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Social determinants of health (SDoH) play a critical role in patient outcomes, yet their documentation is often missing or incomplete in the structured data of electronic health records (EHRs). Large language models (LLMs) could enable high-throughput extraction of SDoH from the EHR to support research and clinical care. However, class imbalance and data limitations present challenges for this sparsely documented yet critical information. Here, we investigated the optimal methods for using LLMs to extract six SDoH categories from narrative text in the EHR: employment, housing, transportation, parental status, relationship, and social support. The best-performing models were fine-tuned Flan-T5 XL for any SDoH mentions (macro-F1 0.71), and Flan-T5 XXL for adverse SDoH mentions (macro-F1 0.70). Adding LLM-generated synthetic data to training varied across models and architecture, but improved the performance of smaller Flan-T5 models (delta F1 + 0.12 to +0.23). Our best-fine-tuned models outperformed zero- and few-shot performance of ChatGPT-family models in the zero- and few-shot setting, except GPT4 with 10-shot prompting for adverse SDoH. Fine-tuned models were less likely than ChatGPT to change their prediction when race/ethnicity and gender descriptors were added to the text, suggesting less algorithmic bias (p < 0.05). Our models identified 93.8% of patients with adverse SDoH, while ICD-10 codes captured 2.0%. These results demonstrate the potential of LLMs in improving real-world evidence on SDoH and assisting in identifying patients who could benefit from resource support. [ABSTRACT FROM AUTHOR]

Lean muscle mass (LMM) is an important aspect of human health. Temporalis muscle thickness is a promising LMM marker but has had limited utility due to its unknown normal growth trajectory and reference ranges and lack of standardized measurement. Here, we develop an automated deep learning pipeline to accurately measure temporalis muscle thickness (iTMT) from routine brain magnetic resonance imaging (MRI). We apply iTMT to 23,876 MRIs of healthy subjects, ages 4 through 35, and generate sex-specific iTMT normal growth charts with percentiles. We find that iTMT was associated with specific physiologic traits, including caloric intake, physical activity, sex hormone levels, and presence of malignancy. We validate iTMT across multiple demographic groups and in children with brain tumors and demonstrate feasibility for individualized longitudinal monitoring. The iTMT pipeline provides unprecedented insights into temporalis muscle growth during human development and enables the use of LMM tracking to inform clinical decision-making. Temporalis muscle thickness is a promising marker of lean muscle mass but has had limited utility due to its unknown normal growth trajectory and lack of standardized measurement. Here, the authors develop an automated deep learning pipeline to accurately measure temporalis muscle thickness from routine brain magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Background Falls in patients with cancer harbor potential for serious sequelae. Patients with brain metastases (BrM) may be especially susceptible to falls but supporting investigations are lacking. We assessed the frequency, etiologies, risk factors, and sequelae of falls in patients with BrM using 2 data sources. Methods We identified 42 648 and 111 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana-Farber Cancer Institute (BWH/DFCI) institutional data (2015), respectively, and characterized falls in these populations. Results Among SEER-Medicare patients, 10 267 (24.1%) experienced a fall that prompted medical evaluation, with cumulative incidences at 3, 6, and 12 months of 18.0%, 24.3%, and 34.1%, respectively. On multivariable Fine/Gray's regression, older age (≥81 or 76-80 vs 66-70 years, hazard ratio [HR] 1.18 [95% CI, 1.11-1.25], P <.001 and HR 1.10 [95% CI, 1.04-1.17], P <.001, respectively), Charlson comorbidity score of >2 vs 0-2 (HR 1.08 [95% CI, 1.03-1.13], P =.002) and urban residence (HR 1.08 [95% CI, 1.01-1.16], P =.03) were associated with falls. Married status (HR 0.94 [95% CI, 0.90-0.98], P =.004) and Asian vs white race (HR 0.90 [95% CI, 0.81-0.99], P =.03) were associated with reduced fall risk. Identified falls were more common among BWH/DFCI patients (N = 56, 50.4% of cohort), resulting in emergency department visits, hospitalizations, fractures, and intracranial hemorrhage in 33%, 23%, 11%, and 4% of patients, respectively. Conclusions Falls are common among patients with BrM, especially older/sicker patients, and can have deleterious consequences. Risk-reduction measures, such as home safety checks, physical therapy, and medication optimization, should be considered in this population. [ABSTRACT FROM AUTHOR]

