Search

Background: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields., Methods: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test., Results: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR., Conclusions: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SGD has received travel expenses from Loxo, Roche, and Salarius and consulting fees from Amgen, Bayer, and Jazz. TIY receives in-kind software support from MIM software to support a multicenter pediatric registry. Prior Presentation: Presented in part at the 64th Annual Meeting of the American Society for Radiation Oncology, San Antonio, TX, October 23–26, 2022., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses., Methods: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes., Results: In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC., Conclusion: Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.

Purpose To develop, externally test, and evaluate clinical acceptability of a deep learning pediatric brain tumor segmentation model using stepwise transfer learning. Materials and Methods In this retrospective study, the authors leveraged two T2-weighted MRI datasets (May 2001 through December 2015) from a national brain tumor consortium ( n = 184; median age, 7 years [range, 1-23 years]; 94 male patients) and a pediatric cancer center ( n = 100; median age, 8 years [range, 1-19 years]; 47 male patients) to develop and evaluate deep learning neural networks for pediatric low-grade glioma segmentation using a stepwise transfer learning approach to maximize performance in a limited data scenario. The best model was externally tested on an independent test set and subjected to randomized blinded evaluation by three clinicians, wherein they assessed clinical acceptability of expert- and artificial intelligence (AI)-generated segmentations via 10-point Likert scales and Turing tests. Results The best AI model used in-domain stepwise transfer learning (median Dice score coefficient, 0.88 [IQR, 0.72-0.91] vs 0.812 [IQR, 0.56-0.89] for baseline model; P = .049). With external testing, the AI model yielded excellent accuracy using reference standards from three clinical experts (median Dice similarity coefficients: expert 1, 0.83 [IQR, 0.75-0.90]; expert 2, 0.81 [IQR, 0.70-0.89]; expert 3, 0.81 [IQR, 0.68-0.88]; mean accuracy, 0.82). For clinical benchmarking ( n = 100 scans), experts rated AI-based segmentations higher on average compared with other experts (median Likert score, 9 [IQR, 7-9] vs 7 [IQR 7-9]) and rated more AI segmentations as clinically acceptable (80.2% vs 65.4%). Experts correctly predicted the origin of AI segmentations in an average of 26.0% of cases. Conclusion Stepwise transfer learning enabled expert-level automated pediatric brain tumor autosegmentation and volumetric measurement with a high level of clinical acceptability. Keywords: Stepwise Transfer Learning, Pediatric Brain Tumors, MRI Segmentation, Deep Learning Supplemental material is available for this article . © RSNA, 2024.

Background: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration., Methods: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured., Results: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free., Conclusions: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population., Competing Interests: Competing interests: MBA has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Exelixis, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio, Pliant Therapeutics, Atreca, OncoRena, Sanofi and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Agenus, Asher Bio, and AstraZeneca. He reports research support to his institution from Bristol-Myers Squibb and Merck. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. OAJ—none. NBH is a paid consultant to BMS, Eisai, Exelixis, Merck and Roche Genentech. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, Inc, EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Technologies, Calithera Biosciences, Synthekine, Inc., Johnson served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum. He also reports Spouse salary from Gamida Cell, Arvinas. DJP holds stock in Bristol-Myers Squibb and Merck. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, Mink Therapeutics, Novartis, Puma Biotechnology, and Sanofi, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. PJC—none. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study. MMR reports research funding to institution from AstraZeneca, Bayer, Biotheranostics, Bristol-Myers Squibb, DebioPharm, Ipsen, Novartis, Pfizer, Roche, TerSera Therapeutics, all outside of the current study, and a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, DebioPharm, Ipsen, TerSera Therapeutics, Tolmar Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors., Experimental Design: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus., Conclusions: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value., (©2023 American Association for Cancer Research.)

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., (© 2024. The Author(s).)

