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Background: Tissue-based genomic classifiers (GCs) have been developed to improve prostate cancer (PCa) risk assessment and treatment recommendations., Purpose: To summarize the impact of the Decipher, Oncotype DX Genomic Prostate Score (GPS), and Prolaris GCs on risk stratification and patient-clinician decisions on treatment choice among patients with localized PCa considering first-line treatment., Data Sources: MEDLINE, EMBASE, and Web of Science published from January 2010 to August 2024., Study Selection: Two investigators independently identified studies on risk classification and treatment choice after GC testing for patients with localized PCa considering first-line treatment., Data Extraction: Relevant data extracted by 1 researcher and overread by a second. Risk of bias (ROB) was assessed in duplicate., Data Synthesis: Ten studies reported risk reclassification after GC testing. In low ROB observational studies, very low- or low-risk patients with PCa were more likely to have their risk levels classified as the same or lower (GPS, 100% to 88.1%; Decipher, 87.2% to 82.9%; Prolaris, 76.9%). However, 1 randomized trial found that GC testing with GPS reclassified 34.5% of very low-risk and 29.4% of low-risk patients to a higher risk category. Twelve observational studies indicated that treatment decisions after GC testing either remained unchanged or slightly favored active surveillance. In contrast, analyses from a single randomized trial found fewer choices for active surveillance after GPS testing., Limitations: Heterogeneity in screening patterns, risk-determination cutoffs, pathology, and clinical practices. Studies on treatment choice were moderate to high ROB., Conclusion: Although GC tests do not consistently influence risk classification or treatment decisions, the differences observed between observational and randomized studies highlight a need for well-designed trials to explore the role of GC tests in patients with newly diagnosed PCa considering first-line treatment., Primary Funding Source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42022347950)., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: Recipients of radiation therapy (RT) for head and neck cancer (HNC) are at significantly increased risk for carotid artery stenosis (CAS) and cerebrovascular disease (CVD). We sought to determine (1) cumulative incidences of CAS and CVD among HNC survivors after RT and (2) whether CAS is associated with a RT dose response effect., Methods: This single-institution retrospective cohort study examined patients with nonmetastatic HNC who completed (chemo)RT from January 2000 through October 2020 and subsequently received carotid imaging surveillance ≤2 years following RT completion and, in the absence of CAS, every 3 years thereafter. Exclusion criteria included history of known CAS/CVD. Asymptomatic CAS was defined as ≥50% reduction of luminal diameter, symptomatic CAS as stroke or transient ischemic attack, and composite CAS as asymptomatic or symptomatic CAS., Results: Of 628 patients undergoing curative intent RT for HNC, median follow-up was 4.8 years (interquartile range, 2.6-8.3), with 97 patients followed ≥10 years. Median age was 61 years and 69% of patients received concurrent chemotherapy and 28% were treated postoperatively. Actuarial 10-year incidences of asymptomatic, symptomatic, and composite CAS were 29.6% (95% CI, 23.9-35.5), 10.1% (95% CI, 7.0-13.9), and 27.2% (95% CI, 22.5-32.1), respectively. Multivariable Cox models significant association between asymptomatic CAS and absolute carotid artery volume receiving ≥10 Gy (per mL: hazard ratio, 1.09; 95% CI, 1.02-1.16)., Conclusions: HNC survivors are at high risk for post-RT CAS. A dose response effect was observed for asymptomatic CAS at doses as low as 10 Gy., Plain Language Summary: Recipients of radiation therapy for head and neck cancer are at significantly increased risk for carotid artery stenosis and cerebrovascular disease. However, carotid artery screening is not routinely performed among head and neck survivors following radiation therapy. In this single-institution retrospective cohort study, patients with head and neck cancer were initially screened for carotid artery stenosis ≤2 years following radiation therapy completion, then every 3 years thereafter. The 10-year actuarial incidence of carotid artery stenosis was >25% and stroke/transient ischemic attack >10%. Multivariable analysis demonstrated significant associations between asymptomatic carotid artery stenosis and artery volumes receiving ≥10 Gy., (© 2023 American Cancer Society.)

