Maximum Total Dose Research Articles

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Use of RESRAD-Onsite 7.2 Code to Assess Environmental Risk around Tudor Shaft Mine Tailing Sites

The RESRAD-onsite 7.2 code has been used to assess the total dose rate in Tudor shaft site contaminated over an area of 10 km2. The risk analysis simulation was span over a period of 1.0E+3 years. The maximum total dose of 1.64 mSv/yr was obtain at t = 8.17 ± 0.02 years. The total peak dose at time t = 0 yr. is 1.63 ± 1.0 mSv/yr for all pathways. This value is 6.53 times higher compare to the basic radiation dose limit of 2.5E-01 mSv/yr. The evaluated excess cancer risk was 3.46E-3 and is 10 times higher compared to the recommended limit of WHO. A cover layer depth of 1.25 m was simulated using the code and a total maximum peak dose for all pathways was 2.52E-01 mSv/yr at t = 5.0E+2 ± 1.0 years.

OA090] A Study on the consistency of treatment planning and delivery for endometrial cancer treatments with multi-lumen cylinders for high dose rate brachytherapy

Purpose To develop a method to evaluate the cumulative dose when using Multi Lumen Cylinder (MLC) applicator in vaginal cuff brachytherapy. Methods A retrospective analysis of 25 patients treated in 2017 with the MLC applicator 3 cm diameter, were considered for this study. All patients received 5 fractions with 5 Gy each delivered twice a week and prescribed to the applicator’s surface for2/3 of the vaginal length. The CT scans of these patients, taken for treatment plan were separately imported into the treatment planning system and paired with the initial CT scan after completing the contouring. Two sets of CT images were fused at a time together with respective to the applicator, using mutual registration. Dosimetric evaluations were performed. The maximum doses received by the rectum wall, bladder wall, bowels and PTV on were analyzed and traced over the five fractions to determine the total dose distribution over the entire prescribed treatment. Results No contour of any of the OAR was exactly similar when the CT images were fused each other. Depending on the depth of the insertion the PTV varied minimal. Each plan was performed independently and cumulated 2 at a time until all 5 fractions were added to the initial fraction. There is a difference between the doses received by the OARs between treatments and between the points of maximum dose. The maximum dose varied between 15% and 25% in rectum wall and bladder neck. The minimum dose varied between 3% and 6% in rectum wall and bladder neck. The average dose varied between 10% and 22% in rectum and bladder. The cumulative treatment does do not indicate a total maximum dose exceeding the tolerances for the rectum and bladder. Conclusion The variations in volumes of the PTVs and isodoses are minor, indicating that the desired area receives the entire prescribed treatment. Rectum wall will not exceed 85% of the prescribed cumulative dose and the bladder neck will not exceed 75% of the prescribed dose.

Quality improvement initiative to reduce adverse effects associated with parenteral nutrition overfeeding

ObjectiveParenteral nutrition (PN) overfeeding is a potential risk factor in the development of infections and other complications including hyperglycaemia, refeeding syndrome and liver dysfunction. This study was conducted to evaluate...

Effect of gaseous chlorine dioxide (ClO2 ) with different concentrations and numbers of treatments on controlling berry decay and rachis browning of table grape

Chlorine dioxide (ClO2) gas was used to control berry decay and rachis browning of table grape due to its antimicrobial and anti-browning properties. It was proposed that if ClO2 gas is fully absorbed by the fruit, the maximum total ClO2 dose can be calculated based on the maximum allowable residual concentration. To avoid possible bleaching effects on grape peel from high concentrations of ClO2, the total amount of ClO2 gas needs to be injected into the packages in many small doses at specific time intervals over the course of the 90-day storage period. Spoilage microorganism counts, decay rate, electrolyte leakage, rachis browning and residual ClO2 in berry were investigated. The results showed that ClO2 treatment could significantly reduce berry decay and rachis browning (p ≤ .05) compared to the control. Grape treated with 1.0 mg L−1 ClO2 6 times at 15-day intervals maintained better fruit quality without any risks from the residual ClO2. Practical applications The present research found that ClO2 treatment is useful for improving the microbial safety of grapes and reducing berry decay and rachis browning during storage, and low doses of ClO2 spread over many treatment can yield better results.