Background Older patients with brain metastases (BrM) commonly experience symptoms that prompt acute medical evaluation. We characterized emergency department (ED) visits and inpatient hospitalizations in this population. Methods We identified 17 789 and 361 Medicare enrollees diagnosed with BrM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2010-2016) and an institutional database (2007-2016), respectively. Predictors of ED visits and hospitalizations were assessed using Poisson regression. Results The institutional cohort averaged 3.3 ED visits/1.9 hospitalizations per person-year, with intracranial disease being the most common reason for presentation/admission. SEER-Medicare patients averaged 2.8 ED visits/2.0 hospitalizations per person-year. For patients with synchronous BrM (N = 7834), adjusted risk factors for ED utilization and hospitalization, respectively, included: male sex (rate ratio [RR] = 1.15 [95% CI = 1.09-1.22], P <.001; RR = 1.21 [95% CI = 1.13-1.29], P <.001); African American vs white race (RR = 1.30 [95% CI = 1.18-1.42], P <.001; RR = 1.25 [95% CI = 1.13-1.39], P <.001); unmarried status (RR = 1.07 [95% CI = 1.01-1.14], P =.02; RR = 1.09 [95% CI = 1.02-1.17], P =.01); Charlson comorbidity score >2 (RR = 1.27 [95% CI = 1.17-1.37], P <.001; RR = 1.36 [95% CI = 1.24-1.49], P <.001); and receipt of non-stereotactic vs stereotactic radiation (RR = 1.44 [95% CI = 1.34-1.55, P <.001; RR = 1.49 [95% CI = 1.37-1.62, P <.001). For patients with metachronous BrM (N = 9955), ED visits and hospitalizations were more common after vs before BrM diagnosis (2.6 vs 1.2 ED visits per person-year; 1.8 vs 0.9 hospitalizations per person-year, respectively; RR = 2.24 [95% CI = 2.15-2.33], P <.001; RR = 2.06 [95% CI = 1.98-2.15], P <.001, respectively). Conclusions Older patients with BrM commonly receive hospital-level care secondary to intracranial disease, especially in select subpopulations. Enhanced care coordination, closer outpatient follow-up, and patient navigator programs seem warranted for this population. [ABSTRACT FROM AUTHOR]

Background: To retrospectively assess liver tumor ablation margins using intraprocedural PET/CT images from FDG PET/CT-guided microwave or cryoablation procedures and to correlate minimum margin measurements with local progression outcomes. Methods: Fifty-six patients (ages 36 to 85, median 62; 32 females) with 77 FDG-avid liver tumors underwent 60 FDG PET/CT guided, percutaneous microwave, or cryoablation procedures. Single breath-hold PET/CT images were used for intraprocedural assessment of the tumor ablation margin: liver tumors remained visible on PET immediately following ablation; microwave ablation zones were visible using contrast-enhanced CT; cryoablation zones (ice balls) were visible using unenhanced CT. Two readers retrospectively determined ablation margin assessability and measured the minimum ablation margin on intraprocedural PET/CT (n = 77) and postprocedural MRI (n = 56). Local tumor progression was assessed on all available follow-up imaging (1–49 months, mean 15). Local tumor progression was correlated with PET/CT minimum margin measurements using clustered survival models for 61 tumors. Results: Minimum ablation margins were more often assessable using intraprocedural PET/CT (≥ 73/77 tumors, 95%) than postprocedural MRI (≤ 35/56 tumors, 63%). In 61 tumors with PET/CT-assessable margins (excluding tumors with overlapping ablations after PET/CT), there was a 6-fold increased risk of local tumor progression [hazard ratio (HR) 6.05; P = 0.004] for minimum ablation margins < 5 mm. Conclusion: Breath-hold PET/CT scans, during PET/CT-guided microwave or cryoablation procedures for FDG-avid liver tumors, enable reliable intraprocedural assessment of the entire tumor ablation margin; a minimum PET/CT ablation margin threshold of 5 mm correlates well with local tumor progression outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate 18F-fluorodeoxyglucose (FDG) perfusion PET during FDG PET/CT-guided liver tumor microwave ablation procedures for assessing the ablation margin and correlating minimum margin measurements with local progression. Methods: This IRB-approved, HIPAA-compliant study included 20 adult patients (11 M, 9 F; mean age 65) undergoing FDG PET/CT-guided liver microwave ablation to treat 31 FDG-avid tumors. Intraprocedural FDG perfusion PET was performed to assess the ablation margin. Intraprocedural decisions regarding overlapping ablations were recorded. Two readers retrospectively interpreted intraprocedural perfusion PET and postprocedural contrast-enhanced MRI. Assessability of the ablation margin and minimum margin measurements were recorded. Imaging follow-up for local progression ranged from 30 to 574 days (mean 310). Regression modeling of minimum margin measurements was performed. Hazard ratios were calculated to correlate an ablation margin threshold of 5 mm with outcomes. Results: Intraprocedural perfusion PET prompted additional overlapping ablations of two tumors, neither of which progressed. Incomplete ablation or local progression occurred in 8/31 (26%) tumors. With repeat ablation, secondary efficacy was 26 (84%) of 31. Both study readers deemed ablation margins fully assessable more often using perfusion PET than MRI (OR 69.7; CI 6.0, 806.6; p = 0.001). Minimum ablation margins ≥ 5 mm on perfusion PET correlated with a low risk of incomplete ablation/local progression by both study readers (HR 0.08 and 0.02, p < 0.001). Conclusion: Intraprocedural FDG perfusion PET consistently enabled complete liver tumor microwave ablation margin assessments, and the perfusion PET minimum ablation margin measurements correlated well with local outcomes. Clinical trial registration clinicaltrials.gov (NCT02018107). [ABSTRACT FROM AUTHOR]