Purpose: Myxopapillary ependymoma (MPE) is a rare, typically slow-growing subtype of spinal ependymomas. There are no standard guidelines for radiotherapy and long-term outcomes after radiation, particularly patterns of relapse, for pediatric and young adult (YA) patients with MPE remain under-characterized., Methods and Materials: This is an Institutional Review Board-approved multi-institutional retrospective cohort study of 60 pediatric and YA patients diagnosed with MPE and received radiotherapy between 2000-2020. Clinical and treatment characteristics, and long-term outcomes were recorded. Site(s) of progression was compared to radiation fields. Survival outcomes were analyzed using Kaplan-Meier method. Cumulative incidence of local in-field progression (CILP) after initial radiotherapy was analyzed using Gray's method with out-of-field-only progression as a competing risk. Univariate analyses were performed using Cox proportional hazard's model., Results: The median age at radiation was 14.8 years (range: 7.1-26.5). At time of radiotherapy, 45 (75.0%) and 35 (58.3%) patients had gross residual and multifocal disease, respectively. Forty-eight (80.0%), seven (11.7%) and five (8.3%) patients received involved field radiotherapy, craniospinal irradiation, and whole spine radiation, respectively. Median follow-up from end of radiotherapy was 6.2 years (range: 0.6-21.0). Five-year overall survival, progression-free survival, and CILP were 100%, 60.8% and 4.1%, respectively. Both local recurrences were at sites of gross residual disease. Of the eighteen out-of-field first recurrences after radiotherapy, all were superior to the initial treatment field and nine had intracranial relapse. On univariate analyses, distant-only recurrence before radiation (HR: 4.00, 95% CI: 1.54-10.43, p = 0.005) was significantly associated with shorter time to progression., Conclusions: While the risk of recurrence within the radiation field is low, pediatric and YA patients with high-risk MPE remain at risk for recurrences in the spine above the radiation field and intracranially after radiotherapy. Future prospective studies are needed to investigate the appropriate radiation field and dose based on the extent of metastases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. We developed a DNA-based signature of radiotherapeutic efficacy among patients with BrM to better characterize recurrence risk., Methods: We identified 570 patients with 1487 BrM managed with whole-brain (WBRT) or stereotactic radiation therapy at Brigham and Women's Hospital/Dana-Farber Cancer Institute (2013-2020) for whom next-generation sequencing panel data (OncoPanel) were available. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with versus without somatic alterations of likely biological significance across 84 genes. Genes with a q-value ≤ 0.10 were utilized to develop a "Brain-Radiation Prediction Score" ("Brain-RPS")., Results: Genomic alterations in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, and MDM4) and 2 genes (FBXW7 and AURKA) were associated with decreased or increased risk of local recurrence, respectively (q-value ≤ 0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray's competing risks regression, RPS [1.66 (1.44-1.91, P < .001)], metastasis-associated edema [1.60 (1.16-2.21), P = .004], baseline size [1.02 (1.01-1.03), P < .001] and receipt of WBRT without local therapy [4.04 (2.49-6.58), P < .001] were independent predictors of local failure., Conclusions: We developed a genomic score to quantify local recurrence risk following brain-directed radiation. To the best of our knowledge, this represents the first study to systematically correlate DNA-based alterations with radiotherapeutic outcomes in BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation in BrM., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prescribed nature walks frequently yield improvements to mood and cognition as observed in experimental studies. Research that uses real life settings such as self-determined time exercising outdoors for restorative health benefits may more accurately elicit effects than time-specified study protocols. This study examined in situ psycho-cognitive outcomes of routine walks in urban greenspace to test the concept that self-set exposure duration and not context alone is related to magnitude of psycho-cognitive benefit. Pre-post measurements taken on a diverse participant pool of individuals walking in urban parks and recruited on random days over a two-week period found significant associations between outdoor activity duration and cognitive and mood improvements. Greater outdoor walking duration linearly predicted stronger processing speeds but non-linearly in tests of other cognitive domains. Results of fixed effects model for mean mood change following green exercise show outdoor walking influenced mood change at highest levels of significance, even after accounting for individual level variability in duration. Mood improved for all durations of outdoor walking under a random effects model with high significance. Untethering fixed intervals of outdoor exercise from formal study design revealed briefer but more frequent nature engagement aligned with nature affinity. The influence of unmeasured factors, e.g., nature affinity or restorative conditioning, for prescriptive durations of urban green exercise merits further investigation toward designing wellbeing interventions directed at specific urban populations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Linda Powers Tomasso reports financial support was provided by National Institutes of Health.

Importance: Sarcopenia is an established prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC); the quantification of sarcopenia assessed by imaging is typically achieved through the skeletal muscle index (SMI), which can be derived from cervical skeletal muscle segmentation and cross-sectional area. However, manual muscle segmentation is labor intensive, prone to interobserver variability, and impractical for large-scale clinical use., Objective: To develop and externally validate a fully automated image-based deep learning platform for cervical vertebral muscle segmentation and SMI calculation and evaluate associations with survival and treatment toxicity outcomes., Design, Setting, and Participants: For this prognostic study, a model development data set was curated from publicly available and deidentified data from patients with HNSCC treated at MD Anderson Cancer Center between January 1, 2003, and December 31, 2013. A total of 899 patients undergoing primary radiation for HNSCC with abdominal computed tomography scans and complete clinical information were selected. An external validation data set was retrospectively collected from patients undergoing primary radiation therapy between January 1, 1996, and December 31, 2013, at Brigham and Women's Hospital. The data analysis was performed between May 1, 2022, and March 31, 2023., Exposure: C3 vertebral skeletal muscle segmentation during radiation therapy for HNSCC., Main Outcomes and Measures: Overall survival and treatment toxicity outcomes of HNSCC., Results: The total patient cohort comprised 899 patients with HNSCC (median [range] age, 58 [24-90] years; 140 female [15.6%] and 755 male [84.0%]). Dice similarity coefficients for the validation set (n = 96) and internal test set (n = 48) were 0.90 (95% CI, 0.90-0.91) and 0.90 (95% CI, 0.89-0.91), respectively, with a mean 96.2% acceptable rate between 2 reviewers on external clinical testing (n = 377). Estimated cross-sectional area and SMI values were associated with manually annotated values (Pearson r = 0.99; P < .001) across data sets. On multivariable Cox proportional hazards regression, SMI-derived sarcopenia was associated with worse overall survival (hazard ratio, 2.05; 95% CI, 1.04-4.04; P = .04) and longer feeding tube duration (median [range], 162 [6-1477] vs 134 [15-1255] days; hazard ratio, 0.66; 95% CI, 0.48-0.89; P = .006) than no sarcopenia., Conclusions and Relevance: This prognostic study's findings show external validation of a fully automated deep learning pipeline to accurately measure sarcopenia in HNSCC and an association with important disease outcomes. The pipeline could enable the integration of sarcopenia assessment into clinical decision making for individuals with HNSCC.