Predictive factors of acute skin reactions to carbon ion radiotherapy for the treatment of malignant bone and soft tissue tumors

BackgroundThe skin is considered a critical organ at risk in carbon ion radiotherapy (CIRT) for locally advanced malignant bone and soft tissue tumors (MBSTs). The predictive factors for acute skin reactions after CIRT have not been investigated. The present study aimed to identify these factors and evaluate the correlation between the severity of acute skin reactions and skin dose parameters.MethodsCIRT with total doses of 64.0–70.4 Gy (relative biological effectiveness [RBE]) was administered to 22 patients with MBSTs. The skin-tumor distance (STD), maximum skin total dose (Dmax), and area of the skin receiving a total dose of X Gy (RBE) were evaluated.ResultsAll patients developed acute skin reactions after CIRT, including Grades 1 and 2 dermatitis in 15 (71%) and 6 (29%) patients, respectively. There was a significant difference in the STD between the two groups (P = 0.007), and the cut-off value of STD for predicting Grade 2 acute skin reactions was 11 mm. There was a significant difference in Dmax between the groups (P < 0.001), and the cut-off value of Dmax for predicting Grade 2 acute skin reactions was 52 Gy (RBE). Significant differences between the two groups were observed in terms of the area irradiated with 40 Gy (RBE) (S40), and the cut-off value of S40 for predicting Grade 2 acute skin reactions was 25 cm2.ConclusionsIn acute skin reactions after CIRT for MBSTs, STD, Dmax, and S40 were found to be significant predictive factors for acute skin reactions.

PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group

The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

National Survey of Japan for Myeloablative Total Body Irradiation Prior to Hematopoietic Stem Cell Transplantation

In hematopoietic stem cell transplantation, survival rate of total body irradiation (TBI) containing myeloablative regimens tended to be superior, compared with other regimens without TBI. So TBI is increasingly being used, but the method varies among institutions. The last national survey of TBI in Japan was performed in 2002 and there are no recent data on TBI in Japan. In this time, the Japanese Radiation Oncology Study Group (JROSG) designed and performed the national survey of myeloablative TBI by questionnaire. The survey was performed in October 2015 and patients treated between January 2010 and December 2014 were reviewed. The questionnaire included questions regarding disease variation and TBI method. All 186 Japanese institutes in which TBI was done in 2015 in Japanese Radiation Oncology Database were approached. Ninety institutes (90/186; 48 %) replied and 82 institutes performed myeloablative TBI in this period. There were 2699 patients with malignant disease, the leukemia; 2082 patients (77 %), malignant lymphoma; 378 patients (14 %). There were 37 patients with nonmalignant disease, severe aplastic anemia; 20 patients (54 %), inborn errors of metabolism; 5 patients (14 %). Timing of TBI was after conditioning chemotherapy in 38 institutes (46 %), before conditioning chemotherapy in 19 institutes (23 %), not decided in 18 institutes (22 %). All institutes used linear accelerator. The radiation technique of long SSD was used in 72 institutes (87.8 %), moving couch in 7 institutes (8.5 %). The beam energy was 10MV in 54 institutes (66 %), 6 MV in 20 institutes (24 %). The most frequent total dose/fractions/days was 12 Gy/6 fr/3 days in 50 institutes (61 %), 12/4/4 in 11 institutes (13 %), 12/4/2 in 9 institutes (11 %), 10/4/2 in 3 institutes (4 %). The dose rate varied among the institutes, 10-26 cGy/min in 44 institutes (53.7 %), 5-9.88 cGy/min in 33 institutes (40.2 %) and 50-250 cGy/min in 5 institutes (6.1 %). Patient positions during TBI was supine position in 65 institutes (79.3 %), supine and prone position in 7 institutes (8.5 %). The beam arangement was Right-Left in 60 institutes (73.1 %), Anterior-Posterior in 13 institutes (15.9 %). Organs routinely shielded during TBI was lungs and lenses in 47 institutes (57.3 %), only lungs in 21 institutes (25.6 %), only lenses in 5 institutes (6.1 %) and no shielding in 8 institutes (9.8 %). In lung shielding institutes, the maximum acceptable total dose for lungs varied largely among the institutes and raged from 0 Gy to 12 Gy and most frequent dose was 8 Gy (19 institutes; 27.5 %). The results of the current survey indicate that TBI method varies strongly among institutes even in Japan. Because it is difficult to design multicenter randomized trials on TBI method, this survey results have been helpful to standardize the methods of TBI and conduct of multicenter clinical trials containing TBI.

Efficacy and Safety of Ibuprofen in Infants Aged Between 3 and 6 Months.