Background: Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. Methods: A total of 199 patients with melanoma and non–small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per‐metastasis basis, using a sandwich estimator to account for intrapatient correlation. Results: The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P <.001), with correspondingly lower rates of progressive disease (5% vs 26%; P <.001). On multivariable analysis, concurrent treatment was found to be associated with improved time to response (hazard ratio, 1.76; 95% CI, 1.18‐2.63 [P =.006]) and decreased local recurrence (hazard ratio, 0.42; 95% CI, 0.23‐0.78 [P =.006]). This effect appeared to be greater for melanoma than for non–small cell lung cancer, although interaction tests were not statistically significant. Only 1 of 103 metastases which had a complete response later developed disease progression. Conclusions: Concurrent RT and ICT may improve response rates and decrease local recurrence of brain metastases compared with treatment that was nonconcurrent but delivered within 90 days. Further study of this combination in prospective, randomized trials is warranted. There is significant interest in potential synergy between radiotherapy and immune checkpoint therapy, but the optimal timing of each therapy remains unclear. The current study examines a cohort of patients with melanoma and non–small cell lung cancer with brain metastases who were managed with immune checkpoint therapy and brain‐directed radiotherapy within a 90‐day period. Compared with nonconcurrent therapy, concurrent therapy is associated with an improved brain metastasis response rate and decreased local recurrence. [ABSTRACT FROM AUTHOR]

Background: Brain metastases are associated with considerable morbidity and mortality. Integration of hospice at the end of life offers patients symptom relief and improves quality of life, particularly for elderly patients who are less able to tolerate brain-directed therapy. Population-level investigations of hospice utilization among elderly patients with brain metastases are limited.Methods: Using the Surveillance, Epidemiology and End Results-Medicare database for primary cancer sites that commonly metastasize to the brain, we identified 50 148 patients (aged 66 years and older) diagnosed with brain metastases between 2005 and 2016. We calculated the incidence, timing, and predictors of hospice enrollment using descriptive techniques and multivariable logistic regression. All statistical tests were 2-sided.Results: The incidence of hospice enrollment was 71.4% (95% confidence interval [CI] = 71.0 to 71.9; P < .001), a rate that increased over the study period (P < .001). The odds of enrollment for black (odds ratio [OR] = 0.76, 95% CI = 0.71 to 0.82; P < .001), Hispanic (OR = 0.80, 95% CI = 0.72 to 0.87; P < .001), and Asian patients (OR = 0.52, 95% CI = 0.48 to 0.57; P < .001) were substantially lower than white patients; men were less likely to be enrolled in hospice than women (OR = 0.78, 95% CI = 0.74 to 0.81; P < .001). Among patients enrolled in hospice, 32.6% (95% CI = 32.1 to 33.1; P < .001) were enrolled less than 7 days prior to death, a rate that was stable over the study period.Conclusions: Hospice is used for a majority of elderly patients with brain metastases although a considerable percentage of patients die without hospice services. Many patients enroll in hospice late and, concerningly, statistically significant sociodemographic disparities exist in hospice utilization. Further investigations to facilitate targeted interventions addressing such disparities are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Whole brain radiation therapy (WBRT) remains an important component of treatment for patients with multiple brain metastases (BrM) but is associated with significant neurotoxicity and memory impairment. Although RTOG 0614 demonstrated that administration of memantine to patients receiving WBRT may reduce radiation-associated cognitive decline, prior literature has suggested that radiation oncologists are hesitant to prescribe memantine. We sought to assess the frequency of memantine prescription in patients managed with non-stereotactic, brain-directed radiation for BrM. Methods: Patients > 65 years old with newly diagnosed BrM between 2007 and 2016 receiving non-stereotactic, brain-directed radiation (including WBRT) were identified using the SEER–Medicare database. Receipt of memantine with non-stereotactic, brain-directed radiation was defined as any Part D claim for memantine 30 days before or after initiation of non-stereotactic, brain-directed radiation. Clinical and demographic variables among patients who did and did not receive memantine were compared. Results: Between 2007 and 2016, we identified 6220 patients with BrM receiving non-stereotactic, brain-directed radiation. Only 2.20% of patients (n = 137) received memantine with radiation. Rates were 1.10% versus 5.14% in the period preceding (2007–2013) and following (2014–2016) the publication of RTOG 0614, respectively. Overall utilization of memantine remained low across several clinical, demographic, and prognostic variables. Conclusion: Despite phase 3 evidence supporting memantine utilization among patients receiving WBRT, our population-based study indicates that rates of memantine prescription are strikingly low, although memantine utilization seems to be increasing since publication of RTOG 0614. Further investigation is needed to identify provider and practice-related barriers preventing incorporation of memantine into management paradigms. [ABSTRACT FROM AUTHOR]

