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 μM*h in EM2s to 5.8 ± 1.7 μM*h, 16.3 ± 2.9 μM*h, and 50.2 ± 7.3 μM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males.

PubMed

Seng, Kok-Yong; Loke, Weng-Keong; Moochhala, Shabbir; Zhao, Bin; Lee, Jon-Deoon Edmund

2009-09-01

We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide. Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 x 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory E(max) model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM. The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 l/h, 130 l and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (E(max)) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males. The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.

Statin Safety in Chinese: A Population-Based Study of Older Adults.

PubMed

Li, Daniel Q; Kim, Richard B; McArthur, Eric; Fleet, Jamie L; Hegele, Robert A; Shah, Baiju R; Weir, Matthew A; Molnar, Amber O; Dixon, Stephanie; Tu, Jack V; Anand, Sonia; Garg, Amit X

2016-01-01

Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statin-associated adverse events amongst Chinese patients. We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases. The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose. We observed no higher risk of serious statin toxicity in Chinese than matched non-Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted.

The use of rotation to fentanyl in cancer-related pain

PubMed Central

Dima, Delia; Tomuleasa, Ciprian; Frinc, Ioana; Pasca, Sergiu; Magdo, Lorand; Berindan-Neagoe, Ioana; Muresan, Mihai; Lisencu, Cosmin; Irimie, Alexandru; Zdrenghea, Mihnea

2017-01-01

Pain is commonly diagnosed with respect to cancer and heart diseases, being a major symptom in most neoplastic diseases. Uncontrolled pain leads to a decrease in the quality of life and an increase in the morbidity of the patient. Opioids represent the best analgetic supportive therapy and are frequently used in patients suffering from cancer and experiencing a high level of pain. Opioid treatment starts with a gradual titration of the dose until the minimum effective dose and the maximum tolerated dose are determined. Opioid rotation refers to the switch from one opioid to another in order to get a better response to analgetic therapy and reduce side effects. Fentanyl therapy is recommended to be continued during chemotherapy, radiotherapy, or in the case of surgical intervention. Rotation to fentanyl patches is an efficient and elegant solution for cancer patients, with reduced side effects. Opioid rotation, especially to fentanyl, was shown to increase the quality of life in patients with malignant disease. Finally, rotation to fentanyl is also advantageous from an economic point of view. PMID:28223843

[The use of sodium chloride baths in children with a heart lesion subjected to long-term exposure to low radiation doses].

PubMed

Poberskaia, V A; Dement'eva, O I

1997-01-01

Children exposed to low-dose radiation are often treated in sanatoria with mineral baths. Of the latter balneoprocedures widely practiced are sodium chloride (SC) baths with mineralization 20-30 g/l. Mineralization 40 g/l is less frequently used. To specify changes in the function of cardiovascular system induced by SC baths of different concentration (40 versus 20 g/l) 131 senior schoolchildren exposed to low-dose radiation or other environmental pollutants were examined both after a single balneological procedure and after the course treatment (maximum 10 procedures). The baths lasted 8-15 min at water temperature 36-38 OC in a day intervals. The response was assessed by ECG, tetrapolar chest rheography, bicycle exercise. All the children had cardiovascular disorders of non-rheumatic origin. Therapeutic effect was more pronounced after baths with SC concentration 40 g/l. These baths are recommended for improvement of vegetative regulation of the heart, correction of hemodynamic defects. Baths with mineralization 20 g/l are better in upgrading function of the autonomic nervous system.

Risk assessment and monitoring of dinotefuran and its metabolites for Chinese consumption of apples.

PubMed

Yu, Weiwei; Huang, Min; Chen, Jiaojiao; Wu, Sizhuo; Zheng, Kunming; Zeng, Song; Zhang, Kankan; Hu, Deyu

2017-09-26

Residues of dinotefuran and its metabolites, 1-methyl-3-(tetrahydro-3-furylmethyl)urea (UF) and 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine (DN), in apple were investigated using a "QuEChERS" (quick, easy, cheap, effective, rugged, safe) pretreatment and liquid chromatography-tandem mass spectrometry. Limits of detection (LODs) and quantification (LOQs) of dinotefuran, UF, and DN in apples were 0.011-0.960 and 0.037-3.200 μg/kg, respectively. The average recoveries of dinotefuran, UF, and DN in apple ranged from 70.0 to 83.6% with relative standard deviations less than 13%. A formulation of 20% water-dispersible dinotefuran granules was sprayed at 1-1.5-fold the recommended dose 3-4 times on apple trees. Total terminal residues of dinotefuran in apple were less than 2 mg/kg, which is the maximum residue limit (MRL) set by Japan. When following the recommended application guidelines, dinotefuran is unlikely to present significant health concerns to the Chinese population because the risk quotient (RQ) is less than 100%. This work could provide guidance for the safe use of dinotefuran and serve as a reference for the establishment of a maximum residue limit of dinotefuran in apple in China.

Dose optimization of contrast-enhanced carotid MR angiography.

PubMed

Unterweger, M; Froehlich, J M; Kubik-Huch, R A; Seifert, B; Birrer, M; Huber, T; Otto, R

2005-09-01

The purpose of this work was to compare the diagnostic performance of a single-contrast or a double-contrast dose of carotid contrast-enhanced MR angiography (MRA). One-hundred nineteen patients (mean age 65+/-14.4 years) underwent carotid contrast-enhanced MRA with a standardized protocol (repetition time/echo 3.73 ms/1.38 ms, flip-angle 25 degrees, acquisition-time 19 s, voxel size 1.2 x 1.2 x 0.9 mm3) on a 1.5-T scanner (Sonata, Siemens-Medical-Systems) using a neck phased-array coil. Contrast agent was administered intravenously at a rate of 3.0 ml/s, either as a single dose (n=57; 0.1 mmol/kg body weight) or as a double dose (n=62; 0.2 mmol/kg body weight) of meglumine gadoterate (0.5 M/l), followed by 30 ml saline. Qualitative image analysis was performed on maximum intensity projections using a five-point scale. Signal intensities were measured at three different vascular levels on both sides to assess the contrast-to-noise ratios (CNRs). Image quality was rated as good or excellent in all cases. A double dose did not influence the efficacy of carotid enhancement (CNR single dose 69.12+/-19.8; CNR double dose 70.01+/-20.7; p = 0.81) compared with a single dose. In both dose groups the mean CNRs were inversely related to bodyweight, despite adjusted contrast volumes (p=0.0005). Double-dose contrast-enhanced carotid MRA is not superior to single-dose MRA, as overall diagnostic performance and quantitative contrast enhancement are equal. Being more cost-efficient, a single-dose administration of contrast agent is recommended for MRA of the carotid arteries.

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

PubMed

Dougherty, T B; Porche, V H; Thall, P F

2000-04-01

This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

Total target volume is a better predictor of whole brain dose from gamma stereotactic radiosurgery than the number, shape, or location of the lesions

PubMed Central

Narayanasamy, Ganesh; Smith, Adam; Van Meter, Emily; McGarry, Ronald; Molloy, Janelle A.

2013-01-01

Purpose: To assess the hypothesis that the volume of whole brain that receives a certain dose level is primarily dependent on the treated volume rather than on the number, shape, or location of the lesions. This would help a physician validate the suitability of GammaKnife® based stereotactic radiosurgery (GKSR) prior to treatment. Methods: Simulation studies were performed to establish the hypothesis for both oblong and spherical shaped lesions of various numbers and sizes. Forty patients who underwent GKSR [mean age of 54 years (range 7–80), mean number of lesions of 2.5 (range 1–6), and mean lesion volume of 4.4 cm3 (range 0.02–22.2 cm3)] were also studied retrospectively. Following recommendations of QUANTEC, the volume of brain irradiated by the 12 Gy (VB12) isodose line was measured and a power-law based relation is proposed here for estimating VB12 from the known tumor volume and the prescription dose. Results: In the simulation study on oblong, spherical, and multiple lesions, the volume of brain irradiated by 50%, 10%, and 1% of maximum dose was found to have linear, linear, and exponentially increasing dependence on the volume of the treated region, respectively. In the retrospective study on 40 GKSR patients, a similar relationship was found to predict the brain dose with a Spearman correlation coefficient >0.9. In both the studies, the volume of brain irradiated by a certain dose level does not have a statistically significant relationship (p ≥ 0.05) with the number, shape, or position of the lesions. The measured VB12 agrees with calculation to within 1.7%. Conclusions: The results from the simulation and the retrospective clinical studies indicate that the volume of whole brain that receives a certain percentage of the maximum dose is primarily dependent on the treated volume and less on the number, shape, and location of the lesions. PMID:24007147

Flight attendant radiation dose from solar particle events.

PubMed

Anderson, Jeri L; Mertens, Christopher J; Grajewski, Barbara; Luo, Lian; Tseng, Chih-Yu; Cassinelli, Rick T

2014-08-01

Research has suggested that work as a flight attendant may be related to increased risk for reproductive health effects. Air cabin exposures that may influence reproductive health include radiation dose from galactic cosmic radiation and solar particle events. This paper describes the assessment of radiation dose accrued during solar particle events as part of a reproductive health study of flight attendants. Solar storm data were obtained from the National Oceanic and Atmospheric Administration Space Weather Prediction Center list of solar proton events affecting the Earth environment to ascertain storms relevant to the two study periods (1992-1996 and 1999-2001). Radiation dose from exposure to solar energetic particles was estimated using the NAIRAS model in conjunction with galactic cosmic radiation dose calculated using the CARI-6P computer program. Seven solar particle events were determined to have potential for significant radiation exposure, two in the first study period and five in the second study period, and over-lapped with 24,807 flight segments. Absorbed (and effective) flight segment doses averaged 6.5 μGy (18 μSv) and 3.1 μGy (8.3 μSv) for the first and second study periods, respectively. Maximum doses were as high as 440 μGy (1.2 mSv) and 20 flight segments had doses greater than 190 μGy (0.5 mSv). During solar particle events, a pregnant flight attendant could potentially exceed the equivalent dose limit to the conceptus of 0.5 mSv in a month recommended by the National Council on Radiation Protection and Measurements.

Occupational radiation exposure in vascular interventional radiology: A complete evaluation of different body regions.

PubMed

Bacchim Neto, Fernando Antonio; Alves, Allan Felipe Fattori; Mascarenhas, Yvone Maria; Nicolucci, Patrícia; Pina, Diana Rodrigues de

2016-08-01

To perform a complete evaluation on radiation doses, received by primary and assistant medical staff, while performing different vascular interventional radiology procedures. We evaluated dose received in different body regions during three categories of vascular procedures: lower limb angiography (Angiography), lower limb percutaneous transluminal angioplasty (Angioplasty) and stent graft placement for abdominal aortic aneurysm treatment (A. A. A. Treatment). We positioned the dosimeters near the eye lens, thyroid, chest, abdomen, hands, and feet of the interventional physicians. Equivalent dose was compared with annual dose limits for workers in order to determine the maximum number of procedures per year that each physician could perform. We assessed 90 procedures. We found the highest equivalent doses in the A. A. A. Treatment, in which 90% of the evaluations indicated at least one region receiving more than 1mSv per procedure. Angioplasty was the only procedural modality that provided statistically different doses for different professionals, which is an important aspect on regards to radiological protection strategies. In comparison with the dose limits, the most critical region in all procedures was the eye lens. Since each body region of the interventionist is exposed to different radiation levels, dose distribution measurements are essential for radiological protection strategies. These results indicate that dosimeters placed in abdomen instead of chest may represent more accurately the whole body doses received by the medical staff. Additional dosimeters and a stationary shield for the eye lens are strongly recommended. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Phase I Trial of Anti-MET Monoclonal Antibody in MET-Overexpressed Refractory Cancer.

PubMed

Lee, Jeeyun; Kim, Seung Tae; Park, Sungju; Lee, Sujin; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Ahn, Hongmo; Bok, Haesook; Kim, Kyoung-Mee; Ahn, Myung Ju; Kang, Won Ki; Park, Young Suk

2018-06-01

Samsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas. SAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound. Sixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II. We successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg. Copyright © 2018 Elsevier Inc. All rights reserved.

Equivalent uniform dose concept evaluated by theoretical dose volume histograms for thoracic irradiation.

PubMed

Dumas, J L; Lorchel, F; Perrot, Y; Aletti, P; Noel, A; Wolf, D; Courvoisier, P; Bosset, J F

2007-03-01

The goal of our study was to quantify the limits of the EUD models for use in score functions in inverse planning software, and for clinical application. We focused on oesophagus cancer irradiation. Our evaluation was based on theoretical dose volume histograms (DVH), and we analyzed them using volumetric and linear quadratic EUD models, average and maximum dose concepts, the linear quadratic model and the differential area between each DVH. We evaluated our models using theoretical and more complex DVHs for the above regions of interest. We studied three types of DVH for the target volume: the first followed the ICRU dose homogeneity recommendations; the second was built out of the first requirements and the same average dose was built in for all cases; the third was truncated by a small dose hole. We also built theoretical DVHs for the organs at risk, in order to evaluate the limits of, and the ways to use both EUD(1) and EUD/LQ models, comparing them to the traditional ways of scoring a treatment plan. For each volume of interest we built theoretical treatment plans with differences in the fractionation. We concluded that both volumetric and linear quadratic EUDs should be used. Volumetric EUD(1) takes into account neither hot-cold spot compensation nor the differences in fractionation, but it is more sensitive to the increase of the irradiated volume. With linear quadratic EUD/LQ, a volumetric analysis of fractionation variation effort can be performed.

Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

PubMed Central

Tiwari, Tejpratap; Moro, Pedro; Messonnier, Nancy E.; Reingold, Arthur; Sawyer, Mark; Clark, Thomas A.

2018-01-01

Summary This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations and replaces all previously published reports and policy notes; it is intended for use by clinicians and public health providers as a resource. ACIP recommends routine vaccination for tetanus, diphtheria, and pertussis. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with one adolescent booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who have never received Tdap also are recommended to receive a booster dose of Tdap. Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks’ gestation, regardless of previous receipt of Tdap. After receipt of Tdap, adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria. PMID:29702631

Influence of composted poultry manure and irrigation regimes on some morpho-physiology parameters of maize under semiarid environments.

PubMed

Farhad, Wajid; Cheema, Mumtaz Akhtar; Hammad, Hafiz Mohkum; Saleem, Muhammad Farrukh; Fahad, Shah; Abbas, Farhat; Khosa, Ikramullah; Bakhat, Hafiz Faiq

2018-05-08

Poultry manure (PM), a rich source for crop nutrients, is produced in ample quantities worldwide. It provides necessary nutrient to soil and has a potential to improve plant water holding availability under semiarid environment. The effect of composted poultry manure (CPM) and irrigation regimes on morpho-physiology of selective maize (Zea mays L.) hybrids (H 1 = drought tolerant, H 2 = drought sensitive) was investigated in this study. Two field experiments were conducted during 2010 and 2011 under randomized complete block design with split split-plot arrangements and three replications of each treatment. Irrigation regimes (I 1  = 300, I 2  = 450, I 3  = 600 mm) were kept in main plots; the two maize hybrids (H 1 and H 2 ) in sub-plots and nutrient levels (L 1 = recommended rate of NPK (control), L 2  = 8 t ha -1 CPM, L 3  = 10 t ha -1 CPM, and L 4  = 12 t ha -1 CPM) were arranged in sub sub-plots. The drought tolerant hybrid showed best growth under all treatments. Results revealed that maximum leaf area index (LAI) was recorded with the application of the recommended dose of NPK. Low irrigation regimes (I 1 and I 2 ) highly significantly (P < 0.01) reduced the photosynthesis and transpiration rate in both hybrids while application of 12 t ha -1 CPM was able to partially alleviate the effect of water stress on these parameters. Resultantly, the application of 12 t ha -1 CPM enhanced the plant growth and increased grain yield (21%; 4.17 vs 5.27) under limited water availability (I 2 L 4 ) as compared to the recommended dose of NPK (I 2 L 1 ). However, the nutrient application under control treatment had maximum grain yield. Therefore, shortage of water for maize production might be partially alleviated by the application of 12 t ha -1 CPM.

Implications of current recommendations for third-generation cephalosporin use in the WHO Western Pacific Region following the emergence of multiresistant gonococci.

PubMed

Tapsall, J W

2009-08-01

To ascertain recommendations for the treatment of gonorrhoea in the WHO Western Pacific Region (WPR) following the emergence of "cephalosporin-resistant" Neisseria gonorrhoeae and to relate these to clinical and laboratory measures directed towards disease and antibiotic resistance control. WHO WPR Gonococcal Antimicrobial Resistance Programme members provided data on the type, dose and source of third-generation cephalosporins recommended for the treatment of gonorrhoea. Ceftriaxone was recommended more widely (11/15 respondents) than cefixime (five centres). No cephalosporins were recommended in three jurisdictions. One other oral (ceftibuten) and injectable (cefodizime) agent was recommended. Uniform (400 mg) doses of cefixime were recommended but ceftriaxone regimens ranged between 125 mg and 1 g, with nine of 11 respondents using a 250 mg dose. Both generic and proprietary preparations were widely used. Third-generation cephalosporins are widely recommended for the treatment of gonorrhoea in the WPR, with injectable ceftriaxone more extensively so than oral cefixime and in an expanded dose range. Few other cephalosporins were recommended. Current knowledge suggests that the trend towards ceftriaxone treatment in higher doses may decrease the impact of the circulation of "cephalosporin-resistant" gonococci in the WPR. These recommendations represent public sector practice only and of themselves are unlikely to contain the further spread of "cephalosporin-resistant" gonococci because of the general clinical use of cephalosporins. Optimisation of strategies for laboratory detection of third-generation cephalosporin resistance can be simplified in the WPR because of the restricted spectrum of cephalosporins recommended. Additional efforts are urgently required for both disease and antibiotic resistance control in gonorrhoea.

Georgia fishery study: implications for dose calculations. Revision 1

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

Turcotte, M.D.S.

Fish consumption will contribute a major portion of the estimated individual and population doses from L-Reactor liquid releases and Cs-137 remobilization in Steel Creek. It is therefore important that the values for fish consumption used in dose calculations be as realistic as possible. Since publication of the L-Reactor Environmental Information Document (EID), data have become available on sport fishing in the Savannah River. These data provide SRP with a site-specific sport fish harvest and consumption values for use in dose calculations. The Georgia fishery data support the total population fish consumption and calculated dose reported in the EID. The datamore » indicate, however, that both the EID average and maximum individual fish consumption have been underestimated, although each to a different degree. The average fish consumption value used in the EID is approximately 3% below the lower limit of the fish consumption range calculated using the Georgia data. Maximum fish consumption in the EID has been underestimated by approximately 60%, and doses to the maximum individual should also be recalculated. Future dose calculations should utilize an average adult fish consumption value of 11.3 kg/yr, and a maximum adult fish consumption value of 34 kg/yr. Consumption values for the teen and child age groups should be increased proportionally: (1) teen average = 8.5; maximum = 25.9 kg/yr; and (2) child average = 3.6; maximum = 11.2 kg/yr. 8 refs.« less

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

PubMed Central

Bendell, Johanna C; Javle, Milind; Bekaii-Saab, Tanios S; Finn, Richard S; Wainberg, Zev A; Laheru, Daniel A; Weekes, Colin D; Tan, Benjamin R; Khan, Gazala N; Zalupski, Mark M; Infante, Jeffrey R; Jones, Suzanne; Papadopoulos, Kyriakos P; Tolcher, Anthony W; Chavira, Renae E; Christy-Bittel, Janna L; Barrett, Emma; Patnaik, Amita

2017-01-01

Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population. PMID:28152546

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom.

PubMed

Lye, Jessica; Kenny, John; Lehmann, Joerg; Dunn, Leon; Kron, Tomas; Alves, Andrew; Cole, Andrew; Williams, Ivan

2014-10-01

The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%-8%. The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.

Efficacy and safety of a modified intravenous recombinant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke.

PubMed

Pan, Shu-Ming; Liu, Jia-Fu; Liu, Ming; Shen, Sa; Li, Hao-Jun; Dai, Li-Hua; Chen, Xiang-Jun

2013-07-01

Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA; 0.90 mg/kg, with a maximum dose of 90 mg) has been recommended as the standard management for acute ischemic stroke (AIS) thrombolysis. However, the dose of IV rtPA in Asia remains controversial. This study was designed to verify the safety and efficacy of IV rtPA treatment for AIS with a lower dosage (0.90 mg/kg, with a maximum dose of 50 mg). Patients were divided into 3 dosage groups according to body weight (BW): group 1, <55 kg for 0.90 mg/kg; group 2, 55 to 67 kg for 0.75 to 0.90 mg/kg; and group 3, >67 kg for <0.75 mg/kg. The following data were collected: patient demographics, vascular risk factors, neuroimaging results, time of rtPA administration, National Institutes of Health Stroke Scale score before treatment and at 24 hours, and a modified Rankin Scale (mRS) score at 3 months. Eighty-three AIS patients who were of Han Chinese descent were included in the study. The baseline characteristics of the 3 dosage groups were well matched. In group 1 (BW <55 kg for 0.90 mg/kg; n = 19), 57.1% had a favorable outcome at 3 months, compared with 61.2% of patients in group 2 (BW 55-67 kg for 0.75-0.90 mg/kg; n = 33) and 51.5% in group 3 (BW >67 kg for <0.75 mg/kg; n = 31; P = .362). There were no significantly statistical differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. This IV rtPA regimen (0.90 mg/kg, with a maximum dose of 50 mg) not only shows sufficient favorable outcome in clinical practice in Chinese patients with AIS but also good health economic savings. This regimen could be suitable for many developing countries. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Detector-specific correction factors in radiosurgery beams and their impact on dose distribution calculations.

PubMed

García-Garduño, Olivia A; Rodríguez-Ávila, Manuel A; Lárraga-Gutiérrez, José M

2018-01-01

Silicon-diode-based detectors are commonly used for the dosimetry of small radiotherapy beams due to their relatively small volumes and high sensitivity to ionizing radiation. Nevertheless, silicon-diode-based detectors tend to over-respond in small fields because of their high density relative to water. For that reason, detector-specific beam correction factors ([Formula: see text]) have been recommended not only to correct the total scatter factors but also to correct the tissue maximum and off-axis ratios. However, the application of [Formula: see text] to in-depth and off-axis locations has not been studied. The goal of this work is to address the impact of the correction factors on the calculated dose distribution in static non-conventional photon beams (specifically, in stereotactic radiosurgery with circular collimators). To achieve this goal, the total scatter factors, tissue maximum, and off-axis ratios were measured with a stereotactic field diode for 4.0-, 10.0-, and 20.0-mm circular collimators. The irradiation was performed with a Novalis® linear accelerator using a 6-MV photon beam. The detector-specific correction factors were calculated and applied to the experimental dosimetry data for in-depth and off-axis locations. The corrected and uncorrected dosimetry data were used to commission a treatment planning system for radiosurgery planning. Various plans were calculated with simulated lesions using the uncorrected and corrected dosimetry. The resulting dose calculations were compared using the gamma index test with several criteria. The results of this work presented important conclusions for the use of detector-specific beam correction factors ([Formula: see text] in a treatment planning system. The use of [Formula: see text] for total scatter factors has an important impact on monitor unit calculation. On the contrary, the use of [Formula: see text] for tissue-maximum and off-axis ratios has not an important impact on the dose distribution calculation by the treatment planning system. This conclusion is only valid for the combination of treatment planning system, detector, and correction factors used in this work; however, this technique can be applied to other treatment planning systems, detectors, and correction factors.

A comprehensive dose reconstruction methodology for former rocketdyne/atomics international radiation workers.

PubMed

Boice, John D; Leggett, Richard W; Ellis, Elizabeth Dupree; Wallace, Phillip W; Mumma, Michael; Cohen, Sarah S; Brill, A Bertrand; Chadda, Bandana; Boecker, Bruce B; Yoder, R Craig; Eckerman, Keith F

2006-05-01

Incomplete radiation exposure histories, inadequate treatment of internally deposited radionuclides, and failure to account for neutron exposures can be important uncertainties in epidemiologic studies of radiation workers. Organ-specific doses from lifetime occupational exposures and radionuclide intakes were estimated for an epidemiologic study of 5,801 Rocketdyne/Atomics International (AI) radiation workers engaged in nuclear technologies between 1948 and 1999. The entire workforce of 46,970 Rocketdyne/AI employees was identified from 35,042 Kardex work histories cards, 26,136 electronic personnel listings, and 14,189 radiation folders containing individual exposure histories. To obtain prior and subsequent occupational exposure information, the roster of all workers was matched against nationwide dosimetry files from the Department of Energy, the Nuclear Regulatory Commission, the Landauer dosimetry company, the U.S. Army, and the U.S. Air Force. Dosimetry files of other worker studies were also accessed. Computation of organ doses from radionuclide intakes was complicated by the diversity of bioassay data collected over a 40-y period (urine and fecal samples, lung counts, whole-body counts, nasal smears, and wound and incident reports) and the variety of radionuclides with documented intake including isotopes of uranium, plutonium, americium, calcium, cesium, cerium, zirconium, thorium, polonium, promethium, iodine, zinc, strontium, and hydrogen (tritium). Over 30,000 individual bioassay measurements, recorded on 11 different bioassay forms, were abstracted. The bioassay data were evaluated using ICRP biokinetic models recommended in current or upcoming ICRP documents (modified for one inhaled material to reflect site-specific information) to estimate annual doses for 16 organs or tissues taking into account time of exposure, type of radionuclide, and excretion patterns. Detailed internal exposure scenarios were developed and annual internal doses were derived on a case-by-case basis for workers with committed equivalent doses indicated by screening criteria to be greater than 10 mSv to the organ with the highest internal dose. Overall, 5,801 workers were monitored for radiation at Rocketdyne/AI: 5,743 for external exposure and 2,232 for internal intakes of radionuclides; 41,169 workers were not monitored for radiation. The mean cumulative external dose based on Rocketdyne/AI records alone was 10.0 mSv, and the dose distribution was highly skewed with most workers experiencing low cumulative doses and only a few with high doses (maximum 500 mSv). Only 45 workers received greater than 200 mSv while employed at Rocketdyne/AI. However, nearly 32% (or 1,833) of the Rocketdyne/AI workers had been monitored for radiation at other nuclear facilities and incorporation of these doses increased the mean dose to 13.5 mSv (maximum 1,005 mSv) and the number of workers with >200 mSv to 69. For a small number of workers (n=292), lung doses from internal radionuclide intakes were relatively high (mean 106 mSv; maximum 3,560 mSv) and increased the overall population mean dose to 19.0 mSv and the number of workers with lung dose>200 mSv to 109. Nearly 10% of the radiation workers (584) were monitored for neutron exposures (mean 1.2 mSv) at Rocketdyne/AI, and another 2% were monitored for neutron exposures elsewhere. Interestingly, 1,477 workers not monitored for radiation at Rocketdyne/AI (3.6%) were found to have worn dosimeters at other nuclear facilities (mean external dose of 2.6 mSv, maximum 188 mSv). Without considering all sources of occupational exposure, an incorrect characterization of worker exposure would have occurred with the potential to bias epidemiologic results. For these pioneering workers in the nuclear industry, 26.5% of their total occupational dose (collective dose) was received at other facilities both prior to and after employment at Rocketdyne/AI. In addition, a small number of workers monitored for internal radionuclides contributed disproportionately to the number of workers with high lung doses. Although nearly 12% of radiation workers had been monitored for neutron exposures during their career, the cumulative dose levels were small in comparison with other external and internal exposure. Risk estimates based on nuclear worker data must be interpreted cautiously if internally deposited radionuclides and occupational doses received elsewhere are not considered.

Prescribing smoked cannabis for chronic noncancer pain: preliminary recommendations.

PubMed

Kahan, Meldon; Srivastava, Anita; Spithoff, Sheryl; Bromley, Lisa

2014-12-01

To offer preliminary guidance on prescribing smoked cannabis for chronic pain before the release of formal guidelines. We reviewed the literature on the analgesic effectiveness of smoked cannabis and the harms of medical and recreational cannabis use. We developed recommendations on indications, contraindications, precautions, and dosing of smoked cannabis, and categorized the recommendations based on levels of evidence. Evidence is mostly level II (well conducted observational studies) and III (expert opinion). Smoked cannabis might be indicated for patients with severe neuropathic pain conditions who have not responded to adequate trials of pharmaceutical cannabinoids and standard analgesics (level II evidence). Smoked cannabis is contraindicated in patients who are 25 years of age or younger (level II evidence); who have a current, past, or strong family history of psychosis (level II evidence); who have a current or past cannabis use disorder (level III evidence); who have a current substance use disorder (level III evidence); who have cardiovascular or respiratory disease (level III evidence); or who are pregnant or planning to become pregnant (level II evidence). It should be used with caution in patients who smoke tobacco (level II evidence), who are at increased risk of cardiovascular disease (level III evidence), who have anxiety or mood disorders (level II evidence), or who are taking higher doses of opioids or benzodiazepines (level III evidence). Cannabis users should be advised not to drive for at least 3 to 4 hours after smoking, for at least 6 hours after oral ingestion, and for at least 8 hours if they experience a subjective "high" (level II evidence). The maximum recommended dose is 1 inhalation 4 times per day (approximately 400 mg per day) of dried cannabis containing 9% delta-9-tetrahydrocannabinol (level III evidence). Physicians should avoid referring patients to "cannabinoid" clinics (level III evidence). Future guidelines should be based on systematic review of the literature on the safety and effectiveness of smoked cannabis. Further research is needed on the effectiveness and long-term safety of smoked cannabis compared with pharmaceutical cannabinoids, opioids, and other standard analgesics. Copyright© the College of Family Physicians of Canada.

Treatment Plan Technique and Quality for Single-Isocenter Stereotactic Ablative Radiotherapy of Multiple Lung Lesions with Volumetric-Modulated Arc Therapy or Intensity-Modulated Radiosurgery

PubMed Central

Quan, Kimmen; Xu, Karen M.; Lalonde, Ron; Horne, Zachary D.; Bernard, Mark E.; McCoy, Chuck; Clump, David A.; Burton, Steven A.; Heron, Dwight E.

2015-01-01

The aim of this study is to provide a practical approach to the planning technique and evaluation of plan quality for the multi-lesion, single-isocenter stereotactic ablative radiotherapy (SABR) of the lung. Eleven patients with two or more lung lesions underwent single-isocenter volumetric-modulated arc therapy (VMAT) radiosurgery or IMRS. All plans were normalized to the target maximum dose. For each plan, all targets were treated to the same dose. Plan conformity and dose gradient were maximized with dose-control tuning structures surrounding targets. For comparison, multi-isocenter plans were retrospectively created for four patients. Conformity index (CI), homogeneity index (HI), gradient index (GI), and gradient distance (GD) were calculated for each plan. V5, V10, and V20 of the lung and organs at risk (OARs) were collected. Treatment time and total monitor units (MUs) were also recorded. One patient had four lesions and the remainder had two lesions. Six patients received VMAT and five patients received intensity-modulated radiosurgery (IMRS). For those treated with VMAT, two patients received 3-arc VMAT and four received 2-arc VMAT. For those treated with IMRS, two patients were treated with 10 and 11 beams, respectively, and the rest received 12 beams. Prescription doses ranged from 30 to 54 Gy in three to five fractions. The median prescribed isodose line was 84% (range: 80–86%). The median maximum dose was 57.1 Gy (range: 35.7–65.1 Gy). The mean combined PTV was 49.57 cm3 (range: 14.90–87.38 cm3). For single-isocenter plans, the median CI was 1.15 (range: 0.97–1.53). The median HI was 1.19 (range: 1.16–1.28). The median GI was 4.60 (range: 4.16–7.37). The median maximum radiation dose (Dmax) to total lung was 55.6 Gy (range: 35.7–62.0 Gy). The median mean radiation dose to the lung (Dmean) was 4.2 Gy (range: 1.1–9.3 Gy). The median lung V5 was 18.7% (range: 3.8–41.3%). There was no significant difference in CI, HI, GI, GD, V5, V10, and V20 (lung, heart, trachea, esophagus, and spinal cord) between single-isocenter and multi-isocenter plans. This multi-lesion, single-isocenter lung SABR planning technique demonstrated excellent plan quality and clinical efficiency and is recommended for radiosurgical treatment of two or more lung targets for well-suited patients. PMID:26500888

Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial.

PubMed

Cestário, Elizabeth do Espirito Santo; Fernandes, Letícia Aparecida Barufi; Giollo-Júnior, Luiz Tadeu; Uyemura, Jéssica Rodrigues Roma; Matarucco, Camila Suemi Sato; Landim, Manoel Idelfonso Paz; Cosenso-Martin, Luciana Neves; Tácito, Lúcia Helena Bonalume; Moreno, Heitor; Vilela-Martin, José Fernando; Yugar-Toledo, Juan Carlos

2018-02-12

Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney. Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.

[Oxytocin administration during spontaneous labour: Guidelines for clinical practice. Guidelines short text].

PubMed

Dupont, C; Carayol, M; Le Ray, C; Barasinski, C; Beranger, R; Burguet, A; Chantry, A; Chiesa, C; Coulm, B; Evrard, A; Fischer, C; Gaucher, L; Guillou, C; Leroy, F; Phan, E; Rousseau, A; Tessier, V; Vendittelli, F; Deneux-Tharaux, C; Riethmuller, D

2017-01-01

To define the different stages of spontaneous labour. To determine the indications, modalities of use and the effects of administering synthetic oxytocin. And to describe undesirable maternal and perinatal outcomes associated with the use of synthetic oxytocin. A systematic review was carried out by searching Medline database and websites of obstetrics learned societies until March 2016. The 1st stage of labor is divided in a latence phase and an active phase, which switch at 5cm of cervical dilatation. Rate of cervical dilatation is considered as abnormal below 1cm per 4hour during the first part of the active phase, and below 1cm per 2hours above 7cm of dilatation. During the latent phase of the first stage of labor, i.e. before 5cm of cervical dilatation, it is recommended that an amniotomy not be performed routinely and not to use oxytocin systematically. It is not recommended to expect the active phase of labor to start the epidural analgesia if patient requires it. If early epidural analgesia was performed, the administration of oxytocin must not be systematic. If dystocia during the active phase, an amniotomy is recommended in first-line treatment. In the absence of an improvement within an hour, oxytocin should be administrated. However, in the case of an extension of the second stage beyond 2hours, it is recommended to administer oxytocin to correct a lack of progress of the presentation. If dynamic dystocia, it is recommended to start initial doses of oxytocin at 2mUI/min, to respect at least 30min intervals between increases in oxytocin doses delivered, and to increase oxytocin doses by 2mUI/min intervals without surpassing a maximum IV flow rate of 20mUI/min. The reported maternal adverse effects concern uterine hyperstimulation, uterine rupture and post-partum haemorrhage, and those of neonatal adverse effects concern foetal heart rate anomalies associated with uterine hyperstimulation, neonatal morbidity and mortality, neonatal jaundice, weak suck/poor breastfeeding latch and autism. The widespread use of oxytocin during spontaneous labour must not be considered as simply another inoffensive prescription without any possible deleterious consequences for mother or foetus. Conditions for administering the oxytocin must therefore respect medical protocols. Indications and patient consent have to be report in the medical file. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

PROBABILISTIC SAFETY ASSESSMENT OF OPERATIONAL ACCIDENTS AT THE WASTE ISOLATION PILOT PLANT

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

Rucker, D.F.

2000-09-01

This report presents a probabilistic safety assessment of radioactive doses as consequences from accident scenarios to complement the deterministic assessment presented in the Waste Isolation Pilot Plant (WIPP) Safety Analysis Report (SAR). The International Council of Radiation Protection (ICRP) recommends both assessments be conducted to ensure that ''an adequate level of safety has been achieved and that no major contributors to risk are overlooked'' (ICRP 1993). To that end, the probabilistic assessment for the WIPP accident scenarios addresses the wide range of assumptions, e.g. the range of values representing the radioactive source of an accident, that could possibly have beenmore » overlooked by the SAR. Routine releases of radionuclides from the WIPP repository to the environment during the waste emplacement operations are expected to be essentially zero. In contrast, potential accidental releases from postulated accident scenarios during waste handling and emplacement could be substantial, which necessitates the need for radiological air monitoring and confinement barriers (DOE 1999). The WIPP Safety Analysis Report (SAR) calculated doses from accidental releases to the on-site (at 100 m from the source) and off-site (at the Exclusive Use Boundary and Site Boundary) public by a deterministic approach. This approach, as demonstrated in the SAR, uses single-point values of key parameters to assess the 50-year, whole-body committed effective dose equivalent (CEDE). The basic assumptions used in the SAR to formulate the CEDE are retained for this report's probabilistic assessment. However, for the probabilistic assessment, single-point parameter values were replaced with probability density functions (PDF) and were sampled over an expected range. Monte Carlo simulations were run, in which 10,000 iterations were performed by randomly selecting one value for each parameter and calculating the dose. Statistical information was then derived from the 10,000 iteration batch, which included 5%, 50%, and 95% dose likelihood, and the sensitivity of each assumption to the calculated doses. As one would intuitively expect, the doses from the probabilistic assessment for most scenarios were found to be much less than the deterministic assessment. The lower dose of the probabilistic assessment can be attributed to a ''smearing'' of values from the high and low end of the PDF spectrum of the various input parameters. The analysis also found a potential weakness in the deterministic analysis used in the SAR, a detail on drum loading was not taken into consideration. Waste emplacement operations thus far have handled drums from each shipment as a single unit, i.e. drums from each shipment are kept together. Shipments typically come from a single waste stream, and therefore the curie loading of each drum can be considered nearly identical to that of its neighbor. Calculations show that if there are large numbers of drums used in the accident scenario assessment, e.g. 28 drums in the waste hoist failure scenario (CH5), then the probabilistic dose assessment calculations will diverge from the deterministically determined doses. As it is currently calculated, the deterministic dose assessment assumes one drum loaded to the maximum allowable (80 PE-Ci), and the remaining are 10% of the maximum. The effective average of drum curie content is therefore less in the deterministic assessment than the probabilistic assessment for a large number of drums. EEG recommends that the WIPP SAR calculations be revisited and updated to include a probabilistic safety assessment.« less

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

PubMed Central

LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

2013-01-01

Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

Identifying the most successful dose (MSD) in dose-finding studies in cancer.

PubMed

Zohar, Sarah; O'Quigley, John

2006-01-01

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1

PubMed Central

Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

2005-01-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 μM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants. PMID:15831235

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Determinants of antipyretic misuse in children up to 5 years of age: a cross-sectional study.

PubMed

Bilenko, Natalya; Tessler, Hedva; Okbe, Ranya; Press, Joseph; Gorodischer, Rafael

2006-05-01

Fever in children is a common and usually benign symptom. It is known that antipyretic treatment is ineffective in the prevention of simple febrile seizures. Caregivers' administration of antipyretic medications to children has been reported, but data concerning the formulations used, actual doses administered, and effects of ethnicity and socioeconomic status on administration practices are incomplete. The aim of this study was to identify the factors affecting antipyretic administration (higher-than-recommended doses in particular) by caregivers to their febrile children in 2 differing cultural-ethnic backgrounds. This cross-sectional survey study, conducted from January to March 2002, was part of a larger, ongoing survey study of the differences in care givers' knowledge, beliefs, and attitudes concerning children's fever in the 2 major cultural-ethnic groups in the Negev District in Israel: Jews and Bedouin Moslems. It was conducted at the Pediatric Emergency Department (PED), Soroka Medical Center, Beer-Sheva, Israel. A structured questionnaire was administered to Jewish and Bedouin Moslem parents or usual caregivers of young (age, 0-60 months) children attending the PED due to fever. Each child's weight was obtained from the PED medical record. After completion of the interview, the reported antipyretic dose per kilogram of body weight was calculated. Less-than-recommended dose was defined as <9 mg/kg for acetaminophen and <4.5 mg/kg for ibuprofen. Higher-than-recommended dose was defined as >16.5 mg/kg for acetaminophen and >11 mg/kg for ibuprofen. The caregivers of a total of 201 children (mean [SD] age, 20 [17] months; mean [SD] weight, 10.4 [4.0] kg) were included in the study. The study included 101 Jewish and 100 Bedouin Moslem caregivers. The proportion of people surveyed who were parents was 98%; grandmothers, 2%. Differences existed between the 2 cultural-ethnic groups in the source of knowledge regarding antipyretic use in children (a significantly larger proportion of Jewish caregivers received their knowledge concerning antipyretic use from package inserts compared with Bedouin caregivers [25.7% vs 6.0%; P < 0.001], and a significantly lower proportion of Jewish caregivers used "other" sources [15.8% vs 39.0%; P < 0.001]). Most (65.2%) caregivers indicated that they administered antipyretics for no or minimal elevations in body temperature (<-38 degrees C); 52.7% administered individual acetaminophen doses within 10% of the recommended dose, 34.8 % administered a higher-than-recommended dose, and 21.4% repeated the dose at intervals of

The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

PubMed

Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

2013-01-01

The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

Toxicokinetics of fumonisin B1 in turkey poults and tissue persistence after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds.