Purpose: Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer., Patients and Methods: Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity., Results: The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively ( P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting., Conclusion: The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

Background: Leptomeningeal disease (LMD) is a relatively uncommon manifestation of advanced cancer. Patients with LMD carry a poor prognosis and often decline rapidly, complicating inclusion in clinical trials. Identification of LMD subsets of greater incidence and more favorable prognosis might facilitate dedicated clinical trials in the future. We hypothesized that patients with breast cancer may represent such a population and sought to assess the relative incidence and prognosis of LMD secondary to breast vs. non-breast primaries., Methods: We identified 2411 patients with intracranial metastases secondary to breast (N = 501) and non-breast (N = 1910) primaries at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 1996 and 2020, of whom 112 presented with and an additional 161 subsequently developed LMD. A log-rank test and Cox modeling were used to compare outcomes in patients with breast vs. non-breast primaries., Results: Among patients with newly diagnosed intracranial disease, the incidence proportion of concurrent LMD was 11.4% vs. 2.9% among patients with breast vs. non-breast primaries (P < .001). Development of LMD among initially LMD-naïve patients was also more common among patients with breast vs. non-breast primaries (HR = 1.49 [1.05-2.11], P = .03). Patients with LMD secondary to breast vs. non-breast primaries displayed lower all-cause mortality (HR 0.70 [0.52-0.93], P = .01; median survival: 5.2 vs. 2.4 months, respectively), with a greater numerical difference observed in patients with LMD at intracranial involvement (7.4 vs. 2.6 months, respectively)., Conclusions: Patients with breast cancer and LMD may represent an ideal population for clinical trials given the higher incidence and potentially more favorable prognosis seen in this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy., Methods: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies., Results: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade > 3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death., Conclusions: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity., Trial Registration Number: NCT03117309., Competing Interests: Competing interests: MBA, has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pneuma, Leads, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Exelixis, Iovance, COTA, Idera, Agenus, Apexigen, Asher Bio, Neoleukin, AstraZeneca, Calithera, SeaGen, and Sanofi. He reports research support to his institution from Bristol-Myers Squibb, Merck and Pfizer. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. NBH has/had an advisory role for Merck, Eisai, Aveo, and Roche. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly and Company, Iovance, Eisai, Werewolf Technologies, Calithera Biosciences, Synthekine, Johnson & Johnson, and Aveo. He has received support to his institution from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes, Checkmate Pharmaceuticals, and CRISPR Therapeutics for work performed outside of the current study. MAB has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed outside of the current study. MS has consulted for Exelixis, Xencor, Janssen, Vaccitech, Bristol-Myers Squibb and reports research funding to his institution from Bellicum, Merck, Janssen, Medivation/Astellas, Advaxis, Harpoon, Bristol-Myers Squibb, Genocea, Lilly, Nektar, SeaGen, Xencor, Tmunity, Exelixis. JS serves on Advisory Boards for Eisai, Apexigen, Iovance, Covus. He reports research funding to his institution from Bristol Myers Squibb, PACT and Corvus. RA has consulted for Eisai, Bayer and Janssen Oncology and participated in Speakers' Bureaus for Astellas Pharma, Janssen Oncology, Bayer, Pfizer, Exelixis, Gilead Sciences, Aveo and Bristol-Myers Squibb. ERP reports consulting or advisory roles for Astellas, AstraZeneca, Aveo, Bristol Myers Squibb, Exelixis, Merck, Natera, Pfizer, Regeneron, SeaGen and research support to institution from Astella, Bristol Myers Squibb, Genentech and Merck. MCO has served in consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol-Myers Squibb; served on speakers’ bureaus for Bristol Myers Squibb; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum He also reports Spouse salary from Gamida Cell, Arvinas. SS reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. CW reports receiving research funding from Pharmacyclics and being an equity holder of BionTech. DB reports personal fees from LM Education and Exchange, Adnovate Strategies, MDedge, Cancer Network, Cancer Expert Now, OncLive, Catenion, AVEO, and grants and personal fees from Exelixis, outside the submitted work. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, and Puma Biotechnology, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS)., Patients and Methods: E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation., Results: A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank P = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, P = .42). MGMT deficiency was associated with response., Conclusion: The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).

Purpose: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy., Methods: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%., Results: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively ( P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab., Conclusion: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

