PSMA PET/CT to evaluate response to SBRT for prostate cancer bone metastases.

BACKGROUND: In the current study we evaluated 68Ga PSMA PET/ CT to measure local control of bone metastasis in oligometastatic prostate cancer patients treated with SBRT. MATERIALS AND METHODS: After the institutional review board approval, a retrospective review of medical records of consecutive prostate cancer patients treated between 2014 and 2018 was conducted. Only medical records of patients that were treated with SBRT for bone metastasis and had pre-and post-SBRT 68Ga PSMA PET/CT scans were included in our study. Data extracted from the medical files included patient-related (age), disease-related (Gleason score, site of metastasis), and treatment-related factors and outcomes. RESULTS: During the study period, a total of 12 patients (15 lesions) were included, with a median age of 73 years. The median follow-up was 26.5 months (range 13-45 months). Median time of 68Ga PSMA PET/ CT follow up was 17.0 months (range 3-39 months). The median pre-treatment PSA was 2 ng/mL (range 0.56-44 ng/mL) vs. post treatment PSA nadir of 0.01 ng/mL (0.01-4.32) with a median time to nadir of 7 months (range, 2-12). Local control was 93% during the follow up period and there was correlation with PS MA avidity on PE T. None patients developed recurrences in the treated bone. None of the patients had grade 3 or more toxicities during follow-up. CONCLUSIONS: SBRT is a highly effective and safe method for treatment of prostate cancer bone metastases. More studies are required to determine if SBRT provides greater clinical benefit than standard fractionation for oligometastatic prostate cancer patients. 68Ga PSMA PET/CT should be further investigated for delineation and follow-up.

Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions.

OBJECTIVES: To assess if improvement of working conditions related to heat stress was associated with improved kidney health outcomes among sugarcane harvest workers in Chichigalpa, Nicaragua, a region heavily affected by the epidemic of chronic kidney disease of non-traditional origin. METHODS: Based on our findings during the 2017-2018 harvest (harvest 1), recommendations that enhanced the rest schedule and improved access to hydration and shade were given before the 2018-2019 harvest (harvest 2). Actual work conditions during harvest 2 were then observed. Serum creatinine (SCr) was measured before and at end-harvest, and cross-harvest changes in estimated glomerular filtration rate (eGFR) and incident kidney injury (IKI, ie, SCr increase by ≥0.30 mg/dL or ≥1.5 times the baseline value) were compared between harvest 1 and harvest 2 for three jobs with different physical workloads using regression modelling. Workers who left during harvest were contacted at home, to address the healthy worker selection effect. RESULTS: In burned cane cutters, mean cross-harvest eGFR decreased 6 mL/min/1.73 m2 (95% CI 2 to 9 mL/min/1.73 m2) less and IKI was 70% (95% CI 90% to 50%) lower in harvest 2 as compared with harvest 1 data. No such improvements were seen among seed cutters groups with less successful intervention implementation. CONCLUSION: Kidney injury risk was again elevated in workers with strenuous jobs. The results support further efforts to prevent kidney injury among sugarcane workers, and other heat-stressed workers, by improving access to water, rest and shade. The distinction between design and implementation of such interventions should be recognised.

Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress.

The death toll of the epidemic of chronic kidney disease of nontraditional origin (CKDnt) in Mesoamerica runs into the tens of thousands, affecting mostly young men. There is no consensus on the etiology. Anecdotal evidence from the 1990s pointed to work in sugarcane; pesticides and heat stress were suspected. Subsequent population-based surveys supported an occupational origin with overall high male-female ratios in high-risk lowlands, but small sex differences within occupational categories, and low prevalence in non-workers. CKDnt was reported in sugarcane and other high-intensity agriculture, and in non-agricultural occupations with heavy manual labor in hot environments, but not among subsistence farmers. Recent studies with stronger designs have shown cross-shift changes in kidney function and hydration biomarkers and cross-harvest kidney function declines related to heat and workload. The implementation of a water-rest-shade intervention midharvest in El Salvador appeared to halt declining kidney function among cane cutters. In Nicaragua a water-rest-shade program appeared sufficient to prevent kidney damage among cane workers with low-moderate workload but not among cutters with heaviest workload. Studies on pesticides and infectious risk factors have been largely negative. Non-occupational risk factors do not explain the observed epidemiologic patterns. In conclusion, work is the main driver of the CKDnt epidemic in Mesoamerica, with occupational heat stress being the single uniting factor shown to lead to kidney dysfunction in affected populations. Sugarcane cutters with extreme heat stress could be viewed as a sentinel occupational population. Occupational heat stress prevention is critical, even more so in view of climate change.