The chronic toxicity of short chain perfluoroalkyl sulfonic acids (PFSAs), such as perfluorobutanesulfonic acid (PFBS) and perfluorohexanesulfonic acid (PFHxS), are relatively understudied despite the increasing detection of these compounds in the environment. We investigated the chronic toxicity and bioconcentration of PFBS and PFHxS using northern leopard frog (Rana [Lithobates] pipiens) tadpoles. We exposed Gosner stage (GS) 25 tadpoles to either PFBS or PFHxS at nominal concentrations of 0.1, 1, 10, 100, and 1000 μg/L until metamorphosis (GS42). We then assessed tadpole growth, development, stress, and immune metrics, and measured fatty acid (FA) composition and PFSA concentrations in liver and whole-body tissues. Tadpole growth and development measures were relatively unaffected by PFSA exposure. However, tadpoles exposed to 1000 μg/L PFBS or PFHxS had significantly increased hepatosomatic indexes (HSI) relative to controls. Further, tadpoles from the 1000 μg/L PFHxS treatment had altered FA profiles relative to controls, with increased total FAs, saturated FAs, monounsaturated FAs, and omega-6 polyunsaturated FAs. In addition, tadpoles from the 1000 μg/L PFHxS treatment had a higher probability of waterborne corticosterone detection. These results suggest that PFBS and PFHxS influence the hepatic health of tadpoles, and that PFHxS may alter lipid metabolism in tadpoles. We also observed a higher probability of tadpoles being phenotypically female after exposure to an environmentally relevant concentration (0.1 μg/L) of PFHxS, suggesting that PFHxS may exert endocrine disrupting effects on tadpoles during early development. The measured bioconcentration factors (BCFs) for both compounds were ≤10 L kg -1 wet weight, suggesting low bioconcentration potential for PFBS and PFHxS in tadpoles. Many of the significant effects observed in this study occurred at concentrations several orders of magnitude above those measured in the environment; however, our work shows effects of PFSAs exposure on amphibians and provides essential information for ecological risk assessments of these compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Purpose: Chat Generative Pre-Trained Transformer (ChatGPT), an artificial intelligence program that uses natural language processing to generate conversational-style responses to questions or inputs, is increasingly being used by both patients and health care professionals. This study aims to evaluate the accuracy and comprehensiveness of ChatGPT in radiation oncology-related domains, including answering common patient questions, summarizing landmark clinical research studies, and providing literature reviews with specific references supporting current standard-of-care clinical practice in radiation oncology., Methods and Materials: We assessed the performance of ChatGPT version 3.5 (ChatGPT3.5) in 3 areas. We evaluated ChatGPT3.5's ability to answer 28 templated patient-centered questions applied across 9 cancer types. We then tested ChatGPT3.5's ability to summarize specific portions of 10 landmark studies in radiation oncology. Next, we used ChatGPT3.5 to identify scientific studies supporting current standard-of-care practice in clinical radiation oncology for 5 different cancer types. Each response was graded independently by 2 reviewers, with discordant grades resolved by a third reviewer., Results: ChatGPT3.5 frequently generated inaccurate or incomplete responses. Only 39.7% of responses to patient-centered questions were considered correct and comprehensive. When summarizing landmark studies in radiation oncology, 35.0% of ChatGPT3.5's responses were accurate and comprehensive, improving to 43.3% when provided the full text of the study. ChatGPT3.5's ability to present a list of studies related to standard-of-care clinical practices was also unsatisfactory, with 50.6% of the provided studies fabricated., Conclusions: ChatGPT should not be considered a reliable radiation oncology resource for patients or providers at this time, as it frequently generates inaccurate or incomplete responses. However, natural language programming-based artificial intelligence programs are rapidly evolving, and future versions of ChatGPT or similar programs may demonstrate improved performance in this domain., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: While moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC) is commonly delivered by intensity modulated radiation therapy, IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in this context. We conducted a secondary analysis of the phase III RTOG 0415 trial comparing survival and toxicity outcomes for low-risk PC following MHRT with IMRT versus 3D-CRT., Methods: RTOG 0415 was a phase III, non-inferiority trial randomizing low-risk PC patients to either MHRT or conventionally fractionated radiation with stratification by RT technique. A secondary analysis for differences in overall survival (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed., Results: 1079 patients received the allocated intervention with a median follow up of 5.8 years. 79.1% of patients were treated with IMRT and radiation technique was balanced between arms. Across all patients, RT technique was not associated with significant differences in BRFS, OS, or rates of acute and late toxicities. For patients completing MHRT, there was a difference in the late GU toxicity distribution between 3D-CRT and IMRT but no difference in late grade 2 or greater GU or GI toxicity. Stratifying patients by RT technique and fractionation, no significant differences were observed in the minimal clinically important difference (MCID) in EPIC urinary and bowel scores following RT., Conclusions: RT technique did not impact clinical outcomes following MHRT for low-risk PC. Despite different late GU toxicity distributions in patients treated with MHRT by IMRT or 3D-CRT, there was no difference in late Grade 2 or greater GU or GI toxicity or patient reported toxicity. Increases in late GU and GI toxicity following MHRT compared to CFRT, as demonstrated in the initial publication of RTOG 0415, do not appear related to a 3D-CRT treatment technique., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Resistance training may offer several unique advantages within breast cancer (BC) survivorship care; however, safety concerns have limited the application of high-intensity compound movements necessary to elicit optimal changes in body composition, strength, and quality of life in this population. The EXERT-BC trial assesses the safety and feasibility of an