PubMed

Tardieu, Didier; Bailly, Jean-Denis; Skiba, Fabien; Grosjean, François; Guerre, Philippe

2008-09-01

The kinetic of fumonisin B1 (FB1) after a single IV and oral dose, and FB1 persistence in tissue were investigated in turkey poults by HPLC after purification of samples on columns. After IV administration (single-dose: 10mg FB1/kg bw), serum concentration-time curves were best described by a three-compartment open model. Elimination half-life and mean residence time of FB1 were 85 and 52min, respectively. After oral administration (single-dose: 100mg FB1/kg bw) bioavailability was 3.2%; elimination half-life and mean residence time were 214 and 408min, respectively. Clearance of FB1 was 7.6 and 7.5ml/min/kg for IV and oral administration, respectively. Twenty-four hours after the administration of FB1 by the intravenous route, liver and kidney contained the highest levels of FB1 in tissues, level in muscle was low or below the limit of detection (LD, 13microg/kg). The persistence of FB1 in tissue was also studied after administration for 9 weeks of a feed that contained 5, 10 and 20mg FB1+FB2/kg diet. Eight hours after the last intake of 20mg FB1+FB2/kg feed (maximum recommended concentration of fumonisins established by the EU for avian feed), hepatic and renal FB1 concentrations were 119 and 22microg/kg, level in muscles was below the LD.

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population.

PubMed

Stumpf, Janice L; Skyles, Amy J; Alaniz, Cesar; Erickson, Steven R

2007-01-01

To evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. Cross-sectional, prospective study. University adult general internal medicine (AGIM) clinic. 104 adult patients presenting to the clinic over consecutive weekdays in December 2003. Three-page, written questionnaire. Ability of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. Although nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

A new biostimulation approach based on the concept of remaining P for soil bioremediation.

PubMed

Júlio, Aline Daniela Lopes; Fernandes, Rita de Cássia Rocha; Costa, Maurício Dutra; Neves, Júlio César Lima; Rodrigues, Edmo Montes; Tótola, Marcos Rogério

2018-02-01

C:N:P ratio is generally adopted to estimate the amount of nitrogen and phosphorus to be added to soils to accelerate biodegradation of organic contaminants. However, differences in P fixation among soils lead to varying amounts of available P when a specific dose of the element is applied to different soils. Thus, the application of fertilizers to achieve a previously established C:P ratio leads to biodegradation rates that can be lower than the theoretical maximum. In this study, we developed an equation to estimate the dose of P required to maximize organic contaminant biodegradation in soils as a function of remaining P (P-rem), using diesel as a model contaminant. The soils were contaminated with diesel and received six doses of P. CO 2 emission was used to estimate biodegradation of hydrocarbons. Biodegradation increased with P doses. The P level that provided the highest hydrocarbon biodegradation rate showed linear and negative correlation with P-rem. The result shows that the requirement for P decreases as the P-rem of the soil increases (or the P-fixing capacity decreases). The dose of P recommended to maximize hydrocarbon biodegradation rate in soil can be estimated by the formula P (mg/dm 3 ) = 436.5-5.39 × P-rem (mg/L). Copyright © 2017 Elsevier Ltd. All rights reserved.

Surface dose measurements for highly oblique electron beams.

PubMed

Ostwald, P M; Kron, T

1996-08-01

Clinical applications of electrons may involve oblique incidence of beams, and although dose variations for angles up to 60 degrees from normal incidence are well documented, no results are available for highly oblique beams. Surface dose measurements in highly oblique beams were made using parallel-plate ion chambers and both standard LiF:Mg, Ti and carbon-loaded LiF Thermoluminescent Dosimeters (TLD). Obliquity factors (OBF) or surface dose at an oblique angle divided by the surface dose at perpendicular incidence, were obtained for electron energies between 4 and 20 MeV. Measurements were performed on a flat solid water phantom without a collimator at 100 cm SSD. Comparisons were also made to collimated beams. The OBFs of surface doses plotted against the angle of incidence increased to a maximum dose followed by a rapid dropoff in dose. The increase in OBF was more rapid for higher energies. The maximum OBF occurred at larger angles for higher-energy beams and ranged from 73 degrees for 4 MeV to 84 degrees for 20 MeV. At the dose maximum, OBFs were between 130% and 160% of direct beam doses, yielding surface doses of up to 150% of Dmax for the 20 MeV beam. At 2 mm depth the dose ratio was found to increase initially with angle and then decrease as Dmax moved closer to the surface. A higher maximum dose was measured at 2 mm depth than at the surface. A comparison of ion chamber types showed that a chamber with a small electrode spacing and large guard ring is required for oblique dose measurement. A semiempirical equation was used to model the dose increase at the surface with different energy electron beams.

Investigation of photon beam models in heterogeneous media of modern radiotherapy.

PubMed

Ding, W; Johnston, P N; Wong, T P Y; Bubb, I F

2004-06-01

This study investigates the performance of photon beam models in dose calculations involving heterogeneous media in modern radiotherapy. Three dose calculation algorithms implemented in the CMS FOCUS treatment planning system have been assessed and validated using ionization chambers, thermoluminescent dosimeters (TLDs) and film. The algorithms include the multigrid superposition (MGS) algorithm, fast Fourier Transform Convolution (FFTC) algorithm and Clarkson algorithm. Heterogeneous phantoms used in the study consist of air cavities, lung analogue and an anthropomorphic phantom. Depth dose distributions along the central beam axis for 6 MV and 10 MV photon beams with field sizes of 5 cm x 5 cm and 10 cm x 10 cm were measured in the air cavity phantoms and lung analogue phantom. Point dose measurements were performed in the anthropomorphic phantom. Calculated results with three dose calculation algorithms were compared with measured results. In the air cavity phantoms, the maximum dose differences between the algorithms and the measurements were found at the distal surface of the air cavity with a 10 MV photon beam and a 5 cm x 5 cm field size. The differences were 3.8%. 24.9% and 27.7% for the MGS. FFTC and Clarkson algorithms. respectively. Experimental measurements of secondary electron build-up range beyond the air cavity showed an increase with decreasing field size, increasing energy and increasing air cavity thickness. The maximum dose differences in the lung analogue with 5 cm x 5 cm field size were found to be 0.3%. 4.9% and 6.9% for the MGS. FFTC and Clarkson algorithms with a 6 MV photon beam and 0.4%. 6.3% and 9.1% with a 10 MV photon beam, respectively. In the anthropomorphic phantom, the dose differences between calculations using the MGS algorithm and measurements with TLD rods were less than +/-4.5% for 6 MV and 10 MV photon beams with 10 cm x 10 cm field size and 6 MV photon beam with 5 cm x 5 cm field size, and within +/-7.5% for 10 MV with 5 cm x 5 cm field size, respectively. The FFTC and Clarkson algorithms overestimate doses at all dose points in the lung of the anthropomorphic phantom. In conclusion, the MGS is the most accurate dose calculation algorithm of investigated photon beam models. It is strongly recommended for implementation in modern radiotherapy with multiple small fields when heterogeneous media are in the treatment fields.

[Doses to organs at risk in conformational and stereotactic body radiation therapy: Liver].

PubMed

Debbi, K; Janoray, G; Scher, N; Deutsch, É; Mornex, F

2017-10-01

The liver is an essential organ that ensures many vital functions such as metabolism of bilirubin, glucose, lipids, synthesis of coagulation factors, destruction of many toxins, etc. The hepatic parenchyma can be irradiated during the management of digestive tumors, right basithoracic, esophagus, abdomen in toto or TBI. In addition, radiotherapy of the hepatic area, which is mainly stereotactic, now occupies a central place in the management of primary or secondary hepatic tumors. Irradiation of the whole liver, or part of it, may be complicated by radiation-induced hepatitis. It is therefore necessary to respect strict dosimetric constraints both in stereotactic and in conformational irradiation in order to limit the undesired irradiation of the hepatic parenchyma which may vary according to the treatment techniques, the basic hepatic function or the lesion size. The liver is an organ with a parallel architecture, so the average tolerable dose in the whole liver should be considered rather than the maximum tolerable dose at one point. The purpose of this article is to propose a development of dose recommendations during conformation or stereotactic radiotherapy of the liver. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy.

PubMed

Lorenzen, Ebbe L; Brink, Carsten; Taylor, Carolyn W; Darby, Sarah C; Ewertz, Marianne

2016-04-01

We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002. Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field. For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens. The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans. Copyright © 2016. Published by Elsevier Ireland Ltd.

Measurement of 131I activity in thyroid of nuclear medical staff and internal dose assessment in a Polish nuclear medical hospital.

PubMed

Brudecki, K; Kowalska, A; Zagrodzki, P; Szczodry, A; Mroz, T; Janowski, P; Mietelski, J W

2017-03-01

This paper presents results of 131 I thyroid activity measurements in 30 members of the nuclear medicine personnel of the Department of Endocrinology and Nuclear Medicine Holy Cross Cancer Centre in Kielce, Poland. A whole-body spectrometer equipped with two semiconductor gamma radiation detectors served as the basic research instrument. In ten out of 30 examined staff members, the determined 131 I activity was found to be above the detection limit (DL = 5 Bq of 131 I in the thyroid). The measured activities ranged from (5 ± 2) Bq to (217 ± 56) Bq. The highest activities in thyroids were detected for technical and cleaning personnel, whereas the lowest values were recorded for medical doctors. Having measured the activities, an attempt has been made to estimate the corresponding annual effective doses, which were found to range from 0.02 to 0.8 mSv. The highest annual equivalent doses have been found for thyroid, ranging from 0.4 to 15.4 mSv, detected for a cleaner and a technician, respectively. The maximum estimated effective dose corresponds to 32% of the annual background dose in Poland, and to circa 4% of the annual limit for the effective dose due to occupational exposure of 20 mSv per year, which is in compliance with the value recommended by the International Commission on Radiological Protection.

HADOC: a computer code for calculation of external and inhalation doses from acute radionuclide releases

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

Strenge, D.L.; Peloquin, R.A.

The computer code HADOC (Hanford Acute Dose Calculations) is described and instructions for its use are presented. The code calculates external dose from air submersion and inhalation doses following acute radionuclide releases. Atmospheric dispersion is calculated using the Hanford model with options to determine maximum conditions. Building wake effects and terrain variation may also be considered. Doses are calculated using dose conversion factor supplied in a data library. Doses are reported for one and fifty year dose commitment periods for the maximum individual and the regional population (within 50 miles). The fractional contribution to dose by radionuclide and exposure modemore » are also printed if requested.« less

A Methodology to Compare Insulin Dosing Recommendations in Real-Life Settings.

PubMed

Groat, Danielle; Grando, Maria A; Thompson, Bithika; Neto, Pedro; Soni, Hiral; Boyle, Mary E; Bailey, Marilyn; Cook, Curtiss B

2017-11-01

We propose a methodology to analyze complex real-life glucose data in insulin pump users. Patients with type 1 diabetes (T1D) on insulin pumps were recruited from an academic endocrinology practice. Glucose data, insulin bolus (IB) amounts, and self-reported alcohol consumption and exercise events were collected for 30 days. Rules were developed to retrospectively compare IB recommendations from the insulin pump bolus calculator (IPBC) against recommendations from a proposed decision aid (PDA) and for assessing the PDA's recommendation for exercise and alcohol. Data from 15 participants were analyzed. When considering instances where glucose was below target, the PDA recommended a smaller dose in 14%, but a larger dose in 13% and an equivalent IB in 73%. For glucose levels at target, the PDA suggested an equivalent IB in 58% compared to the subject's IPBC, but higher doses in 20% and lower in 22%. In events where postprandial glucose was higher than target, the PDA suggested higher doses in 25%, lower doses in 13%, and equivalent doses in 62%. In 64% of all alcohol events the PDA would have provided appropriate advice. In 75% of exercise events, the PDA appropriately advised an IB, a carbohydrate snack, or neither. This study provides a methodology to systematically analyze real-life data generated by insulin pumps and allowed a preliminary analysis of the performance of the PDA for insulin dosing. Further testing of the methodological approach in a broader diabetes population and prospective testing of the PDA are needed.

Radiation skyshine from a 6 MeV medical accelerator.

PubMed

Gossman, Michael S; McGinley, Patton H; Rising, Mary B; Pahikkala, A Jussi

2010-05-06

This study assesses the dose level from skyshine produced by a 6 MeV medical accelerator. The analysis of data collected on skyshine yields professional guidance for future investigators as they attempt to quantify and qualify radiation protection concerns in shielding therapy vaults. Survey measurements using various field sizes and at varying distances from a primary barrier have enabled us to identify unique skyshine behavior in comparison to other energies already seen in literature. In order to correctly quantify such measurements outside a shielded barrier, one must take into consideration the fact that a skyshine maximum may not be observed at the same distance for all field sizes. A physical attribute of the skyshine scatter component was shown to increase to a maximum value at 4.6 m from the barrier for the largest field size used. We recommend that the largest field sizes be used in the field for the determination of skyshine effect and that the peak value be further analyzed specifically when considering shielding designs.

Radiation Exposure to Relatives of Patients Treated with Iodine-131 for Thyroid Cancer at Siriraj Hospital.

PubMed

Tonnonchiang, Siriporn; Sritongkul, Nopamon; Chaudakshetrin, Pachee; Tuntawiroon, Malulee

2016-02-01

Thyroid cancer patients treated with 1-131 are potential source of radiation exposure to relatives who are knowingly and willingly exposed to ionizing radiation as a result of providing comfort to patients undergoing I-131 therapy. This study aims to determine radiation dose received by relatives who care for non self-supporting 1-131 patients at Siriraj Hospital. Twenty caregivers of 20 patients underwent I-131 therapy for thyroid cancer with a standard protocol were given specific instructions with regard to radiation safety and provided with electronic digital dosimeter to continuously measure radiation dose received on daily basis, three days in the hospital. On the day patient is released, thyroid uptake estimates were performed to assess internal radiation dose received by caregivers. The 3-day accumulative doses to caregivers to patients receiving 150 mCi (n = 11) and 200 mCi (n = 9) of I-131 ranged from 37 to 333 uSv and 176 to 1,920 pSv respectively depending on the level of supports required. Thyroid uptake estimates in all caregivers were undetectable. Dosimeter indicated a maximum whole-body dose of1.92 mSv was more than the public dose limit of] mSv but within the dose constraint of 5 mSv for caregivers. Radiation dose to caregivers of a non self-supporting hospitalized patient undergoing 1-131 therapy were well below the limits recommended by the ICRP. The patients can be comforted with confidence that dose to caregivers will be less than the limit. This study provides guidance for medical practitioners to obtain practical radiation safety concerns associated with hospitalized patients receiving I-131 therapy especially when patient needs assistance.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

PubMed

Bautista, Francisco; Moreno, Lucas; Marshall, Lynley; Pearson, Andrew D J; Geoerger, Birgit; Paoletti, Xavier

2017-11-01

Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

TH-AB-201-12: Using Machine Log-Files for Treatment Planning and Delivery QA

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

Stanhope, C; Liang, J; Drake, D

2016-06-15

Purpose: To determine the segment reduction and dose resolution necessary for machine log-files to effectively replace current phantom-based patient-specific quality assurance, while minimizing computational cost. Methods: Elekta’s Log File Convertor R3.2 records linac delivery parameters (dose rate, gantry angle, leaf position) every 40ms. Five VMAT plans [4 H&N, 1 Pulsed Brain] comprised of 2 arcs each were delivered on the ArcCHECK phantom. Log-files were reconstructed in Pinnacle on the phantom geometry using 1/2/3/4° control point spacing and 2/3/4mm dose grid resolution. Reconstruction effectiveness was quantified by comparing 2%/2mm gamma passing rates of the original and log-file plans. Modulation complexity scoresmore » (MCS) were calculated for each beam to correlate reconstruction accuracy and beam modulation. Percent error in absolute dose for each plan-pair combination (log-file vs. ArcCHECK, original vs. ArcCHECK, log-file vs. original) was calculated for each arc and every diode greater than 10% of the maximum measured dose (per beam). Comparing standard deviations of the three plan-pair distributions, relative noise of the ArcCHECK and log-file systems was elucidated. Results: The original plans exhibit a mean passing rate of 95.1±1.3%. The eight more modulated H&N arcs [MCS=0.088±0.014] and two less modulated brain arcs [MCS=0.291±0.004] yielded log-file pass rates most similar to the original plan when using 1°/2mm [0.05%±1.3% lower] and 2°/3mm [0.35±0.64% higher] log-file reconstructions respectively. Log-file and original plans displayed percent diode dose errors 4.29±6.27% and 3.61±6.57% higher than measurement. Excluding the phantom eliminates diode miscalibration and setup errors; log-file dose errors were 0.72±3.06% higher than the original plans – significantly less noisy. Conclusion: For log-file reconstructed VMAT arcs, 1° control point spacing and 2mm dose resolution is recommended, however, less modulated arcs may allow less stringent reconstructions. Following the aforementioned reconstruction recommendations, the log-file technique is capable of detecting delivery errors with equivalent accuracy and less noise than ArcCHECK QA. I am funded by an Elekta Research Grant.« less

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study.

PubMed

Lulla, Rishi R; Goldman, Stewart; Yamada, Tohru; Beattie, Craig W; Bressler, Linda; Pacini, Michael; Pollack, Ian F; Fisher, Paul Graham; Packer, Roger J; Dunkel, Ira J; Dhall, Girish; Wu, Shengjie; Onar, Arzu; Boyett, James M; Fouladi, Maryam

2016-09-01

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Is ICRP guidance on the use of reference levels consistent?

PubMed

Hedemann-Jensen, Per; McEwan, Andrew C

2011-12-01

In ICRP 103, which has replaced ICRP 60, it is stated that no fundamental changes have been introduced compared with ICRP 60. This is true except that the application of reference levels in emergency and existing exposure situations seems to be applied inconsistently, and also in the related publications ICRP 109 and ICRP 111. ICRP 103 emphasises that focus should be on the residual doses after the implementation of protection strategies in emergency and existing exposure situations. If possible, the result of an optimised protection strategy should bring the residual dose below the reference level. Thus the reference level represents the maximum acceptable residual dose after an optimised protection strategy has been implemented. It is not an 'off-the-shelf item' that can be set free of the prevailing situation. It should be determined as part of the process of optimising the protection strategy. If not, protection would be sub-optimised. However, in ICRP 103 some inconsistent concepts have been introduced, e.g. in paragraph 279 which states: 'All exposures above or below the reference level should be subject to optimisation of protection, and particular attention should be given to exposures above the reference level'. If, in fact, all exposures above and below reference levels are subject to the process of optimisation, reference levels appear superfluous. It could be considered that if optimisation of protection below a fixed reference level is necessary, then the reference level has been set too high at the outset. Up until the last phase of the preparation of ICRP 103 the concept of a dose constraint was recommended to constrain the optimisation of protection in all types of exposure situations. In the final phase, the term 'dose constraint' was changed to 'reference level' for emergency and existing exposure situations. However, it seems as if in ICRP 103 it was not fully recognised that dose constraints and reference levels are conceptually different. The use of reference levels in radiological protection is reviewed. It is concluded that the recommendations in ICRP 103 and related ICRP publications seem to be inconsistent regarding the use of reference levels in existing and emergency exposure situations.

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

Uncertainties in Assesment of the Vaginal Dose for Intracavitary Brachytherapy of Cervical Cancer using a Tandem-ring Applicator

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

Berger, Daniel; Dimopoulos, Johannes; Georg, Petra

2007-04-01

Purpose: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators. Methods and Materials: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose-volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)-based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm{sup 3}, 1 cm{sup 3}, 2 cm{sup 3}, and at defined pointsmore » on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup. Results: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose-point and dose-volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%. Conclusions: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated.« less

Geological sources of fluoride and acceptable intake of fluoride in an endemic fluorosis area, southern Iran.

PubMed

Battaleb-Looie, Sedigheh; Moore, Farid; Jacks, Gunnar; Ketabdari, Mohammad Reza

2012-10-01

The present study is the first attempt to put forward possible source(s) of fluoride in the Dashtestan area, Bushehr Province, southern Iran. In response to reports on the high incidence of dental fluorosis, 35 surface and groundwater samples were collected and analysed for fluoride. The results indicate that dissolved fluoride in the study area is above the maximum permissible limit recommended by the World Health Organization (WHO). An additional 35 soil and rock samples were also collected and analysed for fluoride, and rock samples were subjected to petrographic investigations and X-ray diffraction. The results of these analyses show that the most likely source for fluoride in the groundwater is from clay minerals (chlorite) and micas (muscovite, sericite, and biotite) in the soils and rocks in the area. We also note that due to the high average temperatures all year round and excessive water consumption in the area, the optimum fluoride dose level should be lower than that recommended by the WHO.

ASSESSMENT OF RADON IN SOIL AND WATER IN DIFFERENT REGIONS OF KOLHAPUR DISTRICT, MAHARASHTRA, INDIA.

PubMed

Raste, P M; Sahoo, B K; Gaware, J J; Sharma, Anil; Waikar, M R; Shaikh, A A; Sonkawade, R G

2018-03-19

Researchers have already established that inhalation of high radon concentration is hazardous to human health. Radon concentration has been measured in water and soil, in various part of Kolhapur district has been carried out by the AQTEK Smart RnDuo which is an active device technique. The observed minimum value of the radon mass exhalation rate of the soil is 13.16 ± 0.83 mBq/kg/h and maximum is 35.11 ± 1.84 mBq/kg/h. The minimum value of the Radon concentration in water is 0.33 ± 0.052 Bq/L and maximum is 7.32 ± 0.078 Bq/L. These values of radon concentration are below the action of recommended level by the USEPA, which is set as the maximum contaminant level of 11.1-148 Bq/L of radon in drinking water. Total annual effective dose rate of water is 11 μSv/y. The purpose of present study is to assess radiological risk from consumption of water that provide in Kolhapur district and to evaluate the radon mass exhalation rate of soil in few places of Kolhapur district.

Influence of intravenous opioid dose on postoperative ileus.

PubMed

Barletta, Jeffrey F; Asgeirsson, Theodor; Senagore, Anthony J

2011-07-01

Intravenous opioids represent a major component in the pathophysiology of postoperative ileus (POI). However, the most appropriate measure and threshold to quantify the association between opioid dose (eg, average daily, cumulative, maximum daily) and POI remains unknown. To evaluate the relationship between opioid dose, POI, and length of stay (LOS) and identify the opioid measure that was most strongly associated with POI. Consecutive patients admitted to a community teaching hospital who underwent elective colorectal surgery by any technique with an enhanced-recovery protocol postoperatively were retrospectively identified. Patients were excluded if they received epidural analgesia, developed a major intraabdominal complication or medical complication, or had a prolonged workup prior to surgery. Intravenous opioid doses were quantified and converted to hydromorphone equivalents. Classification and regression tree (CART) analysis was used to determine the dosing threshold for the opioid measure most associated with POI and define high versus low use of opioids. Risk factors for POI and prolonged LOS were determined through multivariate analysis. The incidence of POI in 279 patients was 8.6%. CART analysis identified a maximum daily intravenous hydromorphone dose of 2 mg or more as the opioid measure most associated with POI. Multivariate analysis revealed maximum daily hydromorphone dose of 2 mg or more (p = 0.034), open surgical technique (p = 0.045), and days of intravenous narcotic therapy (p = 0.003) as significant risk factors for POI. Variables associated with increased LOS were POI (p < 0.001), maximum daily hydromorphone dose of 2 mg or more (p < 0.001), and age (p = 0.005); laparoscopy (p < 0.001) was associated with a decreased LOS. Intravenous opioid therapy is significantly associated with POI and prolonged LOS, particularly when the maximum hydromorphone dose per day exceeds 2 mg. Clinicians should consider alternative, nonopioid-based pain management options when this occurs.

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study.

PubMed

Dupuis, Jehan; Morschhauser, Franck; Ghesquières, Hervé; Tilly, Hervé; Casasnovas, Olivier; Thieblemont, Catherine; Ribrag, Vincent; Bossard, Céline; Le Bras, Fabien; Bachy, Emmanuel; Hivert, Bénédicte; Nicolas-Virelizier, Emmanuelle; Jardin, Fabrice; Bastie, Jean-Noel; Amorim, Sandy; Lazarovici, Julien; Martin, Antoine; Coiffier, Bertrand

2015-04-01

Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia. Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. Celgene. Copyright © 2015 Elsevier Ltd. All rights reserved.

Human papillomavirus vaccination coverage using two-dose or three-dose schedule criteria.

PubMed

Lin, Xia; Rodgers, Loren; Zhu, Liping; Stokley, Shannon; Meites, Elissa; Markowitz, Lauri E

2017-10-13

In October 2016, the Advisory Committee on Immunization Practices (ACIP) updated the human papillomavirus (HPV) vaccination recommendation to include a 2-dose schedule for U.S. adolescents initiating the vaccine series before their 15th birthday. We analyzed records for >4million persons aged 9-17years receiving any HPV vaccine by the end of each quarter during January 1, 2014-September 30, 2016 from six Immunization Information Systems Sentinel Sites, and reclassified HPV vaccination up-to-date coverage according to the updated recommendations. Compared with HPV vaccination up-to-date coverage by the 3-dose schedule only, including criteria for either a 2-dose or 3-dose schedule increased up-to-date coverage in 11-12, 13-14, and 15-17 year-olds by 4.5-8.5 percentage points. The difference between 3-dose up-to-date coverage and 2- or 3-dose up-to-date coverage was greatest in late 2016. These data provide baseline HPV vaccination coverage using current ACIP recommendations. Published by Elsevier Ltd.

Dose‐finding methods for Phase I clinical trials using pharmacokinetics in small populations

PubMed Central

Zohar, Sarah; Lentz, Frederike; Alberti, Corinne; Friede, Tim; Stallard, Nigel; Comets, Emmanuelle

2017-01-01

The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose‐finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker‐defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose‐finding and PK analyses to allow better estimation of the dose‐toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose‐finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose‐toxicity curve while maintaining the performance in terms of MTD selection compared to dose‐finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose‐toxicity relationship, facilitating better dose recommendation for subsequent trials. PMID:28321893

Direct measurement of a patient's entrance skin dose during pediatric cardiac catheterization

PubMed Central

Sun, Lue; Mizuno, Yusuke; Iwamoto, Mari; Goto, Takahisa; Koguchi, Yasuhiro; Miyamoto, Yuka; Tsuboi, Koji; Chida, Koichi; Moritake, Takashi

2014-01-01

Children with complex congenital heart diseases often require repeated cardiac catheterization; however, children are more radiosensitive than adults. Therefore, radiation-induced carcinogenesis is an important consideration for children who undergo those procedures. We measured entrance skin doses (ESDs) using radio-photoluminescence dosimeter (RPLD) chips during cardiac catheterization for 15 pediatric patients (median age, 1.92 years; males, n = 9; females, n = 6) with cardiac diseases. Four RPLD chips were placed on the patient's posterior and right side of the chest. Correlations between maximum ESD and dose–area products (DAP), total number of frames, total fluoroscopic time, number of cine runs, cumulative dose at the interventional reference point (IRP), body weight, chest thickness, and height were analyzed. The maximum ESD was 80 ± 59 (mean ± standard deviation) mGy. Maximum ESD closely correlated with both DAP (r = 0.78) and cumulative dose at the IRP (r = 0.82). Maximum ESD for coiling and ballooning tended to be higher than that for ablation, balloon atrial septostomy, and diagnostic procedures. In conclusion, we directly measured ESD using RPLD chips and found that maximum ESD could be estimated in real-time using angiographic parameters, such as DAP and cumulative dose at the IRP. Children requiring repeated catheterizations would be exposed to high radiation levels throughout their lives, although treatment influences radiation dose. Therefore, the radiation dose associated with individual cardiac catheterizations should be analyzed, and the effects of radiation throughout the lives of such patients should be followed. PMID:24968708

Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose.

PubMed

Dickie, Colleen I; Parent, Amy L; Griffin, Anthony M; Fung, Sharon; Chung, Peter W M; Catton, Charles N; Ferguson, Peter C; Wunder, Jay S; Bell, Robert S; Sharpe, Michael B; O'Sullivan, Brian

2009-11-15

To examine the relationship between tumor location, bone dose, and irradiated bone length on the development of radiation-induced fractures for lower extremity soft tissue sarcoma (LE-STS) patients treated with limb-sparing surgery and radiotherapy (RT). Of 691 LE-STS patients treated from 1989 to 2005, 31 patients developed radiation-induced fractures. Analysis was limited to 21 fracture patients (24 fractures) who were matched based on tumor size and location, age, beam arrangement, and mean total cumulative RT dose to a random sample of 53 nonfracture patients and compared for fracture risk factors. Mean dose to bone, RT field size (FS), maximum dose to a 2-cc volume of bone, and volume of bone irradiated to >or=40 Gy (V40) were compared. Fracture site dose was determined by comparing radiographic images and surgical reports to fracture location on the dose distribution. For fracture patients, mean dose to bone was 45 +/- 8 Gy (mean dose at fracture site 59 +/- 7 Gy), mean FS was 37 +/- 8 cm, maximum dose was 64 +/- 7 Gy, and V40 was 76 +/- 17%, compared with 37 +/- 11 Gy, 32 +/- 9 cm, 59 +/- 8 Gy, and 64 +/- 22% for nonfracture patients. Differences in mean, maximum dose, and V40 were statistically significant (p = 0.01, p = 0.02, p = 0.01). Leg fractures were more common above the knee joint. The risk of radiation-induced fracture appears to be reduced if V40 <64%. Fracture incidence was lower when the mean dose to bone was <37 Gy or maximum dose anywhere along the length of bone was <59 Gy. There was a trend toward lower mean FS for nonfracture patients.

Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.

PubMed

Arem, Hannah; Moore, Steven C; Patel, Alpa; Hartge, Patricia; Berrington de Gonzalez, Amy; Visvanathan, Kala; Campbell, Peter T; Freedman, Michal; Weiderpass, Elisabete; Adami, Hans Olov; Linet, Martha S; Lee, I-Min; Matthews, Charles E

2015-06-01

The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. Leisure time moderate- to vigorous-intensity physical activity. The upper limit of mortality benefit from high levels of leisure time physical activity. Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

A systematic evaluation of the dose-rate constant determined by photon spectrometry for 21 different models of low-energy photon-emitting brachytherapy sources.

PubMed

Chen, Zhe Jay; Nath, Ravinder

2010-10-21

The aim of this study was to perform a systematic comparison of the dose-rate constant (Λ) determined by the photon spectrometry technique (PST) with the consensus value ((CON)Λ) recommended by the American Association of Physicists in Medicine (AAPM) for 21 low-energy photon-emitting interstitial brachytherapy sources. A total of 63 interstitial brachytherapy sources (21 different models with 3 sources per model) containing either (125)I (14 models), (103)Pd (6 models) or (131)Cs (1 model) were included in this study. A PST described by Chen and Nath (2007 Med. Phys. 34 1412-30) was used to determine the dose-rate constant ((PST)Λ) for each source model. Source-dependent variations in (PST)Λ were analyzed systematically against the spectral characteristics of the emitted photons and the consensus values recommended by the AAPM brachytherapy subcommittee. The values of (PST)Λ for the encapsulated sources of (103)Pd, (125)I and (131)Cs varied from 0.661 to 0.678 cGyh(-1) U(-1), 0.959 to 1.024 cGyh(-1)U(-1) and 1.066 to 1.073 cGyh(-1)U(-1), respectively. The relative variation in (PST)Λ among the six (103)Pd source models, caused by variations in photon attenuation and in spatial distributions of radioactivity among the source models, was less than 3%. Greater variations in (PST)Λ were observed among the 14 (125)I source models; the maximum relative difference was over 6%. These variations were caused primarily by the presence of silver in some (125)I source models and, to a lesser degree, by the variations in photon attenuation and in spatial distribution of radioactivity among the source models. The presence of silver generates additional fluorescent x-rays with lower photon energies which caused the (PST)Λ value to vary from 0.959 to 1.019 cGyh(-1)U(-1) depending on the amount of silver used by a given source model. For those (125)I sources that contain no silver, their (PST)Λ was less variable and had values within 1% of 1.024 cGyh(-1)U(-1). For the 16 source models that currently have an AAPM recommended (CON)Λ value, the agreement between (PST)Λ and (CON)Λ was less than 2% for 15 models and was 2.6% for 1 (103)Pd source model. Excellent agreement between (PST)Λ and (CON)Λ was observed for all source models that currently have an AAPM recommended consensus dose-rate constant value. These results demonstrate that the PST is an accurate and robust technique for the determination of the dose-rate constant for low-energy brachytherapy sources.

Degradation of chlorpyrifos residues in apple under temperate conditions of Kashmir Valley.

PubMed

Mukhtar, Malik; Sherwani, Asma; Wani, Ashraf Alam; Ahmed, Sheikh Bilal; Sofi, Javid Ahmad; Bano, Parveena

2015-08-01

The present studies were carried out to observe the dissipation pattern of chlorpyrifos on apple in Kashmir Valley. Persistence of chlorpyrifos in apple was studied following two applications rates of chlorpyrifos (Dursban 20 EC) at 200 g a.i. ha(-1) (single dose T 1) and 400 g a.i. ha(-1) (double dose T 2). The average initial deposit of chlorpyrifos was found to be 1.61 and 1.98 μg g(-1) for T 1 and T 2 application rates respectively on apple. The residues dissipated to 0.09 and 0.06 μg g(-1) after 15- and 30-day post treatment with half-life periods of 3.34 and 5.47 days in T 1 and T 2 application rates, respectively. The residues of chlorpyrifos dissipated to below limit of quantification (LOQ) of 0.04 μg g(-1) after 30 day at T 1 application rate. A waiting period of 6 days must be observed for chlorpyrifos on apple at recommended application rate for the safety of consumers. Theoretical maximum residue contribution (TMRC) values were found to be far less than maximum permissible intake (MPI) at 0 day in both the dosages suggesting chlorpyrifos on apple in Kashmir is unlikely to cause health risks.

Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.

PubMed

Wright, Jennifer Gordon; Quinn, Conrad P; Shadomy, Sean; Messonnier, Nancy

2010-07-23

These recommendations from the Advisory Committee on Immunization Practices (ACIP) update the previous recommendations for anthrax vaccine adsorbed (AVA) (CDC. Use of anthrax vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2000;49:1-20; CDC. Use of anthrax vaccine in response to terrorism: supplemental recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2002;51:1024-6) and reflect the status of anthrax vaccine supplies in the United States. This statement 1) provides updated information on anthrax epidemiology; 2) summarizes the evidence regarding the effectiveness and efficacy, immunogenicity, and safety of AVA; 3) provides recommendations for pre-event and preexposure use of AVA; and 4) provides recommendations for postexposure use of AVA. In certain instances, recommendations that did not change were clarified. No new licensed anthrax vaccines are presented. Substantial changes to these recommendations include the following: 1) reducing the number of doses required to complete the pre-event and preexposure primary series from 6 doses to 5 doses, 2) recommending intramuscular rather than subcutaneous AVA administration for preexposure use, 3) recommending AVA as a component of postexposure prophylaxis in pregnant women exposed to aerosolized Bacillus anthracis spores, 4) providing guidance regarding preexposure vaccination of emergency and other responder organizations under the direction of an occupational health program, and 5) recommending 60 days of antimicrobial prophylaxis in conjunction with 3 doses of AVA for optimal protection of previously unvaccinated persons after exposure to aerosolized B. anthracis spores.

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.

Recommendation of the Advisory Committee on Immunization Practices for Use of a Third Dose of Mumps Virus-Containing Vaccine in Persons at Increased Risk for Mumps During an Outbreak.

PubMed

Marin, Mona; Marlow, Mariel; Moore, Kelly L; Patel, Manisha

2018-01-12

A substantial increase in the number of mumps outbreaks and outbreak-associated cases has occurred in the United States since late 2015 (1,2). To address this public health problem, the Advisory Committee on Immunization Practices (ACIP) reviewed the available evidence and determined that a third dose of measles, mumps, rubella (MMR) vaccine is safe and effective at preventing mumps. During its October 2017 meeting, ACIP recommended a third dose of a mumps virus-containing vaccine* for persons previously vaccinated with 2 doses who are identified by public health authorities as being part of a group or population at increased risk for acquiring mumps because of an outbreak. The purpose of the recommendation is to improve protection of persons in outbreak settings against mumps disease and mumps-related complications. This recommendation supplements the existing ACIP recommendations for mumps vaccination (3).

Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer.

PubMed

Sarduy, M R; García, I; Coca, M A; Perera, A; Torres, L A; Valenzuela, C M; Baladrón, I; Solares, M; Reyes, V; Hernández, I; Perera, Y; Martínez, Y M; Molina, L; González, Y M; Ancízar, J A; Prats, A; González, L; Casacó, C A; Acevedo, B E; López-Saura, P A; Alonso, D F; Gómez, R; Perea-Rodríguez, S E

2015-05-12

We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose. Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using (99)Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry. Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1 ± 8.9 vs 31.3 ± 12.9 mg (P = 0.01). Both, AUC24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P < 0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P = 0.03) in tumour specimens. Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.

Radon estimation in water resources of Mandi - Dharamshala region of Himachal Pradesh, India for health risk assessments

NASA Astrophysics Data System (ADS)

Kumar, Gulshan; Kumari, Punam; Kumar, Mukesh; Kumar, Arvind; Prasher, Sangeeta; Dhar, Sunil

2017-07-01

The present study deals with the radon estimation in 40 water samples collected from different natural resources and radium content in the soils of Mandi-Dharamshala Region. Radon concentration is determined by using RAD-7 detector and radium contents of the soil in vicinity of water resources is as well measured by using LR-115 type - II detector, which is further correlated with radon concentration in water samples. The potential health risks related with 222Rn have also been estimated. The results show that the radon concentrations within the range of 1.51 to 22.7Bq/l with an average value of 5.93 Bq/l for all type of water samples taken from study area. The radon concentration in water samples is found lower than 100Bq/l, the exposure limit of radon in water recommended by the World Health Organization. The calculated average effective dose of radon received by the people of study area is 0.022 mSv/y with maximum of 0.083 mSv/y and minimum 0.0056 mSv/y. The total effective dose in all sites of the studied area is found to be within the safe limit (0.1 mSv/year) recommended by World Health Organization. The average value of radium content in the soil of study area is 6.326 Bq/kg.

Dosimetric evaluation of high-dose-rate interstitial brachytherapy boost treatments for localized prostate cancer.

PubMed

Fröhlich, Georgina; Agoston, Péter; Lövey, József; Somogyi, András; Fodor, János; Polgár, Csaba; Major, Tibor

2010-07-01

To quantitatively evaluate the dose distributions of high-dose-rate (HDR) prostate implants regarding target coverage, dose homogeneity, and dose to organs at risk. Treatment plans of 174 implants were evaluated using cumulative dose-volume histograms (DVHs). The planning was based on transrectal ultrasound (US) imaging, and the prescribed dose (100%) was 10 Gy. The tolerance doses to rectum and urethra were 80% and 120%, respectively. Dose-volume parameters for target (V90, V100, V150, V200, D90, D(min)) and quality indices (DNR [dose nonuniformity ratio], DHI [dose homogeneity index], CI [coverage index], COIN [conformal index]) were calculated. Maximum dose in reference points of rectum (D(r)) and urethra (D(u)), dose to volume of 2 cm(3) of the rectum (D(2ccm)), and 0.1 cm(3) and 1% of the urethra (D(0.1ccm) and D1) were determined. Nonparametric correlation analysis was performed between these parameters. The median number of needles was 16, the mean prostate volume (V(p)) was 27.1 cm(3). The mean V90, V100, V150, and V200 were 99%, 97%, 39%, and 13%, respectively. The mean D90 was 109%, and the D(min) was 87%. The mean doses in rectum and urethra reference points were 75% and 119%, respectively. The mean volumetric doses were D(2ccm) = 49% for the rectum, D(0.1ccm) = 126%, and D1 = 140% for the urethra. The mean DNR was 0.37, while the DHI was 0.60. The mean COIN was 0.66. The Spearman rank order correlation coefficients for volume doses to rectum and urethra were R(D(r),D(2ccm)) = 0.69, R(D(u),D0.(1ccm)) = 0.64, R(D(u),D1) = 0.23. US-based treatment plans for HDR prostate implants based on the real positions of catheters provided acceptable dose distributions. In the majority of the cases, the doses to urethra and rectum were kept below the defined tolerance levels. For rectum, the dose in reference points correlated well with dose-volume parameters. For urethra dose characterization, the use of D1 volumetric parameter is recommended.

Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose.

PubMed

Wang, Qiong; Tan, Yonghong; Zhang, Na; Xu, Yingyi; Wei, Wei; She, Yingjun; Bi, Xiaobao; Zhao, Baisong; Ruan, Xiangcai

2017-07-01

The developing brains of pediatric patients are highly vulnerable to anesthetic regimen (e.g., lidocaine), potentially causing neurological impairment. Recently, dexmedetomidine (DEX) has been used as an adjunct for sedation, and was shown to exert dose-dependent neuroprotective effects during brain injury. However, the maximum safe dose of DEX is unclear, and its protective effects against lidocaine-related neurotoxicity need to be confirmed. In this study, PC12 and NG108-15 cells were used to estimate safe, non-cytotoxic doses of DEX. We found that 100 and 60μM are the maximum safe dose of DEX for PC12 and NG108-15 cells, respectively, with no significant cytotoxicity. Lidocaine was found to remarkably inhibit cell vitality, but could be reversed by different doses of DEX, especially its maximum safe dose. Furthermore, the apoptosis induced by lidocaine was also assessed, and 100 and 60μM DEX showed optimal protective effects in PC12 and NG108-15 cells, respectively. Mechanistically, DEX activated the mitogen-activated protein kinase (MAPK) pathway, impaired caspase-3 expression, and enhanced anti-apoptotic factor Bcl-2 to resist lidocaine-induced apoptosis, indicating that the optimal dose of DEX alleviates lidocaine-induced cytotoxicity and should be considered in clinical application. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

Loupot, S; Han, T; Salehpour, M

Purpose: To quantify the difference in dose to PTV-EVAL and OARs (skin and rib) as calculated by (TG43) and heterogeneous calculations (CCC). Methods: 25 patient plans (5 Contura and 20 SAVI) were selected for analysis. Clinical dose distributions were computed with a commercially available treatment planning algorithm (TG43-D-(w,w)) and then recomputed with a pre-clinical collapsed cone convolution algorithm (CCCD-( m,m)). PTV-EVAL coverage (V90%, V95%), and rib and skin maximum dose were compared via percent difference. Differences in dose to normal tissue (V150cc, V200cc of PTV-EVAL) were also compared. Changes in coverage and maximum dose to organs at risk are reportedmore » in percent change, (100*(TG43 − CCC) / TG43)), and changes in maximum dose to normal tissue are absolute change in cc (TG43 − CCC). Results: Mean differences in V90, V95, V150, and V200 for the SAVI cases were −0.2%, −0.4%, −0.03cc, and −0.14cc, respectively, with maximum differences of −0.78%, −1.7%, 1.28cc, and 1.01cc, respectively. Mean differences in the 0.1cc dose to the rib and skin were −1.4% and −0.22%, respectively, with maximum differences of −4.5% and 16%, respectively. Mean differences in V90, V95, V150, and V200 for the Contura cases were −1.2%, −2.1%, −1.8cc, and −0.59cc, respectively, with maximum differences of −2.0%, −3.16%, −2.9cc, and −0.76cc, respectively. Mean differences in the 0.1cc dose to the rib and skin were −2.6% and −3.9%, respectively, with maximum differences of −3.2% and −5.7%, respectively. Conclusion: The effects of translating clinical knowledge based on D-(w,w) to plans reported in D-(m,m) are minimal (2% or less) on average, but vary based on the type and placement of the device, source, and heterogeneity information.« less

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination.

PubMed

Metsvaht, Tuuli; Nellis, Georgi; Varendi, Heili; Nunn, Anthony J; Graham, Susan; Rieutord, Andre; Storme, Thomas; McElnay, James; Mulla, Hussain; Turner, Mark A; Lutsar, Irja

2015-04-16

Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement. A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis. In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations. The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

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 study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study.

PubMed

Sato, Yasushi; Hirakawa, Masahiro; Ohnuma, Hiroyuki; Takahashi, Minoru; Okamoto, Tetsuro; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Furuhata, Tomohisa; Takemasa, Ichiro; Kato, Junji; Takayama, Tetsuji

2017-12-01

The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100 mg/m 2 , day 1), capecitabine (1700 mg/m 2 per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m 2 for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m 2 , day 1 and, thereafter, 250 mg/m 2 every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m 2 . Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m 2 . The observed response rate was promising and warrants further investigation.

42 CFR 82.31 - How can the public recommend changes to scientific elements underlying the dose reconstruction...

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false How can the public recommend changes to scientific... ACTIVITIES METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT OF 2000 Updating the Scientific Elements Underlying Dose Reconstructions § 82.31 How...

42 CFR 82.31 - How can the public recommend changes to scientific elements underlying the dose reconstruction...

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false How can the public recommend changes to scientific... ACTIVITIES METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT OF 2000 Updating the Scientific Elements Underlying Dose Reconstructions § 82.31 How...

42 CFR 82.31 - How can the public recommend changes to scientific elements underlying the dose reconstruction...

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false How can the public recommend changes to scientific... ACTIVITIES METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT OF 2000 Updating the Scientific Elements Underlying Dose Reconstructions § 82.31 How...

42 CFR 82.31 - How can the public recommend changes to scientific elements underlying the dose reconstruction...

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false How can the public recommend changes to scientific... ACTIVITIES METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT OF 2000 Updating the Scientific Elements Underlying Dose Reconstructions § 82.31 How...

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide

PubMed Central

Abel, Samantha; Nichols, Donald J; Brearley, Christopher J; Eve, Malcolm D

2000-01-01

Aims The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Methods Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 μg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1–2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. Results Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml−1 increase in plasma dofetilide concentration produced a 17–19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. Conclusions These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative. PMID:10606839

Use of gastroprotective agents in recommended doses in hospitalized patients receiving NSAIDs: a drug utilization study.

PubMed

Erdeljic, Viktorija; Francetic, Igor; Macolic Sarinic, Viola; Bilusic, Marinko; Makar Ausperger, Ksenija; Huic, Mirjana; Mercep, Iveta

2006-10-01

In recent years, studies investigated to what extend recommendations for co-prescribing gastroprotective agents in prevention of NSAID-induced gastrointestinal complications are followed in clinical practice. However, only a few studies have also taken into consideration the recommended dose of gastroprotectives prescribed in NSAID-induced ulcer prophylaxis. The aim of our study was to evaluate the prevalence of concomitant use of gastroprotectives with NSAIDs in hospitalized patients, with emphasis on the recommended dose of gastroprotectives for ulcer prophylaxis. This observational, cross-sectional, drug utilization study included all adult patients receiving NSAIDs hospitalized in the Clinical Hospital Center Zagreb on the day of the study. Data on age, sex, comorbidities, indications for NSAID use, type/dose of NSAIDs and gastroprotectives, history of gastrointestinal events, active gastrointestinal symptoms and risk factors were evaluated. Study outcomes were: (1) prevalence of prescription of gastroprotectives among NSAID-users at risk; (2) prevalence of prescription of gastroprotective in recommended dose; (3) association between risk factors and prescription of GPAs. The rates of gastroprotectives prescription were significantly higher in NSAID-users with concomitant risk factors as compared to patients without risk factors [47/70 (67.1%) and 8/22 (36.4%), respectively; p=0.01072]. However, gastroprotection in recommended ulcer-preventive dose was low in both groups [8/70 (11.4%) and 9/92 (9.8%), respectively]. The number of concomitant risk factors did not increase the odds of receiving anti-ulcer therapy (odds ratio 0.7279). Thirty-three percent of patients with concomitant risk factors were not prescribed gastroprotectives. Ibuprofen, NSAID with the lowest risk of inducing gastrointestinal complications, was prescribed in only two patients. The results indicate high awareness among hospital physicians about possible NSAID-induced gastrointestinal complications, but insufficient knowledge about risk factors related to NSAID-induced gastrointestinal toxicity, recommended dose of gastroprotectives in NSAID-induced ulcer prophylaxis and gastrointestinal toxicity of different types of NSAIDs.

Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study.

PubMed

Merchan, Jaime R; Qin, Rui; Pitot, Henry; Picus, Joel; Liu, Glenn; Fitch, Tom; Maples, William J; Flynn, Patrick J; Fruth, Briant F; Erlichman, Charles

2015-03-01

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

A PET Prototype for “In-Beam” Monitoring of Proton Therapy

NASA Astrophysics Data System (ADS)

Vecchio, Sara; Attanasi, Francesca; Belcari, Nicola; Camarda, Manuela; Cirrone, G. A. Pablo; Cuttone, Giacomo; Di Rosa, Francesco; Lanconelli, Nico; Moehrs, Sascha; Rosso, Valeria; Russo, Giorgio; Del Guerra, Alberto

2009-02-01

The in-beam PET is a novel PET application to image the beta+ activity induced in biological tissues by hadronic therapeutic beams. Thanks to the correlation existing between beam-delivered dose profiles and beam-induced activity profiles, in vivo information about the effective ion paths can be extracted from the in-beam pet image. in situ measurements, immediately after patient irradiation, are recommended in order to exploit the maximum statistics, by also detecting the contribution provided by the very short lived isotopes, e.g. 15O. A compact, dedicated tomograph should then be developed for such an application, so as to be used in the treatment room. We developed a small PET prototype in order to demonstrate the feasibility of such a technique for the monitoring of proton therapy of ocular tumors at the CATANA facility (Catania, Italy). The prototype consists of two planar heads with an active area of about 5 cm times 5 cm. Each head is made up of a square position sensitive photomultiplier (Hamamatsu H8500) coupled to a matrix of the same size of LYSO scintillating crystals (2 mm times 2 mm times 18 mm pixel dimensions). Dedicated, compact electronic boards are used for the signal multiplexing, amplification and digitization. The distance between the pair can be varied from 10 cm up to a maximum of about 20 cm. The validation of the prototype was performed on plastic phantoms using 62 MeV protons at the CATANA beam line. Different dose distributions were delivered and a good correlation between the distal fall-off of the activity profiles and of the dose profiles was found, i.e., better than 2 mm along the beam direction.

Variation in provider vaccine purchase prices and payer reimbursement.

PubMed

Freed, Gary L; Cowan, Anne E; Gregory, Sashi; Clark, Sarah J

2009-12-01

The purpose of this work was to collect data regarding vaccine prices and reimbursements in private practices. Amid reports of physicians losing money on vaccines, there are limited supporting data to show how much private practices are paying for vaccines and how much they are being reimbursed by third-party payers. We conducted a cross-sectional survey of a convenience sample of private practices in 5 states (California, Georgia, Michigan, New York, and Texas) that purchase vaccines for administration to privately insured children/adolescents. Main outcome measures included prices paid to purchase vaccines recommended for children and adolescents and reimbursement from the 3 most common, non-Medicaid payers for vaccine purchase and administration. Detailed price and reimbursement data were provided by 76 practices. There was a considerable difference between the maximum and minimum prices paid by practices, ranging from $4 to more than $30 for specific vaccines. There was also significant variation in insurance reimbursement for vaccine purchase, with maximum and minimum reimbursements for a single vaccine differing from $8 to more than $80. Mean net yield per dose (reimbursement for vaccine purchase minus price paid per dose) varied across vaccines from a low of approximately $3 to more than $24. Reimbursement for the first dose of vaccine administered ranged from $0 to more than $26, with a mean of $16.62. There is a wide range of prices paid by practices for the same vaccine product and in the reimbursement for vaccines and administration fees by payers. This variation highlights the need for individual practices to understand their own costs and reimbursements and to seek opportunities to reduce costs and increase reimbursements.

Variation in provider vaccine purchase prices and payer reimbursement.

PubMed

Freed, Gary L; Cowan, Anne E; Gregory, Sashi; Clark, Sarah J

2008-12-01

The purpose of this work was to collect data regarding vaccine prices and reimbursements in private practices. Amid reports of physicians losing money on vaccines, there are limited supporting data to show how much private practices are paying for vaccines and how much they are being reimbursed by third-party payers. We conducted a cross-sectional survey of a convenience sample of private practices in 5 states (California, Georgia, Michigan, New York, and Texas) that purchase vaccines for administration to privately insured children/adolescents. Main outcome measures included prices paid to purchase vaccines recommended for children and adolescents and reimbursement from the 3 most common, non-Medicaid payers for vaccine purchase and administration. Detailed price and reimbursement data were provided by 76 practices. There was a considerable difference between the maximum and minimum prices paid by practices, ranging from $4 to more than $30 for specific vaccines. There was also significant variation in insurance reimbursement for vaccine purchase, with maximum and minimum reimbursements for a single vaccine differing from $8 to more than $80. Mean net yield per dose (reimbursement for vaccine purchase minus price paid per dose) varied across vaccines from a low of approximately $3 to more than $24. Reimbursement for the first dose of vaccine administered ranged from $0 to more than $26, with a mean of $16.62. There is a wide range of prices paid by practices for the same vaccine product and in the reimbursement for vaccines and administration fees by payers. This variation highlights the need for individual practices to understand their own costs and reimbursements and to seek opportunities to reduce costs and increase reimbursements.

Introduction: the goals of antimicrobial therapy.

PubMed

Song, Jae-Hoon

2003-03-01

Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.

Cosmic radiation exposure of biological test systems during the EXPOSE-E mission.

PubMed

Berger, Thomas; Hajek, Michael; Bilski, Pawel; Körner, Christine; Vanhavere, Filip; Reitz, Günther

2012-05-01

In the frame of the EXPOSE-E mission on the Columbus external payload facility EuTEF on board the International Space Station, passive thermoluminescence dosimeters were applied to measure the radiation exposure of biological samples. The detectors were located either as stacks next to biological specimens to determine the depth dose distribution or beneath the sample carriers to determine the dose levels for maximum shielding. The maximum mission dose measured in the upper layer of the depth dose part of the experiment amounted to 238±10 mGy, which relates to an average dose rate of 408±16 μGy/d. In these stacks of about 8 mm height, the dose decreased by 5-12% with depth. The maximum dose measured beneath the sample carriers was 215±16 mGy, which amounts to an average dose rate of 368±27 μGy/d. These values are close to those assessed for the interior of the Columbus module and demonstrate the high shielding of the biological experiments within the EXPOSE-E facility. Besides the shielding by the EXPOSE-E hardware itself, additional shielding was experienced by the external structures adjacent to EXPOSE-E, such as EuTEF and Columbus. This led to a dose gradient over the entire exposure area, from 215±16 mGy for the lowest to 121±6 mGy for maximum shielding. Hence, the doses perceived by the biological samples inside EXPOSE-E varied by 70% (from lowest to highest dose). As a consequence of the high shielding, the biological samples were predominantly exposed to galactic cosmic heavy ions, while electrons and a significant fraction of protons of the radiation belts and solar wind did not reach the samples.

Quantitative Prediction of the Effect of CYP3A Inhibitors and Inducers on Venetoclax Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model.

PubMed

Freise, Kevin J; Shebley, Mohamad; Salem, Ahmed Hamed

2017-06-01

The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (C max R) and area under the curve from time 0 to infinity (AUC ∞ R) from these studies. The verified PBPK model was then used to simulate the effects of different CYP3A inhibitors and inducers on the venetoclax PK. Comparison of the PBPK model predicted to the observed PK parameters indicated good agreement. Verification of the PBPK model demonstrated that the ratios of the predicted:observed C max R and AUC ∞ R of venetoclax were within 0.8- to 1.25-fold range for strong CYP3A inhibitors and inducers. Model simulations indicated no effect of weak CYP3A inhibitors or inducers on C max or AUC ∞ , while both moderate and strong CYP3A inducers were estimated to decrease venetoclax exposure. Moderate and strong CYP3A inhibitors were estimated to increase venetoclax AUC ∞ , by 100% to 390% and 480% to 680%, respectively. The recommended venetoclax dose reductions of at least 50% and 75% when coadministered with moderate and strong CYP3A inhibitors, respectively, maintain venetoclax exposures between therapeutic and maximally administered safe doses. © 2017, The American College of Clinical Pharmacology.

Methylphenidate side effects in advanced cancer: a retrospective analysis.

PubMed

Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Davis, Mellar P; Rivera, Nilo; Khoshknabi, Dilara Seyidova

2010-02-01

Methylphenidate (MP) is often recommended for symptom control in advanced cancer. Little is known about its side effects in frail adults. To evaluate MP-associated symptoms or side effects (S/E). Data was collected from 2 published prospective cohort series and a phase 2 study of MP for symptom control in advanced cancer. All 3 reports had identical dosing schedules and symptom assessments. Initial MP doses were 10 mg/d (5 mg at 8 AM and at 12 noon) titrated up to a maximum of 30 mg/d. Depression, fatigue, and symptoms identified as possible MP S/E were evaluated for presence (prevalence) and for severity (using categorical scales) before MP (day 0) and on days 3, 5, and 7 thereafter. The categorical scale used was none, mild, moderate, and severe. 62 patients were enrolled. Fifty completed 7 days of MP with a median age of 69 (range 30-90) years. Thirty-five received MP 10 mg/day. Most (96%) had improvement in depression and/or fatigue. Among the 62 patients, new symptom prevalence throughout the study was agitation (16%), insomnia (16%), dry mouth (15%), nausea (10%), tremors (6%), anorexia (5%), headache (3%), palpitations (2%), and vomiting (2%). Patients could have more than 1 symptom simultaneously. Seven (11%) withdrew due to MP S/E. Some symptoms present before MP showed significant improvement during MP therapy. (1) Treatment with MP (10-20 mg/d) in advanced cancer is well tolerated. (2) S/E symptoms with MP appeared to improve spontaneously despite continued MP therapy. (3) Depression and fatigue improved at doses lower than those recommended in other clinical conditions. (4) MP improved depression and fatigue, and some secondary symptoms associated with them. Methylphenidate (MP) appears safe when used in the treatment of depression and fatigue in advanced cancer.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

PubMed

Ouwerkerk, W; Voors, A A; Anker, S D; Cleland, J G; Dickstein, K; Filippatos, G; van der Harst, P; Hillege, H L; Lang, C C; Ter Maaten, J M; Ng, L L; Ponikowski, P; Samani, N J; van Veldhuisen, D J; Zannad, F; Metra, M; Zwinderman, A H

2017-06-21

Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats.

PubMed

Faria, Juliana; Barbosa, Joana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Moreira, Roxana; Queirós, Odília; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

2017-06-15

Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50mg/kg - typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Ma, C; Lin, M; Chen, L

Purpose: Recent in vitro and in vivo experimental findings provided strong evidence that pulsed low-dose-rate radiotherapy (PLDR) produced equivalent tumor control as conventional radiotherapy with significantly reduced normal tissue toxicities. This work aimed to implement a PLDR clinical protocol for the management of recurrent cancers utilizing IMRT and VMAT. Methods: Our PLDR protocol requires that the daily 2Gy dose be delivered in 0.2Gy×10 pulses with a 3min interval between the pulses. To take advantage of low-dose hyper-radiosensitivity the mean dose to the target is set at 0.2Gy and the maximum dose is limited to 0.4Gy per pulse. Practical planning strategiesmore » were developed for IMRT and VMAT: (1) set 10 ports for IMRT and 10 arcs for VMAT with each angle/arc as a pulse; (2) set the mean dose (0.2Gy) and maximum dose (0.4Gy) to the target per pulse as hard constraints (no constraints to OARs); (3) select optimal port/arc angles to avoid OARs; and (4) use reference structures in or around target/OARs to reduce maximum dose to the target/OARs. IMRT, VMAT and 3DCRT plans were generated for 60 H and N, breast, lung, pancreas and prostate patients and compared. Results: All PLDR treatment plans using IMRT and VMAT met the dosimetry requirements of the PLDR protocol (mean target dose: 0.20Gy±0.01Gy; maximum target dose < 0.4Gy). In comparison with 3DCRT, IMRT and VMAT exhibited improved target dose conformity and OAR dose sparing. A single arc can minimize the difference in the target dose due to multi-angle incidence although the delivery time is longer than 3DCRT and IMRT. Conclusion: IMRT and VMAT are better modalities for PLDR treatment of recurrent cancers with superior target dose conformity and critical structure sparing. The planning strategies/guidelines developed in this work are practical for IMRT/VMAT treatment planning to meet the dosimetry requirements of the PLDR protocol.« less

Survey of Occupational Noise Exposure in CF Personnel in Selected High-Risk Trades

DTIC Science & Technology

2003-11-01

peak, maximum level , minimum level , average sound level , time weighted average, dose, projected 8-hour dose, and upper limit time were measured for...10 4.4.2 Maximum Sound Level ...11 4.4.3 Minimum Sound Level

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

PubMed

Camacho, Luis H; Olson, Jon; Tong, William P; Young, Charles W; Spriggs, David R; Malkin, Mark G

2007-04-01

Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer

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

Sudo, Kentaro; Yamaguchi, Taketo; Ishihara, Takeshi

Purpose: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m{sup 2}/day. Results: Sixteen patients were enrolled in this study. Three patients received S-1more » at 60 mg/m{sup 2}/day, 3 at 70 mg/m{sup 2}/day, and 10 at 80 mg/m{sup 2}/day. Though 1 patient at the final dose level (80 mg/m{sup 2}/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. Conclusions: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m{sup 2}/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.« less

Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

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

Kaira, Kyoichi; Sunaga, Noriaki; Yanagitani, Noriko

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m{sup -2}/day{sup -1}]/cisplatin [mg/m{sup -2}/day{sup -1}]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to amore » total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed {>=}Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.« less

SU-E-T-117: Analysis of the ArcCHECK Dosimetry Gamma Failure Using the 3DVH System

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

Cho, S; Choi, W; Lee, H

2015-06-15

Purpose: To evaluate gamma analysis failure for the VMAT patient specific QA using ArcCHECK cylindrical phantom. The 3DVH system(Sun Nuclear, FL) was used to analyze the dose difference statistic between measured dose and treatment planning system calculated dose. Methods: Four case of gamma analysis failure were selected retrospectively. Our institution gamma analysis indexes were absolute dose, 3%/3mm and 90%pass rate in the ArcCHECK dosimetry. The collapsed cone convolution superposition (CCCS) dose calculation algorithm for VMAT was used. Dose delivery was performed with Elekta Agility. The A1SL(standard imaging, WI) and cavity plug were used for point dose measurement. Delivery QA plansmore » and images were used for 3DVH Reference data instead of patient plan and image. The measured data of ‘.txt’ file was used for comparison at diodes to acquire a global dose level. The,.acml’ file was used for AC-PDP and to calculated point dose. Results: The global dose of 3DVH was calculated as 1.10 Gy, 1.13, 1.01 and 0.2 Gy respectively. The global dose of 0.2 Gy case was induced by distance discrepancy. The TPS calculated point dose of was 2.33 Gy to 2.77 Gy and 3DVH calculated dose was 2.33 Gy to 2.68 Gy. The maximum dose differences were −2.83% and −3.1% for TPS vs. measured dose and TPS vs. 3DVH calculated respectively in the same case. The difference between measured and 3DVH was 0.1% in that case. The 3DVH gamma pass rate was 98% to 99.7%. Conclusion: We found the TPS calculation error by 3DVH calculation using ArcCHECK measured dose. It seemed that our CCCS algorithm RTP system over estimated at the central region and underestimated scattering at the peripheral diode detector point. The relative gamma analysis and point dose measurement would be recommended for VMAT DQA in the gamma failure case of ArcCHECK dosimetry.« less

Electron fluence correction factors for various materials in clinical electron beams.

PubMed

Olivares, M; DeBlois, F; Podgorsak, E B; Seuntjens, J P

2001-08-01

Relative to solid water, electron fluence correction factors at the depth of dose maximum in bone, lung, aluminum, and copper for nominal electron beam energies of 9 MeV and 15 MeV of the Clinac 18 accelerator have been determined experimentally and by Monte Carlo calculation. Thermoluminescent dosimeters were used to measure depth doses in these materials. The measured relative dose at dmax in the various materials versus that of solid water, when irradiated with the same number of monitor units, has been used to calculate the ratio of electron fluence for the various materials to that of solid water. The beams of the Clinac 18 were fully characterized using the EGS4/BEAM system. EGSnrc with the relativistic spin option turned on was used to optimize the primary electron energy at the exit window, and to calculate depth doses in the five phantom materials using the optimized phase-space data. Normalizing all depth doses to the dose maximum in solid water stopping power ratio corrected, measured depth doses and calculated depth doses differ by less than +/- 1% at the depth of dose maximum and by less than 4% elsewhere. Monte Carlo calculated ratios of doses in each material to dose in LiF were used to convert the TLD measurements at the dose maximum into dose at the center of the TLD in the phantom material. Fluence perturbation correction factors for a LiF TLD at the depth of dose maximum deduced from these calculations amount to less than 1% for 0.15 mm thick TLDs in low Z materials and are between 1% and 3% for TLDs in Al and Cu phantoms. Electron fluence ratios of the studied materials relative to solid water vary between 0.83+/-0.01 and 1.55+/-0.02 for materials varying in density from 0.27 g/cm3 (lung) to 8.96 g/cm3 (Cu). The difference in electron fluence ratios derived from measurements and calculations ranges from -1.6% to +0.2% at 9 MeV and from -1.9% to +0.2% at 15 MeV and is not significant at the 1sigma level. Excluding the data for Cu, electron fluence correction factors for open electron beams are approximately proportional to the electron density of the phantom material and only weakly dependent on electron beam energy.

Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years--India, 2014 and updates on immunization.

PubMed

Vashishtha, Vipin M; Choudhury, Panna; Kalra, Ajay; Bose, Anuradha; Thacker, Naveen; Yewale, Vijay N; Bansal, C P; Mehta, Pravin J

2014-10-01

There is a need to review/revise recommendations about existing vaccines in light of recent developments in the field of vaccinology. Following an IAP ACVIP meeting on April 19 and 20, 2014, a draft of revised recommendations for the year 2014 and updates on certain vaccine formulations was prepared and circulated among the meeting participants to arrive at a consensus. To review and revise recommendations for 2014 Immunization timetable for pediatricians in office practice and issue statements on certain new and existing vaccine formulations. The major changes in the 2014 Immunization Timetable include two doses of MMR vaccine at 9 and 15 months of age, single dose recommendation for administration of live attenuated H2 strain hepatitis A vaccine, inclusion of two new situations in high-risk category of children in context with pre-exposure prophylaxis of rabies, creation of a new slot at 9-12 months of age for typhoid conjugate vaccine for primary immunization, and recommendation of two doses of human papilloma virus vaccines with a minimum interval of 6 months between doses for primary schedule of adolescent/preadolescent girls aged 9-14 years. There would not be any change to the committee's last year's (2013) recommendations on pertussis vaccination and administration schedule of monovalent human rotavirus vaccine. There is no need of providing additional doses of whole-cell pertussis vaccine to children who have earlier completed their primary schedule with acellular pertussis vaccine-containing products. A brief update on the new Indian Rotavirus vaccine, 116E is also provided. The committee has reviewed and offered its recommendations on the currently available pentavalent vaccine (DTwP+Hib+Hepatitis-B) combinations in Indian market. The comments and footnotes for several vaccines are also updated and revised.

Integration of drug dosing data with physiological data streams using a cloud computing paradigm.

PubMed

Bressan, Nadja; James, Andrew; McGregor, Carolyn

2013-01-01

Many drugs are used during the provision of intensive care for the preterm newborn infant. Recommendations for drug dosing in newborns depend upon data from population based pharmacokinetic research. There is a need to be able to modify drug dosing in response to the preterm infant's response to the standard dosing recommendations. The real-time integration of physiological data with drug dosing data would facilitate individualised drug dosing for these immature infants. This paper proposes the use of a novel computational framework that employs real-time, temporal data analysis for this task. Deployment of the framework within the cloud computing paradigm will enable widespread distribution of individualized drug dosing for newborn infants.

Role of step size and max dwell time in anatomy based inverse optimization for prostate implants

PubMed Central

Manikandan, Arjunan; Sarkar, Biplab; Rajendran, Vivek Thirupathur; King, Paul R.; Sresty, N.V. Madhusudhana; Holla, Ragavendra; Kotur, Sachin; Nadendla, Sujatha

2013-01-01

In high dose rate (HDR) brachytherapy, the source dwell times and dwell positions are vital parameters in achieving a desirable implant dose distribution. Inverse treatment planning requires an optimal choice of these parameters to achieve the desired target coverage with the lowest achievable dose to the organs at risk (OAR). This study was designed to evaluate the optimum source step size and maximum source dwell time for prostate brachytherapy implants using an Ir-192 source. In total, one hundred inverse treatment plans were generated for the four patients included in this study. Twenty-five treatment plans were created for each patient by varying the step size and maximum source dwell time during anatomy-based, inverse-planned optimization. Other relevant treatment planning parameters were kept constant, including the dose constraints and source dwell positions. Each plan was evaluated for target coverage, urethral and rectal dose sparing, treatment time, relative target dose homogeneity, and nonuniformity ratio. The plans with 0.5 cm step size were seen to have clinically acceptable tumor coverage, minimal normal structure doses, and minimum treatment time as compared with the other step sizes. The target coverage for this step size is 87% of the prescription dose, while the urethral and maximum rectal doses were 107.3 and 68.7%, respectively. No appreciable difference in plan quality was observed with variation in maximum source dwell time. The step size plays a significant role in plan optimization for prostate implants. Our study supports use of a 0.5 cm step size for prostate implants. PMID:24049323

Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging

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

Zhu, Tong; Chapman, Christopher H.; Tsien, Christina

2016-11-01

Purpose: Previous efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial, and dosimetric patterns of radiation damage to whole-brain white matter (WM) after partial-brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiation therapy (RT)–induced damage to whole-brain WM bundles. Methods and Materials: An atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade or benign brain tumors treated by RT. Sixmore » DTI scans per patient were performed from before RT to 18 months after RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial diffusivity (AD) and radial diffusivity (RD) from before RT. Results: Among 22 fiber bundles, AD or RD changes in 12 bundles were affected significantly by doses (P<.05), as the effect was progressive over time. In 9 elongated tracts, decreased AD or RD was significantly related to maximum doses received, consistent with a serial structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months after RT. The dose effect on WM was greater in older female patients than younger male patients. Conclusions: Our study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-RT damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function after RT.« less

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

Small, Katherine; Kelly, Chris; Beldham-Collins, Rachael

A comparative study was conducted comparing the difference between (1) conformal radiotherapy (CRT) to the whole breast with sequential boost excision cavity plans and (2) intensity-modulated radiation therapy (IMRT) to the whole breast with simultaneously integrated boost to the excision cavity. The computed tomography (CT) data sets of 25 breast cancer patients were used and the results analysed to determine if either planning method produced superior plans. CT data sets from 25 past breast cancer patients were planned using (1) CRT prescribed to 50 Gy in 25 fractions (Fx) to the whole-breast planning target volume (PTV) and 10 Gy inmore » 5Fx to the excision cavity and (2) IMRT prescribed to 60 Gy in 25Fx, with 60 Gy delivered to the excision cavity PTV and 50 Gy delivered to the whole-breast PTV, treated simultaneously. In total, 50 plans were created, with each plan evaluated by PTV coverage using conformity indices, plan maximum dose, lung dose, and heart maximum dose for patients with left-side lesions. CRT plans delivered the lowest plan maximum doses in 56% of cases (average CRT = 6314.34 cGy, IMRT = 6371.52 cGy). They also delivered the lowest mean lung dose in 68% of cases (average CRT = 1206.64 cGy, IMRT = 1288.37 cGy) and V20 in 88% of cases (average CRT = 20.03%, IMRT = 21.73%) and V30 doses in 92% of cases (average CRT = 16.82%, IMRT = 17.97%). IMRT created more conformal plans, using both conformity index and conformation number, in every instance, and lower heart maximum doses in 78.6% of cases (average CRT = 5295.26 cGy, IMRT = 5209.87 cGy). IMRT plans produced superior dose conformity and shorter treatment duration, but a slightly higher planning maximum and increased lung doses. IMRT plans are also faster to treat on a daily basis, with shorter fractionation.« less

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom

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

Lye, Jessica; Dunn, Leon, E-mail: leon.dunn@arpansa.gov.au; Alves, Andrew

Purpose: The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. Methods: The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantomsmore » are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. Results: At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%–8%. Conclusions: The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.« less

Consideration of the ICRP 2006 revised tissue weighting factors on age-dependent values of the effective dose for external photons

NASA Astrophysics Data System (ADS)

Lee, Choonsik; Lee, Choonik; Han, Eun Young; Bolch, Wesley E.

2007-01-01

The effective dose recommended by the International Commission on Radiological Protection (ICRP) is the sum of organ equivalent doses weighted by corresponding tissue weighting factors, wT. ICRP is in the process of revising its 1990 recommendations on the effective dose where new values of organs and tissue weighting factors have been proposed and published in draft form for consultation by the radiological protection community. In its 5 June 2006 draft recommendations, new organs and tissues have been introduced in the effective dose which do not exist within the 1987 Oak Ridge National Laboratory (ORNL) phantom series (e.g., salivary glands). Recently, the investigators at University of Florida have updated the series of ORNL phantoms by implementing new organ models and adopting organ-specific elemental composition and densities. In this study, the effective dose changes caused by the transition from the current recommendation of ICRP Publication 60 to the 2006 draft recommendations were investigated for external photon irradiation across the range of ICRP reference ages (newborn, 1-year, 5-year, 10-year, 15-year and adult) and for six idealized irradiation geometries: anterior-posterior (AP), posterior-anterior (PA), left-lateral (LLAT), right-lateral (RLAT), rotational (ROT) and isotropic (ISO). Organ-absorbed doses were calculated by implementing the revised ORNL phantoms in the Monte Carlo radiation transport code, MCNPX2.5, after which effective doses were calculated under the 1990 and draft 2006 evaluation schemes of the ICRP. Effective doses calculated under the 2006 draft scheme were slightly higher than estimated under ICRP Publication 60 methods for all irradiation geometries exclusive of the AP geometry where an opposite trend was observed. The effective doses of the adult phantom were more greatly affected by the change in tissue weighting factors than that seen within the paediatric members of the phantom series. Additionally, dose conversion coefficients for newly identified radiosensitive organs—salivary glands, gall bladder, heart and prostate—were reported, as well as the brain, which was originally considered in ICRP Publication 60 as a member of the remainder category of the effective dose.

A Framework for "Fit for Purpose" Dose Response Assessment

EPA Science Inventory

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two ...

Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).

PubMed

Marin, Mona; Broder, Karen R; Temte, Jonathan L; Snider, Dixie E; Seward, Jane F

2010-05-07

This report presents new recommendations adopted in June 2009 by CDC's Advisory Committee on Immunization Practices (ACIP) regarding use of the combination measles, mumps, rubella, and varicella vaccine (MMRV, ProQuad, Merck & Co., Inc.). MMRV vaccine was licensed in the United States in September 2005 and may be used instead of measles, mumps, rubella vaccine (MMR, M-M-RII, Merck & Co., Inc.) and varicella vaccine (VARIVAX, Merck & Co., Inc.) to implement the recommended 2-dose vaccine schedule for prevention of measles, mumps, rubella, and varicella among children aged 12 months-12 years. At the time of its licensure, use of MMRV vaccine was preferred for both the first and second doses over separate injections of equivalent component vaccines (MMR vaccine and varicella vaccine), which was consistent with ACIP's 2006 general recommendations on use of combination vaccines (CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2006;55;[No. RR-15]). Since July 2007, supplies of MMRV vaccine have been temporarily unavailable as a result of manufacturing constraints unrelated to efficacy or safety. MMRV vaccine is expected to be available again in the United States in May 2010. In February 2008, on the basis of preliminary data from two studies conducted postlicensure that suggested an increased risk for febrile seizures 5-12 days after vaccination among children aged 12-23 months who had received the first dose of MMRV vaccine compared with children the same age who had received the first dose of MMR vaccine and varicella vaccine administered as separate injections at the same visit, ACIP issued updated recommendations regarding MMRV vaccine use (CDC. Update: recommendations from the Advisory Committee on Immunization Practices [ACIP] regarding administration of combination MMRV vaccine. MMWR 2008;57:258-60). These updated recommendations expressed no preference for use of MMRV vaccine over separate injections of equivalent component vaccines for both the first and second doses. The final results of the two postlicensure studies indicated that among children aged 12--23 months, one additional febrile seizure occurred 5-12 days after vaccination per 2,300-2,600 children who had received the first dose of MMRV vaccine compared with children who had received the first dose of MMR vaccine and varicella vaccine administered as separate injections at the same visit. Data from postlicensure studies do not suggest that children aged 4--6 years who received the second dose of MMRV vaccine had an increased risk for febrile seizures after vaccination compared with children the same age who received MMR vaccine and varicella vaccine administered as separate injections at the same visit. In June 2009, after consideration of the postlicensure data and other evidence, ACIP adopted new recommendations regarding use of MMRV vaccine for the first and second doses and identified a personal or family (i.e., sibling or parent) history of seizure as a precaution for use of MMRV vaccine. For the first dose of measles, mumps, rubella, and varicella vaccines at age 12--47 months, either MMR vaccine and varicella vaccine or MMRV vaccine may be used. Providers who are considering administering MMRV vaccine should discuss the benefits and risks of both vaccination options with the parents or caregivers. Unless the parent or caregiver expresses a preference for MMRV vaccine, CDC recommends that MMR vaccine and varicella vaccine should be administered for the first dose in this age group. For the second dose of measles, mumps, rubella, and varicella vaccines at any age (15 months-12 years) and for the first dose at age >or=48 months, use of MMRV vaccine generally is preferred over separate injections of its equivalent component vaccines (i.e., MMR vaccine and varicella vaccine). This recommendation is consistent with ACIP's 2009 provisional general recommendations regarding use of combination vaccines (available at http://www.cdc.gov/vaccines/recs/provisional/downloads/combo-vax-Aug2009-508.pdf), which state that use of a combination vaccine generally is preferred over its equivalent component vaccines.

“Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs

PubMed Central

Barrett, Frederick S.; Schlienz, Nicolas J.; Lembeck, Natalie; Waqas, Muhammad; Vandrey, Ryan

2018-01-01

Abstract Introduction: Cannabis has been historically classified as a hallucinogen. However, subjective cannabis effects do not typically include hallucinogen-like effects. Empirical reports of hallucinogen-like effects produced by cannabis in controlled settings, particularly among healthy research volunteers, are rare and have mostly occurred after administration of purified Δ-9 tetrahydrocannabinol (THC) rather than whole plant cannabis. Methods: The case of a healthy 30-year-old male who experienced auditory and visual hallucinations in a controlled laboratory study after inhaling vaporized cannabis that contained 25 mg THC (case dose) is presented. Ratings on the Hallucinogen Rating Scale (HRS) following the case dose are compared with HRS ratings obtained from the participant after other doses of cannabis and with archival HRS data from laboratory studies involving acute doses of cannabis, psilocybin, dextromethorphan (DXM), and salvinorin A. Results: Scores on the Volition subscale of the HRS were greater for the case dose than for the maximum dose administered in any other comparison study. Scores on the Intensity and Perception subscales were greater for the case dose than for the maximum dose of cannabis, psilocybin, or salvinorin A. Scores on the Somaesthesia subscale were greater for the case dose than for the maximum dose of DXM, salvinorin A, or cannabis. Scores on the Affect and Cognition subscales for the case dose were significantly lower than for the maximum doses of psilocybin and DXM. Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis. PMID:29682608

Combined carboplatin plus ifosfamide and cisplatin in patients with advanced ovarian carcinoma. A phase I-II study. GOCS (Gynecological Oncology Cooperative Study).