La mortalidad por la epidemia de enfermedad renal crónica de origen no tradicional (ERCnt) en Mesoamérica asciende a decenas de miles de personas, principalmente hombres jóvenes. No existe consenso sobre su etiología. En la década de 1990, informes anecdóticos apuntaban como factor de riesgo al trabajo en plantaciones de caña de azúcar; se consideró como posibles causantes a los plaguicidas y el estrés térmico. Estudios de prevalencia de base poblacional subsiguientes apoyaron un origen ocupacional, con una proporción elevada de hombres respecto de las mujeres en las tierras bajas donde el riesgo era elevado, pero con pequeñas diferencias de sexo dentro de las categorías ocupacionales y baja prevalencia en el ámbito no laboral. Se reportó ERCnt en los trabajadores de la caña de azúcar y otros cultivos con alta exigencia física y en ocupaciones no agrícolas que implican trabajo manual intenso en ambientes calurosos, pero no entre los agricultores de subsistencia. Estudios recientes con diseños más sólidos han demostrado cambios en la función renal y en los biomarcadores de hidratación en el curso de los turnos laborales, y disminución de la función renal relacionada con el calor y la carga de trabajo en el curso de la cosecha. La implementación de una intervención basada en la provisión de agua, descanso y sombra a mitad de la cosecha en El Salvador detuvo la disminución de la función renal en los cortadores de caña. En Nicaragua, un programa de provisión de agua, descanso y sombra evitó la lesión renal en los trabajadores de la caña con una carga de trabajo baja y moderada, pero no entre los cortadores, quienes tienen la mayor carga de trabajo. Los estudios sobre plaguicidas y factores de riesgo infecciosos han sido en gran medida negativos. Los factores de riesgo no ocupacionales no explican los patrones epidemiológicos observados. En conclusión, el trabajo es el principal desencadenante de la epidemia de ERCnt en Mesoamérica, y el estrés térmico ocupacional es el único factor que consistentemente conduce a la disfunción renal en las poblaciones afectadas. Los cortadores que trabajan en los ingenios azucareros y están expuestos a un estrés térmico extremo podrían ser considerados una población ocupacional centinela. La prevención del estrés térmico ocupacional es crítica, más aún si se consideran los efectos del cambio climático.

A mortalidade devida à epidemia de doença renal crônica de origem não tradicional (DRCnt) na Mesoamérica atinge dezenas de milhares de pessoas, principalmente homens jovens. Não há consenso sobre a sua etiologia. Na década de 1990, informações empíricas apontavam o trabalho em plantações de cana de açúcar como um fator de risco; pesticidas e estresse térmico também eram considerados causas possíveis. As pesquisas populacionais subsequentes sustentam uma origem ocupacional da doença, com uma elevada proporção de homens quando comparados à de mulheres, em areas de baixa altitude, onde o risco da doença é mais elevado, mas com pequenas diferenças de gênero quando se consideram as categorias ocupacionais e baixa prevalência no ambiente não-ocupacional. A DRCnt foi identificada em trabalhadores agrícolas da cana de açúcar e de outras culturas que exigem trabalho físico de alta intensidade e em ocupações não agrícolas envolvendo um trabalho manual intenso em ambientes quentes, mas não entre os agricultores de subsistência. Estudos recentes com desenhos mais robustos demonstraram mudanças na função renal e nos biomarcadores de hidratação ao longo dos turnos de trabalho, e diminuição da função renal relacionada à exposição ao calor e à carga de trabalho ao longo da colheita. A implementação de uma intervenção de água-descanso-sombra durante a colheita em El Salvador interrompeu o declínio da função renal em cortadores de cana. Na Nicarágua, intervenções água-descanso-sombra parecem ter sido suficientes para evitar lesões renais em trabalhadores canavieiros com cargas de trabalho baixa e moderada, mas não entre os cortadores de cana que têm carga de trabalho mais pesada. Estudos sobre exposição a pesticidas e a fatores de risco de origem infecciosa têm sido largamente negativos. Os fatores de risco não-ocupacionais não explicam os padrões epidemiológicos observados. Em conclusão, ocupação é o principal desencadeador da epidemia de DRCnt na Mesoamérica, e o estresse térmico ocupacional é o único fator comprovado que leva à disfunção renal nas populações afetadas. Os cortadores de cana que trabalham em engenhos de açúcar e expostos a um estresse térmico extremo podem ser considerados uma população ocupacional sentinela. A prevenção do estresse térmico ocupacional é crítica, especialmente considerando os efeitos das mudanças climáticas.

Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort.

OBJECTIVES: To examine the association between workload and kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest, and to assess whether the existing heat prevention efforts at a leading occupational safety and health programme are sufficient to mitigate kidney injury. METHODS: Biological and questionnaire data were collected before (n=545) and at the end (n=427) of harvest among field support staff (low workload), drip irrigation workers (moderate), seed cutters (high) and burned sugarcane cutters (very high). Dropouts were contacted (87%) and reported the reason for leaving work. Cross-harvest incident kidney injury (IKI) was defined as serum creatinine increase ≥0.30 mg/dL or ≥1.5 times the baseline value, or among dropouts reporting kidney injury leading to leaving work. RESULTS: Mean cross-harvest estimated glomerular filtration rate change was significantly associated with workload, increasing from 0 mL/min/1.73 m2 in the low-moderate category to -5 mL/min/1.73 m2 in the high and -9 mL/min/1.73 m2 in the very high workload group. A similar pattern occurred with IKI, where low-moderate workload had 2% compared with 27% in the very high workload category. A healthy worker selection effect was detected, with 32% of dropouts reporting kidney injury. Fever and C reactive protein elevation were associated with kidney injury. CONCLUSIONS: Workers considered to have the highest workload had more cross-harvest kidney damage than workers with less workload. Work practices preventing heat stress should be strengthened and their role in preventing kidney damage examined further. Future occupational studies on chronic kidney disease of unknown aetiology should account for a healthy worker effect by pursuing those lost to follow-up.

Kidney Injury from Recurrent Heat Stress and Rhabdomyolysis: Protective Role of Allopurinol and Sodium Bicarbonate.

BACKGROUND: Heat stress and rhabdomyolysis are major risk factors for the occurrence of repeated acute kidney injury in workers exposed to heat and strenuous work. These episodes, in turn, may progress to chronic kidney disease. OBJECTIVE: The purpose of this study was to test the effect of allopurinol (AP) and sodium bicarbonate on the kidney injury induced by recurrent heat stress dehydration with concomitant repeated episodes of rhabdomyolysis. METHODS: The model consisted of heat stress exposure (1 h, 37°C) plus rhabdomyolysis (R) induced by repetitive IM injections of glycerol (7.5 mL/kg BW days) in the rat. In addition, to replicate the human situation, uricase was inhibited (oxonic acid [OA] 750 mg/K/d) to increase uric acid (UA) levels. Additional groups were treated either with AP 150 mg/L, n = 10, bicarbonate (BC; 160 mM, n = 10), or both (AP + BC, n = 10) in drinking water. We also included 2 control groups consisting of normal controls (N-Ref, n = 5) and uricase-inhibited rats (OA, n = 5) that were not exposed to heat or muscle injury. Groups were studied for 35 days. RESULTS: Uricase-inhibited rats exposed to heat and rhabdomyolysis developed pathway and increased intrarenal oxidative stress and inflammasome activation. Kidney injury could be largely prevented by AP, and also BC, although the treatments were not synergistic. CONCLUSION: Increased levels of UA may play an important role in the renal alterations induced by heat stress and continuous episodes of rhabdomyolysis. Therefore, treatments aimed to reduce hyperuricemia may help to decrease the renal burden in these conditions. Clinical trials are suggested to test whether this is also true in humans.

Salvage Radiation Therapy for Biochemical Failure Following Radical Prostatectomy.