Background: Artificial intelligence (AI) and deep learning have shown great potential in streamlining clinical tasks. However, most studies remain confined to in silico validation in small internal cohorts, without external validation or data on real-world clinical utility. We developed a strategy for the clinical validation of deep learning models for segmenting primary non-small-cell lung cancer (NSCLC) tumours and involved lymph nodes in CT images, which is a time-intensive step in radiation treatment planning, with large variability among experts., Methods: In this observational study, CT images and segmentations were collected from eight internal and external sources from the USA, the Netherlands, Canada, and China, with patients from the Maastro and Harvard-RT1 datasets used for model discovery (segmented by a single expert). Validation consisted of interobserver and intraobserver benchmarking, primary validation, functional validation, and end-user testing on the following datasets: multi-delineation, Harvard-RT1, Harvard-RT2, RTOG-0617, NSCLC-radiogenomics, Lung-PET-CT-Dx, RIDER, and thorax phantom. Primary validation consisted of stepwise testing on increasingly external datasets using measures of overlap including volumetric dice (VD) and surface dice (SD). Functional validation explored dosimetric effect, model failure modes, test-retest stability, and accuracy. End-user testing with eight experts assessed automated segmentations in a simulated clinical setting., Findings: We included 2208 patients imaged between 2001 and 2015, with 787 patients used for model discovery and 1421 for model validation, including 28 patients for end-user testing. Models showed an improvement over the interobserver benchmark (multi-delineation dataset; VD 0·91 [IQR 0·83-0·92], p=0·0062; SD 0·86 [0·71-0·91], p=0·0005), and were within the intraobserver benchmark. For primary validation, AI performance on internal Harvard-RT1 data (segmented by the same expert who segmented the discovery data) was VD 0·83 (IQR 0·76-0·88) and SD 0·79 (0·68-0·88), within the interobserver benchmark. Performance on internal Harvard-RT2 data segmented by other experts was VD 0·70 (0·56-0·80) and SD 0·50 (0·34-0·71). Performance on RTOG-0617 clinical trial data was VD 0·71 (0·60-0·81) and SD 0·47 (0·35-0·59), with similar results on diagnostic radiology datasets NSCLC-radiogenomics and Lung-PET-CT-Dx. Despite these geometric overlap results, models yielded target volumes with equivalent radiation dose coverage to those of experts. We also found non-significant differences between de novo expert and AI-assisted segmentations. AI assistance led to a 65% reduction in segmentation time (5·4 min; p<0·0001) and a 32% reduction in interobserver variability (SD; p=0·013)., Interpretation: We present a clinical validation strategy for AI models. We found that in silico geometric segmentation metrics might not correlate with clinical utility of the models. Experts' segmentation style and preference might affect model performance., Funding: US National Institutes of Health and EU European Research Council., Competing Interests: Declaration of interests AH reports consultancy fees for Altis Labs; and owning stock in Altis Labs. HJWLA reports being a scientific adviser and shareholder for Onc.Ai, Love Health, Health-AI, and Bristol Myers Squibb. RHM reports a research grant from ViewRay; honoraria from NewRT and ViewRay; is on an advisory board for AstraZeneca; and reports travel expenses from NewRT. DEK reports honoraria from RefleXion; and is a consultant and on an advisory board for Genentech. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Neurologic death is the most serious consequence of intracranial disease among patients with brain metastases. Identifying patients with brain metastases at increased risk of neurologic death can improve care and guide further research. We sought to delineate factors predictive of neurologic death among patients with brain metastases., Methods: We identified 1218 patients with newly diagnosed brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2008-2015. Factors predictive of neurologic death were assessed via univariable and multivariable Fine and Gray competing risks regression., Results: On multivariable analysis, neurologic death was associated with number of brain metastases (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% confidence interval [CI] 1.01-1.02, P < 0.001) and 3 primary tumor sites (reference=non-small cell lung cancer): melanoma (HR 4.67, 95% CI 3.27-6.68, P < 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47-3.68, P < 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28-3.82, P = 0.005). Conversely, a reduction in neurologic death was found in patients with good Karnofsky performance status (90-100 vs. 30-80, HR 0.67, 95% CI 0.48-0.95, P = 0.03) and progressive extracranial metastases at diagnosis of intracranial disease (HR 0.50, 95% CI 0.38-0.67, P = 0.001). Among patients with breast primaries, HER2+ patients displayed increased neurologic death relative to the reference of HR+/HER2- (univariable analysis only: HR 2.41, 95% CI 1.00-5.84, P = 0.05)., Conclusions: Patients with melanoma, small cell lung cancer, gastrointestinal cancer, and HER2+ breast cancer primaries, as well as greater intracranial versus extracranial disease burden, harbor significant risk of neurologic death. Future research investigating novel intracranial approaches should focus on these populations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The variability of nature and the nature construct have complicated interpretations of empirical evidence from nature-based health studies. The challenge of defining nature exposure for purposes of methodological standardization may encompass constructs beyond vegetated landcover. This study offers a new construct for defining 'nature exposure' that considers cultural sets and nature familiarity. Focus group discussions across the United States (N = 126) explored the concept of what constitutes the relationship to nature. The participant diversity included regions, cultural demographics, cumulative nature experience, and everyday nature exposure. Mixed methods of semi-structured discussion and a photo exercise that prompted nature connectedness allowed for data triangulation and the detection of contradictions between approaches. Individuals conceptualized nature in ways reflecting highly personal and differentiated experiences, which defied consensus toward a single nature construct. The group scoring of photo imagery showed consistent high and low levels of nature connectedness with respect to wildness and outdoor urban venues, respectively, but diverged in the assessment of nature within the built environment. Everyday nature exposure significantly differentiated how groups conceptualized and related to nature imagery. This result may indicate an unmet biophilic need among groups with low backgrounds of nature exposure. The contrasts between the discussion content and the observed reactions to nature imagery showed the value of using mixed methods in qualitative research., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Introduction: The diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to care disparities for vulnerable patients., Methods: A multi-institutional, multidisciplinary conference was convened to address the complexity of lung cancer care particularly in patients at high-risk for treatment delay. The resulting care delivery model, called the Lung Cancer Strategist Program (LCSP), was led by a thoracic-trained advanced practice provider (APP) with emphasis on expedited surgery and early oncologic consultation in the assessment of a newly diagnosed suspicious lung nodule. We performed a retrospective review to evaluate care efficiency and oncologic outcomes in the first 100 LCSP patients compared to 100 concurrent patients managed via routine surgical referral., Results: In the 78 LCSP and 41 routine referral patients managed via nodule surveillance, LCSP patients had a shorter time from suspicious finding to work-up (3 vs. 26 days, p < 0.001) and to surveillance decision (12.5 vs. 39 days, p < 0.001). In the 22 LCSP and 59 routine referral patients treated for intrathoracic malignancy, LCSP patients had fewer hospital visits (4 vs 6, p < 0.001), clinicians seen (1.5 vs. 2, p = 0.08), and diagnostic studies (4 vs 5, p = 0.01) with a shorter time to diagnosis (30.5 vs. 48 days, p = 0.02) and treatment (40.5 vs. 68.5 days, p = 0.02)., Conclusions: Patient triage through a thoracic-trained APP in consultation with surgical, medical, and radiation oncology facilitates rapid assessment of benign versus malignant lesions with reduced time to diagnosis and treatment, even among patients at high-risk for treatment delay., (Copyright © 2021. Published by Elsevier Inc.)