evidence-based, dose-escalated resistance training regimen among BC survivors, with the goal of improving physical and metabolic function, mobility, muscle mass, and body composition., Methods: Participants included women with breast cancer underwent a 3-month thrice weekly exercise regimen involving dose escalation of high-intensity compound exercises. Coprimary outcomes included safety and adherence. Pre- and post-regimen assessment included body composition testing, functional mobility and balance, total load (weight × repetitions × sets) across compound exercises, and patient reported quality of life. Pairwise comparison was performed via the paired t test., Results: Fourty participants completed a 3-month exercise regimen, with a median age of 57 years (range, 27-74 years) and 73% having stage 0-2 BC. BC therapies concurrent with exercise included anti-estrogen therapy (80%), radiotherapy (30%), and non-hormonal systemic therapy (15%). No adverse events were observed aside from a single case of self-limited knee pain. Session attendance exceeded a prespecified threshold of 75%, and 98% patients reported ongoing compliance to an exercise regimen following regimen completion. Significant reductions in percent body fat (p < 0.001) and increases in percent muscle mass (p = 0.011) were observed. Significant increases in resting metabolic rate (p = 0.023), bilateral grip strength (p < 0.001), functional movement screen (p < 0.001), bilateral Y-Balance testing (p < 0.001), and Godin questionnaire scores (p < 0.001) were observed., Conclusion: A 3-month dose-escalated resistance training regimen comprising high-intensity compound movements appears safe with a high degree of adherence among breast cancer survivors, resulting in demonstrable improvements in body composition, metabolic parameters, strength increases, and patient-reported quality of life., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Clinical and imaging surveillance of patients with brain metastases is important after stereotactic radiosurgery (SRS) because many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood., Methods and Materials: This was a multi-institutional, retrospective cohort study from 2015 to 2020, including all patients with brain metastases completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP., Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow-up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients, respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median, 10.2 vs 17.9 months, P < .001). SITCP was associated with clinical factors including total treatment volume ( P = .012), melanoma histology ( P = .001), prior whole brain radiation therapy ( P = .003), number of brain metastases ( P < .001), interval of 1 to 2 years from primary and brain metastasis diagnosis ( P = .012), controlled extracranial disease ( P = .042), and receipt of pre-SRS chemotherapy ( P = .015). Patients who were younger and received post-SRS chemotherapy ( P = .001), immunotherapy ( P < .001), and targeted or small-molecule inhibitor therapy ( P < .026) had better FF-SITCP., Conclusions: In this cohort study of patients with brain metastases completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of brain metastases., (© 2024 The Author(s).)

Background: Refinement of the risk classification for localized prostate cancer is warranted to aid in clinical decision making. A systematic analysis was undertaken to evaluate the prognostic ability of three genomic classifiers, Decipher, GPS, and Prolaris, for biochemical recurrence, development of metastases and prostate cancer-specific mortality in patients with localized prostate cancer., Methods: Data sources: MEDLINE, Embase, and Web of Science were queried for reports published from January 2010 to April 2022., Study Selection: prospective or retrospective studies reporting prognosis for patients with localized prostate cancer., Data Extraction: relevant data were extracted into a customized database by one researcher with a second overreading. Risk of bias was assessed using a validated tool for prognostic studies, Quality in Prognosis Studies (QUIPS). Disagreements were resolved by consensus or by input from a third reviewer. We assessed the certainty of evidence by GRADE incorporating adaptation for prognostic studies., Results: Data synthesis: a total of 39 studies (37 retrospective) involving over 10,000 patients were identified. Twenty-two assessed Decipher, 5 GPS, and 14 Prolaris. Thirty-four studies included patients who underwent prostatectomy. Based on very low to low certainty of evidence, each of the three genomic classifiers modestly improved upon the prognostic ability for biochemical recurrence, development of metastases, and prostate cancer-specific mortality compared to standard clinical risk-classification schemes., Limitations: downgrading of confidence in the evidence stemmed largely from bias due to the retrospective nature of the studies, heterogeneity in treatment received, and era in which patients were treated (i.e., prior to the 2000s)., Conclusions: Genomic classifiers provide a small but consistent improvement upon the prognostic ability of clinical classification schemes, which may be helpful when treatment decisions are uncertain. However, evidence from current management-era data and of the predictive ability of these tests is needed., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC)., Methods: Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND)., Results: 255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND., Conclusion: Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort., Competing Interests: We thank Karen Allen for her assistance maintaining the prospective QA database. Authors’ disclosure of potential conflicts of interest The funding sources for this study (NIH grant R38CA24520401 to DJC, K08CA256045 to ZJR and NIH 5R38CA245204 to EJV and an Office of Physician Scientist Development Technician Award to EJV) had no role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication. ZJR has intellectual property managed by Duke University that has been licensed to GeneTron Health related to brain tumor genomic profiling tests, and has received honoraria from Eisai Pharmaceuticals and Oakstone Publishing. JK reported receiving grants from Varian Medical Systems and BioMimetix SBR, receiving personal fees from Monteris Medical, and owning ClearSight LLC outside the submitted work. None of the above entities played a role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication., (© 2024 Old City Publishing, Inc.)