Ibuprofen is a non-steroidal anti-inflammatory drug frequently administered to children of various ages for relief of fever and pain and is approved as an over-the-counter medication in many countries worldwide. Although there are extensive data on its efficacy and safety in children and adults, there are divergent dosing recommendations for analgesia and treatment of fever in infants, especially in the age group between 3 and 6months of age. In this article, we have assessed the safety and efficacy of ibuprofen use in infants in an attempt to find the optimal method of pain and fever management in this specific age group. Based on the current evidence, short-term use of ibuprofen is considered safe in infants older than 3months of age having a body weight above 5-6kg when special attention is given to the hydration of the patient. Ibuprofen should be prescribed based on body weight using a dose of 5-10mg/kg. This dose can be administered 3-4 times a day resulting in a maximum total daily dose of 30-40mg/kg. The rectal route has been shown to be less reliable because of erratic absorption, especially in young infants. Since most efficacy and safety data have been derived from trials in infants with fever, future studies should focus on the efficacy of ibuprofen in young infants with pain.

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

Development of Late Toxicities in Patients with Oral Tongue Cancer Treated with Surgical Resection and Adjuvant Radiation Therapy.

The late effects of RT are not well reported in patients with oral tongue cancer (OTC). This study reports the incidence of late effects and factors associated with the development of late effects in OTC patients. Patients with OTC treated in our institution from 2003 to 2013 were evaluated. The association between RT doses, including mandible maximum and minimum doses and total 3D maximum dose, and late toxicity, defined as development of osteoradionecrosis (ORN), percutaneous endoscopic gastrostomy (PEG) tube dependence for >6 months after treatment, and narcotic dependency >6 months posttreatment were assessed using both univariate and multivariable (MV) analysis. Seventy-six patients with OTC (45% males and 55% females) were treated with definitive surgical resection followed by adjuvant RT. The median follow-up was 4.3 years. Combined late toxicities were reported in 38% of patients. Thirty-four percent of the patients had narcotic dependency and, 3.9% of the patients had ORN of the mandible. Thirteen percent of patients developed PEG tube dependency that was significantly associated with a higher 3D maximum radiation dose on univariate analysis (p < 0.01). On MV analysis, 3D maximum dose remained significantly associated with long-term PEG tube dependency (p = 0.05). Patients with OTC treated with adjuvant RT are at significant risk for development of late toxicities. Increasing maximum dose is associated with long-term PEG tube dependence, and care should be taken to reduce the "hot spot" within radiation treatment plans as much as possible.

Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies.

Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3days during 31days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group (P=0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37μmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350mg/kg) demonstrated significant effect (inhibiting growth by 80% and by 53% in comparison with vehicle and chemotherapy group alone, respectively (P<0.001). Alofanib decreased number of vessels in tumor (-49%; P<0.0001) and number of Ki-67-positive SKOV3 cells (-42%, P<0.05). There were tumor necrosis and cell degeneration in alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies.

OnabotulinumtoxinA Injection for Poststroke Upper-Limb Spasticity: Guidance for Early Injectors From a Delphi Panel Process

BackgroundOnabotulinumtoxinA reduces muscle hypertonia associated with poststroke spasticity (PSS). PSS manifests as several common postures. ObjectiveTo define treatment paradigms for PSS upper-limb common postures. DesignModified Delphi method. SettingExpert panel. ParticipantsTen injectors experienced in the treatment and clinical research of PSS (physiatrists and neurologists) were invited to participate in the Delphi panel. MethodsThe Delphi panel reviewed an electronic worksheet with PSS upper-limb postures to define onabotulinumtoxinA treatment paradigms (Round 1). During Round 2, panel members discussed in person Round 1 results and voted until consensus (≥66% agreement). Recommendations were geared toward those with new or early injection experience. Main Outcome MeasurementsExpert consensus on onabotulinumtoxinA treatment parameters for PSS including muscles to inject, dose per muscle and posture, and treatment adjustments for suboptimal response. ResultsFor each posture, consensus was reached on targeted subsets of muscles. Doses ranged for individual muscles (10-100 U) and total doses per posture (50-200 U). An onabotulinumtoxinA dilution 50 U/mL (2:1 dilution ratio) was considered most appropriate; dilution ratios of 1:1 to 4:1 may be appropriate in some circumstances. The majority (89%) of panel members would increase the dose and/or the number of muscles treated for a suboptimal response to onabotulinumtoxinA. The panel identified 3 common aggregate upper-limb postures: (1) adducted shoulder + flexed elbow + pronated forearm + flexed wrist + clenched fist; (2) flexed elbow + pronated forearm + flexed wrist + clenched fist; and (3) flexed wrist + clenched fist. The recommended starting dose per aggregate was 300 U, 300 U, and 200 U, with a total maximum dose of 400 U, 400 U, and 300 U, respectively. Localization guidance techniques were considered essential for all postures. ConclusionsConsensus on common muscles and onabotulinumtoxinA treatment paradigms for postures associated with upper-limb PSS was achieved via a modified Delphi method. The purpose of this analysis is to educate early onabotulinumtoxinA injectors rather than provide an evidence-based review. Level of EvidenceV

Modelling of Radiological Health Risks from Gold Mine Tailings in Wonderfonteinspruit Catchment Area, South Africa.