PubMed

Lorusso, V; Leone, B; Di Vagno, G; Manzione, L; Palmeri, S; Vallejo, C; Machiavelli, M; Nacci, G; Bilancia, D; Leonardi, V; Catino, A; Gargano, G; Loverro, G; Selvaggi, L; De Lena, M

1998-02-01

Because of the relative lack of overlapping toxicity, carboplatin (PPL) and cisplatin (CDDP) can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity. Ifosfamide (IFO), one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. From January 1991 to December 1993, 34 patients with advanced ovarian cancer, previously untreated with chemo- or radiotherapy, were enrolled in a phase I-II study with the aim of determining the maximum tolerated dose (MTD) of CDDP (on day 8 of a 28-day cycle) in combination with PPL (300 mg/m2 on day 1) and IFO (4,000 mg/m2/24 h by continuous infusion on day 1). The initial dose level of CDDP was 40 mg/m2, which was continuously increased by 10 mg/m2 up to the MTD defined as one dose level below that inducing dose-limiting toxicity (DLT) in at least two-thirds of treated patients; no dose escalation was allowed in the same patient. Grade 3-4 leukopenia and thrombocytopenia were observed in 54 and 49% of patients, respectively. The DLT was reached at 70 mg/m2 and therefore the dose recommended for the phase II study was 60 mg/m2. Complete (CR) plus partial response was observed in 88% of patients with a 21% pathological CR. With a minimum follow-up of 32 months (median 40 months), median progression-free survival and overall survival were 21 and 39 months, respectively. In conclusion, the combination of CDDP, PPL, and IFO provides an effective regimen for ovarian cancer with an acceptable toxicity profile.

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

PubMed

Chisholm, Julia C; Suvada, Jozef; Dunkel, Ira J; Casanova, Michela; Zhang, Weijiang; Ritchie, Natasha; Choi, YounJeong; Park, Jane; Das Thakur, Meghna; Simko, Stephen; Wan Rachel Tam, Nga; Ferrari, Andrea

2018-05-01

Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials. © 2018 Wiley Periodicals, Inc.

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

PubMed

Thakur, Manish K; Heilbrun, Lance; Dobson, Kimberlee; Boerner, Julie; Stark, Karri; Li, Jing; Smith, Daryn; Heath, Elisabeth; Fontana, Joseph; Vaishampayan, Ulka

2018-06-01

Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. Chemotherapy naive mCRPC patients received docetaxel 75 mg/m 2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen. Copyright © 2018 Elsevier Inc. All rights reserved.

Phase I Trial of Neoadjuvant Preoperative Chemotherapy With S-1 and Irinotecan Plus Radiation in Patients With Locally Advanced Rectal Cancer

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

Sato, Takeo; Kokuba, Yukihito; Koizumi, Wasaburo

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. Patients and Methods: We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m{sup 2}/day on Days 1-5, 8-12, 22-26, and 29-33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m{sup 2}/day and gradually increased to determine the MTDmore » and RD of this regimen. Results: Among the 4 patients who received 90 mg/m{sup 2} irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m{sup 2} irinotecan was designated as the MTD. Consequently, 80 mg/m{sup 2} irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. Conclusions: With our new regimen, the MTD of irinotecan was 90 mg/m{sup 2}, and the RD of irinotecan for Phase II studies was 80 mg/m{sup 2}. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies.« less

A retrospective cohort study of long-term immediate-release hydrocodone/acetaminophen use and acetaminophen dosing above the Food and Drug Administration recommended maximum daily limit among commercially insured individuals in the United States (2008-2013).

PubMed

DeVeaugh-Geiss, Angela; Kadakia, Aditi; Chilcoat, Howard; Alexander, Louis; Coplan, Paul

2015-06-01

Immediate-release (IR) hydrocodone/acetaminophen is the most prescribed opioid in the United States; however, patterns of use, including long-term treatment and dose, are not well described. Duration of use, including the percentage of patients on long-term treatment (>90 days of continuous use), was assessed for patients newly prescribed IR hydrocodone/acetaminophen compared to other opioid analgesics in a national commercial insurance database (January 2008-September 2013). Though only a small percentage of IR hydrocodone/acetaminophen patients continued treatment long-term (1.7%), the number was large (104,839) and was nearly 5 times the number receiving extended-release (ER) morphine (n = 22,338) and nearly 4 times the number receiving ER oxycodone (n = 26,946) long-term. Using a less conservative allowable gap in treatment increased the number of patients meeting the criteria for long-term use (approximately 160,000 for IR hydrocodone/acetaminophen vs <30,000 for ER morphine and ER oxycodone). Most patients meeting these criteria received IR hydrocodone doses between >20 and ≤60 mg/d (n = 56,220, 53.6%) in month 4; 5.5% (n = 5,743) received doses >60 mg/d. Moreover, approximately 15% of IR hydrocodone/acetaminophen patients (n > 900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the limit recommended by the U.S. Food and Drug Administration) at their initial IR hydrocodone/acetaminophen prescription or any time during therapy. Although most patients were prescribed IR hydrocodone/acetaminophen for acute pain, the number of patients prescribed long-term therapy exceeds the number of patients prescribed ER opioids. It is important to consider the benefits and risks inherent with long-term opioid therapy, whether with IR or ER opioids, to ensure safe use of these products. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

PubMed

Moreno, Lucas; Casanova, Michela; Chisholm, Julia C; Berlanga, Pablo; Chastagner, Pascal B; Baruchel, Sylvain; Amoroso, Loredana; Melcón, Soledad Gallego; Gerber, Nicolas U; Bisogno, Gianni; Fagioli, Franca; Geoerger, Birgit; Glade Bender, Julia L; Aerts, Isabelle; Bergeron, Christophe; Hingorani, Pooja; Elias, Ileana; Simcock, Mathew; Ferrara, Stefano; Le Bruchec, Yvan; Slepetis, Ruta; Chen, Nianhang; Vassal, Gilles

2018-06-21

nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26. Copyright © 2018 Elsevier Ltd. All rights reserved.

Environmental problems associated with decommissioning the Chernobyl Nuclear Power Plant Cooling Pond.

PubMed

Oskolkov, B Ya; Bondarkov, M D; Gaschak, S P; Maksymenko, A M; Maksymenko, V M; Martynenko, V I; Farfán, E B; Jannik, G T; Marra, J C

2010-11-01

Decommissioning of nuclear power plants and other nuclear fuel cycle facilities associated with residual radioactive contamination of their territories is an imperative issue. Significant problems may result from decommissioning of cooling ponds with residual radioactive contamination. The Chernobyl Nuclear Power Plant (ChNPP) Cooling Pond is one of the largest self-contained water reservoirs in the Chernobyl region and Ukrainian and Belorussian Polesye region. The 1986 ChNPP Reactor Unit Number Four significantly contaminated the ChNPP Cooling Pond. The total radionuclide inventory in the ChNPP Cooling Pond bottom deposits are as follows: ¹³⁷Cs: 16.28 ± 2.59 TBq; ⁹⁰Sr: 2.4 ± 0.48 TBq; and ²³⁹+²⁴⁰Pu: 0.00518 ± 0.00148 TBq. The ChNPP Cooling Pond is inhabited by over 500 algae species and subspecies, over 200 invertebrate species, and 36 fish species. The total mass of the living organisms in the ChNPP Cooling Pond is estimated to range from about 60,000 to 100,000 tons. The territory adjacent to the ChNPP Cooling Pond attracts many birds and mammals (178 bird species and 47 mammal species were recorded in the Chernobyl Exclusion Zone). This article describes several options for the ChNPP Cooling Pond decommissioning and environmental problems associated with its decommissioning. The article also provides assessments of the existing and potential exposure doses for the shoreline biota. For the 2008 conditions, the estimated total dose rate values were 11.4 40 μGy h⁻¹ for amphibians, 6.3 μGy h⁻¹ for birds, 15.1 μGy h⁻¹ for mammals, and 10.3 μGy h⁻¹ for reptiles, with the recommended maximum dose rate being equal to 40 μGy h⁻¹. However, drying the ChNPP Cooling Pond may increase the exposure doses to 94.5 μGy h⁻¹ for amphibians, 95.2 μGy h⁻¹ for birds, 284.0 μGy h⁻¹ for mammals, and 847.0 μGy h⁻¹ for reptiles. All of these anticipated dose rates exceed the recommended values.

Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial.

PubMed

Arthur, Douglas W; Vicini, Frank A; Todor, Dorin A; Julian, Thomas B; Cuttino, Laurie W; Mukhopadhyay, Nitai D

2013-06-01

Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥ 95% of the prescribed dose (PD) covering ≥ 95% of the target volume (TV); maximum skin dose ≤ 125% of the PD; maximum rib dose ≤ 145% of the PD; and V150 ≤50 cc and V200 ≤ 10 cc. Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P ≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals. Copyright © 2013 Elsevier Inc. All rights reserved.

Contura Multi-Lumen Balloon Breast Brachytherapy Catheter: Comparative Dosimetric Findings of a Phase 4 Trial

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

Arthur, Douglas W., E-mail: darthur@mcvh-vcu.edu; Vicini, Frank A.; Todor, Dorin A.

2013-06-01

Purpose: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. Methods and Materials: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥95% of the prescribed dose (PD) covering ≥95% of the target volume (TV); maximum skin dose ≤125%more » of the PD; maximum rib dose ≤145% of the PD; and V150 ≤50 cc and V200 ≤10 cc. Results: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. Conclusions: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals.« less

Evaluation of performance and maximum length of continuous decks in bridges : part 1.

DOT National Transportation Integrated Search

2011-06-01

The purpose of this research was to evaluate the performance history of continuous bridge decks in the State of Georgia, to determine why the current design detail works, to recommend a new design detail, and to recommend the maximum and/or optimum l...

The future of warfarin pharmacogenetics in under-represented minority groups

PubMed Central

Cavallari, Larisa H; Perera, Minoli A

2012-01-01

Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African–Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African–Americans. These data suggest that it is important to consider variants specific for African–Americans when implementing genotype-guided warfarin dosing in this population. PMID:22871196

The effect of dose heterogeneity on radiation risk in medical imaging.

PubMed

Samei, Ehsan; Li, Xiang; Chen, Baiyu; Reiman, Robert

2013-06-01

The current estimations of risk associated with medical imaging procedures rely on assessing the organ dose via direct measurements or simulation. The dose to each organ is assumed to be homogeneous. To take into account the differences in radiation sensitivities, the mean organ doses are weighted by a corresponding tissue-weighting coefficients provided by ICRP to calculate the effective dose, which has been used as a surrogate of radiation risk. However, those coefficients were derived under the assumption of a homogeneous dose distribution within each organ. That assumption is significantly violated in most medical-imaging procedures. In helical chest CT, for example, superficial organs (e.g. breasts) demonstrate a heterogeneous dose distribution, whereas organs on the peripheries of the irradiation field (e.g. liver) might possess a discontinuous dose profile. Projection radiography and mammography involve an even higher level of organ dose heterogeneity spanning up to two orders of magnitude. As such, mean dose or point measured dose values do not reflect the maximum energy deposited per unit volume of the organ. In this paper, the magnitude of the dose heterogeneity in both CT and projection X-ray imaging was reported, using Monte Carlo methods. The lung dose demonstrated factors of 1.7 and 2.2 difference between the mean and maximum dose for chest CT and radiography, respectively. The corresponding values for the liver were 1.9 and 3.5. For mammography and breast tomosynthesis, the difference between mean glandular dose and maximum glandular dose was 3.1. Risk models based on the mean dose were found to provide a reasonable reflection of cancer risk. However, for leukaemia, they were found to significantly under-represent the risk when the organ dose distribution is heterogeneous. A systematic study is needed to develop a risk model for heterogeneous dose distributions.

Human Papillomavirus (HPV) and Oropharyngeal Cancer

MedlinePlus

... CDC recommends that 11- to 12-year-old boys and girls get two doses of HPV vaccine. The second ... after the first dose. CDC also recommends that girls and women through age 26 years and boys and men through age 21 years get the ...

Measles, mumps, and rubella--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP).

PubMed

Watson, J C; Hadler, S C; Dykewicz, C A; Reef, S; Phillips, L

1998-05-22

These revised recommendations of the Advisory Committee on Immunization Practices (ACIP) on measles, mumps, and rubella prevention supersede recommendations published in 1989 and 1990. This statement summarizes the goals and current strategies for measles, rubella, and congenital rubella syndrome (CRS) elimination and for mumps reduction in the United States. Changes from previous recommendations include: Emphasis on the use of combined MMR vaccine for most indications; A change in the recommended age for routine vaccination to 12-15 months for the first dose of MMR, and to 4-6 years for the second dose of MMR; A recommendation that all states take immediate steps to implement a two dose MMR requirement for school entry and any additional measures needed to ensure that all school-aged children are vaccinated with two doses of MMR by 2001; A clarification of the role of serologic screening to determine immunity; A change in the criteria for determining acceptable evidence of rubella immunity; A recommendation that all persons who work in health-care facilities have acceptable evidence of measles and rubella immunity; Changes in the recommended interval between administration of immune globulin and measles vaccination; and Updated information on adverse events and contraindications, particularly for persons with severe HIV infection, persons with a history of egg allergy or gelatin allergy, persons with a history of thrombocytopenia, and persons receiving steroid therapy.

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).

A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314).

PubMed

Schafer, Eric S; Rau, Rachel E; Berg, Stacey; Liu, Xiaowei; Minard, Charles G; D'Adamo, David; Scott, Rachael; Reyderman, Larisa; Martinez, Gresel; Devarajan, Sandhya; Reid, Joel M; Fox, Elizabeth; Weigel, Brenda J; Blaney, Susan M

2018-05-02

Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m 2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m 2 /dose on days 1 and 8 of a 21-day cycle. © 2018 Wiley Periodicals, Inc.

Dose and Dose Risk Caused by Natural Phenomena - Proposed Powder Metallurgy Core Manufacturing Facility

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

Holmes, W.G.

2001-08-16

The offsite radiological effects from high velocity straight winds, tornadoes, and earthquakes have been estimated for a proposed facility for manufacturing enriched uranium fuel cores by powder metallurgy. Projected doses range up to 30 mrem/event to the maximum offsite individual for high winds and up to 85 mrem/event for very severe earthquakes. Even under conservative assumptions on meteorological conditions, the maximum offsite dose would be about 20 per cent of the DOE limit for accidents involving enriched uranium storage facilities. The total dose risk is low and is dominated by the risk from earthquakes. This report discusses this test.

Clinical assessment of the jaw-tracking function in IMRT for a brain tumor

NASA Astrophysics Data System (ADS)

Kim, Jin-Young; Kim, Shin-Wook; Choe, Bo-Young; Suh, Tae-Suk; Park, Sung-Kwang; Jo, Sun-Mi; Oh, Won-Yong; Shin, Jung-Wook; Cho, Gyu-Seok; Nam, Sang-Hee; Chung, Jin-Beom; Kim, Jung-Ki; Lee, Young-Kyu

2015-01-01

Intensity-modulated radiotherapy (IMRT) improves dose conformity and saves critical organs. IMRT is widely used in cases of head and neck, prostate, and brain cancer due to the close location of the targets to critical structures. However, because IMRT has a larger amount of radiation exposure than 3 dimensional-conformal radiation therapy (3D-CRT), it has disadvantages such as increases in the low dose irradiation to normal tissues and in the accumulated dose for the whole volume due to leakage and transmission of the multi-leaf collimator (MLC). The increased accumulated dose and the larger low dose may increase the occurrence of secondary malignant neoplasms. For these reasons, the jaw-tracking function of the TrueBeam (Varian Medical Systems, Palo Alto, CA) was developed to reduce the leakage and the transmission dose of the MLC with linear accelerators. However, the change in the superficial dose has not been verified with a quantitative analysis of the dose reduction in a brain tumor. Therefore, in the present study, we intended to verify the clinical possibility of utilizing the jaw-tracking function for a brain tumor by comparing treatment plans and superficial doses. To accomplish this, we made three types of original treatment plans using Eclipse11 (Varian Medical Systems, Palo Alto, CA): 1) farther than 2 cm from the organs at risk (OAR); 2) within 2 cm of the OAR; and 3) intersecting with the OAR. Jaw-tracking treatment plans were also made with copies of the original treatment plan using Smart LMC Version 11.0.31 (Varian Medical Systems, Palo Alto, CA). A comparison between the original treatment plans and jaw-tracking treatment plans was performed using the difference of the mean dose and maximum dose to the OARs in cumulative Dose Volume Histogram (DVH). In addition, the dependencies of the effects of transmission and the scattering doses according to jaw motion were assessed through the difference in the surface doses. In the DVH comparison, a maximum dose difference of 0.4% was observed between the planning methods in the case of over 2 cm distance, and the maximum dose of 0.6% was obtained for within the 2 cm distance. For the case intersecting with the OAR, the maximum dose difference of 2.3% was achieved. According to these results, the differences in the mean doses and the maximum doses to the OARs ware larger when the OARs and the planning target volume (PTV) were closer. In addition, small differences in the surface dose measurements were observed. In the case of the inside field, the differences were under 2% of the prescription dose while the difference was under 0.1% in the case of the outside field. Therefore, treatment plans with the jaw-tracking function consistently affected the dose reduction for a brain tumor, and the clinical possibility could be verified as the surface dose was not increased.

Residue decline and risk assessment of fluopyram + tebuconazole (400SC) in/on onion (Allium cepa).

PubMed

Patel, Badal V; Chawla, Suchi; Gor, Hetal; Upadhyay, Payal; Parmar, Kaushik D; Patel, Anil R; Shah, Paresh G

2016-10-01

A method was validated for estimating fluopyram and tebuconazole in onion on LC-MS/MS using dispersive QuEChERS. Three sprays of a combination fungicide fluopyram + tebuconazole (Luna experience, 400 SC) were applied @ 75 + 75 and 150 + 150 g a.i. ha -1 at an interval of 10 days on onion using Knapsack sprayer. First spray was made at bulb setting stage. Spring onion samples were drawn at 0 (1 h), 1, 3, 5, 7, 10, 15, and 20 days and matured onion bulb at harvest (52 days) after the last spray. Soil samples were also drawn at harvest. Foliar application of the combination product resulted in 1.14 and 2.86 mg kg -1 fluopyram residues on spring onion at standard and double dose, respectively, one hour after the last application. The levels of fluopyram residues gradually declined and recorded 0.25 and 0.58 mg kg -1 on 20th day of application with half-lives of 8.8 and 9.1 days at standard and double dose, respectively. For tebuconazole, the corresponding residues observed after 1 h (0 day) of application were 0.92 and 2.29 mg kg -1 . The levels declined gradually to 0.12 and 0.33 mg kg -1 on 20th days with half-life of 6.7 to 7.7 days at standard and double dose, respectively. Here, we are proposing a pre-harvest interval of 7 day for fluopyram and tebuconazole in spring onion when applied at 75 + 75 g a.i. ha -1 (400 SC). Risk assessment was done by calculating hazard quotient and by comparing theoretical maximum residue intake (TMRI) with maximum permissible intake (MPI). In all the cases, results of the study showed that HQ (Hazard Quotient) ≤1 and TMDI < MPI. Hence, the use of this combination product can be recommended with pre harvest interval of 7 days. The data can be used in establishing MRLs (maximum residue limits) for spring onion after considering multilocation trials.

Degradation kinetics and safety evaluation of buprofezin residues in grape (Vitis vinifera L.) and three different soils of India.

PubMed

Oulkar, Dasharath P; Banerjee, Kaushik; Patil, Sangram H; Upadhyay, Ajay K; Taware, Praveen B; Deshmukh, Madhukar B; Adsule, Pandurang G

2009-02-01

This work was undertaken to determine the preharvest interval (PHI) of buprofezin to minimize its residues in grapes and thereby ensure consumer safety and avoid possible non-compliance in terms of residue violations in export markets. Furthermore, the residue dynamics in three grapevine soils of India was explored to assess its environmental safety. Residues dissipated following non-linear two-compartment first + first-order kinetics. In grapes, the PHI was 31 days at both treatments (312.5 and 625 g a.i. ha(-1)), with the residues below the maximum permissible intake even 1 h after foliar spraying. Random sampling of 5 kg comprising small bunchlets (8-10 berries) collected from a 1 ha area gave satisfactory homogeneity and representation of the population. A survey on the samples harvested after the PHI from supervised vineyards that received treatment at the recommended dose showed residues below the maximum residue limit (MRL) of 0.02 mg kg(-1) applicable for the European Union. In soil, the degradation rate was fastest in clay soil, followed by sandy loam and silty clay, with a half-life within 16 days in all the soils. The recommendation of the PHI proved to be effective in minimizing buprofezin residues in grapes. Thus, this work is of high practical significance to the domestic and export grape industry of India to ensure safety compliance in respect of buprofezin residues, keeping in view the requirements of international trade.

Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources.

PubMed

Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

2015-09-09

: Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX(®), UpToDate(®), Medscape(®) and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss' kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211-0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292-0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

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.

Prescribing smoked cannabis for chronic noncancer pain

PubMed Central

Kahan, Meldon; Srivastava, Anita; Spithoff, Sheryl; Bromley, Lisa

2014-01-01

Objective To offer preliminary guidance on prescribing smoked cannabis for chronic pain before the release of formal guidelines. Quality of evidence We reviewed the literature on the analgesic effectiveness of smoked cannabis and the harms of medical and recreational cannabis use. We developed recommendations on indications, contraindications, precautions, and dosing of smoked cannabis, and categorized the recommendations based on levels of evidence. Evidence is mostly level II (well conducted observational studies) and III (expert opinion). Main message Smoked cannabis might be indicated for patients with severe neuropathic pain conditions who have not responded to adequate trials of pharmaceutical cannabinoids and standard analgesics (level II evidence). Smoked cannabis is contraindicated in patients who are 25 years of age or younger (level II evidence); who have a current, past, or strong family history of psychosis (level II evidence); who have a current or past cannabis use disorder (level III evidence); who have a current substance use disorder (level III evidence); who have cardiovascular or respiratory disease (level III evidence); or who are pregnant or planning to become pregnant (level II evidence). It should be used with caution in patients who smoke tobacco (level II evidence), who are at increased risk of cardiovascular disease (level III evidence), who have anxiety or mood disorders (level II evidence), or who are taking higher doses of opioids or benzodiazepines (level III evidence). Cannabis users should be advised not to drive for at least 3 to 4 hours after smoking, for at least 6 hours after oral ingestion, and for at least 8 hours if they experience a subjective “high” (level II evidence). The maximum recommended dose is 1 inhalation 4 times per day (approximately 400 mg per day) of dried cannabis containing 9% delta-9-tetrahydrocannabinol (level III evidence). Physicians should avoid referring patients to “cannabinoid” clinics (level III evidence). Conclusion Future guidelines should be based on systematic review of the literature on the safety and effectiveness of smoked cannabis. Further research is needed on the effectiveness and long-term safety of smoked cannabis compared with pharmaceutical cannabinoids, opioids, and other standard analgesics. PMID:25500598

Individual dose adjustment of riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

PubMed

Hill, Nicholas S; Rahaghi, Franck F; Sood, Namita; Frey, Reiner; Ghofrani, Hossein-Ardeschir

2017-08-01

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy.

PubMed

Bastian, Jaime R; Chen, Huijun; Zhang, Hongfei; Rothenberger, Scott; Tarter, Ralph; English, Dennis; Venkataramanan, Raman; Caritis, Steve N

2017-01-01

Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy. This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy. Pregnant women (n = 13), between 18 0/7 and 37 6/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n = 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n = 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n = 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality. Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves (P < .003), maximum buprenorphine concentrations (P < .018), buprenorphine concentrations at 0 hour (P < .002), and buprenorphine concentrations at 12 hours (P < .001). None of these parameters differed significantly during pregnancy (ie, pharmacokinetic-2 vs pharmacokinetic-3). The time to maximum buprenorphine concentrations did not differ significantly between groups. The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period. Copyright © 2016 Elsevier Inc. All rights reserved.

Multileaf collimator tongue-and-groove effect on depth and off-axis doses: A comparison of treatment planning data with measurements and Monte Carlo calculations

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

Kim, Hee Jung; Department of Biomedical Engineering, Seoul National University, Seoul; Department of Radiation Oncology, Soonchunhyang University Hospital, Seoul

2015-01-01

To investigate how accurately treatment planning systems (TPSs) account for the tongue-and-groove (TG) effect, Monte Carlo (MC) simulations and radiochromic film (RCF) measurements were performed for comparison with TPS results. Two commercial TPSs computed the TG effect for Varian Millennium 120 multileaf collimator (MLC). The TG effect on off-axis dose profile at 3 depths of solid water was estimated as the maximum depth and the full width at half maximum (FWHM) of the dose dip at an interleaf position. When compared with the off-axis dose of open field, the maximum depth of the dose dip for MC and RCF rangedmore » from 10.1% to 20.6%; the maximum depth of the dose dip gradually decreased by up to 8.7% with increasing depths of 1.5 to 10 cm and also by up to 4.1% with increasing off-axis distances of 0 to 13 cm. However, TPS results showed at most a 2.7% decrease for the same depth range and a negligible variation for the same off-axis distances. The FWHM of the dose dip was approximately 0.19 cm for MC and 0.17 cm for RCF, but 0.30 cm for Eclipse TPS and 0.45 cm for Pinnacle TPS. Accordingly, the integrated value of TG dose dip for TPS was larger than that for MC and RCF and almost invariant along the depths and off-axis distances. We concluded that the TG dependence on depth and off-axis doses shown in the MC and RCF results could not be appropriately modeled by the TPS versions in this study.« less

Confusion: acetaminophen dosing changes based on NO evidence in adults.

PubMed

Krenzelok, Edward P; Royal, Mike A

2012-06-01

Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900-4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900-4000 mg to 3000-3250 mg. In 2011, McNeil, the producer of the Tylenol® brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used?

The preteen visit: an opportunity for prevention.

PubMed

Campos-Outcalt, Doug

2006-12-01

All early adolescents should visit a physician at age 11 or 12 years to receive a set of recommended vaccines. Two vaccines are recommended for boys in this age group-quadrivalent meningococcal conjugate vaccine (MCV4) and tetanus toxoid, reduced diphtheria, and acellular pertussis vaccine (Tdap). Three vaccines are recommended for girls--MCV4, Tdap, and human papilloma virus (HPV) vaccine. In addition, 2 doses of varicella vaccine are now recommended before age 5 years; both boys and girls at age 11 or 12 who have received only 1 dose should be given a second.

[Immunisation schedule of the Spanish Association of Paediatrics: 2018 recommendations].

PubMed

Moreno-Pérez, David; Álvarez García, Francisco José; Álvarez Aldeán, Javier; Cilleruelo Ortega, María José; Garcés Sánchez, María; García Sánchez, Nuria; Hernández Merino, Ángel; Méndez Hernández, María; Merino Moína, Manuel; Montesdeoca Melián, Abián; Ruiz-Contreras, Jesús

2018-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics annually publishes the immunisation schedule considered optimal for children resident in Spain, according to available evidence on current vaccines. Regarding funded immunisations, 2+1 strategy (2, 4, 11-12 months) with hexavalent (DTPa-IPV-Hib-HB) and 13-valent pneumococcal vaccines are recommended. Administration of the 6-year booster dose with DTPa is recommended, and a poliomyelitis dose for children who had received the 2+1 scheme, as well as Tdap vaccine for adolescents and pregnant women in every pregnancy between 27 and 32 weeks' gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). MMRV vaccine could be applied as the second dose if available. Coverage of human papillomavirus vaccination in girls aged 12 with a two dose scheme (0, 6 months) should be improved. Information and recommendation for male adolescents about potential beneficial effects of this immunisation should be provided as well. The new 9 genotypes vaccine is now available, expanding the coverage for both gender. Regarding non-funded immunisations, Committee on Vaccines of the Spanish Association of Paediatrics recommends meningococcal B vaccination, with a 3+1 schedule, and requests to be included in the National Immunisation Program. Tetravalent meningococcal vaccine (MenACWY) is recommended to adolescents (14-18 years) who are going to live in countries with systematic vaccination against ACWY serogroups, and people >6 weeks of age with risk factors or travellers to countries with very high incidence. Vaccination against rotavirus is recommended in all infants. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature.

PubMed

Bredlau, Amy Lee; Thakur, Rajbala; Korones, David Nathan; Dworkin, Robert H

2013-10-01

Chronic cancer pain is often refractory and difficult to treat. Ketamine is a medication with evidence of efficacy in the treatment of chronic pain. This article presents a synthesis of the data on ketamine for refractory cancer pain in adults and children. There are five randomized, double-blind, controlled trials of ketamine use in cancer pain that demonstrate improvement in pain for some patients. There are six prospective, uncontrolled trials in cancer pain that also demonstrate improvement in pain scores for some patients. There are no randomized, controlled trials in children with cancer pain, although there are a few studies reflecting improved pain control with ketamine for children with cancer pain. Adverse events for adults on ketamine are most commonly somnolence, feelings of insobriety, nausea/vomiting, hallucinations, depersonalization/derealization, and drowsiness. However, when ketamine is combined with benzodiazepines, feelings of insobriety, hallucinations, and depersonalization/derealization are not reported. Children on ketamine have had few reported adverse effects, which include sedation, anorexia, urinary retention, and myoclonic movements. Recommended ketamine infusion dosages are from 0.05 to 0.5 mg/kg/h (intravenous or subcutaneous). Recommended oral dosages of ketamine are 0.2-0.5 mg/kg/dose two to three times daily with a maximum of 50 mg/dose three times daily. Despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain. Wiley Periodicals, Inc.

Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

PubMed Central

Sarduy, M R; García, I; Coca, M A; Perera, A; Torres, L A; Valenzuela, C M; Baladrón, I; Solares, M; Reyes, V; Hernández, I; Perera, Y; Martínez, Y M; Molina, L; González, Y M; Ancízar, J A; Prats, A; González, L; Casacó, C A; Acevedo, B E; López-Saura, P A; Alonso, D F; Gómez, R; Perea-Rodríguez, S E

2015-01-01

Background: We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose. Methods: Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using 99Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry. Results: Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1±8.9 vs 31.3±12.9 mg (P=0.01). Both, AUC24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P<0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P=0.03) in tumour specimens. Conclusion: Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies. PMID:25880012

Radiation dose to the Malaysian populace via the consumption of bottled mineral water

NASA Astrophysics Data System (ADS)

Khandaker, Mayeen Uddin; Nasir, Noor Liyana Mohd; Zakirin, Nur Syahira; Kassim, Hasan Abu; Asaduzzaman, Khandoker; Bradley, D. A.; Zulkifli, M. Y.; Hayyan, Adeeb

2017-11-01

Due to the geological makeup of the various water bodies, mineral- and groundwater can be expected to contain levels of naturally occurring radioactive material (NORM) exceeding that of tap and surface water. Acknowledging mineral water to form a vital component of the intake in maintaining the healthy life of an individual, it nevertheless remains important to study the associated radiological implications of NORM content, especially in regard to the consumption of bottled mineral water, the presence of which is prevalent in modern urban society. In present study, various brands of bottled mineral waters that are commonly available in Malaysia were obtained from local markets, the presence of NORM subsequently being assessed by HPGe γ-ray spectrometry. The activity concentrations of the radionuclides of particular interest, 226Ra, 232Th and 40K, were found to be within the respective ranges of 1.45±0.28‒3.30±0.43, 0.65±0.18‒3.39±0.38 and 21.12±1.74‒25.31±1.84 Bq/L. The concentrations of 226Ra, of central importance in radiological risk assessment, exceed the World Health Organisation (WHO, 2011) recommended maximum permissible limit of 1.0 Bq/L; for all three radionuclides taken together, the annual effective doses are greater than the WHO recommended limit of 0.1 mSv/y, a matter of especial concern for those in the developmental stages of life.

Meeting physical activity recommendations: self-regulatory efficacy characterizes differential adherence during arthritis flares.

PubMed

Gyurcsik, Nancy C; Brawley, Lawrence R; Spink, Kevin S; Sessford, James D

2013-02-01

Using social-cognitive theory, we examined whether adults who experienced an arthritis flare and met/did not meet the disease-specific public health recommended dose for physical activity differed in their self-regulatory efficacy beliefs, overall pain, and flare-related factors. Adults with arthritis (N = 56; M(age) = 49.41 ± 11.56 years) participated in this prospective study. Multivariate analysis of variance comparing groups who met or did not meet the recommended dose (n(met) = 24, ≥ 150 minutes/week vs. n(not met) = 32, < 150 min/week) on efficacy, overall pain, and flare-related factors was significant (p < .01; η(partial)² = .28). People meeting the dose had significantly greater self-regulatory efficacy to overcome arthritis barriers (M(met dose) = 7.33 ± 1.95 vs. M(did not meet dose) = 5.74 ± 2.08, η(partial)² = .14) and to schedule/plan (M(met dose) = 7.27 ± 1.80 vs. M(did not meet dose) = 5.72 ± 1.90, η(partial)² = .15). Overall pain and flare-related factors did not differ (ps > .05). During flares, individuals with greater self-regulatory efficacy to manage disease barriers and plan their physical activity were more adherent to disease-specific public health activity recommendations. This study was the first to demonstrate differences in social cognitions that characterize adherence to recommended activity among people challenged by arthritis flares. Findings support the theoretical position that self-regulatory efficacy is related to better adherence in the face of challenging disease-related circumstances. The importance of studying individual characteristics of people who succeed in being active despite such obstacles is stressed.

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

Li, Heng, E-mail: hengli@mdanderson.org; Zhu, X. Ronald; Zhang, Xiaodong

Purpose: To develop and validate a novel delivery strategy for reducing the respiratory motion–induced dose uncertainty of spot-scanning proton therapy. Methods and Materials: The spot delivery sequence was optimized to reduce dose uncertainty. The effectiveness of the delivery sequence optimization was evaluated using measurements and patient simulation. One hundred ninety-one 2-dimensional measurements using different delivery sequences of a single-layer uniform pattern were obtained with a detector array on a 1-dimensional moving platform. Intensity modulated proton therapy plans were generated for 10 lung cancer patients, and dose uncertainties for different delivery sequences were evaluated by simulation. Results: Without delivery sequence optimization,more » the maximum absolute dose error can be up to 97.2% in a single measurement, whereas the optimized delivery sequence results in a maximum absolute dose error of ≤11.8%. In patient simulation, the optimized delivery sequence reduces the mean of fractional maximum absolute dose error compared with the regular delivery sequence by 3.3% to 10.6% (32.5-68.0% relative reduction) for different patients. Conclusions: Optimizing the delivery sequence can reduce dose uncertainty due to respiratory motion in spot-scanning proton therapy, assuming the 4-dimensional CT is a true representation of the patients' breathing patterns.« less

Monte Carlo modeling of in vivo protoporphyrin IX fluorescence and singlet oxygen production during photodynamic therapy for patients presenting with superficial basal cell carcinomas

NASA Astrophysics Data System (ADS)

Valentine, Ronan M.; Brown, C. Tom A.; Moseley, Harry; Ibbotson, Sally; Wood, Kenny

2011-04-01

We present protoporphyrin IX (PpIX) fluorescence measurements acquired from patients presenting with superficial basal cell carcinoma during photodynamic therapy (PDT) treatment, facilitating in vivo photobleaching to be monitored. Monte Carlo (MC) simulations, taking into account photobleaching, are performed on a three-dimensional cube grid, which represents the treatment geometry. Consequently, it is possible to determine the spatial and temporal changes to the origin of collected fluorescence and generated singlet oxygen. From our clinical results, an in vivo photobleaching dose constant, β of 5-aminolaevulinic acid-induced PpIX fluorescence is found to be 14 +/- 1 J/cm2. Results from our MC simulations suggest that an increase from our typical administered treatment light dose of 75-150 J/cm2 could increase the effective PDT treatment initially achieved at a depth of 2.7-3.3 mm in the tumor, respectively. Moreover, this increase reduces the surface PpIX fluorescence from 0.00012 to 0.000003 of the maximum value recorded before treatment. The recommendation of administrating a larger light dose, which advocates an increase in the treatment time after surface PpIX fluorescence has diminished, remains valid for different sets of optical properties and therefore should have a beneficial outcome on the total treatment effect.

A review of the use of ethionamide and prothionamide in childhood tuberculosis.

PubMed

Thee, S; Garcia-Prats, A J; Donald, P R; Hesseling, A C; Schaaf, H S

2016-03-01

Ethionamide (ETH) and prothionamide (PTH), both thioamides, have proven efficacy in clinical studies and form important components for multidrug-resistant tuberculosis treatment regimens and for treatment of tuberculous meningitis in adults and children. ETH and PTH are pro-drugs that, following enzymatic activation by mycobacterial EthA inhibit InhA, a target shared with isoniazid (INH), and subsequently inhibit mycolic acid synthesis of Mycobacterium tuberculosis. Co-resistance to INH and ETH is conferred by mutations in the mycobacterial inhA promoter region; mutations in the ethA gene often underlie ETH and PTH monoresistance. An oral daily dose of ETH or PTH of 15-20 mg/kg with a maximum daily dose of 1000 mg is recommended in children to achieve adult-equivalent serum concentrations shown to be efficacious in adults, although information on optimal pharmacodynamic targets is still lacking. Gastrointestinal disturbances, and hypothyroidism during long-term therapy, are frequent adverse effects observed in adults and children, but are rarely life-threatening and seldom necessitate cessation of ETH therapy. More thorough investigation of the therapeutic effects and toxicity of ETH and PTH is needed in childhood TB while child-friendly formulations are needed to appropriately dose children. Copyright © 2015 Elsevier Ltd. All rights reserved.

A comparison of skin and chest wall dose delivered with multicatheter, Contura multilumen balloon, and MammoSite breast brachytherapy.

PubMed

Cuttino, Laurie W; Todor, Dorin; Rosu, Mihaela; Arthur, Douglas W

2011-01-01

Skin and chest wall doses have been correlated with toxicity in patients treated with breast brachytherapy . This investigation compared the ability to control skin and chest wall doses between patients treated with multicatheter (MC), Contura multilumen balloon (CMLB), and MammoSite (MS) brachytherapy. 43 patients treated with the MC technique, 45 patients treated with the CMLB, and 83 patients treated with the MS were reviewed. The maximum doses delivered to the skin and chest wall were calculated for all patients. The mean maximum skin doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.2 Gy per fraction (94% of prescription dose), respectively. Although the skin distances were similar (p = 0.23) for the two balloon techniques, the mean skin dose with the CMLB was significantly lower than with the MS (p = 0.05). The mean maximum rib doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.6 Gy per fraction (105% of prescription dose), respectively. Again, the mean rib dose with the CMLB was significantly lower than with the MS (p = 0.002). The MC and CMLB techniques are associated with significantly lower mean skin and rib doses than is the MS. Treatment with the MS was associated with significantly more patients receiving doses to the skin or rib in excess of 125% of the prescription. Treatment with the CMLB may prove to yield less normal tissue toxicity than treatment with the MS. Copyright © 2011 Elsevier Inc. All rights reserved.

A Comparison of Skin and Chest Wall Dose Delivered With Multicatheter, Contura Multilumen Balloon, and MammoSite Breast Brachytherapy

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

Cuttino, Laurie W., E-mail: lcuttino@mcvh-vcu.ed; Todor, Dorin; Rosu, Mihaela

2011-01-01

Purpose: Skin and chest wall doses have been correlated with toxicity in patients treated with breast brachytherapy . This investigation compared the ability to control skin and chest wall doses between patients treated with multicatheter (MC), Contura multilumen balloon (CMLB), and MammoSite (MS) brachytherapy. Methods and Materials: 43 patients treated with the MC technique, 45 patients treated with the CMLB, and 83 patients treated with the MS were reviewed. The maximum doses delivered to the skin and chest wall were calculated for all patients. Results: The mean maximum skin doses for the MC, CMLB, and MS were 2.3 Gy (67%more » of prescription dose), 2.8 Gy (82% of prescription dose), and 3.2 Gy per fraction (94% of prescription dose), respectively. Although the skin distances were similar (p = 0.23) for the two balloon techniques, the mean skin dose with the CMLB was significantly lower than with the MS (p = 0.05). The mean maximum rib doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.6 Gy per fraction (105% of prescription dose), respectively. Again, the mean rib dose with the CMLB was significantly lower than with the MS (p = 0.002). Conclusion: The MC and CMLB techniques are associated with significantly lower mean skin and rib doses than is the MS. Treatment with the MS was associated with significantly more patients receiving doses to the skin or rib in excess of 125% of the prescription. Treatment with the CMLB may prove to yield less normal tissue toxicity than treatment with the MS.« less

Quantifying the impact of immediate reconstruction in postmastectomy radiation: a large, dose-volume histogram-based analysis.