Importance: Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS)., Objective: To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course., Design, Setting, and Participants: This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022., Exposures: Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus., Main Outcomes and Measures: The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach., Results: This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations., Conclusions and Relevance: The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Purpose: Existing brain metastasis prognostic models do not identify patients at risk of very poor survival after radiation therapy (RT). Identifying patient and disease risk factors for 30-day mortality (30-DM) after RT may help identify patients who would not benefit from RT., Methods and Materials: All patients who received stereotactic radiosurgery (SRS) or whole-brain RT (WBRT) for brain metastases from January 1, 2017, to September 30, 2020, at a single tertiary care center were included. Variables regarding demographics, systemic and intracranial disease characteristics, symptoms, RT, palliative care, and death were recorded. Thirty-day mortality was defined as death within 30 days of RT completion. The Kaplan-Meier method was used to estimate median overall survival. Univariate and multivariable logistic regression models were used to assess associations between demographic, tumor, and treatment factors and 30-DM., Results: A total of 636 patients with brain metastases were treated with either WBRT (n = 117) or SRS (n = 519). The most common primary disease types were non-small cell lung (46.7%) and breast (19.8%) cancer. Median survival time was 6 months (95% CI, 5-7 months). Of the 636 patients, 75 (11.7%) died within 30 days of RT. On multivariable analysis, progressive intrathoracic disease (hazard ratio [HR], 4.67; 95% CI, 2.06-10.60; P  = .002), progressive liver and/or adrenal metastases (HR, 2.20; 95% CI, 1.16-3.68; P  = .02), and inpatient status (HR, 4.51; 95% CI, 1.78-11.42; P  = .002) were associated with dying within 30 days of RT. A higher Karnofsky Performance Status (KPS) score (HR, 0.95; 95% CI, 0.93-0.97; P < .001), synchronous brain metastases at time of initial diagnosis (HR, 0.45; 95% CI, 0.21-0.96; P  = .04), and outpatient palliative care utilization (HR, 0.45; 95% CI, 0.20-1.00; P  = .05) were associated with surviving more than 30 days after RT., Conclusions: Multiple factors including a lower KPS, progressive intrathoracic disease, progressive liver and/or adrenal metastases, and inpatient status were associated with 30-DM after RT. A higher KPS, brain metastases at initial diagnosis, and outpatient palliative care utilization were associated with survival beyond 30 days. These data may aid in identifying which patients may benefit from brain metastasis-directed RT., (© 2023 The Authors.)

Purpose: For medically inoperable endometrial cancer (MIEC), the volumetric target of image-guided brachytherapy (IGBT) techniques is not well established. We propose a high-risk CTV (HRCTV) concept and report associated rates of local control and toxicity., Methods and Materials: For all MIEC patients receiving definitive external beam radiotherapy (EBRT) followed by MRI-based IGBT at a single institution, BT dose was prescribed to HRCTV defined as GTV plus endometrial cavity with a planning goal of a summed EQD2 D90 of ≥85 Gy. Freedom from local progression (FFLP) and overall survival (OS) were estimated via Kaplan Meier method., Results: Thirty two MIEC patients received EBRT followed by MRI-based IGBT between December 2015 and August 2020. Median follow up was 19.8 months. A total of 75% of patients had FIGO stage I/II disease, 56% endometrioid histology, and 50% grade 3 disease. OS was 73.6% (95% CI 57.8%-89.3%) at 12 months and 65.8% (95% CI 48.4%-83.2%) at 24 months. FFLP was 93.8% (95% CI 85.3%-100%) at 12 months and 88.8% (95% CI 86.6%-91.0%) at 24 months. 23 (72%) patients experienced no RT-related toxicity, while 2 of 32 patients (6%) experienced late grade 3+ toxicities (grade 3 refractory vomiting; grade 5 GI bleed secondary to RT-induced proctitis)., Conclusions: Patients with MIEC receiving definitive EBRT followed by MRI-based IGBT prescribed to the MRI-defined HRCTV demonstrated favorable long-term local control with an acceptable toxicity profile., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