Objectives. To examine the impact of extreme heat on emergency services in Boston, MA. Methods. We conducted relative risk and time series analyses of 911 dispatches of the Boston Police Department (BPD), Boston Emergency Medical Services (BEMS), and Boston Fire Department (BFD) from November 2010 to April 2014 to assess the impact of extreme heat on emergency services. Results. During the warm season, there were 2% (95% confidence interval [CI] = 0%, 5%) more BPD dispatches, 9% (95% CI = 7%, 12%) more BEMS dispatches, and 10% (95% CI = 5%, 15%) more BFD dispatches on days when the maximum temperature was 90°F or higher, which remained consistent when we considered multiple days of heat. A 10°F increase in daily maximum temperature, from 80° to 90°F, resulted in 1.016, 1.017, and 1.002 times the expected number of daily BPD, BEMS, and BFD dispatch calls, on average, after adjustment for other predictors. Conclusions. The burden of extreme heat on local emergency medical and police services may be agency-wide, and impacts on fire departments have not been previously documented. Public Health Implications. It is important to account for the societal burden of extreme heat impacts to most effectively inform climate change adaptation strategies and planning. [ABSTRACT FROM AUTHOR]

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field. [ABSTRACT FROM AUTHOR]

Biophilia hypothesis suggests humans have an innate connection to nature which may affect our health and productivity. Yet we currently live in a world that is rapidly urbanizing with people spending most of their time indoors. We designed a randomized crossover study to let 30 participants experience three versions of biophilic design in simulated open and enclosed office spaces in virtual reality (VR). Throughout the VR session, we measured blood pressure, heart rate, heart rate variability, and skin conductance level and administered cognitive tests to measure their reaction time and creativity. Compared to the base case, participants in three spaces with biophilic elements had consistently lower level of physiological stress indicators and higher creativity scores. In addition, we captured the variation in the intensity of virtual exposure to biophilic elements by using eye‐tracking technology. These results suggest that biophilic interventions could help reduce stress and improve creativity. Moreover, those effects are related to both the types of biophilic elements and may be different based on the workspace type (open vs enclosed). This research demonstrates that VR‐simulated office spaces are useful in differentiating responses to two configurations and among biophilic elements. [ABSTRACT FROM AUTHOR]

Purpose: Brain metastases from breast cancer are frequently managed with brain-directed radiation but the impact of subtype on intracranial recurrence patterns after radiation has not been well-described. We investigated intracranial recurrence patterns of brain metastases from breast cancer after brain-directed radiation to facilitate subtype-specific management paradigms. Methods: We retrospectively analyzed 349 patients with newly diagnosed brain metastases from breast cancer treated with brain-directed radiation at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Patients were stratified by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), HER2+ positive (HER2+), or triple-negative breast cancer (TNBC). A per-metastasis assessment was conducted. Time-to-event analyses were conducted using multivariable Cox regression. Results: Of the 349 patients, 116 had HR+/HER2− subtype, 164 had HER2+ subtype, and 69 harbored TNBC. Relative to HR+/HER2− subtype, local recurrence was greater in HER2+ metastases (HR 3.20, 95% CI 1.78–5.75, p < 0.001), while patients with TNBC demonstrated higher rates of new brain metastases after initial treatment (HR 3.16, 95% CI 1.99–5.02, p < 0.001) and shorter time to salvage whole brain radiation (WBRT) (HR 3.79, 95% CI 1.36–10.56, p = 0.01) and salvage stereotactic radiation (HR 1.86, 95% CI 1.11–3.10, p = 0.02). Conclusions: We identified a strong association between breast cancer subtype and intracranial recurrence patterns after brain-directed radiation, particularly local progression for HER2+ and distant progression for TNBC patients. If validated, the poorer local control in HER2+ brain metastases may support evaluation of novel local therapy-based approaches, while the increased distant recurrence in TNBC suggests the need for improved systemic therapy and earlier utilization of WBRT. [ABSTRACT FROM AUTHOR]