PubMed

Ohri, Nisha; Cordeiro, Peter G; Keam, Jennifer; Ballangrud, Ase; Shi, Weiji; Zhang, Zhigang; Nerbun, Claire T; Woch, Katherine M; Stein, Nicholas F; Zhou, Ying; McCormick, Beryl; Powell, Simon N; Ho, Alice Y

2012-10-01

To assess the impact of immediate breast reconstruction on postmastectomy radiation (PMRT) using dose-volume histogram (DVH) data. Two hundred forty-seven women underwent PMRT at our center, 196 with implant reconstruction and 51 without reconstruction. Patients with reconstruction were treated with tangential photons, and patients without reconstruction were treated with en-face electron fields and customized bolus. Twenty percent of patients received internal mammary node (IMN) treatment. The DVH data were compared between groups. Ipsilateral lung parameters included V20 (% volume receiving 20 Gy), V40 (% volume receiving 40 Gy), mean dose, and maximum dose. Heart parameters included V25 (% volume receiving 25 Gy), mean dose, and maximum dose. IMN coverage was assessed when applicable. Chest wall coverage was assessed in patients with reconstruction. Propensity-matched analysis adjusted for potential confounders of laterality and IMN treatment. Reconstruction was associated with lower lung V20, mean dose, and maximum dose compared with no reconstruction (all P<.0001). These associations persisted on propensity-matched analysis (all P<.0001). Heart doses were similar between groups (P=NS). Ninety percent of patients with reconstruction had excellent chest wall coverage (D95 >98%). IMN coverage was superior in patients with reconstruction (D95 >92.0 vs 75.7%, P<.001). IMN treatment significantly increased lung and heart parameters in patients with reconstruction (all P<.05) but minimally affected those without reconstruction (all P>.05). Among IMN-treated patients, only lower lung V20 in those without reconstruction persisted (P=.022), and mean and maximum heart doses were higher than in patients without reconstruction (P=.006, P=.015, respectively). Implant reconstruction does not compromise the technical quality of PMRT when the IMNs are untreated. Treatment technique, not reconstruction, is the primary determinant of target coverage and normal tissue doses. Published by Elsevier Inc.

Cosmic Radiation Exposure of Biological Test Systems During the EXPOSE-E Mission

PubMed Central

Hajek, Michael; Bilski, Pawel; Körner, Christine; Vanhavere, Filip; Reitz, Günther

2012-01-01

Abstract In the frame of the EXPOSE-E mission on the Columbus external payload facility EuTEF on board the International Space Station, passive thermoluminescence dosimeters were applied to measure the radiation exposure of biological samples. The detectors were located either as stacks next to biological specimens to determine the depth dose distribution or beneath the sample carriers to determine the dose levels for maximum shielding. The maximum mission dose measured in the upper layer of the depth dose part of the experiment amounted to 238±10 mGy, which relates to an average dose rate of 408±16 μGy/d. In these stacks of about 8 mm height, the dose decreased by 5–12% with depth. The maximum dose measured beneath the sample carriers was 215±16 mGy, which amounts to an average dose rate of 368±27 μGy/d. These values are close to those assessed for the interior of the Columbus module and demonstrate the high shielding of the biological experiments within the EXPOSE-E facility. Besides the shielding by the EXPOSE-E hardware itself, additional shielding was experienced by the external structures adjacent to EXPOSE-E, such as EuTEF and Columbus. This led to a dose gradient over the entire exposure area, from 215±16 mGy for the lowest to 121±6 mGy for maximum shielding. Hence, the doses perceived by the biological samples inside EXPOSE-E varied by 70% (from lowest to highest dose). As a consequence of the high shielding, the biological samples were predominantly exposed to galactic cosmic heavy ions, while electrons and a significant fraction of protons of the radiation belts and solar wind did not reach the samples. Key Words: Space radiation—Dosimetry—Passive radiation detectors—Thermoluminescence—EXPOSE-E. Astrobiology 12, 387–392. PMID:22680685

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

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

Landau, David B., E-mail: david.landau@kcl.ac.uk; Hughes, Laura; Baker, Angela

2016-08-01

Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumormore » doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.« less

Radiological assessment of Abu-Tartur phosphate, Western Desert Egypt.

PubMed

Uosif, M A M; El-Taher, A

2008-01-01

The contents of natural radionuclides ((226)Ra, (232)Th and (40)K) were measured in sedimentary phosphate rock samples (Abu-Tartur phosphate, Western Desert Egypt) by using gamma spectrometry (NaI (Tl) 3"x 3"). Phosphate and environmental samples were collected from Abu-Tartur phosphate mine and the surrounding region. The results are discussed and compared with the levels in phosphate rocks from different countries. The activities of (226)Ra, (232)Th series and (40)K are between (14.9 +/- 0.8 and 302.4 +/- 15.2), (2.6 +/- 1.0 and 154.9 +/- 7.8) and (10.0 +/- 0.5 and 368.4 +/- 18.4) Bq kg(-1), respectively. The Abu-Tartur phosphate deposit was found to have lower activity than many others exploited phosphate sedimentary deposits, with its average total annual dose being only 114.6 microSv y(-1). This value is about 11.46% of the 1.0 mSv y(-1) recommended by the International Commission on Radiological Protection (ICRP-60, 1990) as the maximum annual dose to members of the public.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

PubMed

Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G; Liu, Xiaowei; Kim, AeRang; Bernhardt, Melanie Brooke; Kudgus, Rachel A; Reid, Joel M; Voss, Stephan D; Blaney, Susan; Fox, Elizabeth; Weigel, Brenda J

2018-04-25

We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted. © 2018 Wiley Periodicals, Inc.

Dose Accuracy and Injection Force of Different Insulin Glargine Pens

PubMed Central

Friedrichs, Arnd; Bohnet, Janine; Korger, Volker; Adler, Steffen; Schubert-Zsilavecz, Manfred; Abdel-Tawab, Mona

2013-01-01

Background Dose accuracy and injection force, representing key parameters of insulin pens, were determined for three pens delivering insulin glargine-based copies, Pen Royale (WR) and DispoPen (WD) for Glaritus® (Wockhardt) and GanLee Pen (GL) for Basalin® (Gan & Lee), compared with pens of the originator, ClikSTAR® (CS) and S o l o S TA R® (SS) for Lantus® (Sanofi) . Methods Using the weighing procedure recommended by DIN EN ISO 11608–1:2000, dose accuracy was evaluated based on nonrandomized delivery of low (5 U), mid (30 U), and high (60 U) dosage levels. Injection force was measured by dispensing the maximum dose of insulin (60 U for the GL, WR, and WD; 80 U for the SS and CS) at dose speeds of 6 and 10 U/s. Results All tested pens delivered comparable average doses within the DIN EN ISO 11608–1:2000 limits at all dosage levels. The GL revealed a higher coefficient of variation (CV) at 5 U, and the WR and WD had higher CVs at all dosage levels compared with the CS and SS. Injection force was higher for the WR, WD, and GL compared with the CS and SS at both dose speeds. In contrast to the CS and SS with an end-of-content feature, doses exceeding the remaining insulin could be dialed with the WR, GL, and WD and, apparently, dispensed with the WD. Conclusions All pens fulfilled the dose accuracy requirements defined by DIN EN ISO 11608–1:2000 standards at all three dosage levels, with the WR, WD, and GL showing higher dosage variability and injection force compared with the SS and CS. Thus, the devices that deliver insulin glargine copies show different performance characteristics compared with the originator. J Diabetes Sci Technol 2013;7(5):1346–1353 PMID:24124963

Prehospital Care for the Adult and Pediatric Seizure Patient: Current Evidence-based Recommendations.

PubMed

Silverman, Eric C; Sporer, Karl A; Lemieux, Justin M; Brown, John F; Koenig, Kristi L; Gausche-Hill, Marianne; Rudnick, Eric M; Salvucci, Angelo A; Gilbert, Greg H

2017-04-01

We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of adult and pediatric patients with a seizure and to compare these recommendations against the current protocol used by the 33 emergency medical services (EMS) agencies in California. We performed a review of the evidence in the prehospital treatment of patients with a seizure, and then compared the seizure protocols of each of the 33 EMS agencies for consistency with these recommendations. We analyzed the type and route of medication administered, number of additional rescue doses permitted, and requirements for glucose testing prior to medication. The treatment for eclampsia and seizures in pediatric patients were analyzed separately. Protocols across EMS Agencies in California varied widely. We identified multiple drugs, dosages, routes of administration, re-dosing instructions, and requirement for blood glucose testing prior to medication delivery. Blood glucose testing prior to benzodiazepine administration is required by 61% (20/33) of agencies for adult patients and 76% (25/33) for pediatric patients. All agencies have protocols for giving intramuscular benzodiazepines and 76% (25/33) have protocols for intranasal benzodiazepines. Intramuscular midazolam dosages ranged from 2 to 10 mg per single adult dose, 2 to 8 mg per single pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intranasal midazolam dosages ranged from 2 to 10 mg per single adult or pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intravenous/intrasosseous midazolam dosages ranged from 1 to 6 mg per single adult dose, 1 to 5 mg per single pediatric dose, and 0.05 to 0.1 mg/kg as a weight-based dose. Eclampsia is specifically addressed by 85% (28/33) of agencies. Forty-two percent (14/33) have a protocol for administering magnesium sulfate, with intravenous dosages ranging from 2 to 6 mg, and 58% (19/33) allow benzodiazepines to be administered. Protocols for a patient with a seizure, including eclampsia and febrile seizures, vary widely across California. These recommendations for the prehospital diagnosis and treatment of seizures may be useful for EMS medical directors tasked with creating and revising these protocols.

Evaluation of the dependence of the exposure dose on the attenuation correction in brain PET/CT scans using 18F-FDG

NASA Astrophysics Data System (ADS)

Choi, Eun-Jin; Jeong, Moon-Taeg; Jang, Seong-Joo; Choi, Nam-Gil; Han, Jae-Bok; Yang, Nam-Hee; Dong, Kyung-Rae; Chung, Woon-Kwan; Lee, Yun-Jong; Ryu, Young-Hwan; Choi, Sung-Hyun; Seong, Kyeong-Jeong

2014-01-01

This study examined whether scanning could be performed with minimum dose and minimum exposure to the patient after an attenuation correction. A Hoffman 3D Brain Phantom was used in BIO_40 and D_690 PET/CT scanners, and the CT dose for the equipment was classified as a low dose (minimum dose), medium dose (general dose for scanning) and high dose (dose with use of contrast medium) before obtaining the image at a fixed kilo-voltage-peak (kVp) and milliampere (mA) that were adjusted gradually in 17-20 stages. A PET image was then obtained to perform an attenuation correction based on an attenuation map before analyzing the dose difference. Depending on tube current in the range of 33-190 milliampere-second (mAs) when BIO_40 was used, a significant difference in the effective dose was observed between the minimum and the maximum mAs (p < 0.05). According to a Scheffe post-hoc test, the ratio of the minimum to the maximum of the effective dose was increased by approximately 5.26-fold. Depending on the change in the tube current in the range of 10-200 mA when D_690 was used, a significant difference in the effective dose was observed between the minimum and the maximum of mA (p < 0.05). The Scheffe posthoc test revealed a 20.5-fold difference. In conclusion, because effective exposure dose increases with increasing operating current, it is possible to reduce the exposure limit in a brain scan can be reduced if the CT dose can be minimized for a transmission scan.

Implied Maximum Dose Analysis of Standard Values of 25 Pesticides Based on Major Human Exposure Pathways

PubMed Central

Li, Zijian; Jennings, Aaron A.

2017-01-01

Worldwide jurisdictions are making efforts to regulate pesticide standard values in residential soil, drinking water, air, and agricultural commodity to lower the risk of pesticide impacts on human health. Because human may exposure to pesticides from many ways, such as ingestion, inhalation, and dermal contact, it is important to examine pesticide standards by considering all major exposure pathways. Analysis of implied maximum dose limits for commonly historical and current used pesticides was adopted in this study to examine whether worldwide pesticide standard values are enough to prevent human health impact or not. Studies show that only U.S. has regulated pesticides standard in the air. Only 4% of the total number of implied maximum dose limits is based on three major exposures. For Chlorpyrifos, at least 77.5% of the total implied maximum dose limits are above the acceptable daily intake. It also shows that most jurisdictions haven't provided pesticide standards in all major exposures yet, and some of the standards are not good enough to protect human health. PMID:29546224

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.

Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013.

PubMed

Suh, Hoon Young; Peck, Carl C; Yu, Kyung-Sang; Lee, Howard

2016-01-01

A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, P =0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.

Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL‐2 inhibitor, in patients with non‐Hodgkin lymphoma

PubMed Central

Agarwal, Suresh K.; Danilov, Alexey V.; Hu, Beibei; Puvvada, Soham; Gutierrez, Martin; Chien, David; Lewis, Lionel D.; Wong, Shekman L.

2017-01-01

Aims To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods Twelve patients with non‐Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open‐label, fixed‐sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (C max) and area under the plasma concentration–time curve from time 0 to infinity (AUC∞) by 2.3‐fold (90% confidence interval [CI]: 2.0–2.7) and 6.4‐fold (90% CI: 4.5–9.2; range: 2‐ to 12‐fold), respectively. Conclusions Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp‐up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp‐up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended. PMID:27859472

Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma.

PubMed

Agarwal, Suresh K; Salem, Ahmed Hamed; Danilov, Alexey V; Hu, Beibei; Puvvada, Soham; Gutierrez, Martin; Chien, David; Lewis, Lionel D; Wong, Shekman L

2017-04-01

To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to infinity (AUC ∞ ) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively. Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended. © 2016 The British Pharmacological Society.

Combined MTOR and autophagy inhibition

PubMed Central

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O’Dwyer, Peter J; Amaravadi, Ravi K

2014-01-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted. PMID:24991838

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

2014-08-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study.

PubMed

Pappot, H; von der Maase, H; Ullén, A; Agerbæk, M

2017-10-28

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

PubMed

Suder, A; Ang, J E; Kyle, F; Harris, D; Rudman, S; Kristeleit, R; Solca, F; Uttenreuther-Fischer, M; Pemberton, K; Pelling, K; Schnell, D; de Bono, J; Spicer, J

2015-11-01

This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. ClinicalTrials.gov, NCT00809133. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Phase 1 trial of ontuxizumab (MORAb-004) in children with relapsed or refractory solid tumors: A report from the Children's Oncology Group Phase 1 Pilot Consortium (ADVL1213).

PubMed

Norris, Robin E; Fox, Elizabeth; Reid, Joel M; Ralya, Andrew; Liu, Xiaowei W; Minard, Charles; Weigel, Brenda J

2018-05-01

Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation. Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation. Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg. Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults. © 2018 Wiley Periodicals, Inc.

Safety of high volume lipid emulsion infusion: a first approximation of LD50 in rats.

PubMed

Hiller, David B; Di Gregorio, Guido; Kelly, Kemba; Ripper, Richard; Edelman, Lucas; Boumendjel, Redouane; Drasner, Kenneth; Weinberg, Guy L

2010-01-01

Lipid infusion reverses systemic local anesthetic toxicity. The acceptable upper limit for lipid administration is unknown and has direct bearing on clinical management. We hypothesize that high volumes of lipid could have undesirable effects and sought to identify the dose required to kill 50% of the animals (LD(50)) of large volume lipid administration. Intravenous lines and electrocardiogram electrodes were placed in anesthetized, male Sprague-Dawley rats. Twenty percent lipid emulsion (20, 40, 60, or 80 mL/kg) or saline (60 or 80 mL/kg), were administered over 30 mins; lipid dosing was assigned by the Dixon "up-and-down" method. Rats were recovered and observed for 48 hrs then euthanized for histologic analysis of major organs. Three additional rats were administered 60 mL/kg lipid emulsion and euthanized at 1, 4, and 24 hrs to identify progression of organ damage. The maximum likelihood estimate for LD(50) was 67.72 (SE, 10.69) mL/kg. Triglycerides were elevated immediately after infusion but returned to baseline by 48 hrs when laboratory abnormalities included elevated amylase, aspartate aminotransferase, and serum urea nitrogen for all lipid doses. Histologic diagnosis of myocardium, brain, pancreas, and kidneys was normal at all doses. Microscopic abnormalities in lung and liver were observed at 60 and 80 mL/kg; histopathology in the lung and liver was worse at 1 hr than at 4 and 24 hrs. The LD(50) of rapid, high volume lipid infusion is an order of magnitude greater than doses typically used for lipid rescue in humans and supports the safety of lipid infusion at currently recommended doses for toxin-induced cardiac arrest. Lung and liver histopathology was observed at the highest infused volumes.

Single shot of 17D vaccine may not confer life-long protection against yellow fever.

PubMed

Vasconcelos, Pedro Fc

2018-02-01

The yellow fever (YF) vaccine has been used since the 1930s to prevent YF, which is a severe infectious disease caused by the yellow fever virus (YFV), and mainly transmitted by Culicidae mosquitoes from the genera Aedes and Haemagogus . Until 2013, the World Health Organization (WHO) recommended the administration of a vaccine dose every ten years. A new recommendation of a single vaccine dose to confer life-long protection against YFV infection has since been established. Recent evidence published elsewhere suggests that at least a second dose is needed to fully protect against YF disease. Here, we discuss the feasibility of administering multiple doses, the necessity for a new and modern vaccine, and recommend that the WHO conveys a meeting to discuss YFV vaccination strategies for people living in or travelling to endemic areas.

Evaluation and mitigation of potential errors in radiochromic film dosimetry due to film curvature at scanning.

PubMed

Palmer, Antony L; Bradley, David A; Nisbet, Andrew

2015-03-08

This work considers a previously overlooked uncertainty present in film dosimetry which results from moderate curvature of films during the scanning process. Small film samples are particularly susceptible to film curling which may be undetected or deemed insignificant. In this study, we consider test cases with controlled induced curvature of film and with film raised horizontally above the scanner plate. We also evaluate the difference in scans of a film irradiated with a typical brachytherapy dose distribution with the film naturally curved and with the film held flat on the scanner. Typical naturally occurring curvature of film at scanning, giving rise to a maximum height 1 to 2 mm above the scan plane, may introduce dose errors of 1% to 4%, and considerably reduce gamma evaluation passing rates when comparing film-measured doses with treatment planning system-calculated dose distributions, a common application of film dosimetry in radiotherapy. The use of a triple-channel dosimetry algorithm appeared to mitigate the error due to film curvature compared to conventional single-channel film dosimetry. The change in pixel value and calibrated reported dose with film curling or height above the scanner plate may be due to variations in illumination characteristics, optical disturbances, or a Callier-type effect. There is a clear requirement for physically flat films at scanning to avoid the introduction of a substantial error source in film dosimetry. Particularly for small film samples, a compression glass plate above the film is recommended to ensure flat-film scanning. This effect has been overlooked to date in the literature.

Is eye lens dosimetry needed in nuclear medicine?

PubMed

Wrzesień, M; Królicki, L; Albiniak, Ł; Olszewski, J

2018-06-01

The exact level of exposure experienced by nuclear medicine personnel, whose work often requires performing manual procedures involving radioactive isotopes, is associated with the form of radiation source used. The variety of radionuclides and medical procedures, and the yearly increase in the number of patients, as well as the change of the individual dose limit for the lens of the eye from a value of 150 mSv yr -1 to 20 mSv yr -1 , mean that issues of eye lens routine dosimetry become interesting from the radiation protection point of view. This paper presents an analysis of the exposure of the eye lenses of nuclear medicine department personnel, as well as those of personnel in the facilities that produce radiopharmaceuticals for the purpose of diagnosis by positron emission tomography, from the viewpoint of the advisability of routine eye lens exposure monitoring, taking into account changes in the dose limit for the lens of the eye. The paper considers the two most commonly used radionuclides for diagnostic purposes 99m Tc, 18 F, and-for therapeutic purposes- 131 I. Dose measurements were made using thermoluminescent detectors. The estimated exposure analysis identifies the cases when the maximum annual value of the personal dose equivalent, in terms of Hp(3), exceeds threefold the new limit value (20 mSv yr -1 ). It is recommended that Hp(3) doses be routinely monitored in the group of radiopharmacists who label pharmaceuticals with the radionuclide 99m Tc and in chemists working in 18 F-FDG quality control departments in production units, where this is carried out manually.

A new approach using coagulation rate constant for evaluation of turbidity removal

NASA Astrophysics Data System (ADS)

Al-Sameraiy, Mukheled

2017-06-01

Coagulation-flocculation-sedimentation processes for treating three levels of bentonite synthetic turbid water using date seeds (DS) and alum (A) coagulants were investigated in the previous research work. In the current research, the same experimental results were used to adopt a new approach on a basis of using coagulation rate constant as an investigating parameter to identify optimum doses of these coagulants. Moreover, the performance of these coagulants to meet (WHO) turbidity standard was assessed by introducing a new evaluating criterion in terms of critical coagulation rate constant (kc). Coagulation rate constants (k2) were mathematically calculated in second order form of coagulation process for each coagulant. The maximum (k2) values corresponded to doses, which were obviously to be considered as optimum doses. The proposed criterion to assess the performance of coagulation process of these coagulants was based on the mathematical representation of (WHO) turbidity guidelines in second order form of coagulation process stated that (k2) for each coagulant should be ≥ (kc) for each level of synthetic turbid water. For all tested turbid water, DS coagulant could not satisfy it. While, A coagulant could satisfy it. The results obtained in the present research are exactly in agreement with the previous published results in terms of finding optimum doses for each coagulant and assessing their performances. On the whole, it is recommended considering coagulation rate constant to be a new approach as an indicator for investigating optimum doses and critical coagulation rate constant to be a new evaluating criterion to assess coagulants' performance.

Rate of degradation of lambda-cyhalothrin and methomyl in grapes (Vitis vinifera L.).

PubMed

Banerjee, Kaushik; Upadhyay, Ajay Kumar; Adsule, Pandurang G; Patil, Sangram H; Oulkar, Dasharath P; Jadhav, Deepak R

2006-10-01

Rates of degradation of lambda-cyhalothrin and methomyl residues in grape are reported. The dissipation behavior of both insecticides followed first-order rate kinetics with similar patterns at standard and double-dose applications. Residues of lambda-cyhalothrin were lost with pre-harvest intervals (PHI) of 12.0-12.5 and 15.0-15.5 days, corresponding to the applications at 25 and 50 g a.i. ha-1, respectively. In the case of methomyl, residues were lost with PHI of 55.0 and 61.0 days, following applications at 1 and 2 kg a.i. ha-1, respectively. The PHI, recommended on the basis of the experimental results, was shown to be effective in minimizing residue load of these insecticides below their maximum residue limits (MRLs) in vineyard samples.

Energy determination in industrial X-ray processing facilities

NASA Astrophysics Data System (ADS)

Cleland, M. R.; Gregoire, O.; Stichelbaut, F.; Gomola, I.; Galloway, R. A.; Schlecht, J.

2005-12-01

In industrial irradiation facilities, the determination of maximum photon or electron energy is important for regulated processes, such as food irradiation, and for assurance of treatment reproducibility. With electron beam irradiators, this has been done by measuring the depth-dose distribution in a homogeneous material. For X-ray irradiators, an analogous method has not yet been recommended. This paper describes a procedure suitable for typical industrial irradiation processes, which is based on common practice in the field of therapeutic X-ray treatment. It utilizes a measurement of the slope of the exponential attenuation curve of X-rays in a thick stack of polyethylene plates. Monte Carlo simulations and experimental tests have been performed to verify the suitability and accuracy of the method between 3 MeV and 8 MeV.

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.

Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine - Illinois, 2015-2016.

PubMed

Albertson, Justin P; Clegg, Whitney J; Reid, Heather D; Arbise, Benjamin S; Pryde, Julie; Vaid, Awais; Thompson-Brown, Rachella; Echols, Fredrick

2016-07-29

Mumps is an acute viral disease characterized by fever and swelling of the parotid or other salivary glands. On May 1, 2015, the Illinois Department of Public Health (IDPH) confirmed a mumps outbreak at the University of Illinois at Urbana-Champaign. IDPH and the Champaign-Urbana Public Health District (C-UPHD) conducted an investigation and identified 317 cases of mumps during April 2015-May 2016. Because of sustained transmission in a population with high 2-dose coverage with measles-mumps-rubella (MMR) vaccine, a third MMR dose was recommended by IDPH, C-UPHD, and the university's McKinley Health Center. No formal recommendation for or against the use of a third MMR dose has been issued by the Advisory Committee on Immunization Practices (ACIP) (1). However, CDC has provided guidelines for use of a third dose as a control measure during mumps outbreaks in settings in which persons are in close contact with one another, where transmission is sustained despite high 2-dose MMR coverage, and when traditional control measures fail to slow transmission (2).

Dosimetric Evaluation Between Megavoltage Cone-Beam Computed Tomography and Body Mass Index for Intracranial, Thoracic, and Pelvic Localization

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

VanAntwerp, April E.; Raymond, Sarah M., E-mail: raymons9@ccf.org; Addington, Mark C.

2011-10-01

The aim of this study was to evaluate radiation dose for organs at risk (OAR) within the cranium, thorax, and pelvis from megavoltage cone-beam computed tomography (MV-CBCT). Using a clinical treatment planning system, CBCT doses were calculated from 60 patient datasets using 27.4 x 27.4 cm{sup 2} field size and 200{sup o} arc length. The body mass indices (BMIs) for these patients range from 17.2-48.4 kg/m{sup 2}. A total of 60 CBCT plans were created and calculated with heterogeneity corrections, with monitor units (MU) that varied from 8, 4, and 2 MU per plan. The isocenters of these plans weremore » placed at defined anatomical structures. The maximum dose, dose to the isocenter, and mean dose to the selected critical organs were analyzed. The study found that maximum and isocenter doses were weakly associated with BMI, but linearly associated with the total MU. Average maximum/isocenter doses in the cranium were 10.0 ({+-} 0.18)/7.0 ({+-} 0.08) cGy, 5.0 ({+-} 0.09)/3.5 ({+-} 0.05) cGy, and 2.5 ({+-} .04)/1.8 ({+-} 0.05) cGy for 8, 4, and 2 MU, respectively. Similar trends but slightly larger maximum/isocenter doses were found in the thoracic and pelvic regions. For the cranial region, the average mean doses with a total of 8 MU to the eye, lens, and brain were 9.7 ({+-} 0.12) cGy, 9.1 ({+-} 0.16) cGy, and 7.2 ({+-} 0.10) cGy, respectively. For the thoracic region, the average mean doses to the lung, heart, and spinal cord were 6.6 ({+-} 0.05) cGy, 6.9 ({+-} 1.2) cGy, and 4.7 ({+-} 0.8) cGy, respectively. For the pelvic region, the average mean dose to the femoral heads was 6.4 ({+-} 1.1) cGy. The MV-CBCT doses were linearly associated with the total MU but weakly dependent on patients' BMIs. Daily MV-CBCT has a cumulative effect on the total body dose and critical organs, which should be carefully considered for clinical impacts.« less

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

Pokhrel, D; Sood, S; Badkul, R

Purpose: To evaluate XVMC computed rib doses for peripherally located non-small-cell-lung tumors treated with SBRT following RTOG-0915 guidelines. Methods: Twenty patients with solitary peripherally located non-small-cell-lung tumors were treated using XVMC-based SBRT to 50–54Gy in 5−3 fractions, respectively, for PTV(V100%)=95%. Based on 4D-CT, ITV was delineated on MaximumIP images and organs-at-risk(OARs) including ribs were contoured on MeanIP images. Mean PTV(ITV+5mm uniform margin) was 46.1±38.7cc (range, 11.1–163.0cc). XVMC SBRT treatment plans were generated with a combination of non-coplanar 3D-conformal arcs/beams, and were delivered by Novalis-TX consisting of HD-MLCs and a 6MV-SRS(1000MU/min) beam, following RTOG-0915 criteria. XVMC rib maximum dose and dosemore » to <1cc, <5cc, <10cc were evaluated as a function of PTV, prescription dose and 3D-distance from tumor isocenter to the most proximal rib contour. Plans were re-computed using heterogeneity-corrected pencil-beam (PB-hete) algorithm utilizing identical beam geometry/MLC positions and MUs and subsequently compared to XVMC. Results: XVMC average maximum rib dose was 50.9±6.4Gy (range, 35.1–59.3Gy). XVMC mean rib dose to <1cc was 41.6±5.6Gy (range, 27.9–47.9Gy), <5cc was 31.2±7.3Gy (range, 10.6–43.1Gy), and <10cc was 21.2±8.7Gy (range, 1.1–36Gy), respectively. For the given prescription, correlation between PTV and rib doses to <5cc (p=0.005) and <10cc (p=0.018) was observed. 3D-distance from the tumor isocenter to the proximal rib contour strongly correlated with maximum rib dose (p=0.0001). PB-hete algorithm overestimated maximum rib dose and dose to <1cc, <5cc, and <10cc of ribs by 5%, 3%, 3%, and 3%, respectively. Conclusion: PB-hete overestimates ribs dose relative to XVMC. Since all the clinical XVMC plans were generated without compromising the target coverage (per RTOG-0915), almost all patient’s ribs doses were higher than the protocol guidelines. As expected, larger tumor size and proximity to ribs received higher absolute dose to ribs. Prospective observation is needed to determine if XVMC delivered rib doses correlates with patient symptoms including chest wall pain and/or rib fractures.« less

Dosimetric verification of IMRT treatment planning using Monte Carlo simulations for prostate cancer

NASA Astrophysics Data System (ADS)

Yang, J.; Li, J.; Chen, L.; Price, R.; McNeeley, S.; Qin, L.; Wang, L.; Xiong, W.; Ma, C.-M.

2005-03-01

The purpose of this work is to investigate the accuracy of dose calculation of a commercial treatment planning system (Corvus, Normos Corp., Sewickley, PA). In this study, 30 prostate intensity-modulated radiotherapy (IMRT) treatment plans from the commercial treatment planning system were recalculated using the Monte Carlo method. Dose-volume histograms and isodose distributions were compared. Other quantities such as minimum dose to the target (Dmin), the dose received by 98% of the target volume (D98), dose at the isocentre (Diso), mean target dose (Dmean) and the maximum critical structure dose (Dmax) were also evaluated based on our clinical criteria. For coplanar plans, the dose differences between Monte Carlo and the commercial treatment planning system with and without heterogeneity correction were not significant. The differences in the isocentre dose between the commercial treatment planning system and Monte Carlo simulations were less than 3% for all coplanar cases. The differences on D98 were less than 2% on average. The differences in the mean dose to the target between the commercial system and Monte Carlo results were within 3%. The differences in the maximum bladder dose were within 3% for most cases. The maximum dose differences for the rectum were less than 4% for all the cases. For non-coplanar plans, the difference in the minimum target dose between the treatment planning system and Monte Carlo calculations was up to 9% if the heterogeneity correction was not applied in Corvus. This was caused by the excessive attenuation of the non-coplanar beams by the femurs. When the heterogeneity correction was applied in Corvus, the differences were reduced significantly. These results suggest that heterogeneity correction should be used in dose calculation for prostate cancer with non-coplanar beam arrangements.

Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kabul, Samaneh; Alatorre, Carlos; Montejano, Leslie B; Farr, Amanda M; Clemow, David B

2015-12-01

The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P < 0.001) and had fewer patients with pre-index use of other ADHD medications (17% vs. 20%, P < 0.001) compared with the recommended dosing cohort. Adult patients with ADHD receiving atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD. © 2015 Eli Lilly and Company. CNS Neuroscience and Therapeutics published by John Wiley & Sons Ltd.

Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.

PubMed

Castelli, Joel; Simon, Antoine; Louvel, Guillaume; Henry, Olivier; Chajon, Enrique; Nassef, Mohamed; Haigron, Pascal; Cazoulat, Guillaume; Ospina, Juan David; Jegoux, Franck; Benezery, Karen; de Crevoisier, Renaud

2015-01-09

Large anatomical variations occur during the course of intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNC). The risks are therefore a parotid glands (PG) overdose and a xerostomia increase. The purposes of the study were to estimate: - the PG overdose and the xerostomia risk increase during a "standard" IMRT (IMRTstd); - the benefits of an adaptive IMRT (ART) with weekly replanning to spare the PGs and limit the risk of xerostomia. Fifteen patients received radical IMRT (70 Gy) for LAHNC. Weekly CTs were used to estimate the dose distributions delivered during the treatment, corresponding either to the initial planning (IMRTstd) or to weekly replanning (ART). PGs dose were recalculated at the fraction, from the weekly CTs. PG cumulated doses were then estimated using deformable image registration. The following PG doses were compared: pre-treatment planned dose, per-treatment IMRTstd and ART. The corresponding estimated risks of xerostomia were also compared. Correlations between anatomical markers and dose differences were searched. Compared to the initial planning, a PG overdose was observed during IMRTstd for 59% of the PGs, with an average increase of 3.7 Gy (10.0 Gy maximum) for the mean dose, and of 8.2% (23.9% maximum) for the risk of xerostomia. Compared to the initial planning, weekly replanning reduced the PG mean dose for all the patients (p<0.05). In the overirradiated PG group, weekly replanning reduced the mean dose by 5.1 Gy (12.2 Gy maximum) and the absolute risk of xerostomia by 11% (p<0.01) (30% maximum). The PG overdose and the dosimetric benefit of replanning increased with the tumor shrinkage and the neck thickness reduction (p<0.001). During the course of LAHNC IMRT, around 60% of the PGs are overdosed of 4 Gy. Weekly replanning decreased the PG mean dose by 5 Gy, and therefore by 11% the xerostomia risk.

[Development of a perforated peptic ulcer in a child during high dose prednisolone treatment].

PubMed

Moll Harboe, Kirstine; Midtgaard, Helle; Wewer, Vibeke; Cortes, Dina

2012-09-24

Since perforated peptic ulcer is uncommon in children proton pump inhibitor prophylaxis is not routinely recommended when children are treated with high dose steroids. We describe a case of perforated ulcer in a six-year-old patient with nephrotic syndrome treated with high dose prednisolone. Initially, ulcer was not suspected due to uncharacteristic symptoms. The child developed peritoneal signs and surgery revealed a perforated peptic ulcer in the stomach. We recommend treatment with proton pump inhibitors if children, who are treated with high dose steroids develop abdominal symptoms, which can be caused by an ulcus.

Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer.

PubMed

Lee, Keun-Wook; Lee, Kyung Hee; Zang, Dae Young; Park, Young Iee; Shin, Dong Bok; Kim, Jin Won; Im, Seock-Ah; Koh, Sung Ae; Yu, Kyung-Sang; Cho, Joo-Youn; Jung, Jin-A; Bang, Yung-Jue

2015-08-01

Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m(2) per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m(2). In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea. Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

PubMed Central

Estlin, E. J.; Lashford, L.; Ablett, S.; Price, L.; Gowing, R.; Gholkar, A.; Kohler, J.; Lewis, I. J.; Morland, B.; Pinkerton, C. R.; Stevens, M. C.; Mott, M.; Stevens, R.; Newell, D. R.; Walker, D.; Dicks-Mireaux, C.; McDowell, H.; Reidenberg, P.; Statkevich, P.; Marco, A.; Batra, V.; Dugan, M.; Pearson, A. D.

1998-01-01

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted. Images Figure 5 p658-b Figure 6 p659-b PMID:9744506

SU-F-BRE-16: VMAT Commissioning and Quality Assurance (QA) of An Elekta Synergy-STM Linac Using ICOM Test HarnessTM

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

Nguyen, A; Ironwood CRC, Phoenix, AZ; Rajaguru, P

2014-06-15

Purpose: To establish a set of tests based on the iCOM software that can be used to commission and perform periodic QA of VMAT delivery on the Elekta Synergy-S, commonly known as the Beam Modulator (BM). Methods: iCOM is used to create and deliver customized treatment fields to characterize the system in terms of 1) MLC positioning accuracy under static and dynamic delivery with full gantry rotation, 2) MLC positioning with known errors, 3) Maximum dose rate, 4) Maximum MLC speed, 5) Maximum gantry speed, 6) Synchronization: gantry speed versus dose rate, and 7) Synchronization: MLC speed versus dose rate.more » The resulting images were captured on the iView GT and exported in DICOM format to Dosimetry Check™ system for visual and quantitative analysis. For the initial commissioning phase, the system tests described should be supplemented with extensive patient QAs covering all clinically relevant treatment sites. Results: The system performance test suite showed that on our Synergy-S, MLC positioning was accurate under both static and dynamic deliveries. Intentional errors of 1 mm were also easily identified on both static and dynamic picket fence tests. Maximum dose rate was verified with stop watch to be consistently between 475-480 MU/min. Maximum gantry speed and MLC speed were 5.5 degree/s and 2.5 cm/s respectively. After accounting for beam flatness, both synchronization tests, gantry versus dose rate and MLC speed versus dose rate, were successful as the fields were uniform across the strips and there were no obvious cold/hot spots. Conclusion: VMAT commissioning and quality assurance should include machine characterization tests in addition to patient QAs. Elekta iCOM is a valuable tool for the design of customized VMAT field with specific MU, MLC leaf positions, dose rate, and indirect control of MLC and gantry speed at each of its control points.« less

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

Pokharel, S; Rana, S

Purpose: purpose of this study is to evaluate the effect of grid size in Eclipse AcurosXB dose calculation algorithm for SBRT lung. Methods: Five cases of SBRT lung previously treated have been chosen for present study. Four of the plans were 5 fields conventional IMRT and one was Rapid Arc plan. All five cases have been calculated with five grid sizes (1, 1.5, 2, 2.5 and 3mm) available for AXB algorithm with same plan normalization. Dosimetric indices relevant to SBRT along with MUs and time have been recorded for different grid sizes. The maximum difference was calculated as a percentagemore » of mean of all five values. All the plans were IMRT QAed with portal dosimetry. Results: The maximum difference of MUs was within 2%. The time increased was as high as 7 times from highest 3mm to lowest 1mm grid size. The largest difference of PTV minimum, maximum and mean dose were 7.7%, 1.5% and 1.6% respectively. The highest D2-Max difference was 6.1%. The highest difference in ipsilateral lung mean, V5Gy, V10Gy and V20Gy were 2.6%, 2.4%, 1.9% and 3.8% respectively. The maximum difference of heart, cord and esophagus dose were 6.5%, 7.8% and 4.02% respectively. The IMRT Gamma passing rate at 2%/2mm remains within 1.5% with at least 98% points passing with all grid sizes. Conclusion: This work indicates the lowest grid size of 1mm available in AXB is not necessarily required for accurate dose calculation. The IMRT passing rate was insignificant or not observed with the reduction of grid size less than 2mm. Although the maximum percentage difference of some of the dosimetric indices appear large, most of them are clinically insignificant in absolute dose values. So we conclude that 2mm grid size calculation is best compromise in light of dose calculation accuracy and time it takes to calculate dose.« less

[Value of early application of different doses of amino acids in parenteral nutrition among preterm infants].

PubMed

Liu, Zhi-Juan; Liu, Guo-Sheng; Chen, Yong-Ge; Zhang, Hui-Li; Wu, Xue-Fen

2015-01-01

To study the short-term response and tolerance of different doses of amino acids in parenteral nutrition among preterm infants. This study included 86 preterm infants who had a birth weight between 1 000 to 2 000 g and were admitted to the hospital within 24 hours of birth between March 2013 and June 2014. According to the early application of different doses of amino acids, they were randomized into low-dose group (n=29, 1.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.5 g/kg per day), medium-dose group (n=28, 2.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.7 g/kg per day), and high-dose group (n=29, 3.0 g/kg per day with an increase of 0.5-1.0 g/kg daily and a maximum of 4.0 g/kg per day). Other routine parenteral nutrition and enteral nutrition support were also applied. The maximum weight loss was lower and the growth rate of head circumference was greater in the high-dose group than in the low-dose group (P<0.05). The infants in the medium- and high-dose groups had faster recovery of birth weight, earlier attainment of 100 kcal/(kg·d) of enteral nutrition, shorter duration of hospital stay, and less hospital cost than those in the low-dose group (P<0.05). Blood urea nitrogen (BUN) levels in the high-dose group increased compared with the other two groups 7 days after birth (P<0.05). The levels of creatinine, pH, bicarbonate, bilirubin, and transaminase and the incidence of complications showed no significant differences between groups (P>0.05). Parenteral administration of high-dose amino acids in preterm infants within 24 hours after birth can improve the short-term nutritional status of preterm infants, but there is a transient increase in BUN level.