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.

Purpose: To evaluate 18 F-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).

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Prognostic estimates for patients with brain metastases (BM) stem from younger, healthier patients enrolled in clinical trials or databases from academic centers. We characterized population-level prognosis in elderly patients with BM., Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified 9882 patients ≥65 years old with BM secondary to lung, breast, skin, kidney, esophageal, colorectal, and ovarian primaries between 2014 and 2016. Survival was assessed by primary site and evaluated with Cox regression., Results: In total, 2765 versus 7117 patients were diagnosed with BM at primary cancer diagnosis (synchronous BM, median survival = 2.9 mo) versus thereafter (metachronous BM, median survival = 3.4 mo), respectively. Median survival for all primary sites was ≤4 months, except ovarian cancer (7.5 mo). Patients with non-small-cell lung cancer (NSCLC) receiving epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-based therapy for synchronous BM displayed notably better median survival at 12.5 and 20.1 months, respectively, versus 2.8 months exhibited by other patients with NSCLC; survival estimates in melanoma patients based on receipt of BRAF/MEK therapy versus not were 6.7 and 2.8 months, respectively. On multivariable regression, older age, greater comorbidity, and type of managing hospital were associated with poorer survival; female sex, higher median household income, and use of brain-directed stereotactic radiation, neurosurgical resection, or systemic therapy (versus brain-directed non-stereotactic radiation) were associated with improved survival (all P < 0.05)., Conclusions: Elderly patients with BM have a poorer prognosis than suggested by prior algorithms. If prognosis is driven by systemic and not intracranial disease, brain-directed therapy with potential for significant toxicity should be utilized cautiously., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We sought to validate levels of CD8 + tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025)., Experimental Design: Tumor tissues (nivo: n = 116, evero: n = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months)., Results: In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, P = 0.01) and DRR (33.3% vs. 14.1%, P = 0.03) and longer median PFS (9.6 vs. 3.7 months, P = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways ( q < 0.1) and immune-related gene signature scores ( q < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. ERVE-4 expression was associated with increased DRR and longer PFS in nivo-treated patients., Conclusions: High levels of CD8 + TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE-4 expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings., (©2020 American Association for Cancer Research.)

Objective: To test the hypothesis that subets of patients with brain metastases (BrM) without seizures at intracranial presentation are at increased risk for developing seizures, we characterized the incidence and risk factors for seizure development among seizure-naive patients with BrMs., Methods: We identified 15,863 and 1,453 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana Farber Cancer Institute (2000-2015) institutional data, respectively. Cumulative incidence curves and Fine/Gray competing risks regression were used to characterize seizure incidence and risk factors, respectively., Results: Among SEER-Medicare and institutional patients, 1,588 (10.0%) and 169 (11.6%) developed seizures, respectively. On multivariable regression of the SEER-Medicare cohort, Black vs White race (hazard ratio [HR] 1.45 [95% confidence interval (CI), 1.22-1.73], p < 0.001), urban vs nonurban residence (HR 1.41 [95% CI, 1.17-1.70], p < 0.001), melanoma vs non-small cell lung cancer (NSCLC) as primary tumor type (HR 1.44 [95% CI, 1.20-1.73], p < 0.001), and receipt of brain-directed stereotactic radiation (HR 1.67 [95% CI, 1.44-1.94], p < 0.001) were associated with greater seizure risk. On multivariable regression of the institutional cohort, melanoma vs NSCLC (HR 1.70 [95% CI, 1.09-2.64], p = 0.02), >4 BrM at diagnosis (HR 1.60 [95% CI, 1.12-2.29], p = 0.01), presence of BrM in a high-risk location (HR 3.62 [95% CI, 1.60-8.18], p = 0.002), and lack of local brain-directed therapy (HR 3.08 [95% CI, 1.45-6.52], p = 0.003) were associated with greater risk of seizure development., Conclusions: The role of antiseizure medications among select patients with BrM should be re-explored, particularly for those with melanoma, a greater intracranial disease burden, or BrM in high-risk locations., (© 2021 American Academy of Neurology.)