Purpose: Brain metastases can be radiographically cystic or solid. Cystic metastases are associated with a greater intracranial disease burden and poorer oncologic outcomes, but the impact of cystic versus solid appearance on local control after radiation remains unknown. We investigated whether cystic versus solid nature is predictive of local control after management with stereotactic or whole brain radiation (WBRT) and whether the radiation modality utilized is an effect modifier. Methods: We identified 859 patients with 2211 newly-diagnosed brain metastases managed with upfront stereotactic radiation or WBRT without preceding resection/aspiration at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Multivariable Cox regression with an interaction term and sandwich covariance matrix was used to quantify local failure. Results: Cystic lesions were more likely to recur than solid ones when managed with stereotactic radiation (HR 2.33, 95% CI 1.32–4.10, p = 0.004) but not WBRT (HR 0.92, 95% CI 0.62–1.36, p = 0.67), p-interaction = 0.007. 1 year local control rates for cystic versus solid metastases treated with stereotactic radiation were 75% versus 88%, respectively; estimates with WBRT were 76% versus 76%, respectively. However, no significant differences were noted between the two cohorts in post-radiation outcomes including all-cause mortality and neurologic death (p > 0.05). Conclusions: Among patients with brain metastases, stereotactic radiation yields improved local control and less morbidity than WBRT, and consequently for many patients the cystic versus solid designation does not impact treatment selection. However, our results suggest that in patients with a large number of cystic brain metastases, a lower threshold to consider WBRT, as opposed to stereotactic radiation, should be employed. If our results can be confirmed, further investigation into the underlying mechanism(s) would be warranted. [ABSTRACT FROM AUTHOR]

Background There are currently no circulating biomarkers used for clinical monitoring of clear cell renal cell carcinoma (ccRCC). Such a biomarker could facilitate individualized treatment decisions and minimize exposure to ineffective therapies. Prior studies have suggested that circulating KIM-1 is a potential minimally invasive biomarker for ccRCC, but the utility of KIM-1 for identifying early response to nivolumab therapy is not known. Methods CheckMate-009 was a prospective trial investigating nivolumab (every 3 weeks at 0.3, 2, or 10 mg/kg) in patients with metastatic clear cell RCC. We measured serum KIM-1 at baseline and after 3 weeks of treatment (prior to cycle 2) using a custom sandwich immunoassay using the R-PLEX platform. Human KIM-1 antibody (R&D systems, #AF1750) was used to prepare biotin conjugated antibodies and detection antibodies. The assay lowest limit of detection for KIM-1 was 4.88 pg/mL. We assessed the association between early changes in serum KIM-1 and treatment related clinical outcomes. Results Clinical data and serum KIM-1 was analyzed in 54 patients. KIM-1 was high in all patients at baseline (median serum KIM-1 5913 pg/mL, IQR 2137-25101 pg/mL). 25 patients (48%) had a decrease in KIM-1 at 3 weeks after a single dose of nivolumab. Decrease in KIM-1 at 3 weeks was associated with improved PFS (univariable HR 0.26, 95% CI 0.13-0.52; multivariable HR 0.22, 95% CI 0.097-0.50 after adjustment for sex, prior nephrectomy, nivolumab dose, and IMDC risk factors). Conclusions Serum KIM-1 is elevated in patients with metastatic ccRCC and is associated with clinical outcomes. Among patients treated with nivolumab in the CheckMate-009 trial, early decrease in KIM-1 from baseline to 3 weeks was predictive for PFS. CDMRP DOD Funding: yes [ABSTRACT FROM AUTHOR]

Abstract: Background: This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC). Experimental Design: This prospective, phase II, single‐institution trial enrolled patients with platinum‐failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression‐free survival (PFS), and toxicity. Immunohistochemistry for VEGFR‐2, MET, and HGF expression and next‐generation sequencing of tumor tissue were performed and correlated with outcome. Results: Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor‐skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR‐2 was identified in tumor cells by immunohistochemistry of patients’ tissue samples. Conclusion: Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum‐failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476) Implications for Practice: This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue. [ABSTRACT FROM AUTHOR]

Background: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors.Methods: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses).Results: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different.Conclusions: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

National performance measurement programs used to improve quality and/or accountability are prevalent. Professional society-based programs largely assess practice or provider performance. We tested the limitations of the Quality Oncology Practice Initiative (QOPI), a well-established program.~Background~Background~We investigated the potential limitations of the QOPI limited sampling strategy and end-of-life (EOL) metrics through a retrospective review of all decedents meeting the QOPI eligibility criteria at a large three-site community oncology practice. Relative precision for each EOL metric was measured and simulated scenarios modeled via log-normal distributions were compared.~Methods~Methods~A total of 246 deaths were identified; only 14% of decedents were included in the QOPI limited sample. Important differences in relative precision between samples were evident. Chemotherapy administered at the EOL was 2.8 times greater among the full cohort compared to the sample.~Results~Results~The limited sampling strategy demonstrated the lack of precision explained by sampling variability confounded in smaller sample sizes. Our analyses demonstrated that practices reporting the same metric may stem from very different underlying distributions, which limits the ability to understand complex practice patterns and improve care. These findings may be of significance to other performance measurement programs that utilize similar testing strategies.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Objectives This study aimed to evaluate the efficacy of a safety communication and recognition program (B-SAFE), designed to encourage improvement of physical working conditions and hazard reduction in construction. Methods A matched pair cluster randomized controlled trial was conducted on eight worksites (four received the B-SAFE intervention, four served as control sites) for approximately five months per site. Pre- and post-exposure worker surveys were collected at all sites (N=615, pre-exposure response rate of 74%, post-exposure response rate of 88%). Multi-level mixed-effect regression models evaluated the effect of B-SAFE on safety climate as assessed from surveys. Focus groups (N=6-8 workers/site) were conducted following data collection. Transcripts were coded and analyzed for thematic content using Atlas.ti (version 6). Results The mean safety climate score at intervention sites, as measured on a 0-50 point scale, increased 0.5 points (1%) between pre- and post-B-SAFE exposure, compared to control sites that decreased 0.8 points (1.6%). The intervention effect size was 1.64 (3.28%) (P-value=0.01) when adjusted for month the worker started on-site, total length of time on-site, as well as individual characteristics (trade, title, age, and race/ethnicity). At intervention sites, workers noted increased levels of safety awareness, communication, and teamwork compared to control sites. Conclusions B-SAFE led to many positive changes, including an improvement in safety climate, awareness, teambuilding, and communication. B-SAFE was a simple intervention that engaged workers through effective communication infrastructures and had a significant, positive effect on worksite safety. [ABSTRACT FROM AUTHOR]