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PubMed

Masters, G A; Mauer, A M; Hoffman, P C; Wyka, D; Samuels, B L; Krauss, S A; Watson, S; Golomb, H; Vokes, E E

1998-06-01

We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

SU-F-T-443: Quantification of Dosimetric Effects of Dental Metallic Implant On VMAT Plans

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

Lin, C; Jiang, W; Feng, Y

Purpose: To evaluate the dosimetric impact of metallic implant that correlates with the size of targets and metallic implants and distance in between on volumetric-modulated arc therapy (VMAT) plans for head and neck (H&N) cancer patients with dental metallic implant. Methods: CT images of H&N cancer patients with dental metallic implant were used. Target volumes with different sizes and locations were contoured. Metal artifact regions excluding surrounding critical organs were outlined and assigned with CT numbers close to water (0HU). VMAT plans with half-arc, one-full-arc and two-full-arcs were constructed and same plans were applied to structure sets with and withoutmore » CT number assignment of metal artifact regions and compared. D95% was utilized to investigate PTV dose coverage and SNC Patient− Software was used for the analysis of dose distribution difference slice by slice. Results: For different targets sizes, variation of PTV dose coverage (Delta-D95%) with and without CT number replacement reduced with larger target volume for all half-arc, one-arc and two-arc VMAT plans even though there were no clinically significant differences. Additionally, there were no significant variations of the maximum percent difference (max.%diff) of dose distribution. With regard to the target location, Delta-D95% and max. %diff dropped with increasing distance between target and metallic implant. Furthermore, half-arc plans showed greater impact than one-arc plans, and two-arc plans had smallest influence for PTV dose coverage and dose distribution. Conclusion: The target size has less correlation of doseimetric impact than the target location relative to metallic implants. Plans with more arcs alleviate the dosimetric effect of metal artifact because of less contribution to the target dose from beams going through the regions with metallic artifacts. Incorrect CT number causes inaccurate dose distribution, therefore appropriately overwriting metallic artifact regions with reasonable CT numbers is recommended. More patient data are collected and under further analysis.« less

Occupational and patient exposure as well as image quality for full spine examinations with the EOS imaging system

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

Damet, J., E-mail: jerome.damet@chuv.ch; Fournier, P.; Monnin, P.

Purpose: EOS (EOS imaging S.A, Paris, France) is an x-ray imaging system that uses slot-scanning technology in order to optimize the trade-off between image quality and dose. The goal of this study was to characterize the EOS system in terms of occupational exposure, organ doses to patients as well as image quality for full spine examinations. Methods: Occupational exposure was determined by measuring the ambient dose equivalents in the radiological room during a standard full spine examination. The patient dosimetry was performed using anthropomorphic phantoms representing an adolescent and a five-year-old child. The organ doses were measured with thermoluminescent detectorsmore » and then used to calculate effective doses. Patient exposure with EOS was then compared to dose levels reported for conventional radiological systems. Image quality was assessed in terms of spatial resolution and different noise contributions to evaluate the detector's performances of the system. The spatial-frequency signal transfer efficiency of the imaging system was quantified by the detective quantum efficiency (DQE). Results: The use of a protective apron when the medical staff or parents have to stand near to the cubicle in the radiological room is recommended. The estimated effective dose to patients undergoing a full spine examination with the EOS system was 290μSv for an adult and 200 μSv for a child. MTF and NPS are nonisotropic, with higher values in the scanning direction; they are in addition energy-dependent, but scanning speed independent. The system was shown to be quantum-limited, with a maximum DQE of 13%. The relevance of the DQE for slot-scanning system has been addressed. Conclusions: As a summary, the estimated effective dose was 290μSv for an adult; the image quality remains comparable to conventional systems.« less

SU-F-T-269: Preliminary Experience of Kuwait Cancer Control Center (KCCC) On IMRT Treatment Planning and Pre-Treatment Verification

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

Sethuraman, TKR; Sherif, M; Subramanian, N

Purpose: The complexity of IMRT delivery requires pre-treatment quality assurance and plan verification. KCCC has implemented IMRT clinically in few sites and will extend to all sites. Recently, our Varian linear accelerator and Eclipse planning system were upgraded from Millennium 80 to 120 Multileaf Collimator (MLC) and from v8.6 to 11.0 respectively. Our preliminary experience on the pre-treatment quality assurance verification is discussed. Methods: Eight Breast, Three Prostate and One Hypopharynx cancer patients were planned with step and shoot IMRT. All breast cases were planned before the upgrade with 60% cases treated. The ICRU 83 recommendations were followed for themore » dose prescription and constraints to OAR for all cases. Point dose measurement was done with CIRS cylindrical phantom and PTW 0.125 cc ionization chamber. Measured dose was compared with calculated dose at the point of measurement. Map CHECK diode array phantom was used for the plan verification. Planned and measured doses were compared by applying gamma index of 3% (dose difference) / 3 mm DTA (average distance to agreement). For all cases, a plan is considered to be successful if more than 95% of the tested diodes pass the gamma test. A prostate case was chosen to compare the plan verification before and after the upgrade. Results: Point dose measurement results were in agreement with the calculated doses. The maximum deviation observed was 2.3%. The passing rate of average gamma index was measured higher than 97% for the plan verification of all cases. Similar result was observed for plan verification of the chosen prostate case before and after the upgrade. Conclusion: Our preliminary experience from the obtained results validates the accuracy of our QA process and provides confidence to extend IMRT to all sites in Kuwait.« less

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.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

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.

Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.

PubMed

Axelrod, David E; Vedula, Sudeepti; Obaniyi, James

2017-05-01

The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.

SU-E-T-365: Dosimetric Impact of Dental Amalgam CT Image Artifacts On IMRT and VMAT Head and Neck Plans

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

Cao, N; Young, L; Parvathaneni, U

Purpose: The presence of high density dental amalgam in patient CT image data sets causes dose calculation errors for head and neck (HN) treatment planning. This study assesses and compares dosimetric variations in IMRT and VMAT treatment plans due to dental artifacts. Methods: Sixteen HN patients with similar treatment sites (oropharynx), tumor volume and extensive dental artifacts were divided into two groups: IMRT (n=8, 6 to 9 beams) and VMAT (n=8, 2 arcs with 352° rotation). All cases were planned with the Pinnacle 9.2 treatment planning software using the collapsed cone convolution superposition algorithm and a range of prescription dosemore » from 60 to 72Gy. Two different treatment plans were produced, each based on one of two image sets: (a)uncorrected; (b)dental artifacts density overridden (set to 1.0g/cm{sup 3}). Differences between the two treatment plans for each of the IMRT and VMAT techniques were quantified by the following dosimetric parameters: maximum point dose, maximum spinal cord and brainstem dose, mean left and right parotid dose, and PTV coverage (V95%Rx). Average differences generated for these dosimetric parameters were compared between IMRT and VMAT plans. Results: The average absolute dose differences (plan a minus plan b) for the VMAT and IMRT techniques, respectively, caused by dental artifacts were: 2.2±3.3cGy vs. 37.6±57.5cGy (maximum point dose, P=0.15); 1.2±0.9cGy vs. 7.9±6.7cGy (maximum spinal cord dose, P=0.026); 2.2±2.4cGy vs. 12.1±13.0cGy (maximum brainstem dose, P=0.077); 0.9±1.1cGy vs. 4.1±3.5cGy (mean left parotid dose, P=0.038); 0.9±0.8cGy vs. 7.8±11.9cGy (mean right parotid dose, P=0.136); 0.021%±0.014% vs. 0.803%±1.44% (PTV coverage, P=0.17). Conclusion: For the HN plans studied, dental artifacts demonstrated a greater dose calculation error for IMRT plans compared to VMAT plans. Rotational arcs appear on the average to compensate dose calculation errors induced by dental artifacts. Thus, compared to VMAT, density overrides for dental artifacts are more important when planning IMRT of HN.« less

Dose Trends of Aripiprazole from 2004 to 2014 in Psychiatric Inpatients in Korea.

PubMed

Woo, Young Sup; Shim, In Hee; Lee, Sang-Yeol; Lee, Dae-Bo; Kim, Moon-Doo; Jung, Young-Eun; Lee, Jonghun; Won, Seunghee; Jon, Duk-In; Bahk, Won-Myong

2017-05-31

Although aripiprazole has been widely used to treat various psychiatric disorders, little is known about the adequate dosage for Asian patients in clinical practice. Hence, we evaluated the initial and maximum doses of aripiprazole from 2004 to 2014 to estimate the appropriate dosage for Korean psychiatric inpatients in clinical practice. In this retrospective study, we reviewed the medical records of patients who were hospitalized in five university hospitals in Korea from March 2004 to December 2014. The psychiatric diagnosis according to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition during index hospitalization and the initial and maximum doses of aripiprazole were evaluated. There were 74 patients in Wave 1 (2004-2006), 201 patients in Wave 2 (2007-2010), and 353 patients in Wave 3 (2011-2014). The initial doses of aripiprazole in all diagnostic groups were significantly lower in Wave 3 than in Wave 2. The maximum doses of aripiprazole in each diagnostic group were not significantly different among Waves 1, 2, and 3. The relatively low initial doses of aripiprazole documented in our study may reflect a strategy by clinicians to minimize the side effects associated with aripiprazole use, such as akathisia.

Persistence and dissipation kinetics of chlorantraniliprole 0.4G in the soil of tropical sugarcane ecosystem.

PubMed

Ramasubramanian, T; Paramasivam, M; Jayanthi, R; Nirmala, R

2016-01-01

Chlorantraniliprole 0.4 % GR has been in use for managing early shoot borer and top borer of sugarcane. Persistence and dissipation kinetics of granular formulation of chlorantraniliprole were studied in the soil of tropical sugarcane ecosystem by employing simple and sensitive analytical method. Limit of quantification of the method was 0.01 mg/kg and the recovery of chlorantraniliprole was in the range of 92.3-99.7 % with RSD of 1.14-3.0 %. The initial deposit of chlorantraniliprole in the soil was 0.513 and 1.031 mg/kg for the recommended (75 g a.i./ha) and double the recommended (150 g a.i./ha) doses, respectively. The residues were quantified up to 30 days after treatment irrespective of the doses applied. Half-life (t 1/2) was 6.60 and 6.73 days, respectively, for recommended and double the recommended doses of chlorantraniliprole.

Report of Task Group on the implications of the implementation of the ICRP recommendations for a revised dose limit to the lens of the eye.

PubMed

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

2013-12-01

This report was commissioned by the IRPA President to provide an assessment of the impact on members of IRPA Associate Societies of the introduction of ICRP recommendations for a reduced dose limit for the lens of the eye. The report summarises current practice and considers possible changes that may be required. Recommendations for further collaboration, clarification and changes to working practices are suggested.

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study

PubMed Central

Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver

2017-01-01

Objective To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. Design This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35). Methods GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. Results In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). Conclusions GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. PMID:28522645

[Immunisation schedule of the Spanish Association of Paediatrics: 2017 recommendations].

PubMed

Moreno-Pérez, David; Álvarez García, Francisco José; Arístegui Fernández, Javier; Cilleruelo Ortega, María José; Corretger Rauet, José María; García Sánchez, Nuria; Hernández Merino, Ángel; Hernández-Sampelayo Matos, Teresa; Merino Moína, Manuel; Ortigosa Del Castillo, Luis; Ruiz-Contreras, Jesús

2017-02-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV- AEP) annually publishes the immunisation schedule which, in our opinion, is considered optimal for children resident in Spain, taking into account the evidence available on current vaccines. Pneumococcal and varicella immunisation in early childhood is already included in all funded vaccines present in the regional immunisation programmes. Furthermore, this committee establishes recommendations on vaccines not included in official calendars (non-funded immunisations), such as rotavirus, meningococcal B, and meningococcal ACWY. As regards funded immunisations, 2+1 strategy (2, 4, 11-12 months) with hexavalent (DTaP-IPV-Hib-HB) and 13-valent pneumococcal vaccines is recommended. Administration of the 6-year booster dose with DTaP is recommended, as well as a poliomyelitis dose for children who had received the 2+1 scheme, with the Tdap vaccine for adolescents and pregnant women between 27 and 32 weeks gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). Coverage of human papillomavirus vaccination in girls aged 12 with a two-dose scheme (0, 6 months) should be improved. Information and recommendations for male adolescents about potential beneficial effects of the tetravalent HPV vaccine should also be provided. ACWY meningococcal vaccine is the optimal choice in adolescents. For recommended unfunded immunisations, the CAV-AEP recommends the administration of meningococcal B vaccine, due to the current availability in Spanish community pharmacies, with a 3+1 scheme. CAV-AEP requests the incorporation of this vaccine in the funded unified schedule. Vaccination against rotavirus is recommended in all infants. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

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.

Guided medication dosing for elderly emergency patients using real-time, computerized decision support.

PubMed

Griffey, Richard T; Lo, Helen G; Burdick, Elisabeth; Keohane, Carol; Bates, David W

2012-01-01

To evaluate the impact of a real-time computerized decision support tool in the emergency department that guides medication dosing for the elderly on physician ordering behavior and on adverse drug events (ADEs). A prospective controlled trial was conducted over 26 weeks. The status of the decision support tool alternated OFF (7/17/06-8/29/06), ON (8/29/06-10/10/06), OFF (10/10/06-11/28/06), and ON (11/28/06-1/16/07) in consecutive blocks during the study period. In patients ≥65 who were ordered certain benzodiazepines, opiates, non-steroidals, or sedative-hypnotics, the computer application either adjusted the dosing or suggested a different medication. Physicians could accept or reject recommendations. The primary outcome compared medication ordering consistent with recommendations during ON versus OFF periods. Secondary outcomes included the admission rate, emergency department length of stay for discharged patients, 10-fold dosing orders, use of a second drug to reverse the original medication, and rate of ADEs using previously validated explicit chart review. 2398 orders were placed for 1407 patients over 1548 visits. The majority (49/53; 92.5%) of recommendations for alternate medications were declined. More orders were consistent with dosing recommendations during ON (403/1283; 31.4%) than OFF (256/1115; 23%) periods (p≤0.0001). 673 (43%) visits were reviewed for ADEs. The rate of ADEs was lower during ON (8/237; 3.4%) compared with OFF (31/436; 7.1%) periods (p=0.02). The remaining secondary outcomes showed no difference. Single institution study, retrospective chart review for ADEs. Though overall agreement with recommendations was low, real-time computerized decision support resulted in greater acceptance of medication recommendations. Fewer ADEs were observed when computerized decision support was active.

Predictions of Leukemia Risks to Astronauts from Solar Particle Events

NASA Technical Reports Server (NTRS)

Cucinotta, F. A.; Atwell, W.; Kim, M. Y.; George, K. A.; Ponomarev, A.; Nikjoo, H.; Wilson, J. W.

2006-01-01

Leukemias consisting of acute and chronic myeloid leukemia and acute lymphatic lymphomas represent the earliest cancers that appear after radiation exposure, have a high lethality fraction, and make up a significant fraction of the overall fatal cancer risk from radiation for adults. Several considerations impact the recommendation of a preferred model for the estimation of leukemia risks from solar particle events (SPE's): The BEIR VII report recommends several changes to the method of calculation of leukemia risk compared to the methods recommended by the NCRP Report No. 132 including the preference of a mixture model with additive and multiplicative components in BEIR VII compared to the additive transfer model recommended by NCRP Report No. 132. Proton fluences and doses vary considerably across marrow regions because of the characteristic spectra of primary solar protons making the use of an average dose suspect. Previous estimates of bone marrow doses from SPE's have used an average body-shielding distribution for marrow based on the computerized anatomical man model (CAM). We have developed an 82-point body-shielding distribution that faithfully reproduces the mean and variance of SPE doses in the active marrow regions (head and neck, chest, abdomen, pelvis and thighs) allowing for more accurate estimation of linear- and quadratic-dose components of the marrow response. SPE's have differential dose-rates and a pseudo-quadratic dose response term is possible in the peak-flux period of an event. Also, the mechanistic basis for leukemia risk continues to improve allowing for improved strategies in choosing dose-rate modulation factors and radiation quality descriptors. We make comparisons of the various choices of the components in leukemia risk estimates in formulating our preferred model. A major finding is that leukemia could be the dominant risk to astronauts for a major solar particle event.

Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose.

PubMed

de Vries, Ymkje Anna; de Jonge, Peter; Kalverdijk, Luuk; Bos, Jens H J; Schuiling-Veninga, Catharina C M; Hak, Eelko

2016-11-01

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence.

SU-E-T-169: Characterization of Pacemaker/ICD Dose in SAVI HDR Brachytherapy

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

Kalavagunta, C; Lasio, G; Yi, B

2015-06-15

Purpose: It is important to estimate dose to pacemaker (PM)/Implantable Cardioverter Defibrillator (ICD) before undertaking Accelerated Partial Breast Treatment using High Dose Rate (HDR) brachytherapy. Kim et al. have reported HDR PM/ICD dose using a single-source balloon applicator. To the authors knowledge, there have so far not been any published PM/ICD dosimetry literature for the Strut Adjusted Volume Implant (SAVI, Cianna Medical, Aliso Viejo, CA). This study aims to fill this gap by generating a dose look up table (LUT) to predict maximum dose to the PM/ICD in SAVI HDR brachytherapy. Methods: CT scans for 3D dosimetric planning were acquiredmore » for four SAVI applicators (6−1-mini, 6−1, 8−1 and 10−1) expanded to their maximum diameter in air. The CT datasets were imported into the Elekta Oncentra TPS for planning and each applicator was digitized in a multiplanar reconstruction window. A dose of 340 cGy was prescribed to the surface of a 1 cm expansion of the SAVI applicator cavity. Cartesian coordinates of the digitized applicator were determined in the treatment leading to the generation of a dose distribution and corresponding distance-dose prediction look up table (LUT) for distances from 2 to 15 cm (6-mini) and 2 to 20 cm (10–1).The deviation between the LUT doses and the dose to the cardiac device in a clinical case was evaluated. Results: Distance-dose look up table were compared to clinical SAVI plan and the discrepancy between the max dose predicted by the LUT and the clinical plan was found to be in the range (−0.44%, 0.74%) of the prescription dose. Conclusion: The distance-dose look up tables for SAVI applicators can be used to estimate the maximum dose to the ICD/PM, with a potential usefulness for quick assessment of dose to the cardiac device prior to applicator placement.« less

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline

PubMed Central

Arrossi, Silvina; Temin, Sarah; Garland, Suzanne; Eckert, Linda O’Neal; Bhatla, Neerja; Castellsagué, Xavier; Alkaff, Sharifa Ezat; Felder, Tamika; Hammouda, Doudja; Konno, Ryo; Lopes, Gilberto; Mugisha, Emmanuel; Murillo, Rául; Scarinci, Isabel C.; Stanley, Margaret; Tsu, Vivien; Wheeler, Cosette M.; Adewole, Isaac Folorunso; de Sanjosé, Silvia

2017-01-01

Purpose To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally. Methods The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings. Results Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%. Recommendations In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus–related cancers and diseases. Basic settings: vaccinating boys is not recommended. It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines. PMID:29094100

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit.

PubMed

Castberg, Ingrid; Spigset, Olav

2008-10-01

The aim of this study was to investigate the use of psychotropic medication and therapeutic drug monitoring in a high-security psychiatric unit and to compare the doses and serum concentrations both with the recommended intervals and with the doses and serum concentrations in a control group. One hundred thirty-two patients were admitted in the period from January 2000 to December 2005. All available samples were used when comparing serum concentrations and doses with the recommended ranges. For the comparison of doses and serum concentration-to-dose (C:D) ratios with the control group only 1 sample from each patient was used. A total of 459 analyses of 27 different drugs in samples from 8 women and 73 men were included. The median number of therapeutic drug monitoring analyses per patient was 4 (range 1-29). Thirty-seven of the 81 patients (46%) used 2 or more antipsychotics at the same time. Clozapine, lamotrigine, olanzapine, quetiapine, ziprasidone, and zuclopenthixol were often given in doses above the recommended. The serum levels were frequently above those recommended for clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zuclopenthixol. The serum levels were significantly higher in the study group than in the control group for clozapine, lamotrigine, quetiapine, and zuclopenthixol. The given dose was significantly higher in the study group than in the control group for clozapine, lamotrigine and zuclopenthixol. The C:D ratio was significantly lower in the study group than in the control group for olanzapine but higher for quetiapine. The non-evidence based practice of high-dose polypharmacy with several antipsychotics is widely used in this unit. The use of higher doses in the study group than in the control group was not due to differences in metabolism or adherence to treatment between the 2 groups. The frequent use of therapeutic drug monitoring did not seem to have a great impact on the prescribed doses.

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

PubMed

Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

2017-10-03

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest antitumor activity in patients with MET -amplified gastric cancer.

A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.

PubMed

Chi, K N; Yu, E Y; Jacobs, C; Bazov, J; Kollmannsberger, C; Higano, C S; Mukherjee, S D; Gleave, M E; Stewart, P S; Hotte, S J

2016-06-01

Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. NCT00487786. © The Author 2016. 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.

Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk

PubMed Central

Aljazaf, Khalidah; Hale, Thomas W; Ilett, Kenneth F; Hartmann, Peter E; Mitoulas, Leon R; Kristensen, Judith H; Hackett, L Peter

2003-01-01

Aims To assess the effects of pseudoephedrine on breast blood flow, temperature and milk production, and to estimate the likely infant dose during breastfeeding. Methods Eight lactating women (mean age 35 years and weight 69 kg) participated in a single-blind randomized crossover study of 60 mg pseudoephedrine hydrochloride vs placebo. Breast blood flow and surface temperature were measured from 0 to 4 h following the dose, and change in plasma prolactin was measured as the difference between predose and 1 h postdose concentrations. Milk production was measured for 24 h following placebo and pseudoephedrine. Infant dose of pseudoephedrine for a 60-mg dose administered four times daily to the mother was quantified as the product of average steady-state drug concentration in milk and an estimated milk production rate of 0.15 l kg−1 day−1 and expressed relative to the maternal weight-adjusted dose. Results There were no physiologically significant changes in breast blood flow or temperature between the placebo and pseudoephedrine periods. The mean change in plasma prolactin was slightly (13.5%), but not significantly lower (t = 1.245, P = 0.253) after pseudoephedrine (1775 mU l−1) compared with placebo (2014 mU l−1). However, the mean milk volume was reduced by 24% from 784 ml day−1 in the placebo period to 623 ml day−1 in the pseudoephedrine period (difference between means 161 ml day−1 (95% CI: 63, 259 ml day−1); t = 3.9, P = 0.006). Assuming maternal intake of 60 mg pseudoephedrine hydrochloride four times daily, the estimated infant dose of pseudoephedrine was 4.3% (95% CI, 3.2, 5.4%) of the weight-adjusted maternal dose. Conclusions A single dose of pseudoephedrine significantly reduced milk production. This effect was not attributable to changes in blood flow, but depression of prolactin secretion may be a contributing factor. At the maximum recommended pseudoephedrine doses, the calculated infant dose delivered via milk was < 10% of the maternal dose, and is unlikely to affect the infant adversely. The ability of pseudoephedrine to suppress lactation suggests a novel use for the drug. PMID:12848771

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.

Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.

PubMed

Veitch, Andrew M; Vanbiervliet, Geoffroy; Gershlick, Anthony H; Boustiere, Christian; Baglin, Trevor P; Smith, Lesley-Ann; Radaelli, Franco; Knight, Evelyn; Gralnek, Ian M; Hassan, Cesare; Dumonceau, Jean-Marc

2016-04-01

The risk of endoscopy in patients on antithrombotics depends on the risks of procedural haemorrhage vs. thrombosis due to discontinuation of therapy. P2Y12 receptor antagonists (clopidogrel, prasugrel, ticagrelor): For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or dual antiplatelet therapy (low quality evidence, strong recommendation);For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists five days before the procedure (moderate quality evidence, strong recommendation). In patients on dual antiplatelet therapy, we suggest continuing aspirin (low quality evidence, weak recommendation).For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a cardiologist about the risk/benefit of discontinuation of P2Y12 receptor antagonists (high quality evidence, strong recommendation). Warfarin: The advice for warfarin is fundamentally unchanged from BSG 2008 guidance. Direct Oral Anticoagulants (DOAC): For low-risk endoscopic procedures we suggest omitting the morning dose of DOAC on the day of the procedure (very low quality evidence, weak recommendation). For high-risk endoscopic procedures, we recommend that the last dose of DOAC be taken ≥ 48 hours before the procedure (very low quality evidence, strong recommendation). For patients on dabigatran with CrCl (or estimated glomerular filtration rate, eGFR) of 30 - 50 mL/min we recommend that the last dose of DOAC be taken 72 hours before the procedure (very low quality evidence, strong recommendation). In any patient with rapidly deteriorating renal function a haematologist should be consulted (low quality evidence, strong recommendation). © Georg Thieme Verlag KG Stuttgart · New York.

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.

Monte Carlo and Phantom Study of the Radiation Dose to the Body from Dedicated Computed Tomography of the Breast

PubMed Central

Sechopoulos, Ioannis; Vedantham, Srinivasan; Suryanarayanan, Sankararaman; D’Orsi, Carl J.; Karellas, Andrew

2008-01-01

Purpose To prospectively determine the radiation dose absorbed by the organs and tissues of the body during a dedicated computed tomography of the breast (DBCT) study using Monte Carlo methods and a phantom. Materials and Methods Using the Geant4 Monte Carlo toolkit, the Cristy anthropomorphic phantom and the geometry of a prototype DBCT was simulated. The simulation was used to track x-rays emitted from the source until their complete absorption or exit from the simulation limits. The interactions of the x-rays with the 65 different volumes representing organs, bones and other tissues of the anthropomorphic phantom that resulted in energy deposition were recorded. These data were used to compute the radiation dose to the organs and tissues during a complete DBCT acquisition relative to the average glandular dose to the imaged breast (ROD, relative organ dose), using the x-ray spectra proposed for DBCT imaging. The effectiveness of a lead shield for reducing the dose to the organs was investigated. Results The maximum ROD among the organs was for the ipsilateral lung with a maximum of 3.25%, followed by the heart and the thymus. Of the skeletal tissues, the sternum received the highest dose with a maximum ROD to the bone marrow of 2.24%, and to the bone surface of 7.74%. The maximum ROD to the uterus, representative of that of an early-stage fetus, was 0.026%. These maxima occurred for the highest energy x-ray spectrum (80 kVp) analyzed. A lead shield does not protect substantially the organs that receive the highest dose from DBCT. Discussion Although the dose to the organs from DBCT is substantially higher than that from planar mammography, they are comparable or considerably lower than those reached by other radiographic procedures and much lower than other CT examinations. PMID:18292479

Impact of cardiosynchronous brain pulsations on Monte Carlo calculated doses for synchrotron micro- and minibeam radiation therapy.

PubMed

Manchado de Sola, Francisco; Vilches, Manuel; Prezado, Yolanda; Lallena, Antonio M

2018-05-15

The purpose of this study was to assess the effects of brain movements induced by heartbeat on dose distributions in synchrotron micro- and minibeam radiation therapy and to develop a model to help guide decisions and planning for future clinical trials. The Monte Carlo code PENELOPE was used to simulate the irradiation of a human head phantom with a variety of micro- and minibeam arrays, with beams narrower than 100 μm and above 500 μm, respectively, and with radiation fields of 1 × 2 cm and 2 × 2 cm. The dose in the phantom due to these beams was calculated by superposing the dose profiles obtained for a single beam of 1 μm × 2 cm. A parameter δ, accounting for the total displacement of the brain during the irradiation and due to the cardiosynchronous pulsation, was used to quantify the impact on peak-to-valley dose ratios and the full width at half maximum. The difference between the maximum (at the phantom entrance) and the minimum (at the phantom exit) values of the peak-to-valley dose ratio reduces when the parameter δ increases. The full width at half maximum remains almost constant with depth for any δ value. Sudden changes in the two quantities are observed at the interfaces between the various tissues (brain, skull, and skin) present in the head phantom. The peak-to-valley dose ratio at the center of the head phantom reduces when δ increases, remaining above 70% of the static value only for minibeams and δ smaller than ∼200 μm. Optimal setups for brain treatments with synchrotron radiation micro- and minibeam combs depend on the brain displacement due to cardiosynchronous pulsation. Peak-to-valley dose ratios larger than 90% of the maximum values obtained in the static case occur only for minibeams and relatively large dose rates. © 2018 American Association of Physicists in Medicine.

Older adults and high-risk medication administration in the emergency department.

PubMed

Kim, Mitchell; Mitchell, Steven H; Gatewood, Medley; Bennett, Katherine A; Sutton, Paul R; Crawford, Carol A; Bentov, Itay; Damodarasamy, Mamatha; Kaplan, Stephen J; Reed, May J

2017-01-01

Older adults are susceptible to adverse effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and benzodiazepines (BZDs). We investigated factors associated with the administration of elevated doses of these medications of interest to older adults (≥65 years old) in the emergency department (ED). ED records were queried for the administration of medications of interest to older adults at two academic medical center EDs over a 6-month period. Frequency of recommended versus elevated ("High doses" were defined as doses that ranged between 1.5 and 3 times higher than the recommended starting doses; "very high doses" were defined as higher than high doses) starting doses of medications, as determined by geriatric pharmacy/medicine guidelines and expert consensus, was compared by age groups (65-69, 70-74, 75-79, 80-84, and ≥85 years), gender, and hospital. There were 17896 visits representing 11374 unique patients >65 years of age (55.3% men, 44.7% women). A total of 3394 doses of medications of interest including 1678 high doses and 684 very high doses were administered to 1364 different patients. Administration of elevated doses of medications was more common than that of recommended doses. Focusing on opioids and BZDs, the 65-69-year age group was much more likely to receive very high doses (1481 and 412 doses, respectively) than the ≥85-year age groups (relative risk [RR] 5.52, 95% CI 2.56-11.90), mainly reflecting elevated opioid dosing (RR 8.28, 95% CI 3.69-18.57). Men were more likely than women to receive very high doses (RR 1.47, 95% CI 1.26-1.72), primarily due to BZDs (RR 2.12, 95% CI 2.07-2.16). Administration of elevated doses of opioids and BZDs in the older population occurs frequently in the ED, especially to the 65-69-year age group and men. Further attention to potentially unsafe dosing of high-risk medications to older adults in the ED is warranted.

Malfunctions of Implantable Cardiac Devices in Patients Receiving Proton Beam Therapy: Incidence and Predictors

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

Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Poenisch, Falk; Pinnix, Chelsea C.

2013-11-01

Purpose: Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT. Methods and Materials: From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIED; 28 pacemakers and 14 cardioverter-defibrillators) underwent 42 courses of PBT for thoracic (23, 55%), prostate (15, 36%), liver (3, 7%), or base of skull (1, 2%) tumors at a single institution. The median prescribed dose was 74 Gy (relativemore » biological effectiveness; range 46.8-87.5 Gy), and the median distance from the treatment field to the CIED was 10 cm (range 0.8-40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment. Results: Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13-21 Gy) and 346 Sv (range 11-1100 mSv). Six CIED malfunctions occurred in 5 patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and 1 patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9-8 cm), and the mean maximum neutron dose was 655 mSv (range 330-1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the elective replacement indicator message was replaced uneventfully after treatment. Conclusions: The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving thoracic PBT be followed closely.« less

C-A4-01: Computerized Clinical Decision Support During Drug Ordering for Long-term Care Residents With Renal Insufficiency

PubMed Central

Field, Terry S; Rochon, Paula; Lee, Monica; Gavendo, Linda; Baril, Joann L; Gurwitz, Jerry H

2010-01-01

Objective: To determine whether a computerized clinical decision support system (CDSS) providing patient specific recommendations in real- time improves the quality of prescribing for long-term care residents with renal insufficiency. Design: A randomized trial within the long-stay units of a large long-term care facility. Randomization was within blocks by unit type. Alerts related to medication prescribing for residents with renal insufficiency were displayed to prescribers in the intervention units and hidden but tracked in control units. Measurement: The proportions of final drug orders that were appropriate were compared between intervention and control units within alert categories: recommended medication doses; recommended administration frequencies; recommendations to avoid the drug; 4) warnings of missing information. Results: The rates of alerts were nearly equal in the intervention and control units: 2.5 per 1000 resident days in the intervention units and 2.4 in the control units. The proportions of dose alerts for which the final drug orders were appropriate were similar between the intervention and control units (relative risk 0.95, 95% confidence interval 0.83, 1.1). For the remaining alert categories significantly higher proportions of final drug orders were appropriate in the intervention units: relative risk 2.4 for maximum frequency (1.4, 4.4); 2.6 for drugs that should be avoided (1.4, 5.0); and 1.8 for alerts to acquire missing information (1.1, 3.4). Overall, final drug orders were appropriate significantly more often than a relative risk 1.2 (1.0, 1.4). By tracking personnel time and expenditures, we estimated the cost of developing the CDSS as $48,668.57. Drug costs saved during the 12 months of the trial are estimated at $2,137. Conclusion: Clinical decision support for physicians prescribing medications for long-term care residents with renal insufficiency can improve the quality of prescribing decisions. However, patient well-being and quality of care rather than the business case related to cost savings are likely to be the key drivers for adoption of this HIT application.

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.

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline.

PubMed

Arrossi, Silvina; Temin, Sarah; Garland, Suzanne; Eckert, Linda O'Neal; Bhatla, Neerja; Castellsagué, Xavier; Alkaff, Sharifa Ezat; Felder, Tamika; Hammouda, Doudja; Konno, Ryo; Lopes, Gilberto; Mugisha, Emmanuel; Murillo, Rául; Scarinci, Isabel C; Stanley, Margaret; Tsu, Vivien; Wheeler, Cosette M; Adewole, Isaac Folorunso; de Sanjosé, Silvia

2017-10-01

To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally. The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings. Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%. In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus-related cancers and diseases. Basic settings: vaccinating boys is not recommended. It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Dose calculation for photon-emitting brachytherapy sources with average energy higher than 50 keV: report of the AAPM and ESTRO.

PubMed

Perez-Calatayud, Jose; Ballester, Facundo; Das, Rupak K; Dewerd, Larry A; Ibbott, Geoffrey S; Meigooni, Ali S; Ouhib, Zoubir; Rivard, Mark J; Sloboda, Ron S; Williamson, Jeffrey F

2012-05-01

Recommendations of the American Association of Physicists in Medicine (AAPM) and the European Society for Radiotherapy and Oncology (ESTRO) on dose calculations for high-energy (average energy higher than 50 keV) photon-emitting brachytherapy sources are presented, including the physical characteristics of specific (192)Ir, (137)Cs, and (60)Co source models. This report has been prepared by the High Energy Brachytherapy Source Dosimetry (HEBD) Working Group. This report includes considerations in the application of the TG-43U1 formalism to high-energy photon-emitting sources with particular attention to phantom size effects, interpolation accuracy dependence on dose calculation grid size, and dosimetry parameter dependence on source active length. Consensus datasets for commercially available high-energy photon sources are provided, along with recommended methods for evaluating these datasets. Recommendations on dosimetry characterization methods, mainly using experimental procedures and Monte Carlo, are established and discussed. Also included are methodological recommendations on detector choice, detector energy response characterization and phantom materials, and measurement specification methodology. Uncertainty analyses are discussed and recommendations for high-energy sources without consensus datasets are given. Recommended consensus datasets for high-energy sources have been derived for sources that were commercially available as of January 2010. Data are presented according to the AAPM TG-43U1 formalism, with modified interpolation and extrapolation techniques of the AAPM TG-43U1S1 report for the 2D anisotropy function and radial dose function.

Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia.

PubMed

Fitzhugh, Courtney D; Hsieh, Matthew M; Allen, Darlene; Coles, Wynona A; Seamon, Cassie; Ring, Michael; Zhao, Xiongce; Minniti, Caterina P; Rodgers, Griffin P; Schechter, Alan N; Tisdale, John F; Taylor, James G

2015-01-01

Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia

PubMed Central

Fitzhugh, Courtney D.; Hsieh, Matthew M.; Allen, Darlene; Coles, Wynona A.; Seamon, Cassie; Ring, Michael; Zhao, Xiongce; Minniti, Caterina P.; Rodgers, Griffin P.; Schechter, Alan N.; Tisdale, John F.; Taylor, James G.

2015-01-01

Background Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. Objectives We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. Methods An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Results Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003–1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00–1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23–4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34–0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15–35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17–0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Conclusions Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings. PMID:26576059

Is it possible to avoid hypopituitarism after irradiation of pituitary adenomas by the Leksell gamma knife?

PubMed

Marek, Josef; Jezková, Jana; Hána, Václav; Krsek, Michal; Bandúrová, L'ubomíra; Pecen, Ladislav; Vladyka, Vilibald; Liscák, Roman

2011-02-01

Radiation therapy is one of the treatment options for pituitary adenomas. The most common side effect associated with Leksell gamma knife (LGK) irradiation is the development of hypopituitarism. The aim of this study was to verify that hypopituitarism does not develop if the maximum mean dose to pituitary is kept under 15 Gy and to evaluate the influence of maximum distal infundibulum dose on the development of hypopituitarism. We followed the incidence of hypopituitarism in 85 patients irradiated with LGK in 1993-2003. The patients were divided in two subgroups: the first subgroup followed prospectively (45 patients), irradiated with a mean dose to pituitary <15 Gy; the second subgroup followed retrospectively 1993-2001 and prospectively 2001-2009 (40 patients), irradiated with a mean dose to pituitary >15 Gy. Serum TSH, free thyroxine, testosterone or 17β-oestradiol, IGF1, prolactin and cortisol levels were evaluated before and every 6 months after LGK irradiation. Hypopituitarism after LGK irradiation developed only in 1 out of 45 (2.2%) patients irradiated with a mean dose to pituitary <15 Gy, in contrast to 72.5% patients irradiated with a mean dose to pituitary >15 Gy. The radiation dose to the distal infundibulum was found as an independent factor of hypopituitarism with calculated maximum safe dose of 17 Gy. Keeping the mean radiation dose to pituitary under 15 Gy and the dose to the distal infundibulum under 17 Gy prevents the development of hypopituitarism following LGK irradiation.

Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common

PubMed Central

2012-01-01

In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated. PMID:23237606

Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common.

PubMed

White, Nicholas J; Qiao, Li Guo; Qi, Gao; Luzzatto, Lucio

2012-12-14

In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated.

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.

Acarbose bioequivalence: exploration of new pharmacodynamic parameters.

PubMed

Zhang, Min; Yang, Jin; Tao, Lei; Li, Lingjun; Ma, Pengcheng; Fawcett, John Paul

2012-06-01

To investigate bioequivalence (BE) testing of an acarbose formulation in healthy Chinese volunteers through the use of recommended and innovative pharmacodynamic (PD) parameters. Following the Food and Drug Administration (FDA) guidance, a randomized, cross-over study of acarbose test (T) and reference (R) (Glucobay®) formulations was performed with a 1-week wash-out period. Preliminary pilot studies showed that the appropriate dose of acarbose was 2 × 50 mg, and the required number of subjects was 40. Serum glucose concentrations after sucrose administration (baseline) and co-administration of sucrose/acarbose on the following day were both determined. Three newly defined PD measures of glucose fluctuation (glucose excursion (GE), GE' (glucose excursion without the effect of the homeostatic glucose control), and fAUC (degree of fluctuation of serum glucose based on AUC)), the plateau glucose concentration (C(ss)), and time of maximum reduction in glucose concentration (T (max)) were tested in the evaluation. The adequacy of the two parameters recommended by the FDA, ΔC(SG,max) (maximum reduction in serum glucose concentration) and AUEC((0-4h)) (reduction in the AUC((0-4h)) of glucose between baseline and acarbose formulation) was also evaluated. The T (max) values were comparable, and the 90% confidence intervals of the geometric test/reference ratios (T/R) for ΔC(SG,max), C(ss), GE, and fAUC were all within 80-125%. The parameter GE' was slightly outside the limits, and the parameter AUEC((0-4h)) could not be computed due to the presence of negative values. In acarbose BE evaluation, while the recommended parameter ΔC(SG,max) is valuable, the combination of C(ss) and one of the newly defined glucose fluctuation parameters, GE, GE', and fAUC is preferable than AUEC((0-4h)). The acarbose test formulation can be initially considered to be bioequivalent to Glucobay®.