Mining is one of the major causes of elevation of naturally-occurring radionuclide material (NORM) concentrations on the Earth’s surface. The aim of this study was to evaluate the human risk associated with exposure to NORMs in soils from mine tailings around a gold mine. A broad-energy germanium detector was used to measure activity concentrations of these NORMs in 66 soil samples (56 from five mine tailings and 10 from the control area). The RESidual RADioactivity (RESRAD) OFFSITE modeling program (version 3.1) was then used to estimate the radiation doses and the cancer morbidity risk of uranium-238 (238U), thorium-232 (232Th), and potassium-40 (40K) for a hypothetical resident scenario. According to RESRAD prediction, the maximum total effective dose equivalent (TEDE) during 100 years was found to be 0.0315 mSv/year at year 30, while the maximum total excess cancer morbidity risk for all the pathways was 3.04 × 10−5 at year 15. The US Environmental Protection Agency considers acceptable for regulatory purposes a cancer risk in the range of 10−6 to 10−4. Therefore, results obtained from RESRAD OFFSITE code has shown that the health risk from gold mine tailings is within acceptable levels according to international standards.

238U and 232Th concentrations measured in different medical drugs by using solid-state nuclear track detectors and resulting radiation doses to the skin of patients

Urban populations in Morocco receive free medical drugs as prescribed by doctors in district health centres. To explore the exposure pathway of 238U and 232Th and their decay products on the skin of patients, these radionuclides were measured in various medical drugs by using solid-state nuclear track detectors (SSNTDs).The measured concentrations range of 238U and 232Th in the medical drug samples of interest vary from (4.3 ± 0.3) to (11.1 ± 0.7) mBq l−1 and (0.49 ± 0.03) to (1.3 ± 0.1) mBq l−1, respectively. A new dosimetric model, based on the concept of specific alpha-dose and alpha-particle residual energy, was developed for evaluating radiation doses to skin following the application of different medical drugs by patients. The maximum total equivalent effective dose to skin due to the 238U and 232Th series from cutaneous application of different medical drugs by patients was found to be 2.8 mSv year−1 cm−2.

Randomized trial of standard pain control with or without gabapentin for pain related to radiation-induced mucositis in head and neck cancer.

Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable. This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted.

A multi-institutional phase II study of high-dose hypofractionated proton beam therapy (HF-PBT) for unresectable primary liver cancers: Long-term outcomes in patients (pts) with hepatocellular carcinoma (HCC).

376 Background: Retrospective reports of PBT in hepatocellular carcinoma (HCC) demonstrate local control (LC) rates exceeding 85%. We prospectively replicate these findings and explore predictors of overall survival (OS) in pts with unresectable HCC receiving high dose, HF-PBT. Methods: Pts were enrolled on an NCI sponsored, multi-institutional, phase II study (NCT00976898). Key eligibility were unresectable HCC; Child’s A/B; ECOG PS 0-2; no extrahepatic disease; no prior RT. Maximum tumor size was 12 cm if solitary, 10 cm if 2 tumors, and 6 cm if 3. PBT was given in 15 fractions to a maximum total dose of 67.5 GyE. Sample size was calculated to demonstrate &gt; 80% LC at 2 yrs (LC-2). Results: From 2009-2015, 44 patients were treated. Median age was 70 years (53-89) and 37 (84.1%) were male. 35 (79.5%) pts had Child A or no cirrhosis. 32 (72.7%) pts had 1 tumor, 12 (27.2%) had multiple tumors. Median longest tumor dimension was 5.0 cm (range 1.9-12.0). Median baseline AFP was 18.6 ng/mL (range 1.3-66081) and 29 pts (67.4%) had elevated AFP ( &gt; 7.9 ng/mL). Median RT dose delivered was 58.0 GyE (range 40.5-67.5). 1 pt (2%) had grade 3 RT related toxicity (thrombocytopenia). With a median follow up 21.8 mo among 28 survivors, the LC-2 was 94.8% (95% CI 84.5-99.1%). mOS was 49.9 mo (95% CI 17.8 months- upper limit not reached) and mPFS was 13.9 mo (95% CI 8.4-49.9). OS did not differ by CLIP score, PS, prior treatment, vascular thrombus, baseline AFP, size, or dose. Median AFP change from baseline to 3 mo post treatment was a 32.8% reduction. Median time to AFP nadir in pts with elevated baseline levels was 3.9 mo (0-30.5). % decrease in AFP from baseline to 6 mo post-treatment was significantly associated with lower hazard of death. (HR = 0.993, p = 0.016). Conclusions: High dose hypofractionated proton beam therapy demonstrated a high local control rate for HCC with favorable safety profiles, supporting the ongoing evaluation of radiation in HCC in phase III studies. AFP decrease from baseline to 6 months post-radiation is associated with improved overall survival. Clinical trial information: NCT00976898.