There are many benefits to the addition of exercise to cancer treatment and survivorship, particularly with resistance training regimens that target hypertrophy, bone mineral density, strength, functional mobility, and body composition. These goals are best achieved through a series of individualized high-intensity compound movements that mirror functional mobility patterns and sufficiently stress the musculoskeletal system. As a result of adequate stress, the body will engage compensatory cellular mechanisms that improve the structural integrity of bones and muscles, stimulate metabolism and the immune system, optimize functional performance, and minimize mechanical injury risk. The current evidence suggests that application of the above exercise principles, practiced in a safe environment under expert observation, may offer patients with cancer an effective means of improving overall health and cancer-specific outcomes. The following article poses several important questions certified exercise specialists and physicians should consider when prescribing resistance exercise for patients with cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Hypofractionated stereotactic radiosurgery (HF-SRS) with or without surgical resection is potentially a preferred treatment for larger or symptomatic brain metastases (BMs). Herein, we report clinical outcomes and predictive factors following HF-SRS., Methods and Materials: Patients undergoing HF-SRS for intact (iHF-SRS) or resected (rHF-SRS) BMs from 2008 to 2018 were retrospectively identified. Linear accelerator-based image-guided HF-SRS consisted of 5 fractions at 5, 5.5, or 6 Gy per fraction. Time to local progression (LP), time to distant brain progression (DBP), and overall survival (OS) were calculated. Cox models assessed effect of clinical factors on OS. Fine and Gray's cumulative incidence model for competing events examined effect of factors on LP and DBP. The occurrence of leptomeningeal disease (LMD) was determined. Logistic regression examined predictors of LMD., Results: Among 445 patients, median age was 63.5 years; 87% had Karnofsky performance status ≥70. Fifty-three % of patients underwent surgical resection, and 75% received 5 Gy per fraction. Patients with resected BMs had higher Karnofsky performance status (90-100, 41 vs 30%), less extracranial disease (absent, 25 vs 13%), and fewer BMs (multiple, 32 vs 67%). Median diameter of the dominant BM was 3.0 cm (interquartile range, 1.8-3.6 cm) for intact BMs and 4.6 cm (interquartile range, 3.9-5.5 cm) for resected BMs. Median OS was 5.1 months (95% confidence interval [CI], 4.3-6.0) following iHF-SRS and 12.8 months (95% CI, 10.8-16.2) following rHF-SRS ( P < .01). Cumulative LP incidence was 14.5% at 18 months (95% CI, 11.4-18.0%), significantly associated with greater total GTV (hazard ratio, 1.12; 95% CI, 1.05-1.20) following iFR-SRS, and with recurrent versus newly diagnosed BMs across all patients (hazard ratio, 2.28; 95% CI, 1.01-5.15). Cumulative DBP incidence was significantly greater following rHF-SRS than iHF-SRS ( P  = .01), with respective 24-month rates of 50.0 (95% CI, 43.3-56.3) and 35.7% (95% CI, 29.2-42.2). LMD (57 events total; 33% nodular, 67% diffuse) was observed in 17.1% of rHF-SRS and 8.1% of iHF-SRS cases (odds ratio, 2.46; 95% CI, 1.34-4.53). Any radionecrosis and grade 2+ radionecrosis events were observed in 14 and 8% of cases, respectively., Conclusions: HF-SRS demonstrated favorable rates of LC and radionecrosis in postoperative and intact settings. Corresponding LMD and RN rates were comparable to those of other studies., (© 2022 The Authors.)

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan−Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1−11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1−17.1 months) and 7.6 months (95% CI 6.4−9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Background: The purpose of this review article is to summarize the existing literature surrounding wound healing mechanisms in laryngotracheal stenosis., Methods: A review of general wound healing pathophysiology, followed by a focused review of iatrogenic laryngotracheal stenosis (iLTS) and idiopathic subglottic stenosis (iSGS) as conditions of aberrant wound healing., Results: iLTS is the scarring of the laryngotracheal complex, coming secondary to injury from prolonged intubation. iSGS is a chronic fibroinflammatory scarring and narrowing of the subglottic airway in the absence of any obvious preceding injury or trauma. They are both thought to result from a prolonged and dysregulated wound healing response that promotes the deposition of pathologic scar in the airway., Conclusions: Understanding the mechanisms that underlie wound healing will help identify and intervene on the process early in its development and discover future therapies that target individual wound healing mechanisms limiting the incidence of this recalcitrant disease process., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer; however, limited MHRT data address high-risk prostate cancer (HRPC) and/or African American patients. We report clinical outcomes and toxicity profiles for individuals with HRPC treated in an equal access system., Methods: We identified patients with HRPC treated with MHRT at a US Department of Veterans Affairs referral center. Exclusion criteria included < 12 months follow-up and elective nodal irradiation. MHRT included 70 Gy over 28 fractions or 60 Gy over 20 fractions. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events, version 5.0. Clinical endpoints, including biochemical recurrence-free survival (BRFS), distant metastases-free survival (DMFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using Kaplan-Meier methods. Clinical outcomes, acute toxicity, and late toxicity-free survival were compared between African American and White patients with logistic regression and log-rank testing., Results: Between November 2008 and August 2018, 143 patients with HRPC were treated with MHRT and followed for a median of 38.5 months; 82 (57%) were African American and 61 were White patients. Concurrent androgen deprivation therapy (ADT) was provided for 138 (97%) patients for a median duration of 24 months. No significant differences between African American and White patients were observed for 5-year OS (73% [95% CI, 58%-83%] vs 77% [95% CI, 60%-97%]; P = .55), PCSS (90% [95% CI, 79%-95%] vs 87% [95 % CI, 70%-95%]; P = .57), DMFS (91% [95% CI, 80%-96%] vs 81% [95% CI, 62%-91%]; P = .55), or BRFS (83% [95% CI, 70%-91%] vs 71% [95% CI, 53%-82%]; P = .57), respectively. Rates of acute grade 3+ GU and GI were low overall (4% and 1%, respectively). Late toxicities were similarly favorable with no significant differences by race., Conclusions: Individuals with HRPC treated with MHRT in an equal access setting demonstrated favorable clinical outcomes that did not differ by race, alongside acceptable rates of acute and late toxicities., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2022 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Purpose: To evaluate the effect of prostate volume on outcomes after moderately hypofractionated radiation therapy (mHFRT) for prostate cancer., Methods and Materials: Prostate cancer patients treated with mHFRT at a Veteran's Affairs Medical Center from August 20, 2008, to January 31, 2018, were identified. Patients were placed into a large prostate planning target volume (LPTV) cohort if their prostate PTV was in the highest quartile. Acute/late genitourinary (GU) and gastrointestinal toxicity events among patients with and without LPTV were compared. Multivariable analyses estimated the effect of factors on toxicity. Overall survival, biochemical recurrence-free survival, and freedom from late GU/gastrointestinal toxicity of patients with and without LPTV were estimated via Kaplan-Meier., Results: Four hundred and seventy-two patients were included. Ninety-three percent received 70 Gy in 2.5 Gy fractions; 75% received androgen deprivation therapy. Median follow-up was 69 months. Patients with LPTV (PTV >138.4 cm 3 ) had a higher late 2 + GU toxicity compared with those without (59% vs 48%, P  = .03). Earlier time to late 2 + GU toxicity was associated with LPTV (hazard ratio 1.36; 95% confidence interval [CI], 1.00-1.86; P  = .047), androgen deprivation therapy use (hazard ratio 1.60; 95% CI, 1.13-2.27; P  = .01), and higher baseline American Urologic Association symptom score (odds ratio 1.03; 95% CI, 1.02-1.05; P < .001). At 2 years, freedom from late 2 + GU toxicity was 46% (95% CI, 47%-54%) for those with LPTV versus 61% (95% CI, 55%-65%) for those without ( P  = .04). Late grade 3 GU toxicity was 7% for those with LPTV and 4% for those without. No differences in overall survival or biochemical recurrence-free survival were observed between patients with or without LPTV., Conclusions: LPTV did not affect efficacy of mHFRT for prostate cancer; however, it was associated with increased risk and earlier onset of late grade 2 + GU toxicity., (© 2021 The Authors.)

Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

Herbicides have been shown to reduce flower production and to delay flowering, with results varying among herbicides and tested plant species. We investigated the effects of herbicides on flowering in an extensive greenhouse study conducted in Canada and Denmark. The effects of low doses of 5 different herbicides (bromoxynil, ioxynil + bromoxynil, metsulfuron-methyl, clopyralid, and glyphosate), simulating realistic drift scenarios (1 and 5% recommended field rates), on plant flowering were examined using 9 wild plant species exposed at either the seedling (6- to 8-leaf) or flower bud stage. Following herbicide exposure, initial flowering date as well as flower production over time were recorded over the growing period. The effect of herbicides on cumulative flower numbers and flowering time were modeled using Gompertz growth models. Significant delays to peak flowering and/or reductions in flower production were observed in at least one plant species for all tested herbicides, with glyphosate often exhibiting the greatest negative effects, that is, plant death. Except for ioxynil + bromoxynil, there was no clear evidence of either the seedling or the flower bud stage being more sensitive. Overall, 58% of all species × life stage × herbicide treatments resulted in either a statistically significant or a strong decline in flower production with herbicide application rates up to 5% of recommended field rates, whereas significant or strong delays in peak flowering were also detected but were slightly less common. Effects at 1% label rates were minimal. Simultaneous delays to peak flowering and reductions in total flower production occurred in approximately 25% of all cases, indicating that herbicide application rates simulating realistic drift scenarios would likely have negative effects on wild floral communities. Environ Toxicol Chem 2020;39:1244-1256. © 2020 SETAC., (© 2020 SETAC.)