BACKGROUND: Radiotherapy to the prostate bed is used to eradicate residual microscopic disease following radical prostatectomy for prostate cancer. Recommendations are based on historical series. OBJECTIVES: To determine outcomes and toxicity of contemporary salvage radiation therapy (SRT) to the prostate bed. METHODS: We reviewed a prospective ethics committee-approved database of 229 patients referred for SRT. Median pre-radiation prostate-specific antigen (PSA) was 0.5 ng/ml and median follow-up was 50.4 months (range 13.7-128). Treatment was planned and delivered using modern three-dimensional radiation techniques. Mean bioequivalent dose was 71 Gy (range 64-83 Gy). Progression was defined as two consecutive increases in PSA level > 0.2 ng/ml, metastases on follow-up imaging, commencement of anti-androgen treatment for any reason, or death from prostate cancer. Kaplan-Meier survival estimates and multivariate analysis was performed using STATA. RESULTS: Five year progression-free survival was 68% (95%CI 59.8-74.8%), and stratified by PSA was 87%, 70% and 47% for PSA < 0.3, 0.3-0.7, and > 0.7 ng/ml (P < 0.001). Metastasis-free survival was 92.5%, prostate cancer-specific survival 96.4%, and overall survival 94.9%. Low pre-radiation PSA value was the most important predictor of progression-free survival (HR 2.76, P < 0.001). Daily image guidance was associated with reduced risk of gastrointestinal and genitourinary toxicity (P < 0.005). CONCLUSIONS: Contemporary SRT is associated with favorable outcomes. Early initiation of SRT at PSA < 0.3 ng/ml improves progression-free survival. Daily image guidance with online correction is associated with a decreased incidence of late toxicity.

Stereotactic Ablative Body Radiation for Stage I Lung Cancer in Israel: A Retrospective Single-Center Report.

BACKGROUND: Stereotactic ablative radiation therapy (SABR) is the application of a very high radiation dose to a small treatment volume. It is the new standard of care in medically inoperable early-stage lung cancer. OBJECTIVES: To report the outcomes of SABR in stage I lung cancer at Sheba Medical Center since its introduction in 2009. METHODS: We conducted a retrospective chart review of patients with stage I lung cancer treated during the period 2009-2015. Survival status was retrieved from the electronic medical records and confirmed with the national registry. Local failure was defined as increased FDG uptake on PETCT scan within a 2 cm radius of the treated region. Toxicity was estimated from medical records and graded according to common toxicity criteria for adverse events (CTCAE) version 4.03. Overall survival and local control were estimated by the Kaplan-Meier method. RESULTS: During the study period 114 patients were treated for 122 stage I lung cancer lesions. Median follow-up time was 27 months (range 8.2-69.5 months), median age was 76 years. Eighty-two percent of the tumors were stage IA (size ≤ 3 cm). Median survival was 46 months; estimated 3 year overall survival was 59% (95%CI 47-69%) and local control was 88% (95%CI 78-94%). Toxicity included chest wall pain in 8.4% of patients, rib fracture in 0.9%, grade 1-2 pneumonitis in 12%, grade 3 in 12% and grade 5 (death) in 0.9%. CONCLUSIONS: SABR has been successfully implemented at Sheba Medical Center for the treatment of stage I lung cancer in inoperable patients. It is associated with excellent local control, minor toxicity and an acceptable overall survival.

Neo-adjuvant Chemo-Radiation to 60 Gray Followed by Surgery for Locally Advanced Non-Small Cell Lung Cancer Patients: Evaluation of Trimodality Strategy.

BACKGROUND: Neoadjuvant chemo-radiation therapy (CRT) dosages in locally advanced non-small cell lung cancer (NSCLC) were traditionally limited to 45 Gray (Gy). OBJECTIVES: To retrospectively analyze outcomes of patients treated with 60 Gy CRT followed by surgery. METHODS: A retrospective chart review identified patients selected for CRT to 60 Gy followed by surgery between August 2012 and April 2016. Selection for surgery was based on the extent of disease, cardiopulmonary function, and response to treatment. Pathological response after neoadjuvant CRT was scored using the modified tumor regression grading. Local control (LC), disease free survival (DFS), and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: Our cohort included 52 patients: 75% (39/52) were stage IIIA. A radiation dose of 60 Gy (range 50-62Gy) was delivered in 82.7%. Surgeries performed included: lobectomy, chest-wall resection, and pneumonectomy in 67.3%, 13.4%, and 19.2%, respectively. At median follow-up of 22.4 months, the 3 year OS was 74% (95% confidence interval [CI] 52-87%), LC was 84% (95%CI 65-93), and DFS 35% (95%CI 14-59). Grade 4-5 postoperative complications were observed in 17.3% of cases and included chest wall necrosis (5.7%), bronco-pleural fistula (7.7%), and death (3.8%). A major pathologic regression with < 10% residual tumor occurred in 68.7% of patients (36/52) and showed a trend to improved OS (P = 0.1). Pneumonectomy cases had statistically worse OS (P = 0.01). CONCLUSIONS: Major pathologic regression was observed 68.7% with 60 Gy neoadjuvant CRT with a trend to improved survival. Pneumonectomy correlated with worse survival.

Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy.

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

Kidney function in sugarcane cutters in Nicaragua--A longitudinal study of workers at risk of Mesoamerican nephropathy.

BACKGROUND: Chronic kidney disease is common among sugarcane workers in Central America. The main risk factor seems to be repeated high-intensity work in hot environments. Several cross-sectional studies have been performed but few longitudinal studies. OBJECTIVES: The aim of the study was to examine whether kidney function changes over a few months of work during the harvest period. METHODS: A group of male sugarcane cutters in Nicaragua (N=29, aged 17-38 years) was examined with renal biomarkers before and after shift on the first day at the start of harvest, on the sixth day during acclimatization, and then in mid-harvest 9 weeks later. A reference group (N=25, mainly office workers) was examined with the same biomarkers at start of harvest, and then at end of harvest 5 months later. RESULTS: The pre-shift renal function decreased significantly during 9 weeks of work in the cane cutters. Mean serum creatinine increased (20%), mean estimated glomerular filtration rate decreased (9%, 10mL/min), serum urea N (BUN) increased (41%), and mean urinary neutrophil gelatinase-associated lipocalin (NGAL) increased (four times). The cane cutters also developed cross-shift increases in these biomarkers, in particular serum creatinine and BUN, and in urinary uric acid. The longitudinal decrease in eGFR tended to be associated with the cross-shift increase in serum creatinine. CONCLUSIONS: There was a remarkable decrease of glomerular kidney function, after only 9 weeks of harvest. The cross-shift increase in serum creatinine may be caused by dehydration (pre-renal dysfunction), and when repeated on a daily basis this may cause permanently reduced GFR.

Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--A cross-shift study of workers at risk of Mesoamerican nephropathy.

BACKGROUND: An epidemic of progressive kidney failure afflicts sugarcane workers in Central America. Repeated high-intensity work in hot environments is a possible cause. OBJECTIVES: To assess heat stress, dehydration, biomarkers of renal function and their possible associations. A secondary aim was to evaluate the prevalence of pre-shift renal damage and possible causal factors. METHODS: Sugarcane cutters (N=189, aged 18-49 years, 168 of them male) from three regions in El Salvador were examined before and after shift. Cross-shift changes in markers of dehydration and renal function were examined and associations with temperature, work time, region, and fluid intake were assessed. Pre-shift glomerular filtration rate was estimated (eGFR) from serum creatinine. RESULTS: The mean work-time was 4 (1.4-11) hours. Mean workday temperature was 34-36 °C before noon, and 39-42 °C at noon. The mean liquid intake during work was 0.8L per hour. There were statistically significant changes across shift. The mean urine specific gravity, urine osmolality and creatinine increased, and urinary pH decreased. Serum creatinine, uric acid and urea nitrogen increased, while chloride and potassium decreased. Pre-shift serum uric acid levels were remarkably high and pre-shift eGFR was reduced (<60 mL/min) in 23 male workers (14%). CONCLUSIONS: The high prevalence of reduced eGFR, and the cross-shift changes are consistent with recurrent dehydration from strenuous work in a hot and humid environment as an important causal factor. The pathophysiology may include decreased renal blood flow, high demands on tubular reabsorption, and increased levels of uric acid.

Total dose, fraction dose and respiratory motion management impact adrenal SBRT outcome.