Lockdown aiming at slowing COVID-19 transmission has altered nature accessibility patterns, creating quasi-experimental conditions to assess if retracted nature contact and perceived nature deprivation influence physical and emotional wellbeing. We measure through on-line survey methods ( n = 529) how pandemic mandates limiting personal movement and outdoor nature access within the United States affect self-assessed nature exposure, perceived nature deprivation, and subsequent flourishing as measured by the Harvard Flourishing Index. Results indicate that perceived nature deprivation strongly associates with local nature contact, time in nature, and access to municipal nature during the pandemic, after controlling for lockdown mandates, job status, household composition, and sociodemographic variables. Our hypothesis is that individuals with strong perceived nature deprivation under COVID-19 leads to diminished wellbeing proved true. Interaction models of flourishing showed positive modification of nature affinity with age and qualitative modification of nature deprivation with race. Our results demonstrate the potential of local nature contact to support individual wellbeing in a background context of emotional distress and social isolation, important in guiding public health policies beyond pandemics.

Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV-H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion. See related Spotlight on p. 128 ., (©2020 American Association for Cancer Research.)

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., (© 2020 American Cancer Society.)

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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Evidence regarding the dose-related impact of doxorubicin on subsequent cardiovascular diseases (CVDs) in Asian patients with diffuse large B-cell lymphoma (DLBCL) without preexisting CVDs is lacking. From a territory-wide electronic database in Hong Kong, we identified adults who were diagnosed with DLBCL and treated with chemotherapy between 2000 and 2018. We evaluated the patients for incident CVDs (including ischemic heart disease, heart failure, and cardiomyopathy). We evaluated the cause-specific cumulative incidence (csCI) of CVD with levels of doxorubicin exposure by using flexible parametric competing risk analysis and adjusting for demographics, comorbidities, therapeutic exposure, cardiovascular risk factors, and lifestyle factors. Controls were age- and sex-matched to DLBCL patients. We analyzed 2600 patients and 13 000 controls. The adjusted cause-specific hazard ratio (HR) for CVD in patients treated with >500 mg doxorubicin compared with non-doxorubicin regimens was 2.65 (95% confidence interval [CI], 1.23-5.74; P = .013). The 5-, 10-, and 15-year csCIs were 8.2%, 11.3%, and 12.8% in patients vs 3.1%, 4.4%, and 5.2% in controls, respectively. Hypertension (HR, 6.20; 95% CI, 0.79-48.44; P = .082) and use of aspirin/angiotensin-converting enzyme inhibitor/beta-blocker at baseline (HR, 2.13-4.63; P < .001 to .002) might confer a higher risk of subsequent CVDs. In this Hong Kong population-based study, doxorubicin exposure (absolute dose >500 mg), together with hypertension or baseline use of medication for cardiovascular risk factors, was found to be associated with an increase in csCIs of CVDs. Tailoring therapeutic strategies to underlying CVD risk factors and risk-adapted monitoring and follow-up of susceptible DLBCL patients are advisable., (© 2020 by The American Society of Hematology.)

Background: Brain metastases (BM) cause symptoms that supportive medications can alleviate. We assessed whether racial disparities exist in supportive medication utilization after BM diagnosis., Methods: Medicare-enrolled patients linked with the Surveillance, Epidemiology, and End Results program (SEER) who had diagnoses of BM between 2007 and 2016 were identified. Fourteen supportive medication classes were studied: non-opioid analgesics, opioids, anti-emetics, anti-epileptics, headache-targeting medications, steroids, cognitive aids, antidepressants, anxiolytics, antidelirium/antipsychotic agents, muscle relaxants, psychostimulants, sleep aids, and appetite stimulants. Drug administration ≤30 days following BM diagnosis was compared by race using multivariable logistic regression., Results: Among 17,957 patients, headache aids, antidepressants, and anxiolytics were prescribed less frequently to African Americans (odds ratio [95% CI] = 0.81 [0.73-0.90], P < 0.001; OR = 0.68 [0.57-0.80], P < 0.001; and OR = 0.68 [0.56-0.82], P < 0.001, respectively), Hispanics (OR = 0.83 [0.73-0.94], P = 0.004 OR = 0.78 [0.64-0.97], P = 0.02; and OR = 0.63 [0.49-0.81], P < 0.001, respectively), and Asians (OR = 0.81 [0.72-0.92], P = 0.001, OR = 0.67 [0.53-0.85], P = 0.001, and OR = 0.62 [0.48-0.80], P < 0.001, respectively) compared with non-Hispanic Whites. African Americans also received fewer anti-emetics (OR = 0.75 [0.68-0.83], P < 0.001), steroids (OR = 0.84 [0.76-0.93], P < 0.001), psychostimulants (OR = 0.14 [0.03-0.59], P = 0.007), sleep aids (OR = 0.71 [0.61-0.83], P < 0.001), and appetite stimulants (OR = 0.85 [0.77-0.94], P = 0.002) than Whites. Hispanic patients less frequently received antidelirium/antipsychotic drugs (OR = 0.57 [0.38-0.86], P = 0.008), sleep aids (OR = 0.78 [0.64-0.94, P = 0.01), and appetite stimulants (OR = 0.87 [0.76-0.99], P = 0.04). Asian patients received fewer opioids (OR = 0.86 [0.75-0.99], P = 0.04), anti-emetics (OR = 0.83 [0.73-0.94], P = 0.004), anti-epileptics (OR = 0.83 [0.71-0.97], P = 0.02), steroids (OR = 0.81 [0.72-0.92], P = 0.001), muscle relaxants (OR = 0.60 [0.41-0.89], P = 0.01), and appetite stimulants (OR = 0.87 [0.76-0.99], P = 0.03). No medication class was prescribed significantly less frequently to Whites., Conclusions: Disparities in supportive medication prescription for non-White/Hispanic groups with BM exist; improved provider communication and engagement with at-risk patients is needed., Key Points: 1. Patients with BM commonly experience neurologic symptoms.2. Supportive medications improve quality of life among patients with BM.3. Non-White patients with BM receive fewer supportive medications than White patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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.