Glyphosate and AMPA, "pseudo-persistent" pollutants under real-world agricultural management practices in the Mesopotamic Pampas agroecosystem, Argentina.

PubMed

Primost, Jezabel E; Marino, Damián J G; Aparicio, Virginia C; Costa, José Luis; Carriquiriborde, Pedro

2017-10-01

In the Pampas, public concern has strongly risen because of the intensive use of glyphosate for weed control and fallow associated with biotech crops. The present study was aimed to evaluate the occurrence and concentration of the herbicide and its main metabolite (AMPA) in soil and other environmental compartments of the mentioned agroecosystem, including groundwater, in relation to real-world agricultural management practices in the region. Occurrence was almost ubiquitous in solid matrices (83-100%) with maximum concentrations among the higher reported in the world (soil: 8105 and 38939; sediment: 3294 and 7219; suspended particulate matter (SPM): 584 and 475 μg/kg of glyphosate and AMPA). Lower detection frequency was observed in surface water (27-55%) with maximum concentrations in whole water of 1.80 and 1.90 μg/L of glyphosate and AMPA, indicating that SPM analysis would be more sensitive for detection in the aquatic ecosystem. No detectable concentrations of glyphosate or AMPA were observed in groundwater. Glyphosate soil concentrations were better correlated with the total cumulative dose and total number of applications than the last spraying event dose, and an increment of 1 mg glyphosate/kg soil every 5 spraying events was estimated. Findings allow to infer that, under current practices, application rates are higher than dissipation rates. Hence, glyphosate and AMPA should be considered "pseudo-persistent" pollutants and a revisions of management procedures, monitoring programs, and ecological risk for soil and sediments should be also recommended. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developing consumer-centered, nonprescription drug labeling a study in acetaminophen.

PubMed

King, Jennifer P; Davis, Terry C; Bailey, Stacy Cooper; Jacobson, Kara L; Hedlund, Laurie A; Di Francesco, Lorenzo; Parker, Ruth M; Wolf, Michael S

2011-06-01

In the U.S., acetaminophen overdose has surpassed viral hepatitis as the leading cause of acute liver failure, and misuse contributes to more than 30,000 hospitalizations annually. Half to two thirds of acetaminophen overdoses are unintentional, suggesting the root cause is likely poor understanding of medication labeling or failure to recognize the consequences of exceeding the recommended maximum daily dosage. Elicit subject feedback about active ingredient and dosing information on over-the-counter (OTC) acetaminophen and elicit feedback on proposed plain-language text and icons. Six focus groups, preceded by individual interviews, were conducted in April 2010 among 45 adults in two cities from two clinics and an adult basic education center. The individual interviews evaluated knowledge of OTC pain relievers, attention to product label information and literacy level while the group discussion elicited preference for label messages and icons. Analyses were conducted from April to June 2010. Forty-four percent read at or below the 6th-grade level. Individual interviews revealed that <50% of participants routinely examine product label information. Only 31% know acetaminophen is in Tylenol®. The groups achieved consensus on a preferred icon for acetaminophen, desired explicit statement of potential liver damage in the warning against simultaneous use of acetaminophen products, and indicated preference for an icon and wording for maximum dose. With the high prevalence of OTC use, a consumer-centered approach to developing icons and messages to promote awareness and safe use of acetaminophen could benefit consumers. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

SU-E-T-534: Dosimetric Effect of Multileaf Collimator Leaf Width On Volumetric Modulated Arc Stereotactic Radiotherapy for Spine Tumors

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

Amoush, A; Djemil, T; Subedi, L

2014-06-01

Purpose: To study the dosimetric impact of MLC leaf width in patients treated with Volumetric Modulated Arc Therapy (VMAT) for spine Stereotactic Body radiation Therapy (SBRT). Methods: Twelve spine SBRT patients were retrospectively selected for this study. The patients were treated with IMRT following the RTOG-0631 of spine metastasis. The prescription dose was 16 Gy in one fraction to 90% of the target volume (V16 > 90%). The maximum spinal cord dose of 14 Gy and 10% of the cord receiving < 10 Gy (V10) were set as dose constraints. For purpose of this study, three dual arc VMAT plansmore » were created for each patient using three different MLC leaf widths: 2.5 mm, 4mm, and 5mm. The compliance to RTOG 0631, conformal index (CI), dose gradient index (DGI), and number of monitor units (MUs) were compared. Results: The average V16 of the target was 91.91±1.36%, 93.73±2.38%, and 92.25±2.49% for 2.5 mm, 4 mm, and 5 mm leaf widths, respectively (p=0.39). Accordingly, the average CI was 1.36±0.39, 1.36±0.34, and 1.41±0.3 (0.96), respectively. The average DGI was 0.24 ± 0.05, 0.22 ± 0.05, and 0.23 ± 0.04, respectively (p=0.86). The average spinal cord maximum dose was 12.10 ± 0.88 Gy, 12.52 ± 1.15 Gy, and 12.05 ± 1.12 (p=0.75) and V10 was 2.69 ± 1.71 cc, 5.43 ± 2.16 cc, and 3.71 ± 2.34 cc (p=0.15) for 2.5 mm, 4 mm, and 5 mm leaf widths, respectively. According, the average number of MUs was 4255 ± 431 MU, 5049 ± 1036 MU, and 4231 ± 580 MU respectively (p=0.17). Conclusion: The use of 2.5 mm, 4 mm, and 5 mm MLCs achieved similar VMAT plan quality as recommended by RTOG-0631. The dosimetric parameters were also comparable for the three MLCs.« less

Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older--United States, 2016.

PubMed

Kim, David K; Bridges, Carolyn B; Harriman, Kathleen H

2016-02-05

In October 2015, the Advisory Committee on Immunization Practices (ACIP)* approved the Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2016. This schedule provides a summary of ACIP recommendations for the use of vaccines routinely recommended for adults aged 19 years or older in two figures, footnotes for each vaccine, and a table that describes primary contraindications and precautions for commonly used vaccines for adults. Although the figures in the adult immunization schedule illustrate recommended vaccinations that begin at age 19 years, the footnotes contain information on vaccines that are recommended for adults that may begin at age younger than age 19 years. The footnotes also contain vaccine dosing, intervals between doses, and other important information and should be read with the figures.

Practical aspects in the management of statin-associated muscle symptoms (SAMS).

PubMed

Laufs, Ulrich; Filipiak, Krysztof J; Gouni-Berthold, Ioanna; Catapano, Alberico L

2017-04-01

Statin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS. An expert working group combined current evidence, published guidelines and experiences surrounding a number of topics concerning SAMS to provide recommendations on how to best assess and manage this condition and reach the highest tolerated dose of statin for each individual patient. The group collaborated to provide guidance on definitions in the SAMS field, psychological issues, re-challenging and switching treatments, as well as interpretation of current guidelines and optimal treatment of SAMS in different patient populations. An algorithm was developed to guide the management of patients with SAMS. In addition, the expert working group considered some of the more complex scenarios in a series of frequently asked questions and suggested answers. The expert working group gave recommendations for healthcare professionals on the management of SAMS but highlighted the importance of tailoring the treatment approach to each individual patient. Evidence supporting the role of nutraceuticals and complementary therapies, such as vitamin D, was lacking, however the majority of the group favoured combination therapy with ezetimibe and the addition of PCSK9 inhibitors in high-risk patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Residue behaviors and risk assessment of flonicamid and its metabolites in the cabbage field ecosystem.

PubMed

Wang, Shanshan; Jin, Fen; Cao, Xiaolin; Shao, Yong; Wang, Jian; She, Yongxin; Qi, Yan; Zhang, Chao; Li, Hui; Jin, Maojun; Wang, Jing; Shao, Hua; Zheng, Lufei

2018-06-13

Flonicamid, a novel selective systemic pesticide, can effectively control a broad range of insect pests. However, the dissipation behaviors and the terminal residues of flonicamid and its metabolites in some crops and soils remain unclear. Herein, an easy, sensitive and reliable method using a modified QuEChERS extraction coupled with LC-MS/MS for the simultaneous analysis of flonicamid and its metabolites in cabbage and soil was developed. Based on this method, the dissipation behaviors of flonicamid and its metabolites as well as their persistence in cabbage and soil during harvest were investigated. Flonicamid degraded rapidly, and the half-lives of flonicamid only and total residues (the sum of flonicamid and its metabolites) were 1.49-4.59 and 1.97-4.99 days in cabbage, and 2.12-7.97 and 2.04-7.62 days in soil, respectively. When 50% flonicamid WG was sprayed once or twice at the recommended dose and 1.5-fold the recommended dose, the highest residues of total flonicamid in cabbage and soil from different pre-harvest intervals (3, 7 and 14 days) were 0.070 and 0.054 mg kg -1 , respectively. The risk quotient (RQ) of flonicamid based on the consumption data from China was below 16.84%, indicating that the use of flonicamid is non-hazardous to humans. These results could not only guide the safe and responsible use of flonicamid in agriculture but also help the Chinese government establish the maximum residue level (MRL) for flonicamid in cabbage. Copyright © 2018 Elsevier Inc. All rights reserved.

Bioefficacy evaluation and dissipation pattern of nanoformulation versus commercial formulation of pyridalyl in tomato (Solanum lycopersicum).

PubMed

Saini, Priya; Gopal, Madhuban; Kumar, Rajesh; Gogoi, Robin; Srivastava, Chitra

2015-08-01

A study was undertaken to evaluate the decline of the residues of pyridalyl in tomatoes grown in two different cultivation systems: open field (conventional cultivation) and net house (pot experiment). Field experiment was conducted with commercial (10 EC) and nanoformulation of pyridalyl on tomato crop. Tomato plants were subjected to pesticide spray, when fruits were close to ripeness. Fruit samples were taken periodically and cleaned up using QuEChERS methodology, and the residue of pyridalyl was analyzed by ultrahigh-performance liquid chromatography (UHPLC). It dissipated in tomato fruit following the first-order kinetics. In field, average initial deposit of pyridalyl in tomato was observed to be 0.222 and 0.371 μg g(-1) at recommended and double the recommended application rate, respectively, using nanoformulation while it was 0.223 and 0.393 μg g(-1) on using commercial formulation, respectively. The half-life (t1/2) value of nanopyridalyl in tomato fruit was 2.8 and 3.2 days while for commercial formulation, it was 2.5 and 2.6 days for recommended and double the recommended dose, respectively. In India, maximum residue limit (MRL) on tomato has not been fixed for pyridalyl but its residues were always below European MRLs (5 μg g(-1)) on tomato at both application rates. The results of terminal residue showed that pyridalyl residues were below the available MRL. Low residues in tomatoes suggested that this pesticide is safe to use under the recommended dosage. No statistical differences were observed between the cultivation systems in relation to the residue levels of pyridalyl.

Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations.

PubMed

Sugiarto, Sri Riyati; Davis, Timothy M E; Salman, Sam

2017-11-01

Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy. Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (C max ), area under the plasma concentration-time curve (AUC) and elimination half-life (t ½β ) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status. Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.

Volumetric tumor burden and its effect on brachial plexus dosimetry in head and neck intensity-modulated radiotherapy

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

Romesser, Paul B.; Qureshi, Muhammad M.; Kovalchuk, Nataliya

2014-07-01

To determine the effect of gross tumor volume of the primary (GTV-P) and nodal (GTV-N) disease on planned radiation dose to the brachial plexus (BP) in head and neck intensity-modulated radiotherapy (IMRT). Overall, 75 patients underwent definitive IMRT to a median total dose of 69.96 Gy in 33 fractions. The right BP and left BP were prospectively contoured as separate organs at risk. The GTV was related to BP dose using the unpaired t-test. Receiver operating characteristics curves were constructed to determine optimized volumetric thresholds of GTV-P and GTV-N corresponding to a maximum BP dose cutoff of > 66 Gy.more » Multivariate analyses were performed to account for factors associated with a higher maximal BP dose. A higher maximum BP dose (> 66 vs ≤ 66 Gy) correlated with a greater mean GTV-P (79.5 vs 30.8 cc; p = 0.001) and ipsilateral GTV-N (60.6 vs 19.8 cc; p = 0.014). When dichotomized by the optimized nodal volume, patients with an ipsilateral GTV-N ≥ 4.9 vs < 4.9 cc had a significant difference in maximum BP dose (64.2 vs 59.4 Gy; p = 0.001). Multivariate analysis confirmed that an ipsilateral GTV-N ≥ 4.9 cc was an independent predictor for the BP to receive a maximal dose of > 66 Gy when adjusted individually for BP volume, GTV-P, the use of a low anterior neck field technique, total planned radiation dose, and tumor category. Although both the primary and the nodal tumor volumes affected the BP maximal dose, the ipsilateral nodal tumor volume (GTV-N ≥ 4.9 cc) was an independent predictor for high maximal BP dose constraints in head and neck IMRT.« less

Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study

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

McGarry, Ronald C.; Papiez, Lech; Williams, Mark

Purpose: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. Methods and Materials: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. Results: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy),more » but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses {<=}16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. Conclusions: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.« less

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

PubMed

Seymour, John F; Ma, Shuo; Brander, Danielle M; Choi, Michael Y; Barrientos, Jacqueline; Davids, Matthew S; Anderson, Mary Ann; Beaven, Anne W; Rosen, Steven T; Tam, Constantine S; Prine, Betty; Agarwal, Suresh K; Munasinghe, Wijith; Zhu, Ming; Lash, L Leanne; Desai, Monali; Cerri, Elisa; Verdugo, Maria; Kim, Su Young; Humerickhouse, Rod A; Gordon, Gary B; Kipps, Thomas J; Roberts, Andrew W

2017-02-01

Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m 2 in month 1 and 500 mg/m 2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. AbbVie Inc and Genentech Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

PubMed Central

Seymour, John F; Ma, Shuo; Brander, Danielle M; Choi, Michael Y; Barrientos, Jacqueline; Davids, Matthew S; Anderson, Mary Ann; Beaven, Anne W; Rosen, Steven T; Tam, Constantine S; Prine, Betty; Agarwal, Suresh K; Munasinghe, Wijith; Zhu, Ming; Lash, L Leanne; Desai, Monali; Cerri, Elisa; Verdugo, Maria; Kim, Su Young; Humerickhouse, Rod A; Gordon, Gary B; Kipps, Thomas J; Roberts, Andrew W

2017-01-01

Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3–4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66–91) and 89% (95% CI 72–96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. Interpretation A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. PMID:28089635

Aflibercept treatment for neovascular AMD beyond the first year: consensus recommendations by a UK expert roundtable panel, 2017 update

PubMed Central

Patel, Praveen J; Devonport, Helen; Sivaprasad, Sobha; Ross, Adam H; Walters, Gavin; Gale, Richard P; Lotery, Andrew J; Mahmood, Sajjad; Talks, James S; Napier, Jackie

2017-01-01

National recommendations on continued administration of aflibercept solution for injection after the first year of treatment for neovascular age-related macular degeneration (nAMD) have been developed by an expert panel of UK retina specialists, based on clinician experience and treatment outcomes seen in year 2. The 2017 update reiterates that the treatment goal is to maintain or improve the macular structural and functional gains achieved in year 1 while attempting to reduce or minimize the treatment burden, recognizing the need for ongoing treatment. At the end of year 1 (ie, the decision visit at month 11), two treatment options should be considered: do not extend the treatment interval and maintain fixed 8-weekly dosing, or extend the treatment interval using a treat-and-extend regimen up to a maximum 12 weeks. Criteria for considering not extending the treatment interval are persistent macular fluid with stable vision, recurrent fluid, decrease in vision in the presence of fluid, macular hemorrhage, new choroidal neovascularization or any other sign(s) of exudative disease activity considered vision threatening in the opinion of the treating clinician. Treatment extension is recommended for eyes with a dry macula (ie, without macular fluid) and stable vision. Under both options, the treatment interval may be shortened if visual and/or anatomic outcomes deteriorate. Monitoring without treatment may be considered for eyes with a fluid-free macula for a minimum duration of 48 weeks. A patient completing one full year of monitoring without requiring injections may be considered for discharge from clinic. The treatment algorithm incorporates return to fixed 8-weekly dosing for disease reactivation during treatment extension and reinstatement of treatment for disease recurrence following discontinuation or discharge. For bilateral nAMD, either the eye requiring the more intensive treatment or the eye with the better vision, guided by local clinical practice, should determine the retreatment schedule overall. PMID:29184385

Aflibercept treatment for neovascular AMD beyond the first year: consensus recommendations by a UK expert roundtable panel, 2017 update.

PubMed

Patel, Praveen J; Devonport, Helen; Sivaprasad, Sobha; Ross, Adam H; Walters, Gavin; Gale, Richard P; Lotery, Andrew J; Mahmood, Sajjad; Talks, James S; Napier, Jackie

2017-01-01

National recommendations on continued administration of aflibercept solution for injection after the first year of treatment for neovascular age-related macular degeneration (nAMD) have been developed by an expert panel of UK retina specialists, based on clinician experience and treatment outcomes seen in year 2. The 2017 update reiterates that the treatment goal is to maintain or improve the macular structural and functional gains achieved in year 1 while attempting to reduce or minimize the treatment burden, recognizing the need for ongoing treatment. At the end of year 1 (ie, the decision visit at month 11), two treatment options should be considered: do not extend the treatment interval and maintain fixed 8-weekly dosing, or extend the treatment interval using a treat-and-extend regimen up to a maximum 12 weeks. Criteria for considering not extending the treatment interval are persistent macular fluid with stable vision, recurrent fluid, decrease in vision in the presence of fluid, macular hemorrhage, new choroidal neovascularization or any other sign(s) of exudative disease activity considered vision threatening in the opinion of the treating clinician. Treatment extension is recommended for eyes with a dry macula (ie, without macular fluid) and stable vision. Under both options, the treatment interval may be shortened if visual and/or anatomic outcomes deteriorate. Monitoring without treatment may be considered for eyes with a fluid-free macula for a minimum duration of 48 weeks. A patient completing one full year of monitoring without requiring injections may be considered for discharge from clinic. The treatment algorithm incorporates return to fixed 8-weekly dosing for disease reactivation during treatment extension and reinstatement of treatment for disease recurrence following discontinuation or discharge. For bilateral nAMD, either the eye requiring the more intensive treatment or the eye with the better vision, guided by local clinical practice, should determine the retreatment schedule overall.

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

PubMed

O'Reilly, Eileen M; Lee, Jonathan W; Lowery, Maeve A; Capanu, Marinela; Stadler, Zsofia K; Moore, Malcolm J; Dhani, Neesha; Kindler, Hedy L; Estrella, Hayley; Maynard, Hannah; Golan, Talia; Segal, Amiel; Salo-Mullen, Erin E; Yu, Kenneth H; Epstein, Andrew S; Segal, Michal; Brenner, Robin; Do, Richard K; Chen, Alice P; Tang, Laura H; Kelsen, David P

2018-04-01

A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Gemcitabine and cisplatin were dosed at 600 and 25 mg/m 2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society. © 2018 American Cancer Society.

The Impact of the Grid Size on TomoTherapy for Prostate Cancer

PubMed Central

Kawashima, Motohiro; Kawamura, Hidemasa; Onishi, Masahiro; Takakusagi, Yosuke; Okonogi, Noriyuki; Okazaki, Atsushi; Sekihara, Tetsuo; Ando, Yoshitaka; Nakano, Takashi

2017-01-01

Discretization errors due to the digitization of computed tomography images and the calculation grid are a significant issue in radiation therapy. Such errors have been quantitatively reported for a fixed multifield intensity-modulated radiation therapy using traditional linear accelerators. The aim of this study is to quantify the influence of the calculation grid size on the dose distribution in TomoTherapy. This study used ten treatment plans for prostate cancer. The final dose calculation was performed with “fine” (2.73 mm) and “normal” (5.46 mm) grid sizes. The dose distributions were compared from different points of view: the dose-volume histogram (DVH) parameters for planning target volume (PTV) and organ at risk (OAR), the various indices, and dose differences. The DVH parameters were used Dmax, D2%, D2cc, Dmean, D95%, D98%, and Dmin for PTV and Dmax, D2%, and D2cc for OARs. The various indices used were homogeneity index and equivalent uniform dose for plan evaluation. Almost all of DVH parameters for the “fine” calculations tended to be higher than those for the “normal” calculations. The largest difference of DVH parameters for PTV was Dmax and that for OARs was rectal D2cc. The mean difference of Dmax was 3.5%, and the rectal D2cc was increased up to 6% at the maximum and 2.9% on average. The mean difference of D95% for PTV was the smallest among the differences of the other DVH parameters. For each index, whether there was a significant difference between the two grid sizes was determined through a paired t-test. There were significant differences for most of the indices. The dose difference between the “fine” and “normal” calculations was evaluated. Some points around high-dose regions had differences exceeding 5% of the prescription dose. The influence of the calculation grid size in TomoTherapy is smaller than traditional linear accelerators. However, there was a significant difference. We recommend calculating the final dose using the “fine” grid size. PMID:28974860

Evaluation and implementation of triple‐channel radiochromic film dosimetry in brachytherapy

PubMed Central

Bradley, David; Nisbet, Andrew

2014-01-01

The measurement of dose distributions in clinical brachytherapy, for the purpose of quality control, commissioning or dosimetric audit, is challenging and requires development. Radiochromic film dosimetry with a commercial flatbed scanner may be suitable, but careful methodologies are required to control various sources of uncertainty. Triple‐channel dosimetry has recently been utilized in external beam radiotherapy to improve the accuracy of film dosimetry, but its use in brachytherapy, with characteristic high maximum doses, steep dose gradients, and small scales, has been less well researched. We investigate the use of advanced film dosimetry techniques for brachytherapy dosimetry, evaluating uncertainties and assessing the mitigation afforded by triple‐channel dosimetry. We present results on postirradiation film darkening, lateral scanner effect, film surface perturbation, film active layer thickness, film curling, and examples of the measurement of clinical brachytherapy dose distributions. The lateral scanner effect in brachytherapy film dosimetry can be very significant, up to 23% dose increase at 14 Gy, at ± 9 cm lateral from the scanner axis for simple single‐channel dosimetry. Triple‐channel dosimetry mitigates the effect, but still limits the useable width of a typical scanner to less than 8 cm at high dose levels to give dose uncertainty to within 1%. Triple‐channel dosimetry separates dose and dose‐independent signal components, and effectively removes disturbances caused by film thickness variation and surface perturbations in the examples considered in this work. The use of reference dose films scanned simultaneously with brachytherapy test films is recommended to account for scanner variations from calibration conditions. Postirradiation darkening, which is a continual logarithmic function with time, must be taken into account between the reference and test films. Finally, films must be flat when scanned to avoid the Callier‐like effects and to provide reliable dosimetric results. We have demonstrated that radiochromic film dosimetry with GAFCHROMIC EBT3 film and a commercial flatbed scanner is a viable method for brachytherapy dose distribution measurement, and uncertainties may be reduced with triple‐channel dosimetry and specific film scan and evaluation methodologies. PACS numbers: 87.55.Qr, 87.56.bg, 87.55.km PMID:25207417

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

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

Ben-Josef, Edgar, E-mail: edgar.ben-josef@uphs.upenn.edu; Schipper, Mathew; Francis, Isaac R.

2012-12-01

Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) wasmore » given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.« less

Assessing dose of the representative person for the purpose of radiation protection of the public. ICRP publication 101. Approved by the Commission in September 2005.

PubMed

2006-01-01

The Commission intended that its revised recommendations should be based on a simple, but widely applicable, system of protection that would clarify its objectives and provide a basis for the more formal systems needed by operating managers and regulators. The recommendations would establish quantified constraints, or limits, on individual dose from specified sources. These dose constraints apply to actual or representative people who encounter occupational, medical, and public exposures. This report updates the previous guidance for estimating dose to the public. Dose to the public cannot be measured directly and, in some cases, it cannot be measured at all. Therefore, for the purpose of protection of the public, it is necessary to characterise an individual, either hypothetical or specific, whose dose can be used for determining compliance with the relevant dose constraint. This individual is defined as the 'representative person'. The Commission's goal of protection of the public is achieved if the relevant dose constraint for this individual for a single source is met and radiological protection is optimised. This report explains the process of estimating annual dose and recognises that a number of different methods are available for this purpose. These methods range from deterministic calculations to more complex probabilistic techniques. In addition, a mixture of these techniques may be applied. In selecting characteristics of the representative person, three important concepts should be borne in mind: reasonableness, sustainability, and homogeneity. Each concept is explained and examples are provided to illustrate their roles. Doses to the public are prospective (may occur in the future) or retrospective (occurred in the past). Prospective doses are for hypothetical individuals who may or may not exist in the future, while retrospective doses are generally calculated for specific individuals. The Commission recognises that the level of detail afforded by its provision of dose coefficients for six age categories is not necessary in making prospective assessments of dose, given the inherent uncertainties usually associated with estimating dose to the public and with identification of the representative person. It now recommends the use of three age categories for estimating annual dose to the representative person for prospective assessments. These categories are 0-5 years (infant), 6-15 years (child), and 16-70 years (adult). For practical implementation of this recommendation, dose coefficients and habit data for a 1-year-old infant, a 10-year-old child, and an adult should be used to represent the three age categories. In a probabilistic assessment of dose, whether from a planned facility or an existing situation, the Commission recommends that the representative person should be defined such that the probability is less than about 5% that a person drawn at random from the population will receive a greater dose. If such an assessment indicates that a few tens of people or more could receive doses above the relevant constraint, the characteristics of these people need to be explored. If, following further analysis, it is shown that doses to a few tens of people are indeed likely to exceed the relevant dose constraint, actions to modify the exposure should be considered. The Commission recognises the role that stakeholders can play in identifying characteristics of the representative person. Involvement of stakeholders can significantly improve the quality, understanding, and acceptability of the characteristics of the representative person and the resulting estimated dose.

Drug Interactions Between Hepatoprotective Agents Ursodeoxycholic Acid or Glycyrrhizin and Ombitasvir/Paritaprevir/Ritonavir in Healthy Japanese Subjects.

PubMed

Zha, Jiuhong; Badri, Prajakta S; Ding, Bifeng; Uchiyama, Naotaka; Alves, Katia; Rodrigues, Lino; Redman, Rebecca; Dutta, Sandeep; Menon, Rajeev M

2015-11-01

The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen. DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC). After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change). No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Budget impact of polio immunization strategy for India: introduction of one dose of inactivated poliomyelitis vaccine and reductions in supplemental polio immunization.

PubMed

Khan, M M; Sharma, S; Tripathi, B; Alvarez, F P

2017-01-01

To conduct a budget impact analysis (BIA) of introducing the immunization recommendations of India Expert Advisory Group (IEAG) for the years 2015-2017. The recommendations include introduction of one inactivated poliomyelitis vaccine (IPV) dose in the regular child immunization programme along with reductions in oral polio vaccine (OPV) doses in supplemental programmes. This is a national level analysis of budget impact of new polio immunization recommendations. Since the states of India vary widely in terms of size, vaccine coverage and supplemental vaccine needs, the study estimated the budget impact for each of the states of India separately to derive the national level budget impact. Based on the recommendations of IEAG, the BIA assumes that all children in India will get an IPV dose at 14 weeks of age in addition to the OPV and DPT (or Pentavalent-3) doses. Cost of introducing the IPV dose was estimated by considering vaccine price and vaccine delivery and administration costs. The cost savings associated with the reduction in number of doses of OPV in supplemental immunization were also estimated. The analysis used India-specific or international cost parameters to estimate the budget impact. Introduction of one IPV dose will increase the cost of vaccines in the regular immunization programme from $20 million to $47 million. Since IEAG recommends lower intensity of supplemental OPV vaccination, polio vaccine cost of supplemental programme is expected to decline from $72 million to $53 million. Cost of administering polio vaccines will also decline from $124 million to $105 million mainly due to the significantly lower intensity of supplemental polio vaccination. The net effect of adopting IEAG's recommendations on polio immunization turns out to be cost saving for India, reducing total polio immunization cost by $6 million. Additional savings could be achieved if India adopts the new policy regarding the handling of multi-dose vials after opening. Introduction of three doses of IPV with the existing polio immunization schedule will increase the budget requirement by $102 million but replacing OPV doses with IPV will increase the budget by about $59 million. Discontinuation of supplemental OPV immunization with replacement of OPV by IPV will reduce the Government of India's (GOI) polio immunization budget by $99 million. Although the overall cost of polio programme will decline with the adoption of IEAG's recommendations, state-level costs will vary widely. In states like Kerala, Karnataka, Uttar Pradesh and Andhra Pradesh, cost of polio immunization will increase while in Punjab and Jharkhand the costs will remain more or less constant. Significant cost reductions will happen in states with high intensity of supplemental polio immunizations (Bihar, Haryana and Delhi). The cost of procuring polio vaccines will more than double from $20 million to about $47 million requiring allocation of additional foreign exchanges. In some states (like Bihar), the decline in polio-related employment will be very high requiring reallocation of personnel from polio to other programmes. Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Fetal radiation dose estimates for I-131 sodium iodide in cases where conception occurs after administration

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

Sparks, R.B.; Stabin, M.G.

1999-01-01

After administration of I-131 to the female patient, the possibility of radiation exposure of the embryo/fetus exists if the patient becomes pregnant while radioiodine remains in the body. Fetal radiation dose estimates for such cases were calculated. Doses were calculated for various maternal thyroid uptakes and time intervals between administration and conception, including euthyroid and hyperthyroid cases. The maximum fetal dose calculating was about 9.8E-03 mGy/MBq, which occurred with 100% maternal thyroid uptake and a 1 week interval between administration and conception. Placental crossover of the small amount of radioiodine remaining 90 days after conception was also considered. Such crossovermore » could result in an additional fetal dose of 9.8E-05 mGy/MBq and a maximum fetal thyroid self dose of 3.5E-04 mGy/MBq.« less

In vivo dosimetry for external photon treatments of head and neck cancers by diodes and TLDS.

PubMed

Tung, C J; Wang, H C; Lo, S H; Wu, J M; Wang, C J

2004-01-01

In vivo dosimetry was implemented for treatments of head and neck cancers in the large fields. Diode and thermoluminescence dosemeter (TLD) measurements were carried out for the linear accelerators of 6 MV photon beams. ESTRO in vivo dosimetry protocols were followed in the determination of midline doses from measurements of entrance and exit doses. Of the fields monitored by diodes, the maximum absolute deviation of measured midline doses from planned target doses was 8%, with the mean value and the standard deviation of -1.0 and 2.7%. If planned target doses were calculated using radiological water equivalent thicknesses rather than patient geometric thicknesses, the maximum absolute deviation dropped to 4%, with the mean and the standard deviation of 0.7 and 1.8%. For in vivo dosimetry monitored by TLDs, the shift in mean dose remained small but the statistical precision became poor.

Whole-remnant and maximum-voxel SPECT/CT dosimetry in {sup 131}I-NaI treatments of differentiated thyroid cancer

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

Mínguez, Pablo, E-mail: pablo.minguezgabina@osakid

Purpose: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). Methods: Eighteen DTC patients were administered 1.11 GBq of {sup 131}I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3–7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimatedmore » using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. Results: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2–176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2–145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. Conclusions: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.« less

Biopesticide-induced behavioral and morphological alterations in the stingless bee Melipona quadrifasciata.

PubMed

Barbosa, Wagner F; Tomé, Hudson Vaner V; Bernardes, Rodrigo C; Siqueira, Maria Augusta L; Smagghe, Guy; Guedes, Raul Narciso C

2015-09-01

Because of their natural origin, biopesticides are assumed to be less harmful to beneficial insects, including bees, and therefore their use has been widely encouraged for crop protection. There is little evidence, however, to support this ingrained notion of biopesticide safety to pollinators. Because larval exposure is still largely unexplored in ecotoxicology and risk assessment on bees, an investigation was performed on the lethal and sublethal effects of a diet treated with 2 bioinsecticides, azadirachtin and spinosad, on the stingless bee, Melipona quadrifasciata, which is one of the most important pollinators in the Neotropics. Survival of stingless bee larvae was significantly compromised at doses above 210 ng a.i./bee for azadirachtin and 114 ng a.i./bee for spinosad. No sublethal effect was observed on larvae developmental time, but doses of both compounds negatively affected pupal body mass. Azadirachtin produced deformed pupae and adults as a result of its insect growth regulator properties, but spinosad was more harmful and produced greater numbers of deformed individuals. Only spinosad compromised walking activity of the adult workers at doses as low as 2.29 ng a.i./bee, which is 1/5000 of the maximum field recommended rate. In conclusion, the results demonstrated that bioinsecticides can pose significant risks to native pollinators with lethal and sublethal effects; future investigations are needed on the likelihood of such effects under field conditions. © 2015 SETAC.

A practical and successful desensitization protocol for immediate hypersensitivity reactions to iron salts.

PubMed

Demir, Semra; Olgac, Muge; Unal, Derya; Gelincik, Asli; Colakoglu, Bahauddin; Buyukozturk, Suna

2014-01-01

Orally administered iron salts (OAS) are widely used in the management of iron deficiency anemia and hypersensitivity reactions to OAS are not common. If an offending drug is the sole option or is significantly more effective than its alternatives, it can be readministered by desensitization. The oral desensitization protocols for iron published so far concern either desensitization that was completed only over a long period or did not attain the recommended therapeutic dose. We aimed to develop a more effective protocol. We report here on 2 patients who experienced hypersensitivity reactions to OAS. After confirming the diagnosis, both patients were desensitized to oral ferrous (II) glycine sulfate complex according to a 2-day desensitization protocol. A commercial suspension of oral ferrous glycine sulfate, which contains 4 mg of elemental iron in 1 ml, was preferred. We started with a dose as low as 0.1 ml from a 1/100 dilution (0.004 mg elemental iron) of the original suspension and reached the maximum effective dose in 2 days. Both patients were successfully desensitized and they went on to complete the 6-month iron treatment without any adverse effects. Although hypersensitvity reactions to iron are not common, there is no alternative for iron administration. Therefore, desensitization has to be the choice. This easy desensitization protocol seems to be a promising option. © 2014 S. Karger AG, Basel.

Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer

PubMed Central

Macarulla, T; Cervantes, A; Tabernero, J; Roselló, S; Van Cutsem, E; Tejpar, S; Prenen, H; Martinelli, E; Troiani, T; Laffranchi, B; Jego, V; von Richter, O; Ciardiello, F

2015-01-01

Background: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib. Methods: Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI. Results: Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated. Conclusions: Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified. PMID:25989270

Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes.

PubMed

Mohamed, Tarek Mostafa; Ghaffar, Hamdy M Abdel; El Husseiny, Rabee M R

2015-12-01

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activities of I, III, and IV complexes but not in the activity of complex II. In conclusion, tramadol but not clonazepam has been found to partially inhibit the activities of respiratory chain complexes I, III, and IV but not the activity of complex II and such inhibition occurred only at doses that exceeded the maximum recommended adult human daily therapeutic doses. This result explains the clinical and histopathological effects of tramadol, such as seizures and red neurons (marker for apoptosis), respectively. © The Author(s) 2012.

Radon Concentration And Dose Assessment In Well Water Samples From Karbala Governorate Of Iraq

NASA Astrophysics Data System (ADS)

Al-Alawy, I. T.; Hasan, A. A.

2018-05-01

There are numerous studies around the world about radon concentrations and their risks to the health of human beings. One of the most important social characteristics is the use of water wells for irrigation, which is a major source of water pollution with radon gas. In the present study, six well water samples have been collected from different locations in Karbala governorate to investigate radon concentration level using CR-39 technique. The maximum value 4.112±2.0Bq/L was in Al-Hurr (Al-Qarih Al-Easariah) region, and the lowest concentration of radon was in Hay Ramadan region which is 2.156±1.4Bq/L, with an average value 2.84±1.65Bq/L. The highest result of annual effective dose (AED) was in Al-Hurr (Al-Qarih Al-Easariah) region which is equal to 15.00±3.9μSv/y, while the minimum was recorded in Hay Ramadan 7.86±2.8μSv/y, with an average value 10.35±3.1μSv/y. The current results have shown that the radon concentrations in well water samples are lower than the recommended limit 11.1Bq/L and the annual effective dose in these samples are lower than the permissible international limit 1mSv/y.

CT Fluoroscopy Shielding: Decreases in Scattered Radiation for the Patient and Operator

PubMed Central

Neeman, Ziv; Dromi, Sergio A.; Sarin, Shawn; Wood, Bradford J.

2008-01-01

PURPOSE High-radiation exposure occurs during computed tomographic (CT) fluoroscopy. Patient and operator doses during thoracic and abdominal interventional procedures were studied in the present experiment, and a novel shielding device to reduce exposure to the patient and operator was evaluated. MATERIALS AND METHODS With a 16-slice CT scanner in CT fluoroscopy mode (120 kVp, 30 mA), surface dosimetry was performed on adult and pediatric phantoms. The shielding was composed of tungsten antimony in the form of a lightweight polymer sheet. Doses to the patient were measured with and without shielding for thoracic and abdominal procedures. Doses to the operator were recorded with and without phantom, gantry, and table shielding in place. Double-layer lead-free gloves were used by the operator during the procedures. RESULTS Tungsten antimony shielding adjacent to the scan plane resulted in a maximum dose reduction of 92.3% to the patient. Maximum 85.6%, 93.3%, and 85.1% dose reductions were observed for the operator’s torso, gonads, and hands, respectively. The use of double-layer lead-free gloves resulted in a maximum radiation dose reduction of 97%. CONCLUSIONS Methods to reduce exposure during CT fluoroscopy are effective and should be searched for. Significant reduction in radiation doses to the patient and operator can be accomplished with tungsten antimony shielding. PMID:17185699

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules.

PubMed

Sankhala, Kamalesh; Takimoto, Chris H; Mita, Alain C; Xiong, Henry; Rodón, Jordi; Mehrvarz Sarshekeh, Amir; Burns, K; Iizuka, Kenzo; Kopetz, Scott

2018-04-18

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m 2 /day. At 3.0 mg/m 2 /day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m 2 /day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m 2 /day. The maximum tolerated dose was 3 mg/m 2 /day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m 2 /day and 3.0 mg/m 2 /day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A, in Patients with Advanced Solid Tumors

PubMed Central

Fischer, Richard; Scharr, Dirk; Büchert, Martin; Stern, Angelika; Gille, Hendrik; Audoly, Laurent P.; Scheulen, Max E.

2013-01-01

Background To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). Methods Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. Results Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity. Conclusions PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. Trial Registration ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257 PMID:24349470

Role of belly board device in the age of intensity modulated radiotherapy for pelvic irradiation

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

Estabrook, Neil C.; Bartlett, Gregory K.; Compton, Julia J.

Small bowel dose often represents a limiting factor for radiation treatment of pelvic malignancies. To reduce small bowel toxicity, a belly board device (BBD) with a prone position is often recommended. Intensity modulated radiotherapy (IMRT) could reduce dose to small bowel based on the desired dose-volume constraints. We investigated the efficacy of BBD in conjunction with IMRT. A total of 11 consecutive patients with the diagnosis of rectal cancer, who were candidates for definitive therapy, were selected. Patients were immobilized with BBD in prone position for simulation and treatment. Supine position computed tomography (CT) data were either acquired at themore » same time or during a diagnostic scan, and if existed was used. Target volumes (TV) as well as organs at risk (OAR) were delineated in both studies. Three-dimensional conformal treatment (3DCRT) and IMRT plans were made for both scans. Thus for each patient, 4 plans were generated. Statistical analysis was conducted for maximum, minimum, and mean dose to each structure. When comparing the normalized mean Gross TV dose for the different plans, there was no statistical difference found between the planning types. There was a significant difference in small bowel sparing when using prone position on BBD comparing 3DCRT and IMRT plans, favoring IMRT with a 29.6% reduction in dose (p = 0.007). There was also a statistically significant difference in small bowel sparing when comparing supine position IMRT to prone-BBD IMRT favoring prone-BBD IMRT with a reduction of 30.3% (p = 0.002). For rectal cancer when small bowel could be a limiting factor, prone position using BBD along with IMRT provides the best sparing. We conclude that whenever a dose escalation in rectal cancer is desired where small bowel could be limiting factor, IMRT in conjunction with BBD should be selected.« less

Patient doses from chest radiography in Victoria.