Purpose/Objectives: Stereotactic body radiotherapy (SBRT) is an effective treatment for oligometastatic disease in multiple sites. However, the optimal radiation dose for long-term local control of adrenal metastases has yet to be determined. The aim of this study is to evaluate outcomes of adrenal SBRT and to evaluate factors that correlate with local control. Materials/Methods: After IRB approval, a retrospective data review of patients treated with SBRT for adrenal metastases at a medical center in Israel between 2015 and 2021 was conducted. A biological effective dose was calculated using an alpha beta ratio of 10. Kaplan Meier and Cox regression were calculated using SPSS software to describe the hazard ratio for local control and survival. Results: 83 cases of adrenal SBRT were identified. The average age was 67 (range 42-92 years old). Non-small cell lung cancer was the primary site in 44 % of patients. A total of 70 % of the patients had oligometastatic disease (less than five lesions), and the rest were polymetastatic, responding to systemic therapy with oligo progression in the adrenal. The average gross tumor volume (GTV) was 42 ml. Respiratory control was applied in 88 % of cases; 49.3 % used 4-D/ITV, and 38.5 % used breath-hold or continuous positive airway pressure (CPAP) with free breathing. On multivariable analysis, Dose above 75 Gy (biological effective Dose) (HR = 0.41, p = 0.031), Dose above 8 Gy per fraction (HR = 0.53p = 0.038), and breath-holds or CPAP (HR = 0.65, p = 0.047) were significant for local control. From multivariable analysis, we computed a predicted nomogram curve using seven clinical parameters to evaluate local control odds. Conclusion: In this single institution series reported to date, we found unilateral adrenal SBRT safe, yet bilateral treatment harbors a risk of adrenal insufficiency. Biological effective Dose > 75 Gy (BED), motion management with breath-hold or CPAP, and Dose per fraction > 8 Gy were the enhanced local controls. We propose a nomogram to help in decision-making regarding total Dose and Dose per fraction when treating adrenal SBRT.

Deep inspiratory breath hold assisted by continuous positive airway pressure ventilation for lung stereotactic body radiotherapy.

PURPOSE: Continuous positive airway pressure (CPAP) ventilation hyperinflates the lungs and reduces diaphragmatic motion. We hypothesized that CPAP could be safely combined with deep inspiratory breath hold (CPAP-DIBH) during lung stereotactic radiotherapy (SBRT). MATERIAL AND METHODS: Patients with stage-1 lung cancer or lung metastasis treated with CPAP-DIBH SBRT between 3/2017-5/2021 were analyzed retrospectively. Patient characteristics, treatment parameters, duration of breath holds in all sessions and tolerance to CPAP-DIBH were recorded. Local control (LC) was assessed from CT or PET-CT imaging. The distances between the tumor and mediastinal organs at risk (OAR) in centrally located tumors using either free breathing (FB) or CPAP-DIBH were compared. Toxicity was graded retrospectively. RESULTS: Forty-five patients with 71 lesions were treated with CPAP-DIBH SBRT. Indications for CPAP-DIBH were prior radiation (35/71, 65%), lower lobe location (34/71, 48%), multiple lesions (26/71, 36.6%) and proximity to mediastinal OAR (7/71, 10%). Patient characteristics were: F:M 43%: 57%; mean gross tumor volume 4.5cm3 (SD 7.9), mean planning target volume 20cm3 (SD 27), primary: metastatic lesions (7%:93%). Mean radiation dose was 52.5 Gray (SD3.5). Mean lung volume was 5292cm3 (SD 1106). Mean duration of CPAP-DIBH was 41.3s (IQR 31-46.8). LC at 2 years was 89.5% (95% CI 76-95.5). In patients with central lesions, the distance between the tumor and mediastinal OAR increased from 0.84cm (SD 0.65) with FB to 1.23cm (SD 0.8) with CPAP-DIBH (p=0.002). Most patients tolerated CPAP well and completed all treatments after starting therapy. Three patients did not receive treatment: 2 were unable to tolerate CPAP and 1 had syncope (pre-existing). Toxicity was grade 2 in 4/65 (6%) and grade 3 in 1/65 (1.5%). There was no grade 2 or higher esophageal or tracheal toxicities. CONCLUSION: CPAP-DIBH assisted lung SBRT was tolerated well and was associated with minimal toxicity and favorable LC. This technique may be considered when treating multiple lung lesions, lesions located in the lower lobes or adjacent to mediastinal OAR.

Targeting workload to ameliorate risk of heat stress in industrial sugarcane workers.

OBJECTIVE: The aim of this study was to quantify the physiological workload of manual laborers in industrial sugarcane and assess the effect of receiving a rest, shade, and hydration intervention to reduce heat stress exposure risk. METHODS: In an observational study, physiological workload was evaluated for burned cane cutters (BCC), seed cutters (SC) and drip irrigation repair workers (DIRW) using heart rate (HR) recorded continuously (Polar®) across a work shift. Workers' percentage of maximal HR (%HRmax), time spent in different HR zones, and estimated core temperature (ECTemp) were calculated. The effect of increasing rest across two harvests was evaluated for BCC and SC. RESULTS: A total of 162 workers participated in this study [52 BCC (all male), 71 SC (13 female) and 39 DIRW (16 female)]. Average %HRmax across a work shift was similar between BCC and SC (BCC: 58%, SC: 59%), but lower in DIRW (51%). BCC and SC spent similar proportions of work shifts at hard/very hard intensities (BCC: 13%, SC: 15%), versus DIRW who worked mostly at light (46%) or light-moderate (39%) intensities. SC maximum ECTemp reached 38.2°C, BCC 38.1°C; while DIRW only reached 37.7°C. Females performed at a higher %HRmax than males across work shifts (SC 64% versus 58%; DIRW 55% versus 49%). An additional rest period was associated with a lower average %HRmax across a work shift in BCC. CONCLUSION: In this setting, BCC and SC both undertake very physiologically demanding work. Females maintained a higher workload than male co-workers. Regulated rest periods each hour, with water and shade access, appears to reduce physiological workload/strain.

Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Hyaluronan synthase and hyaluronidase expression in serous ovarian carcinoma is related to anatomic site and chemotherapy exposure.

The present study investigated the expression and clinical role of hyaluronan synthases (HAS1-3) and hyaluronidases (Hyal1-3) in serous ovarian carcinoma. HAS and HYAL mRNA expression was analyzed in 97 tumors (61 effusions, 27 primary carcinomas, 9 solid metastases) using PCR and further studied for association with clinicopathologic parameters, including survival. HAS1 mRNA was overexpressed in effusions compared to primary carcinomas and solid metastases (p < 0.001), and an alternatively spliced HAS1 was expressed only in effusions. HAS2 mRNA was overexpressed in solid metastases and primary carcinomas compared to effusions (p = 0.043), and HAS3 mRNA was overexpressed in primary carcinomas and effusions compared to solid metastases (p = 0.008). HYAL1 mRNA was absent in all specimens, whereas HYAL2 was expressed as two splice variants, of which HYAL2-var2 was overexpressed in solid metastases compared to effusions and primary carcinomas (p < 0.001). HYAL3 mRNA was expressed as wild-type and variant 1-3 form, the latter more highly in primary carcinomas and effusions compared to solid metastases (p = 0.006). HAS1 mRNA was overexpressed in pre- compared to post-chemotherapy effusions (p < 0.001), with opposite finding for HYAL2-var1 and HYAL3-WT (p = 0.016 and p = 0.024, respectively). Higher HYAL2-var1 and HAS1 splice variant mRNA expression in effusions was associated with longer (p = 0.033) and shorter (p = 0.047) overall survival, respectively. These data are the first to document a role for HAS and Hyal members in tumor progression in ovarian carcinoma, as evidenced by their differential expression as function of anatomic site and chemotherapy exposure, with a possible prognostic role for patients with malignant effusions.

Workplace Intervention for Heat Stress: Essential Elements of Design, Implementation, and Assessment.

Heat stress is associated with numerous health effects that potentially harm workers, especially in a warming world. This investigation occurred in a setting where laborers are confronted with occupational heat stress from physically demanding work in high environmental temperatures. Collaboration with a major Nicaraguan sugarcane producer offered the opportunity to study interventions to prevent occupational heat-stress-related kidney disease. Two aims for this study of a rest-shade-water intervention program were: (1) describe the evolving intervention, summarize findings that motivated proposed improvements, assess impact of those improvements, and identify challenges to successful implementation and (2) extract primary lessons learned about intervention research that have both general relevance to investigations of work-related disease prevention and specific relevance to this setting. The learning curve for the various stakeholders as well as the barriers to success demonstrate that effectiveness of an intervention cannot be adequately assessed without considerations of implementation. Designing, effectively implementing, and assessing both health impacts and implementation quality is a resource-intensive endeavor requiring a transdisciplinary approach. Both general and specific lessons learned are presented for decisions on study design and study elements, implementation assessment, and management engagement in understanding how productivity and health can be successfully balanced and for building effective communication between investigators and all levels of management.

Laboratory experiments reveal intrinsic self-sustained oscillations in ocean relevant rotating fluid flows.

Several ocean Western Boundary Currents (WBCs) encounter a lateral gap along their path. Examples are the Kuroshio Current penetrating into the South China Sea through the Luzon Strait and the Gulf of Mexico Loop Current leaping from the Yucatan peninsula to Florida as part of the Gulf Stream system. Here, we present results on WBC relevant flows, generated in the world's largest rotating platform, where the Earth's sphericity necessary to support WBCs is realized by an equivalent topographic effect. The fluid is put in motion by a pump system, which produces a current that is stationary far from the gap. When the jet reaches the gap entrance, time-dependent patterns with complex spatial structures appear, with the jet leaking, leaping or looping through the gap. The occurrence of these intrinsic self-sustained periodic or aperiodic oscillations depending on current intensity is well known in nonlinear dynamical systems theory and occurs in many real systems. It has been observed here for the first time in real rotating fluid flows and is thought to be highly relevant to explain low-frequency variability in ocean WBCs.