Previous research has demonstrated the positive associations between outdoor nature contact and stress reduction. However, similar effects of incorporating natural elements into indoor environment (i.e. biophilic design) have been less well studied. We hypothesize that exposure to biophilic indoor environments help people recover from stress and anxiety and those effects differ among different types of biophilic elements. To test these hypotheses, we conducted a between-subjects experiment with 100 participants using virtual reality (VR). Participants were randomly assigned to experience one of four virtual offices (i.e. one non-biophilic base office and three similar offices enhanced with different biophilic design elements) after stressor tasks. Their physiological indicators of stress reaction, including heart rate variability, heart rate, skin conductance level and blood pressure, were measured by bio-monitoring sensors. Their anxiety level was measured by using State-Trait Anxiety Inventory test (short version). We found that participants in biophilic indoor environments had consistently better recovery responses after stressor compare to those in the non-biophilic environment, in terms of reduction on stress and anxiety. Effects on physiological responses are immediate after exposure to biophilic environments with the larger impacts in the first four minutes of the 6-minute recovery process. Additionally, these restorative effects differ among three different types of indoor biophilic environments. This research provides evidence that biophilic design elements that impact stress recovery and anxiety. It also demonstrated the potential that virtual reality may be a way to bring nature and its therapeutic benefits to patients in hospitals., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© The Author(s) 2019. Published by Oxford University Press.)

Climate change is resulting in heatwaves that are more frequent, severe, and longer lasting, which is projected to double-to-triple the heat-related mortality in Boston, MA if adequate climate change mitigation and adaptation strategies are not implemented. A case-only analysis was used to examine subject and small-area neighborhood characteristics that modified the association between hot days and mortality. Deaths of Boston, Massachusetts residents that occurred from 2000-2015 were analyzed in relation to the daily temperature and heat index during the warm season as part of the case-only analysis. The modification by small-area (census tract, CT) social, and environmental (natural and built) factors was assessed. At-home mortality on hot days was driven by both social and environmental factors, differentially across the City of Boston census tracts, with a greater proportion of low-to-no income individuals or those with limited English proficiency being more highly represented among those who died during the study period; but small-area built environment features, like street trees and enhanced energy efficiency, were able to reduce the relative odds of death within and outside the home. At temperatures below current local thresholds used for heat warnings and advisories, there was increased relative odds of death from substance abuse and assault-related altercations. Geographic weighted regression analyses were used to examine these relationships spatially within a subset of at-home deaths with high-resolution temperature and humidity data. This revealed spatially heterogeneous associations between at-home mortality and social and environmental vulnerability factors., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed., Methods: The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and "other pharynx"), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality., Results: From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51-4.73] versus 1.82 (95% CI, 1.75-1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58-0.66) versus 1.38 (95% CI, 1.32-1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P < 0.001], but not non-OPSCC (aHR, 1.08; P = 0.81), P interaction = 0.002., Conclusions: The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx., Impact: This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC., (©2019 American Association for Cancer Research.)