A Large Retrospective Cohort of Patients Receiving Intravenous Olanzapine in the Emergency Department.

Olanzapine is an atypical antipsychotic with similar pharmacologic properties to droperidol. Due to the current droperidol shortage, the authors' clinical practice has been to substitute olanzapine for droperidol in many situations. At this time, olanzapine is U.S. Food and Drug Administration approved for oral and intramuscular (IM) use only, but due to its increased utility, intravenous (IV) olanzapine was recently approved for use in the study emergency department (ED). The authors sought to review the use and safety of IV olanzapine in the ED patient population. A retrospective review of consecutive patients receiving IV olanzapine between January 1, 2014, and July 1, 2014, was conducted. Data were collected via an electronic medical record review. The study was deemed exempt from informed consent by our institutional review board. A total of 713 patients received IV olanzapine during the study period. The median age was 38 years (range= 18 to 85 years), and 313 patients were male (43.9%). Primary indications for IV olanzapine administration included acute agitation (n=245, 34.4%), abdominal pain (n=165, 23.1%), headache (n=121, 17.0%), nausea and vomiting (n=107, 15.0%), pain (other; n=60, 8.4%), and unknown (n=15, 2.1%). IV dosing varied: 1.25 mg (n=20, 2.8%), 2.5 mg (n=185, 25.9%), 5 mg (n=507, 71.1%), and 10 mg (n=1, 0.1%). Forty-nine patients required a second dose of olanzapine (22 IV, 26 IM, one oral). The maximum total dose of olanzapine was 20 mg. Ninety-eight patients required a total of 146 doses of additional sedatives during their ED course. Other sedative medications included ketamine (n=17, 2.4%), haloperidol (n=48, 6.7%), and benzodiazepines (n=81, 11.4%). Hypoxia was noted in 74 patients (10.4%). Major respiratory complications, including airway stimulation or repositioning maneuvers and intubation, occurred in 15 patients (2.1%). After consensus review, one intubation was classified as "likely related" to olanzapine administration, and two were classified as "possibly related" to olanzapine. Akathisia likely occurred in four patients (0.6%), and no allergic reactions were identified. Electrocardiograms (ECGs) were performed in 322 patients. A total of 251 patients had an ECG performed before olanzapine administration (median QTc= 404 ms), and 88 patients had an ECG performed after olanzapine administration (median QTc= 415 ms). Acute alcohol and drug intoxication was common, 118 (16.5%) patients were positive for ethanol, and seven of 23 drug screens were positive for sympathomimetics. Thirty-four of 284 admissions (4.5%) were to intermediate or intensive care unit beds. No patients died while in the ED and no cases of sudden cardiac death were noted. In this large retrospective review, IV olanzapine appears to be a safe in the management of a variety of ED indications. Hypoxia was common, but serious airway compromise was rare.

Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.

Effects of very high radiation on SiPMs

During the last 5 years we have successfully completed R&D for the instrumentation of silicon photo multipliers (SiPMs) for the CMS HCAL Phase 1 upgrade in 2018. Much focus was put on radiation damage during these years. For the HCAL we expect a maximum total dose of 1012n/cm2 for a total lifetime integrated luminosity of 3000fb−1. Good correlation between cell size and performance with high radiation was found during this R&D. To evaluate the possibility of using the SiPMs in the wider CMS environment we have exposed the current state of the art smallest cell SiPMs to radiation of 6×1012p/cm2 in 62MeV LIF beam line in 2014 at UCL Belgium and up to 1.3×1014p/cm2 in the CERN PS 23GeV proton beam in late 2014. The SiPM׳s main parameters were measured before and after irradiation. Here we report on the effects of noise increase and breakdown voltage shift due to the extremely high dose.