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Non-recirculating tissue-resident memory T cells (TRMs) are the predominant T cell subset in diverse tissue sites, where they mediate protective immune responses in situ. Here, we reveal a role for TRM in maintaining immune homeostasis in the human pancreas through interactions with resident macrophages and the PD-1/PD-L1 inhibitory pathway. Using tissues obtained from organ donors, we identify that pancreas T cells comprise CD8 + PD-1 hi TRMs, which are phenotypically, functionally, and transcriptionally distinct compared to TRMs in neighboring jejunum and lymph node sites. Pancreas TRMs cluster with resident macrophages throughout the exocrine areas; TRM effector functions are enhanced by macrophage-derived co-stimulation and attenuated by the PD-1/PD-L1 pathways. Conversely, in samples from chronic pancreatitis, TRMs exhibit reduced PD-1 expression and reduced interactions with macrophages. These findings suggest important roles for PD-1 and TRM-macrophage interactions in controlling tissue homeostasis and immune dysfunctions underlying inflammatory disease, with important implications for PD-1-based immunotherapies., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess whether radiographic and metabolic changes on midchemoradiation therapy (CRT) fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for cervical cancer predict outcome., Methods and Materials: Women with International Federation of Gynecology and Obstetrics stage IB1-IVB cervical cancer treated with concurrent cisplatin-based CRT and brachytherapy were enrolled on a single-institution prospective clinical trial; FDG-PET/CT was obtained before CRT and at 30 to 36 Gy. Max and mean standard uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) for the primary tumor and clinically involved lymph nodes from the pre-CRT and intra-CRT FDG-PET/CT were recorded. Clinical endpoints analyzed include overall survival (OS), disease-free survival (DFS), and rates of cervical recurrence (CR), nodal recurrence (NR), and distant metastasis (DM). FDG-PET/CT variables and other prognostic factors associated with clinical endpoints were identified via univariate Cox proportional hazards modeling and competing risk analysis., Results: Thirty women were enrolled from 2012 to 2016. After a median follow-up of 24 months, 2-year rates of OS, DFS, DM, NR, and CR were 68% (95% confidence interval [CI], 51%-85%), 44% (95% CI, 26%-63%), 42% (95% CI, 23%-59%), 14% (95% CI, 4%-30%), and 10% (95% CI, 2%-24%), respectively. Intra-PET metrics and TLG across all PET scans were most consistently associated with OS, DFS, DM, and NR on univariate analysis. Intra-CRT TLG was associated with OS (hazard ratio [HR] 1.35; 95% CI, 1.15-1.55; P = .001), DFS (HR 1.19; 95% CI, 1.04-1.34; P = .018), and NR (HR 1.25; 95% CI, 1.10-1.40; P = .002). No absolute or relative changes between parameters of baseline and mid-CRT FDG-PET/CT were associated with disease outcomes on univariate analysis, with the exception of relative change in mean standard uptake values and CR (P = .004)., Conclusions: In this group of patients with high-risk cervical cancer treated with CRT and brachytherapy, TLG and metabolic tumor volume on intra-CRT FDG-PET/CT was associated with OS. These metrics may provide an early signal for selective treatment intensification with either dose escalation or adjuvant chemotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nearly two-thirds of cancer patients are treated with radiation therapy (RT), often with the intent to achieve complete and permanent tumor regression (local control). RT is the primary treatment modality used to achieve local control for many malignancies, including locally advanced cervical cancer, head and neck cancer, and lung cancer. The addition of concurrent platinum-based radiosensitizing chemotherapy improves local control and patient survival. Enhanced outcomes with concurrent chemoradiotherapy may result from increased direct killing of tumor cells and effects on nontumor cell populations. Many patients treated with concurrent chemoradiotherapy exhibit a decline in neutrophil count, but the effects of neutrophils on radiation therapy are controversial. To investigate the clinical significance of neutrophils in the response to RT, we examined patient outcomes and circulating neutrophil counts in cervical cancer patients treated with definitive chemoradiation. Although pretreatment neutrophil count did not correlate with outcome, lower absolute neutrophil count after starting concurrent chemoradiotherapy was associated with higher rates of local control, metastasis-free survival, and overall survival. To define the role of neutrophils in tumor response to RT, we used genetic and pharmacological approaches to deplete neutrophils in an autochthonous mouse model of soft tissue sarcoma. Neutrophil depletion prior to image-guided focal irradiation improved tumor response to RT. Our results indicate that neutrophils promote resistance to radiation therapy. The efficacy of chemoradiotherapy may depend on the impact of treatment on peripheral neutrophil count, which has the potential to serve as an inexpensive and widely available biomarker., Competing Interests: Conflict of interest statement: D.G.K. is a cofounder of XRAD Therapeutics, which is developing radiosensitizers.

Plant competitive interactions influence the effect of herbicides, and the effect of competitive interactions on plant responses may be important to include in the ecological risk assessment of herbicides. In the present study the effect of competitive interactions and sublethal doses of 2 herbicides on plant species was investigated in competition experiments and fitted to empirical competition models. Two nontarget species commonly found in agroecosystems (Centaurea cyanus L. and Silene noctiflora L.) and 2 herbicides (glyphosate and metsulfuron methyl) were used in separate experiments. Plants were sprayed at the 6- to 8-leaf stage. Effects of herbicide treatments and plant density were modeled by generalization of a discrete hyperbolic competition model. The 10% effective dose (ED10) was calculated for C. cyanus. All experiments showed that as density increased, plants were negatively affected. Furthermore, in all cases, C. cyanus remained a better competitor than S. noctiflora. Nevertheless, the density of S. noctiflora (competitor) was an influential element in determining the ED10 of C. cyanus measured at the mature stage. With herbicide exposure, the competitive interactions were further altered; C. cyanus was less affected by glyphosate when S. noctiflora increased to high density. In contrast, at the young stage, conspecific density was important in determining the sensitivity of C. cyanus to metsulfuron methyl, whereas the density of the competitor S. noctiflora had a limited influence. Overall, the results demonstrate the importance of integrating the effect of herbicide and species interactions measured at the reproductive stage into the ecological risk assessments of pesticides. Environ Toxicol Chem 2019;38:2053-2064. © 2019 SETAC., (© 2019 SETAC.)