Objective: Lower extremity lymphedema adversely affects quality of life by causing discomfort, impaired mobility and increased risk of infection. The goal of this study is to investigate factors that influence the likelihood of lymphedema in patients with endometrial cancer who undergo adjuvant radiation with or without chemotherapy. Methods: A retrospective chart review identified all stage I-III endometrial cancer patients who had a hysterectomy with or without complete staging lymphadenectomy and adjuvant radiation therapy between January 2006 and February 2013. Patients with new-onset lymphedema after treatment were identified. Logistic regression was used to find factors that influenced lymphedema risk. Results: Of 212 patients who met inclusion criteria, 15 patients (7.1%) developed new-onset lymphedema. Lymphedema was associated with lymph-node dissection (odds ratio [OR], 5.6; 95% CI, 1.01 to 105.5; p=0.048) and with the presence of pathologically positive lymph nodes (OR, 4.1; 95% CI, 1.4 to 12.3; p=0.01). Multivariate logistic regression confirmed the association with lymph-node positivity (OR, 3.2; 95% CI, 1.0007 to 10.7; p=0.0499) when controlled for lymph-node dissection. Median time to lymphedema onset was 8 months (range, 1 to 58 months) with resolution or improvement in eight patients (53.3%) after a median of 10 months. Conclusion: Lymph-node positivity was associated with an increased risk of lymphedema in endometrial cancer patients who received adjuvant radiation. Future studies are needed to explore whether node-positive patients may benefit from early lymphedema-controlling interventions. [ABSTRACT FROM AUTHOR]