Purpose: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN., Methods and Materials: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel., Results: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2)., Conclusions: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Postmastectomy radiation therapy (PMRT) delivered to an immediate reconstruction increases the risk of surgical complications. Although acellular dermal matrix (ADM) has been used with immediate tissue expander (TE) reconstruction to improve cosmetic outcomes and minimize capsular contracture, there is a paucity of data on this approach in the setting of PMRT., Methods and Materials: Thirty-two patients with stage I to III breast cancer were treated with mastectomy, immediate TE-ADM reconstruction, and PMRT between 2009 and 2012 in a prospective single-arm study. The primary objective was the "success" rate, determined by the number of patients at 2 years after PMRT having an intact final reconstruction, no major complications, and a cosmetic outcome rated by a physician as excellent or good., Results: The median follow-up was 24 months. Final reconstruction status was known in 31 of 32 patients (96.9%; 1 patient left the country) and completed in 29 of 31 patients (93.5%; implant, n = 26; flap, n = 1; both, n = 2; none, n = 2). At 2 years, 6 patients were unevaluable (metastatic disease, n = 3; withdrawn consent, n = 1; left the country, n = 2). Of 26 evaluable patients, the success rate was 65.4% (17 of 26). Lack of success was the result of "fair" cosmesis (n = 2), infection (n = 2), severe capsular contracture (n = 1), major revision (n = 2), and no final reconstruction (n = 2). Most patients had good-to-excellent 2-year overall cosmesis based on patient perception (15; 62.5%) and physician evaluation (19; 79.2%)., Conclusions: To the best of our knowledge, this is the first dedicated prospective trial evaluating long-term cosmetic and complication outcomes in patients treated with immediate TE-ADM reconstruction followed by PMRT. Most patients (65.4%) met the success criteria in this prospective single-arm series. The great majority (93.5%) achieved final reconstruction; most had good-to-excellent overall cosmetic outcomes (79.2%). The results with longer follow-up will be of interest, and further investigation of strategies to optimize reconstruction with PMRT are warranted., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives: Older patients make up the majority of patients with pancreatic cancer, with a median age of 71 years at diagnosis. However, older patients are underrepresented in clinical trials in pancreatic cancer. This study investigates trends in age distribution of patients enrolled in clinical trials for advanced pancreatic cancer over time, and examines outcomes and toxicity in older patient subgroups from two studies conducted by Eastern Cooperative Oncology Group and American College of Radiology Imaging Network (ECOG-ACRIN) in this disease., Materials and Methods: 16,042 patients from 38 phase III clinical trials for locally advanced or metastatic pancreatic adenocarcinoma published between 1997 and 2016 were identified and included in this analysis. Outcomes and toxicity by age were examined in two of the trials, ECOG-ACRIN trials E2297 and E6201, which included a total of 1146 patients., Results: The median age across the trials was 62.7 years; median ages for individual trials ranged from 57 years to 66 years. Weighted linear regression showed no significant change in median age over time. Combined analysis of the two ECOG-ACRIN trials demonstrated higher rates of fatigue, thrombocytopenia, and infection in those ≥75 years compared with those <75 years, but despite this showed no difference in overall survival (OS) or progression-free survival (PFS) (OS: 5.7 vs. 5.6 months and PFS: 2.8 vs 3.5 months)., Conclusions: Enrollment of older adults in phase III pancreatic cancer clinical trials has not increased over time, despite increasing number of older patients seen in clinic. Increased efforts are needed to enhance enrollment of older patients in clinical trials, and to promote trials specifically for older patients, in order to improve the evidence base for treating this patient population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Importance: Neurosurgical resection represents an important management strategy for patients with large, symptomatic brain metastases and increasingly is followed by stereotactic radiation as opposed to whole-brain radiation. Whether neurosurgical resection is associated with tumor spread beyond the resection site and adjuvant stereotactic radiation field remains unknown., Objective: To characterize the association and incidence of pachymeningeal seeding with neurosurgical resection in patients with brain metastases treated with adjuvant stereotactic radiation., Design, Setting, and Participants: Retrospective cohort study of a consecutive sample of patients with newly diagnosed brain metastases managed with neurosurgical resection and stereotactic radiation (n = 318) vs radiation alone (n = 870) between 2001 and 2015., Main Outcomes and Measures: Incidence of pachymeningeal seeding (dural and/or outer arachnoid) and leptomeningeal disease in patients treated with neurosurgical resection and stereotactic radiation vs radiation alone and the risk factors and outcomes associated with pachymeningeal seeding in patients treated with neurosurgical resection followed by stereotactic radiation., Results: In 1188 patients with newly diagnosed brain metastases, 133 men and 185 women (mean [SD] age, 58.9 [11.5] years) underwent neurosurgical resection. Resection was found to be associated with pachymeningeal seeding (36 of 318 patients vs 0 of 870 patients; P < .001) but not leptomeningeal disease (hazard ratio [HR], 1.14; 95% CI, 0.73-1.77; P = .56). In total, 36 (8.4%) of 428 operations were complicated by pachymeningeal seeding, with a higher incidence noted with resection of previously irradiated vs unirradiated metastases (HR, 2.39; 95% CI, 1.25-4.57; P = .008). Patients with pachymeningeal seeding had relatively low rates of subsequent development of new brain metastases and leptomeningeal disease (8 [16%] of 51 and 6 [13%] of 48, respectively). Among patients with pachymeningeal seeding, neurologic death primarily owing to progressive pachymeningeal disease accounted for 26 (72%) of 36 deaths, but when treated with salvage radiation, 49.1% of patients survived 1 year or longer., Conclusions and Relevance: In the era of omission of adjuvant whole-brain radiation after neurosurgical resection, pachymeningeal seeding beyond the stereotactic radiation field represents a notable oncologic event that often proves difficult to salvage. However, in some patients, disease control can be achieved with radiotherapeutic approaches.

Purpose: Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1)., Experimental Design: Endpoints based on RECISTv1.1 [objective response rate (ORR)/progression-free survival (PFS)] or irRECIST [immune-related ORR (irORR)/immune-related PFS (irPFS)] were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing., Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8 + tumor-infiltrating cells (TIC) that are PD-1 + TIM-3 - LAG-3 - (% CD8 + PD-1 + TIM-3 - LAG-3 - TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8 + PD-1 + TIM-3 - LAG-3 - TIC identified three groups of patients for which irPFS and irORR were significantly different., Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8 + TIC may predict outcome on nivolumab in mccRCC., (©2019 American Association for Cancer Research.)