PubMed

Cardillo, I; Boal, T J; Einsiedel, P F

1997-06-01

This survey examines doses from PA chest radiography at radiology practices, private hospitals and public hospitals throughout metropolitan and country Victoria. Data were collected from 111 individual X-ray units at 86 different practices. Entrance skin doses in air were measured for exposure factors used by the centre for a 23 cm thick male chest. A CDRH LucA1 chest phantom was used when making these measurements. About half of the centres used grid technique and half used non-grid technique. There was a factor of greater than 10 difference in the entrance dose delivered between the highest dose centre and the lowest dose centre for non-grid centres; and a factor of about 5 for centres using grids. Factors contributing to the high doses recorded at some centres were identified. Guidance levels for chest radiography based on the third quartile value of the entrance doses from this survey have been recommended and compared with guidance levels recommended in other countries.

Evaluation and mitigation of potential errors in radiochromic film dosimetry due to film curvature at scanning

PubMed Central

Bradley, David A.; Nisbet, Andrew

2015-01-01

This work considers a previously overlooked uncertainty present in film dosimetry which results from moderate curvature of films during the scanning process. Small film samples are particularly susceptible to film curling which may be undetected or deemed insignificant. In this study, we consider test cases with controlled induced curvature of film and with film raised horizontally above the scanner plate. We also evaluate the difference in scans of a film irradiated with a typical brachytherapy dose distribution with the film naturally curved and with the film held flat on the scanner. Typical naturally occurring curvature of film at scanning, giving rise to a maximum height 1 to 2 mm above the scan plane, may introduce dose errors of 1% to 4%, and considerably reduce gamma evaluation passing rates when comparing film‐measured doses with treatment planning system‐calculated dose distributions, a common application of film dosimetry in radiotherapy. The use of a triple‐channel dosimetry algorithm appeared to mitigate the error due to film curvature compared to conventional single‐channel film dosimetry. The change in pixel value and calibrated reported dose with film curling or height above the scanner plate may be due to variations in illumination characteristics, optical disturbances, or a Callier‐type effect. There is a clear requirement for physically flat films at scanning to avoid the introduction of a substantial error source in film dosimetry. Particularly for small film samples, a compression glass plate above the film is recommended to ensure flat‐film scanning. This effect has been overlooked to date in the literature. PACS numbers: 87.55.Qr, 87.56.bg, 87.55.km PMID:26103181

[A practical procedure to improve the accuracy of radiochromic film dosimetry: a integration with a correction method of uniformity correction and a red/blue correction method].

PubMed

Uehara, Ryuzo; Tachibana, Hidenobu; Ito, Yasushi; Yoshino, Shinichi; Matsubayashi, Fumiyasu; Sato, Tomoharu

2013-06-01

It has been reported that the light scattering could worsen the accuracy of dose distribution measurement using a radiochromic film. The purpose of this study was to investigate the accuracy of two different films, EDR2 and EBT2, as film dosimetry tools. The effectiveness of a correction method for the non-uniformity caused from EBT2 film and the light scattering was also evaluated. In addition the efficacy of this correction method integrated with the red/blue correction method was assessed. EDR2 and EBT2 films were read using a flatbed charge-coupled device scanner (EPSON 10000G). Dose differences on the axis perpendicular to the scanner lamp movement axis were within 1% with EDR2, but exceeded 3% (Maximum: +8%) with EBT2. The non-uniformity correction method, after a single film exposure, was applied to the readout of the films. A corrected dose distribution data was subsequently created. The correction method showed more than 10%-better pass ratios in dose difference evaluation than when the correction method was not applied. The red/blue correction method resulted in 5%-improvement compared with the standard procedure that employed red color only. The correction method with EBT2 proved to be able to rapidly correct non-uniformity, and has potential for routine clinical IMRT dose verification if the accuracy of EBT2 is required to be similar to that of EDR2. The use of red/blue correction method may improve the accuracy, but we recommend we should use the red/blue correction method carefully and understand the characteristics of EBT2 for red color only and the red/blue correction method.

INVESTIGATION OF THE IRRADIATION OF POPULATIONS THAT HAVE UNDERGONE SYSTEMATIC RADIOLOGIC EXAMINATIONS OF THE THORAX (in French)

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

Gernez-Rieux, C.; Bonte, G.; Gervois, M.

1962-06-01

An international survey made in 1958, with the Comite"s Nationaux de Lutte Antituberculeuse, provided a large body of information gathered from Austria, Belgium, Canada, Denmark, France, Great Britain, Japan, Netherlands, Rumania, Switzerland, and Spain, relating to radiation dosages in detection of tuberculosis. It was found that in these countries with the equipment and techniques in use at the time, radiography necessitated a radiation dose of 200- 640 mr as measured on the dorsal surface of the thorax, whereas fluoroscopic examination required doses ranging from 700 mr to 15 r, according to technique employed. Gonadal doses were negligible with radiography, andmore » the significant genetic dose for the entire population was estimated to be not over 80 mu r in one country where approximately 55 million photofluorographic examinations were made in 1958 in persons under 30 years old. The average bone marrow dose per inhabitant varied from 0.2 to 37 mr in the various countries. Plumonary fluoroscopy exposes the individual to greater somatic and gonadic radiation and, it is suggested, should be eliminated from antituberculosis programs. To reduce patient exposure during thoracic radiology, the following precautions are recommended by the Commission de la Radiologie de l'Union Internationale contre la Tuberculose: use of mirror camera: adoption of higher film sensitivity and iniproved development techniques; use of higher maximum kilovoltage; establishment of a screen focus distance at less than 1 m; filtration with 3 mm of aluminum; exposure time of less than 1/10 sec; use of beam-localizing diaphragm and, if necessary, of a lead apron. Chest roentgenography still remains the most effective means for detecting new cases and follow-up examination in tuberculosis, and with adequate safeguards to minimize patient radiation, exposure does not present undue hazards. (BBB)« less

A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer.

PubMed

Cohen, Steven J; Zalupski, Mark M; Modiano, Manuel R; Conkling, Paul; Patt, Yehuda Z; Davis, Peg; Dorr, Robert T; Boytim, Michelle L; Hersh, Evan M

2010-07-01

Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days). One hundred five patients received 340 treatment cycles (median 2, range 1-16). median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

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

Haseeb, Syed Abdul; Ahmad, Syed Bilal; Mirza, Sika

Purpose: To assess the impact of radiation treatment delivery through patient inhomogeneities on the secondary barrier shielding requirements in IMRT treatments using Monte Carlo Simulations. Materials and Methods: Scatter factors were calculated at a distance of 1m from the center of a virtual phantom in Geant4.10.01. Phantom (30×30×30 cm{sup 3}) was inserted with lung (30×30×8 cm{sup 3}), stainless steel (5×5×5 cm{sup 3}) and aluminum (5×5×5 cm{sup 3}) to represent the inhomogeneities. Scatter factor was defined according to the NCRP-151 recommendations and was calculated for angles of 3° to 120° with respect to the beam’s central axis. A virtual radiation source,more » with energy sampled from a histogram representing 6 MV FFF beam, was used for irradiation with a field size of 15×15 cm{sup 2} and SSD of 100 cm. Results: Irradiation through the inhomogeneity affects the patient scattered dose. For high Z material inhomogeneities the scattered dose is reduced due to significant attenuation of the primary radiation. On the other hand if the inhomogeneity is a low Z material such as lung the scattered dose is higher by a maximum of 26%. The average increase in scatter factors for the lung phantom was 17% for angles between 3° and 63° compared to the homogeneous water phantom. Conclusions: In IMRT type treatments delivered through low density patient inhomogeneities (lung) the scattered dose increases significantly. Considering a large proportion of patients receiving radiation therapy for lung cancers the increase in the scattered dose should be incorporated in the shielding calculations for the secondary barriers.« less

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

Alqathami, M; Lee, H; Ibbott, G

Purpose: To develop and evaluate novel radiochromic films for quality assurance in radiotherapy dosimetry. Materials and Methods: Novel radiochromic film compositions were formulated using leuco crystal violet (LCV) as a reporting system and tetrabromoethane as a free radical source. The film matrix used consisted of polyurethane polymer mixed with dibutyl phthalate plasticizer (20 wt%). The concentration of the radical initiator was kept constant at 10 wt% and the concentration of the LCV dye varied (1 and 2 wt%). To ensure uniform thickness of the film, its precursors were sandwiched between two pieces of glass separated by a 1 mm gapmore » between during the curing process. The films were cut into pieces and were irradiated with a 6 MV X-ray beam to selected doses. The change in optical density was measured using a flatbed scanner and a spectrophotometer. Results: The results showed that all film formulations exhibited a linear response with dose and an absorption maximum at ∼ 590 nm. The formulation with 2 wt% LCV was ∼ 30% more sensitive to dose than the formulation with 1 wt% LCV. Both films were very deformable. In addition, the radiochromic response of the film was found to bleach over a short period of time (few weeks) allowing the film to be reused for dose verification measurements. Conclusion: Both film formulations displayed excellent sensitivity and linearity to radiation dose and thus can be used for the 2D dosimetry of clinical megavoltage and kilovoltage X-ray beams. In addition, the thickness of the film could easily be increased allowing for their potential use as a deformable bolus material. However, thicker films would need more optimization of the manufacturing procedure to ensure consistent material uniformity and sensitivity are recommended.« less

Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies.

PubMed

Awan, Farrukh T; Gore, Lia; Gao, Lei; Sharma, Jyoti; Lager, Joanne; Costa, Luciano J

2016-10-01

This phase Ib, dose-escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose-escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty-seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose-limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co-administration with rituximab or rituximab+bendamustine. Of 35 efficacy-evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti-tumour activity in relapsed or refractory B-cell malignancies. © 2016 John Wiley & Sons Ltd.

Tumescent liposuction: standard guidelines of care.

PubMed

Mysore, Venkataram

2008-01-01

Tumescent liposuction is a technique for the removal of subcutaneous fat under a special form of local anesthesia called tumescent anesthesia. PHYSICIAN'S QUALIFICATIONS: The physician performing liposuction should have completed postgraduate training in dermatology or a surgical specialty and should have had adequate training in dermatosurgery at a center that provides training in cutaneous surgery. In addition, the physician should obtain specific liposuction training or experience at the surgical table ("hands on") under the supervision of an appropriately trained and experienced liposuction surgeon. In addition to the surgical technique, training should include instruction in fluid and electrolyte balance, potential complications of liposuction, tumescent and other forms of anesthesia as well as emergency resuscitation and care. Liposuction can be performed safely in an outpatient day care surgical facility, or a hospital operating room. The day care theater should be equipped with facilities for monitoring and handling emergencies. A plan for handling emergencies should be in place with which all nursing staff should be familiar. A physician trained in emergency medical care and acute cardiac emergencies should be available in the premises. It is recommended but not mandatory, that an anesthetist be asked to stand by. Liposuction is recommended for all localized deposits of fat. Novices should restrict themselves to the abdomen, thighs, buttocks and male breasts. Arms, the medial side of the thigh and the female breast need more experience and are recommended for experienced surgeons. Liposuction may be performed for non-cosmetic indications such as hyperhidrosis of axillae after adequate experience has been acquired, but is not recommended for the treatment of obesity. Detailed history is to be taken with respect to any previous disease, drug intake and prior surgical procedures. Liposuction is contraindicated in patients with severe cardiovascular disease, severe coagulation disorders including thrombophilia, and during pregnancy. Physical evaluation should be detailed and should include assessment of general physical health to determine the fitness of the patient for surgery, as well as the examination of specific sites that need liposuction to check for potential problems. The patient should sign a detailed consent form listing details about the procedure and possible complications. The consent form should specifically state the limitations of the procedure and should mention whether more procedures are needed for proper results. The patient should be provided with adequate opportunity to seek information through brochures, computer presentations, and personal discussions. Preoperative laboratory studies to be performed include Hb%, blood counts including platelet counts, bleeding and clotting time (or prothrombin and activated partial thromboplastin time) and blood chemistry profile; ECG is advisable. Liver function tests, and pregnancy test for women of childbearing age are performed as mandated by the individual patient's requirements. Ultrasound examination is recommended in cases of gynecomastia. Preoperative antibiotics and non-sedative analgesics such as paracetamol are recommended. The choice of antibiotic and analgesic agents depends on the individual physician's preference and the prevailing local conditions. Lidocaine is the preferred local anesthetic; its recommended dose is 35-45 mg/kg and doses should not exceed 55 mg/kg wt. The recommended concentration of epinephrine in tumescent solutions is 0.25-1.5 mg/L. The total dosage of epinephrine should be minimized and should not exceed 50 microg/kg. t is always advisable not to combine liposuction with other procedures to avoid exceeding the recommended dosage of lignocaine. However, such combinations may be attempted if the total required dose of lignocaine does not exceed the maximum dose indicated above. The recommended cannula size for liposuction is not to be larger than 3.5 mm in diameter. The recommended volume of fat removed is in proportion to the fat content and/or size and/or weight of the patient being treated. It is recommended that the volume of fat removed not exceed 5000 mL in a single operative session. arge volume liposuctions or mega-liposuctions are not recommended. Baseline vital signs including blood pressure and heart rate, are recorded pre- and postoperatively. Pulse oximeter monitoring is essential in all cases. Postoperative antibiotics should be selected by the physician and taken for five days. Postoperative antiinflammatory drugs such as Cox 2 Inhibiters may be given for 5-7 days; specialized compression garments, binders, and tape help to reduce bruising, hematomas, seromas, and pain. Generally, compression is recommended for two weeks although this is variable according to the needs of the individual patient.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

PubMed

Caetano, Dorgival

2014-02-01

The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. A systematic review of English-language MEDLINE articles was undertaken. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

Imidacloprid application changes microbial dynamics and enzymes in rice soil.

PubMed

Mahapatra, Bibhab; Adak, Totan; Patil, Naveen K B; Pandi G, Guru P; Gowda, G Basana; Jambhulkar, N N; Yadav, Manoj Kumar; Panneerselvam, P; Kumar, Upendra; Munda, Sushmita; Jena, Mayabini

2017-10-01

Extensive use of imidacloprid in rice ecosystem may alter dynamics of microorganisms and can change soil biochemical properties. The objective of this study was to assess the effect of imidacloprid on growth and activities of microbes in tropical rice soil ecosystem. Four treatments, namely, recommended dose (at 25g a.i. ha -1 , RD), double the recommended dose (at 50g a.i. ha -1 , 2RD), five times the recommended dose (at 125g a.i. ha -1 , 5RD) & ten times the recommended dose (at 250g a.i. ha -1 , 10RD) along with control were imposed under controlled condition. Dissipation half lives of imidacloprid in soil were 19.25, 20.38, 21.65 and 33.00 days for RD, 2RD, 5RD and 10RD, respectively. In general bacteria, actinomycetes, fungi and phosphate solubilising bacteria population were disturbed due to imidacloprid application. Changes in diversity indices within bacterial community confirmed that imidacloprid application significantly affected distribution of bacteria. Total soil microbial biomass carbon content was reduced on imidacloprid application. Except dehydrogenase and alkaline phosphatase activities, all other soil enzymes namely, β-glycosidase, fluorescien diacetate hydrolase, acid phosphatase and urease responded negatively to imidacloprid application. The extent of negative effect of imidacloprid depends on dose and exposure time. This study concludes imidacloprid application had transient negative effects on soil microbes. Copyright © 2017 Elsevier Inc. All rights reserved.

Feasibility study of veterinary antibiotic consumption in Germany--comparison of ADDs and UDDs by animal production type, antimicrobial class and indication.

PubMed

Merle, Roswitha; Robanus, Matthias; Hegger-Gravenhorst, Christine; Mollenhauer, Yvonne; Hajek, Peter; Käsbohrer, Annemarie; Honscha, Walther; Kreienbrock, Lothar

2014-01-08

Within a feasibility study the use of antibiotics in pigs and cattle was determined in 24 veterinary practices in Lower Saxony and on 66 farms in North Rhine-Westphalia in Germany. Focus was laid on the comparison of the Used Daily Doses (UDD) (dose per animal and day prescribed by the veterinarians) with the Defined Animal Daily Doses (ADD) (dose per animal and day calculated by means of recommended dosages and estimated live weights). For piglets and calves most of the UDD (50% and 46% of nUDD, respectively) were above the ADD (i.e. UDD/ADD-ratio above 1.25). Regarding sows, fattening pigs, dairy and beef cattle, most of the UDDs (49% to 65% of nUDD) were lower than the respective ADD (i.e. UDD/ADD-ratio below 0.8). In pigs, the UDDs of beta-lactams, fluoroquinolones and cephalosporins, and in cattle, those of macrolides and beta-lactams were often below the ADDs. Tetracyclines were frequently used above the recommended dose.Enteric diseases were more often treated below the recommended dose than respiratory diseases, possibly due to overestimation of the live weight (diarrhea in young animals, respiratory diseases in elder animals) and consequently overestimation of the recommended dose. Comparisons between UDD and ADD can be used to observe differences between antimicrobials and trends in the usage of antibiotics. But individual treatment comparisons of UDD and ADD must be interpreted carefully, because they may be due to lower live weights than estimated. Correlating such data with data on the occurrence of resistant bacteria in future may help to improve resistance prevention and control.

Feasibility study of veterinary antibiotic consumption in Germany - comparison of ADDs and UDDs by animal production type, antimicrobial class and indication

PubMed Central

2014-01-01

Background Within a feasibility study the use of antibiotics in pigs and cattle was determined in 24 veterinary practices in Lower Saxony and on 66 farms in North Rhine-Westphalia in Germany. Focus was laid on the comparison of the Used Daily Doses (UDD) (dose per animal and day prescribed by the veterinarians) with the Defined Animal Daily Doses (ADD) (dose per animal and day calculated by means of recommended dosages and estimated live weights). Results For piglets and calves most of the UDD (50% and 46% of nUDD, respectively) were above the ADD (i.e. UDD/ADD-ratio above 1.25). Regarding sows, fattening pigs, dairy and beef cattle, most of the UDDs (49% to 65% of nUDD) were lower than the respective ADD (i.e. UDD/ADD-ratio below 0.8). In pigs, the UDDs of beta-lactams, fluoroquinolones and cephalosporins, and in cattle, those of macrolides and beta-lactams were often below the ADDs. Tetracyclines were frequently used above the recommended dose. Enteric diseases were more often treated below the recommended dose than respiratory diseases, possibly due to overestimation of the live weight (diarrhea in young animals, respiratory diseases in elder animals) and consequently overestimation of the recommended dose. Conclusion Comparisons between UDD and ADD can be used to observe differences between antimicrobials and trends in the usage of antibiotics. But individual treatment comparisons of UDD and ADD must be interpreted carefully, because they may be due to lower live weights than estimated. Correlating such data with data on the occurrence of resistant bacteria in future may help to improve resistance prevention and control. PMID:24401194

SU-G-201-08: Energy Response of Thermoluminescent Microcube Dosimeters in Water for Kilovoltage X-Ray Beams

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

Di Maso, L; Lawless, M; Culberson, W

Purpose: To characterize the energy dependence for TLD-100 microcubes in water at kilovoltage energies. Methods: TLD-100 microcubes with dimensions of (1 × 1 × 1) mm{sup 3} were irradiated with kilovoltage x-rays in a custom-built thin-window liquid water phantom. The TLD-100 microcubes were held in Virtual Water™ probes and aligned at a 2 cm depth in water. Irradiations were performed using the M-series x-ray beams of energies ranging from 50-250 kVp and normalized to a {sup 60}Co beam located at the UWADCL. Simulations using the EGSnrc Monte Carlo Code System were performed to model the x-ray beams, the {sup 60}Comore » beam, the water phantom and the dosimeters in the phantom. The egs-chamber user code was used to tally the dose to the TLDs and the dose to water. The measurements and calculations were used to determine the intrinsic energy dependence, absorbed-dose energy dependence, and absorbed-dose sensitivity. These values were compared to TLD-100 chips with dimensions of (3.2 × 0.9 × 0.9) mm{sup 3}. Results: The measured TLD-100 microcube response per dose to water among all investigated x-ray energies had a maximum percent difference of 61% relative to {sup 60}Co. The simulated ratio of dose to water to the dose to TLD had a maximum percent difference of 29% relative to {sup 60}Co. The ratio of dose to TLD to the TLD output had a maximum percent difference of 13% relative to {sup 60}Co. The maximum percent difference for the absorbed-dose sensitivity was 15% more than the used value of 1.41. Conclusion: These results confirm that differences in beam quality have a significant effect on TLD response when irradiated in water. These results also indicated a difference in TLD-100 response between microcube and chip geometries. The intrinsic energy dependence and the absorbed-dose energy dependence deviated up to 10% between TLD-100 microcubes and chips.« less

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

Park, J; Kim, J; Park, S

Purpose: To investigate exposure outside the treatment field when treating breast cancer with tri-Co-60 magnetic resonance (MR) image guided radiation therapy (IGRT) system. Methods: A total of 7 patients who treated with accelerated partial breast irradiation (APBI) technique were selected prospectively for this study (prescription dose = 38.5 Gy in 10 fractions). Every patient treated with two plans, one was an initial plan and the other was an adaptive plan generated after finishing 5 fractions (a total of 14 plans). Every plan was calculated with and without magnetic field in the treatment planning system. The EBT3 films were attached onmore » the front and the back of 1 cm bolus, and then it was placed on the patient body vertically to cover patient’s jaw and shoulder. After measurements, the maximum point dose and the mean dose of whole area of EBT3 film were acquired. Results: In the treatment plan with magnetic field, low dose stream outside the patient body was observed, almost reaching the patient’s jaw or shoulder, while it was not observed without magnetic field. The average values of the measured maximum and mean doses at the front of bolus were 30.1 ± 11.1 cGy (7.8% of the daily dose) and 14.7 ± 3.3 cGy (3.8%), respectively. At the back of bolus, those values were 6.0 ± 1.9 cGy (1.6%) and 5.1 ± 1.6 cGy (1.3%), respectively. The largest maximum dose at the front was 54.2 cGy (14.1%) while it was 20.7 cGy (5.4%) at the back. The average decrease of the maximum dose by the bolus was 24.0 ± 11.0 cGy. Conclusion: Due to magnetic field, dose stream outside the patient body can be generated during breast cancer treatment with the tri-Co-60 MR-IGRT system. Since this dose stream irradiated skin outside the treatment field, it should be shielded. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1C1A1A01054192).« less

Prediction of Normal Organ Absorbed Doses for [177Lu]Lu-PSMA-617 Using [44Sc]Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma.

PubMed

Khawar, Ambreen; Eppard, Elisabeth; Sinnes, Jean Phlippe; Roesch, Frank; Ahmadzadehfar, Hojjat; Kürpig, Stefan; Meisenheimer, Michael; Gaertner, Florian C; Essler, Markus; Bundschuh, Ralph A

2018-04-23

In vivo pharmacokinetic analysis of [Sc]Sc-PSMA-617 was used to determine the normal organ-absorbed doses that may result from therapeutic activity of [Lu]Lu-PSMA-617 and to predict the maximum permissible activity of [Lu]Lu-PSMA-617 for patients with metastatic castration-resistant prostate carcinoma. Pharmacokinetics of [Sc]Sc-PSMA-617 was evaluated in 5 patients with metastatic castration-resistant prostate carcinoma using dynamic PET/CT, followed by 3 static PET/CT acquisitions and blood sample collection over 19.5 hours, as well as urine sample collection at 2 time points. Total activity measured in source organs by PET imaging, as well as counts per milliliter measured in blood and urine samples, was decay corrected back to the time of injection using the half-life of Sc. Afterward, forward decay correction using the half-life of Lu was performed, extrapolating the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617. Source organs residence times and organ-absorbed doses for [Lu]Lu-PSMA-617 were calculated using OLINDA/EXM software. Bone marrow self-dose was determined with indirect blood-based method, and urinary bladder contents residence time was estimated by trapezoidal approximation. The maximum permissible activity of [Lu]Lu-PSMA-617 was calculated for each patient considering external beam radiotherapy toxicity limits for radiation absorbed doses to kidneys, bone marrow, salivary glands, and whole body. The predicted mean organ-absorbed doses were highest in the kidneys (0.44 mSv/MBq), followed by the salivary glands (0.23 mSv/MBq). The maximum permissible activity was highly variable among patients; limited by whole body-absorbed dose (1 patient), marrow-absorbed dose (1 patient), and kidney-absorbed dose (3 patients). [Sc]Sc-PSMA-617 PET/CT imaging is feasible and allows theoretical extrapolation of the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617, with the intent of predicting normal organ-absorbed doses and maximum permissible activity in patients scheduled for therapy with [Lu]Lu-PSMA-617.

Results on Dose Distributions in a Human Body from the Matroshka-R Experiment onboard the ISS Obtained with the Tissue-Equivalent Spherical Phantom

NASA Astrophysics Data System (ADS)

Shurshakov, Vyacheslav; Nikolaev, Igor; Kartsev, Ivan; Tolochek, Raisa; Lyagushin, Vladimir

The tissue-equivalent spherical phantom (32 kg mass, 35 cm diameter and 10 cm central spherical cave) made in Russia has been used on board the ISS in Matroshka-R experiment for more than 10 years. Both passive and active space radiation detectors can be located inside the phantom and on its surface. Due to the specially chosen phantom shape and size, the chord length distributions of the detector locations are attributed to self-shielding properties of the critical organs in a human body. Originally the spherical phantom was installed in the star board crew cabin of the ISS Service Module, then in the Piers-1, MIM-2, and MIM-1 modules of the ISS Russian segment, and finally in JAXA Kibo module. Total duration of the detector exposure is more than 2000 days in 9 sessions of the space experiment. In the first phase of the experiment with the spherical phantom the dose measurements were realized with only passive detectors (thermoluminescent and solid state track detectors). The detectors are placed inside the phantom along the axes of 20 containers and on the phantom outer surface in 32 pockets of the phantom jacket. After each session the passive detectors are returned to the ground. The results obtained show the dose difference on the phantom surface as much as a factor of 2, the highest dose being usually observed close to the outer wall of the compartment, and the lowest dose being in the opposite location along the phantom diameter. However, because of the ISS module shielding properties an inverse dose distribution in a human body can be observed when the dose rate maximum is closer to the geometrical center of the module. Maximum dose rate measured in the phantom is obviously due to the action of two radiation sources, namely, galactic cosmic rays (GCR) and Earth’ radiation belts. Minimum dose rate is produced mainly by the strongly penetrating GCR particles and is mostly observed behind more than 5 g/cm2 tissue shielding. Critical organ doses, mean-tissue and effective doses of a crew member in the ISS compartments are also estimated with the spherical phantom data. The estimated effective dose rate is found to be from 10 % to 15 % lower than the averaged dose on the phantom surface as dependent on the attitude of the critical organs. If compared with the anthropomorphic phantom Rando used inside and outside the ISS earlier, the Matroshka-R space experiment spherical phantom has lower mass, smaller size, and requires less crew time for the detector installation/retrieval; its tissue-equivalent properties are closer to the standard human body tissue than the Rando-phantom material. New sessions with the two tissue-equivalent phantoms are of great interest. Development of modified passive and active detector sets is in progress for the future ISS expeditions. Both the spherical and Rando-type phantoms proved their effectiveness to measure the critical organ doses and effective doses in-flight and if supplied with modernized dosimeters can be recommended for future exploratory manned missions to monitor continuously the crew exposure to space radiation.

Effects of the mosquito larvicide GB-1111 on bird eggs

USGS Publications Warehouse

Hoffman, D.J.; Albers, P.H.; Melancon, M.J.; Miles, A.K.

2004-01-01

Golden Bear Oil (GB-1111; legal trade name for GB-1313) is a petroleum distillate used in the United States and other countries as a mosquito larvicide. As part of an evaluation of the potential effects of GB-1111 on birds, fertile eggs of mallards (Anas platyrhynchos) and bobwhite (Colinus virginianus) were incubated in the laboratory, and treated on day 4 of incubation with external applications equivalent to either 0, 1/3, 1, 3 or 10 times the maximum rate (X) of 47 l/ha (5 gal/A) of field application of GB-1111. Hatching success was significantly reduced in mallards treated at 3 and 10 times the maximum field application, with a calculated approximate LD50 of 1.9 times the maximum field application. Most mortality occurred within a week of treatment. Hepatic P450-associated monooxygenase activity (ethoxyresorufin-O-dealkylase; EROD) was negatively related to dose. In the 3X group there was a significant increase in the concentration of hepatic reduced glutathione (GSH) but a decrease in proteinbound thiols (PBSH). Hatching success of bobwhite was marginally reduced at the highest level of treatment (10X). Other effects at this level in bobwhite included a significant increase in incidence of abnormal embryos or hatchlings, lower body and liver weights, and a twofold increase in hepatic microsomal EROD activity in hatchlings. The recommended maximum rate of field application of GB-1111 is unlikely to impair the survival or development of bobwhite embryos but is potentially toxic to mallard embryos under conditions of larvicide drift or spray overlap.

VMAT testing for an Elekta accelerator

PubMed Central

Sweeney, Larry E.; Marshall, Edward I.; Mahendra, Saikanth

2012-01-01

Volumetric‐modulated arc therapy (VMAT) has been shown to be able to deliver plans equivalent to intensity‐modulated radiation therapy (IMRT) in a fraction of the treatment time. This improvement is important for patient immobilization/ localization compliance due to comfort and treatment duration, as well as patient throughput. Previous authors have suggested commissioning methods for this modality. Here, we extend the methods reported for the Varian RapidArc system (which tested individual system components) to the Elekta linear accelerator, using custom files built using the Elekta iComCAT software. We also extend the method reported for VMAT commissioning of the Elekta accelerator by verifying maximum values of parameters (gantry speed, multileaf collimator (MLC) speed, and backup jaw speed), investigating: 1) beam profiles as a function of dose rate during an arc, 2) over/under dosing due to MLC reversals, and 3) over/under dosing at changing dose rate junctions. Equations for construction of the iComCAT files are given. Results indicate that the beam profile for lower dose rates varies less than 3% from that of the maximum dose rate, with no difference during an arc. The gantry, MLC, and backup jaw maximum speed are internally consistent. The monitor unit chamber is stable over the MUs and gantry movement conditions expected. MLC movement and position during VMAT delivery are within IMRT tolerances. Dose rate, gantry speed, and MLC speed are accurately controlled. Over/under dosing at junctions of MLC reversals or dose rate changes are within clinical acceptability. PACS numbers: 87.55.de, 87.55.Qr, 87.56.bd PMID:22402389

Radiation skyshine from a 6 MeV medical accelerator

PubMed Central

McGinley, Patton H.; Rising, Mary B.; Pahikkala, A. Jussi

2010-01-01

This study assesses the dose level from skyshine produced by a 6 MeV medical accelerator. The analysis of data collected on skyshine yields professional guidance for future investigators as they attempt to quantify and qualify radiation protection concerns in shielding therapy vaults. Survey measurements using various field sizes and at varying distances from a primary barrier have enabled us to identify unique skyshine behavior in comparison to other energies already seen in literature. In order to correctly quantify such measurements outside a shielded barrier, one must take into consideration the fact that a skyshine maximum may not be observed at the same distance for all field sizes. A physical attribute of the skyshine scatter component was shown to increase to a maximum value at 4.6 m from the barrier for the largest field size used. We recommend that the largest field sizes be used in the field for the determination of skyshine effect and that the peak value be further analyzed specifically when considering shielding designs. PACS numbers: 87.52.‐g, 87.52.Df, 87.52.Tr, 87.53.‐j, 87.53.Bn, 87.53.Dq, 87.66.‐a, 89., 89.60.+x

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

PubMed

Chevallier, Patrice; Eugene, Thomas; Robillard, Nelly; Isnard, Françoise; Nicolini, Franck; Escoffre-Barbe, Martine; Huguet, Françoise; Hunault, Mathilde; Marcais, Antoine; Gaschet, Joelle; Cherel, Michel; Guillaume, Thierry; Delaunay, Jacques; Peterlin, Pierre; Eveillard, Marion; Thomas, Xavier; Ifrah, Norbert; Lapusan, Simona; Bodet-Milin, Caroline; Barbet, Jacques; Faivre-Chauvet, Alain; Ferrer, Ludovic; Bene, Marie C; Le Houerou, Claire; Goldenberg, David M; Wegener, William A; Kraeber-Bodéré, Françoise

2015-03-01

Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. Immunomedics and Direction de la Recherche Clinique of Nantes. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Bosarge, Christina L., E-mail: cbosarge@umail.iu.edu; Ewing, Marvene M.; DesRosiers, Colleen M.

To demonstrate the dosimetric advantages and disadvantages of standard anteroposterior-posteroanterior (S-AP/PA{sub AAA}), inverse-planned AP/PA (IP-AP/PA) and volumetry-modulated arc (VMAT) radiotherapies in the treatment of children undergoing whole-lung irradiation. Each technique was evaluated by means of target coverage and normal tissue sparing, including data regarding low doses. A historical approach with and without tissue heterogeneity corrections is also demonstrated. Computed tomography (CT) scans of 10 children scanned from the neck to the reproductive organs were used. For each scan, 6 plans were created: (1) S-AP/PA{sub AAA} using the anisotropic analytical algorithm (AAA), (2) IP-AP/PA, (3) VMAT, (4) S-AP/PA{sub NONE} without heterogeneitymore » corrections, (5) S-AP/PA{sub PB} using the Pencil-Beam algorithm and enforcing monitor units from technique 4, and (6) S-AP/PA{sub AAA[FM]} using AAA and forcing fixed monitor units. The first 3 plans compare modern methods and were evaluated based on target coverage and normal tissue sparing. Body maximum and lower body doses (50% and 30%) were also analyzed. Plans 4 to 6 provide a historic view on the progression of heterogeneity algorithms and elucidate what was actually delivered in the past. Averages of each comparison parameter were calculated for all techniques. The S-AP/PA{sub AAA} technique resulted in superior target coverage but had the highest maximum dose to every normal tissue structure. The IP-AP/PA technique provided the lowest dose to the esophagus, stomach, and lower body doses. VMAT excelled at body maximum dose and maximum doses to the heart, spine, and spleen, but resulted in the highest dose in the 30% body range. It was, however, superior to the S-AP/PA{sub AAA} approach in the 50% range. Each approach has strengths and weaknesses thus associated. Techniques may be selected on a case-by-case basis and by physician preference of target coverage vs normal tissue sparing.« less

YouTube Video Educational Package Increased Acceptance of Antibiotic Clinical Decision Support System Recommendations

PubMed Central

Heng, Shi Thong; Tan, Michelle; Young, Barnaby; Lye, David; Ng, Tat Ming

2017-01-01

Abstract Background Antibiotic clinical decision support systems (CDSS) were implemented to provide stewardship at the point of ordering of broad-spectrum antibiotics (piperacillin-tazobactam and carbapenems). We postulated that a YouTube based educational video package (EP) with quizzes can help to improve CDSS acceptance. Methods A before-after study was conducted in general wards at Tan Tock Seng Hospital from April 2016 to March 2017. Baseline data were collected for 6 months before EP was implemented and during the next 6 months with EP dissemination to all doctors. Acceptance of CDSS recommendations between both phases were compared. Independent factors associated with acceptance of specific CDSS recommendations were identified by logistic regression. Results Patients recruited before and after EP was 1642 and 1313 respectively. Overall CDSS acceptance rate was similar before and after EP. There was improved acceptance for recommendations for dose optimizaton, antibiotic optimization and set duration (Figures 1 and 2). Independent factors of CDSS acceptance for dose optimizaton, antibiotic optimization and set duration are shown in Table 1. EP implementation was independently associated with acceptance of recommendations to set duration and optimize antibiotics. Conclusion EP was independently associated with increased CDSS acceptance on antibiotic duration and antibiotic optimization. Although acceptance of dose optimization was improved, EP was not associated independently with acceptance of the recommendations. Figure 2 Acceptance of CDSS recommendations by classifications of recommendations Table 1 3 multivariate models of acceptance of CDSS recommendations on antibiotic optimization, dose optimization and duration setting Set duration Antibiotic optimization Dose optimization Factor Odds ratio [95% CI] Lung infection 2.71[2.13–3.45] 2.08[1.71–2.52] 2.79[2.19-3.55] Unknown sepsis source 1.73[1.27–2.35] – 1.44[1.05-1.96] Piperacillin-tazobactam use 3.02[2.17–4.19] – – Temperature during initiation of antibiotics 0.86[0.79–0.94] – – The presence of oxygen supplementation during initiation of antibiotics – 0.76[0.64–0.91] 0.76[0.64–0.91] EP implementation 1.38[1.18–1.62] 1.21[1.02–1.43] - Disclosures All authors: No reported disclosures.

Radiation doses for pediatric nuclear medicine studies: comparing the North American consensus guidelines and the pediatric dosage card of the European Association of Nuclear Medicine.

PubMed

Grant, Frederick D; Gelfand, Michael J; Drubach, Laura A; Treves, S Ted; Fahey, Frederic H

2015-04-01

Estimated radiation dose is important for assessing and communicating the risks and benefits of pediatric nuclear medicine studies. Radiation dose depends on the radiopharmaceutical, the administered activity, and patient factors such as age and size. Most radiation dose estimates for pediatric nuclear medicine have not been based on administered activities of radiopharmaceuticals recommended by established practice guidelines. The dosage card of the European Association of Nuclear Medicine (EANM) and the North American consensus guidelines each provide recommendations of administered activities of radiopharmaceuticals in children, but there are substantial differences between these two guidelines. For 12 commonly performed pediatric nuclear medicine studies, two established pediatric radiopharmaceutical administration guidelines were used to calculate updated radiation dose estimates and to compare the radiation exposure resulting from the recommendations of each of the guidelines. Estimated radiation doses were calculated for 12 common procedures in pediatric nuclear medicine using administered activities recommended by the dosage card of the EANM (version 1.5.2008) and the 2010 North American consensus guidelines for radiopharmaceutical administered activities in pediatrics. Based on standard models and nominal age-based weights, radiation dose was estimated for typical patients at ages 1, 5, 10 and 15 years and adult. The resulting effective doses were compared, with differences greater than 20% considered significant. Following either the EANM dosage card or the 2010 North American guidelines, the highest effective doses occur with radiopharmaceuticals labeled with fluorine-18 and iodine-123. In 24% of cases, following the North American consensus guidelines would result in a substantially higher radiation dose. The guidelines of the EANM dosage card would lead to a substantially higher radiation dose in 39% of all cases, and in 62% of cases in which patients were age 5 years or younger. For 12 commonly performed pediatric nuclear medicine studies, updated radiation dose estimates can guide efforts to reduce radiation exposure and provide current information for discussing radiation exposure and risk with referring physicians, patients and families. There can be substantial differences in radiation exposure for the same procedure, depending upon which of these two guidelines is followed. This discordance identifies opportunities for harmonization of the guidelines, which may lead to further reduction in nuclear medicine radiation doses in children.

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

Chengqiang, L; Yin, Y; Chen, L

Purpose: To investigate the impact of MLC position errors on simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with nasopharyngeal carcinoma. Methods: To compare the dosimetric differences between the simulated plans and the clinical plans, ten patients with locally advanced NPC treated with SIB-IMRT were enrolled in this study. All plans were calculated with an inverse planning system (Pinnacle3, Philips Medical System{sub )}. Random errors −2mm to 2mm{sub )},shift errors{sub (} 2mm,1mm and 0.5mm) and systematic extension/ contraction errors (±2mm, ±1mm and ±0.5mm) of the MLC leaf position were introduced respectively into the original plans to create the simulated plans.more » Dosimetry factors were compared between the original and the simulated plans. Results: The dosimetric impact of the random and system shift errors of MLC position was insignificant within 2mm, the maximum changes in D95% of PGTV,PTV1,PTV2 were-0.92±0.51%,1.00±0.24% and 0.62±0.17%, the maximum changes in the D0.1cc of spinal cord and brainstem were 1.90±2.80% and −1.78±1.42%, the maximum changes in the Dmean of parotids were1.36±1.23% and −2.25±2.04%.However,the impact of MLC extension or contraction errors was found significant. For 2mm leaf extension errors, the average changes in D95% of PGTV,PTV1,PTV2 were 4.31±0.67%,4.29±0.65% and 4.79±0.82%, the averaged value of the D0.1cc to spinal cord and brainstem were increased by 7.39±5.25% and 6.32±2.28%,the averaged value of the mean dose to left and right parotid were increased by 12.75±2.02%,13.39±2.17% respectively. Conclusion: The dosimetric effect was insignificant for random MLC leaf position errors up to 2mm. There was a high sensitivity to dose distribution for MLC extension or contraction errors.We should pay attention to the anatomic changes in target organs and anatomical structures during the course,individual radiotherapy was recommended to ensure adaptive doses.« less