Background: Ipilimumab improves survival in metastatic melanoma patients. This population frequently develops brain metastases, which have been associated with poor survival and are often treated with radiation. Therefore, outcomes following ipilimumab and radiation are of interest, especially given case reports and animal studies suggest combined treatment may generate abscopal responses outside the radiation field. Findings: We reviewed sixteen consecutive melanoma patients who received 1 to 8 courses of radiation, with a sum total of 51, systematically evaluating abscopal responses by following the largest extra-cranial lesion. We also reviewed other series of patients treated with cranial radiation and ipilimumab. Our patients received between 1 and 8 courses of cranial radiation. Four patients received radiation concurrently with ipilimumab. Median survival was 14 months, and 17 months in patients initially treated with SRS. Interestingly, after radiotherapy, there was a 2.8-fold increased likelihood that the rate of extra-cranial index lesion response improved that didn't reach statistical significance (p = 0.07); this was more pronounced when ipilimumab was administered within three months of radiation (p < 0.01). Conclusion: Our experience and review of recently published series suggest ipilimumab and cranial radiation is well tolerated and can result in prolonged survival. Timing of ipilimumab administration in relation to radiation may impact outcomes. Additionally, our results demonstrate a trend for favorable systemic response following radiotherapy worthy of further evaluation in studies powered to detect potential synergies between radiation and immunotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND Although human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) tends to present at an advanced nodal stage (N stage), the prognosis is generally better than that for HPV-negative OPSCC. Prior work has demonstrated the increasing incidence of HPV-related OPSCC in the United States. This study was designed to determine whether the changing epidemiology of OPSCC is reflected in changes in the prognostic significance of the tumor stage (T stage) and the N stage in a population-based cohort. METHODS The Surveillance, Epidemiology, and End Results program was used to identify 13,328 patients who were 18 years old or older and were diagnosed with OPSCC from 1997 to 2008. The Kaplan-Meier method was used to estimate head and neck cancer-specific survival. Cox proportional hazards models were used to evaluate the associations between head and neck cancer-specific mortality (HNCSM) and T and N stages and the interaction of variables with the year of diagnosis. RESULTS With a median follow-up of 67 months, there were 4099 head and neck cancer deaths. There was a significant interaction between the T stage and time ( P for interaction = .01), with the effect of the T stage on HNCSM increasing from 1997 to 2008. The T stage retained a linear relationship with HNCSM. The effect of the N stage on HNCSM declined over time ( P for interaction = .0004). The current American Joint Committee on Cancer (AJCC) staging system did not subdivide distinct prognostic subgroups for HNCSM by overall stage. CONCLUSIONS In this population-based study of OPSCC, the effect of the N stage on cancer-specific mortality decreased over time as the impact of the T stage increased. The current AJCC staging system did not distinguish prognostic subgroups. These changes may reflect the increasing prevalence of HPV-related OPSCC. Further study in HPV-defined cohorts is needed to tailor the AJCC staging system to better reflect HNCSM risk. Cancer 2015;121:2594-2602. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Because of reported associations of psychosocial factors and computer related musculoskeletal symptoms, we investigated the effects of a workplace psychosocial factor, reward, in the presence of over-commitment, on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use. Methods We measured 120 office workers across four groups (lowest/highest reward/over-commitment), performing their own computer work at their own workstations over a 2-hr period. Results Median trapezius muscle activity ( P = 0.04) and median neck flexion ( P = 0.03) were largest for participants reporting simultaneously low reward and high over-commitment. No differences were observed for other muscle activities or postures. Conclusions These data suggest that the interaction of reward and over-commitment can affect upper extremity muscle activity and postures during computer use in the real work environment. This finding aligns with the hypothesized biomechanical pathway connecting workplace psychosocial factors and musculoskeletal symptoms of the neck and shoulder. Am. J. Ind. Med. 56:1190-1200, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Public health concerns over the occurrence of developmental abnormalities that can occur as a result of prenatal exposure to drugs, chemicals, and other environmental factors has led to a number of developmental toxicity studies and the use of the benchmark dose (BMD) for risk assessment. To characterize risk from multiple sources, more recent analytic methods involve a joint modeling approach, accounting for multiple dichotomous and continuous outcomes. For some continuous outcomes, evaluating all subjects may not be feasible, and only a subset may be evaluated due to limited resources. The subset can be selected according to a prespecified probability model and the unobserved data can be viewed as intentionally missing in the sense that subset selection results in missingness that is experimentally planned. We describe a subset selection model that allows for sampling pups with malformations and healthy pups at different rates, and includes the well-known simple random sample (SRS) as a special case. We were interested in understanding how sampling rates that are selected beforehand influence the precision of the BMD. Using simulations we show how improvements over the SRS can be obtained by oversampling malformations, and how some sampling rates can yield precision that is substantially worse than the SRS. We also illustrate the potential for cost saving with oversampling. Simulations are based on a joint mixed effects model, and to account for subset selection, use of case weights to obtain valid dose-response estimates. [ABSTRACT FROM AUTHOR]