The Prevention of Occupational Heat Stress in Sugarcane Workers in Nicaragua-An Interpretative Phenomenological Analysis.

Background: Chronic kidney disease of non-traditional origin (CKDnt) is an ongoing epidemic that has taken the lives of tens of thousands of people in Mesoamerica, also affecting other tropical geographies. Occupational heat stress, which will increase worldwide as climate change persists, has been identified as a primary trigger of kidney injury and reduced renal function. At Nicaragua's largest sugarcane mill, the water, rest, and shade (WRS) intervention has proven to reduce the risk of heat stress and kidney injury effectively as assessed by the research and policy NGO La Isla Network (LIN) and their academic partners, who have worked with the sugar mill to improve the design of their intervention system. However, discrepancies between intervention design and implementation have been found. This study explores the perceptions of the WRS intervention in the company from the perspective of positions responsible for the workers' environment and heat stress prevention implementation. Methods: A qualitative design was used in the study. Twenty-one key informants of low and middle management, field assistants, and two members from LIN took part in the study. Semi-structured interviews were used to collect the data. Interviews' transcriptions were analyzed using interpretative phenomenological analysis (IPA). Results: Four main themes were developed in the analysis of the data: "A worthwhile struggle," "Culture of care", "Traditional production culture Vs. Culture of care," and "The importance of the formalization of care." Each theme contained sub-themes, all of which were further discussed in the light of organizational psychology. Conclusion and Implications: Discretionary differences resulting in low and middle management prioritizing production over health protection appeared to relate to a fair part of the implementation challenges and indicate that more efforts are needed to align operations' production and health goals. Education enhancement might be necessary, while further focus on health metrics for performance assessment might offer an opportunity to level perceived incentives and value of health and production.

Salvage re-irradiation using stereotactic body radiation therapy for locally recurrent prostate cancer: the impact of castration sensitivity on treatment outcomes.

BACKGROUND: Advances in imaging, biomaterials and precision radiotherapy provide new opportunities to salvage locally recurrent prostate cancer (PC). This study evaluates the efficacy and safety of re-irradiation using stereotactic body radiation therapy (SBRT). We hypothesized that patients with castrate-resistant PC (CRPC) would benefit less from local salvage. METHODS: A prospective clinical database was reviewed to extract 30 consecutive patients treated with prostate re-irradiation. Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography was performed following prostate-specific antigen failure in all patients and biopsy was obtained in 18 patients (60%). Re-irradiation was either focal (n = 13) or whole-gland (n = 17). Endo-rectal balloons were used in twenty-two patients and hydrogel spacers in eight patients. The median prescription dose was 5 fractions of 6.5 (range: 6-8) Gray (Gy). RESULTS: Median follow-up was 28 months. Failure occurred in 10 (out of 11) CRPC patients versus 6 (out of 19) castrate-sensitive patients (91% vs. 32%, p = 0.008) after a median of 13 and 23 months, respectively. Metastases occurred in 64% (n = 7) of CRPC patients versus 16% (n = 3) of castrate-sensitive patients (p = 0.007). Two patients experienced local in-field recurrence, thus local control was 93%. The 2 and 3-year recurrence-free survival were 84% and 79% for castrate-sensitive patients versus 18% and 9% for CRPC patients (p < 0.001), and 3-year metastasis-free survival was 90% versus 27% (p < 0.01) for castrate-sensitive and CRPC patients, respectively. Acute grade II and III genitourinary (GU) toxicity occurred in 27% and 3%, and late GU toxicity in 30% and 3%, respectively. No ≥ grade II acute gastrointestinal (GI) toxicity occurred, and only one patient (3%) developed late grade II toxicity. CONCLUSIONS: Early delivery of salvage SBRT for local recurrence is associated with excellent 3-year disease control and acceptable toxicity in the castrate-sensitive phenotype. PSMA imaging for detection of local recurrence and the use of precision radiotherapy with rectal protective devices should be further investigated as a novel salvage strategy for radio-recurrent PC.