When holding a tablet computer with two hands, the touch keyboard configuration imposes postural constraints on the user because of the need to simultaneously hold the device and type with the thumbs. Designers have provided users with several possible keyboard configurations (device orientation, keyboard layout and location). However, potential differences in performance, usability and postures among these configurations have not been explored. We hypothesize that (1) the narrower standard keyboard layout in the portrait orientation leads to lower self-reported discomfort and less reach than the landscape orientation; (2) a split keyboard layout results in better overall outcomes compared to the standard layout; and (3) the conventional bottom keyboard location leads to the best outcomes overall compared to other locations. A repeated measures laboratory experiment of 12 tablet owners measured typing speed, discomfort, task difficulty, and thumb/wrist joint postures using an active marker system during typing tasks for different combinations of device orientation (portrait and landscape), keyboard layout (standard and split), and keyboard location (bottom, middle, top). The narrower standard keyboard with the device in the portrait orientation was associated with less discomfort (least squares mean (and S.E.) 2.9±0.6) than the landscape orientation (4.5±0.7). Additionally, the split keyboard decreased the amount of reaching required by the thumb in the landscape orientation as defined by a reduced range of motion and less MCP extension, which may have led to reduced discomfort (2.7±0.6) compared to the standard layout (4.5±0.7). However, typing speed was greater for the standard layout (127±5 char./min.) compared to the split layout (113±4 char./min.) regardless of device orientation and keyboard location. Usage guidelines and designers can incorporate these findings to optimize keyboard design parameters and form factors that promote user performance and usability for thumb interaction. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this study was to determine how patient preferences guide the course of palliative chemotherapy for advanced colorectal cancer. METHODS: Eligible patients with metastatic colorectal cancer (mCRC) were enrolled nationwide in a prospective, population-based cohort study. Data were obtained through medical record abstraction and patient surveys. Logistic regression analysis was used to evaluate patient characteristics associated with visiting medical oncology and receiving chemotherapy and patient characteristics, beliefs, and preferences associated with receiving >1 line of chemotherapy and receiving combination chemotherapy. RESULTS: Among 702 patients with mCRC, 91% consulted a medical oncologist; and among those, 82% received chemotherapy. Patients ages 65 to 75 years and aged ≥75 years were less likely to visit an oncologist, as were patients who were too sick to complete their own survey. In adjusted analyses, patients aged ≥75 years who had moderate or severe comorbidity were less likely to receive chemotherapy, as were patients who were too sick to complete their own survey. Patients received chemotherapy even if they believed that chemotherapy would not extend their life (90%) or that chemotherapy would not likely help with cancer-related problems (89%), or patients preferred treatment focusing on comfort even if it meant not living as long (90%). Older patients were less likely to receive combination first-line therapy. Patient preferences and beliefs were not associated with receipt of >1 line of chemotherapy or combination chemotherapy. CONCLUSIONS: The majority of patients received chemotherapy even if they expressed negative or marginal preferences or beliefs regarding chemotherapy. Patient preferences and beliefs were not associated with the intensity or number of chemotherapy regimens. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The Supplemental Nutrition Assistance Program (SNAP) aims to alleviate hunger among its beneficiaries by providing benefits to purchase nutritious foods. Objective: We conducted a comprehensive dietary analysis of low- income adults and examined differences in dietary intake between SNAP participants and nonparticipants. Design: The study population comprised 3835 nonelderly adults with a household income ≤130% of the federal poverty level from the 1999-2008 NHANES. The National Cancer Institute method was used to estimate the distributions of usual intake for dietary outcomes. Relative differences in dietary intake by SNAP participation were estimated with adjustment for sociodemographic characteristics and household food security. Results: Few low-income adults consumed recommended amounts of whole grains, fruit, vegetables, fish, and nuts/seeds/legumes. Conversely, many low-income adults exceeded recommended limits for processed meats, sweets, and bakery desserts and sugar-sweetened beverages. Approximately 13-22% of low-income adults did not meet any food and nutrient guidelines; virtually no adults met all of the guidelines. Compared with nonparticipants, SNAP participants consumed 39% fewer whole grains (95% CI: -57%, -15%), 44% more 100% fruit juice (95% CI: 0%, 107%), 56% more potatoes (95% CI: 18%, 106%), 46% more red meat (95% CI: 4%, 106%), and, in women, 61% more sugar-sweetened beverages (95% CI: 3%, 152%). SNAP participants also had lower dietary quality scores than did nonparticipants, as measured by a modified Alternate Healthy Eating Index. Conclusion: Although the diets of all low-income adults need major improvement, SNAP participants in particular had lower-quality diets than did income-eligible nonparticipants. [ABSTRACT FROM AUTHOR]

A primary objective of current air pollution research is the assessment of health effects related to specific sources of air particles, or particulate matter (PM). Because most PM health studies do not observe the activity of the pollution sources directly, investigators must infer pollution source contributions based on a complex mixture of exposure. Methods such as source apportionment and multivariate receptor modeling use standard factor analytic techniques to estimate the source-specific contributions from a large number of observed chemical components. In the interest of a more flexible source apportionment, we propose a multiplicative factor analysis with a latent mixed model structure on the latent source contributions. A factor analysis with multiplicative errors serves to maintain the non-negativity of the measured chemical concentrations. A mixed model on the latent source contributions provides for systematic effects on source contributions as well as an adjustment for residual correlation in the source-specific exposures. In a simulation study, we examine the impact of (1) accounting for meteorological covariates and (2) adjusting for temporal correlation in the exposures on the estimation of the source profiles and the source contributions. Finally, we explore the influence of meteorological conditions on source-specific exposures in an analysis of PM exposure data from an animal toxicology study. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA. Methods: Eighty-one eligible treatment-naïve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP. Results: The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs. Conclusions: Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus. [ABSTRACT FROM AUTHOR]

Public health concerns over the occurrence of birth defects and developmental abnormalities that may occur as a result of prenatal exposure to drugs, chemicals and other environmental factors has led to an increasing number of developmental toxicity studies. Because fetal pups are commonly evaluated for multiple outcomes, data analysis frequently involves a joint modelling approach. We focus on modelling clustered binary and continuous outcomes in the setting where both outcomes are potentially observable in all offspring but, owing to practical limitations, the continuous outcome is only observed in a subset of offspring. The subset is not a simple random sample but is selected by the experimenter under a prespecified probability model. Although joint models for binary and continuous outcomes have been developed when both outcomes are available for every fetus, many existing approaches are not directly applicable when the continuous outcome is not observed in a simple random sample. We adapt a likelihood-based approach for jointly modelling clustered binary and continuous outcomes when the continuous response is missing by design and missingness depends on the binary trait. The approach takes into account the probability that a fetus is selected in the subset. Through the use of a partial likelihood, valid estimates can be obtained by a simple modification to the partial likelihood score. Data involving the herbicide 2,4,5-trichlorophenoxyacetic-acid are analysed. Simulation results confirm the approach. [ABSTRACT FROM AUTHOR]