Background: Understanding factors that contribute to liver discards and nonusage is urgently needed to improve organ utilization., Methods: Using Scientific Registry of Transplant Recipient data, we studied a national cohort of all US adult, deceased brain dead donor, isolated livers available for transplantation from 2003 to 2016, including organ-specific and system-wide factors that may affect organ procurement and discard rates., Results: Of 73 686 available livers, 65 316 (88.64%) were recovered for transplant, of which 6454 (9.88%) were ultimately discarded. Livers that were not procured or, on recovery, discarded were more frequently from older, heavier, hepatitis B virus (HCV)+, and more comorbid donors (P < 0.001). However, even after adjustment for organ quality, the odds of liver nonusage were 11% higher on the weekend (defined as donor procurements with cross-clamping occurring from 5:00 PM Friday until 11:59 AM Sunday) compared with weekdays (P < 0.001). Nonuse rates were also higher at night (P < 0.001), defined as donor procurements with cross-clamping occurring from 5:00 PM to 5:00 AM; however, weekend nights had significantly higher nonuse rates compared with weekday nights (P = 0.005). After Share 35, weekend nonusage rates decreased from 21.77% to 19.51% but were still higher than weekday nonusage rates (P = 0.065). Weekend liver nonusage was higher in all 11 United Network of Organ Sharing regions, with an absolute average of 2.00% fewer available livers being used on the weekend compared with weekdays., Conclusions: Although unused livers frequently have unfavorable donor characteristics, there are also systemic and operational factors, including time of day and day of the week a liver becomes available, that impact the chance of liver nonprocurement and discard.

Background: Nasal airway obstruction (NAO) due to nasal anatomic deformities is known to be more common among cleft patients than the general population, yet information is lacking regarding severity and variability of cleft-associated nasal obstruction relative to other conditions causing NAO. This preliminary study compares differences in NAO experienced by unilateral cleft lip nasal deformity (uCLND) subjects with noncleft subjects experiencing NAO., Methods: Computational modeling techniques based on patient-specific computed tomography images were used to quantify the nasal airway anatomy and airflow dynamics in 21 subjects: 5 healthy normal subjects; 8 noncleft NAO subjects; and 8 uCLND subjects. Outcomes reported include Nasal Obstruction Symptom Evaluation (NOSE) scores, cross-sectional area, and nasal resistance., Results: uCLND subjects had significantly larger cross-sectional area differences between the left and right nasal cavities at multiple cross sections compared with normal and NAO subjects. Median and interquartile range (IQR) NOSE scores between NAO and uCLND were 75 (IQR = 22.5) and 67.5 (IQR = 30), respectively. Airflow partition difference between both cavities were: median = 9.4%, IQR = 10.9% (normal); median = 31.9%, IQR = 25.0% (NAO); and median = 29.9%, IQR = 44.1% (uCLND). Median nasal resistance difference between left and right nasal cavities were 0.01 pa.s/ml (IQR = 0.03 pa.s/ml) for normal, 0.09 pa.s/ml (IQR = 0.16 pa.s/ml) for NAO and 0.08 pa.s/ml (IQR = 0.25 pa.s/ml) for uCLND subjects., Conclusions: uCLND subjects demonstrated significant asymmetry between both sides of the nasal cavity. Furthermore, there exists substantial disproportionality in flow partition difference and resistance difference between cleft and noncleft sides among uCLND subjects, suggesting that both sides may be dysfunctional.

Purpose: The aim of the current work was to quantify internally inconsistent and anomalous radiation therapy (RT) data in the National Cancer Database (NCDB) and determine their association with overall survival (OS) using node-positive uterine cancer as a test clinical scenario., Materials and Methods: We identified all NCDB participants with International Federation of Gynecology and Obstetrics stage IIIC1 to IIIC2 uterine cancer treated with hysterectomy and adjuvant RT between 1998 and 2012. Variables that were reviewed to identify anomalous data included RT site, modality, dose, fractions, timing, duration, and stage. We used χ 2 testing to associate anomalous data with reporting facility and demographic variables. OS was estimated using the Kaplan-Meier method and comparison between cohorts was performed using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were performed., Results: Of the 14,298 analyzed participants, 2,288 (16.0%) had one or more anomalous data entry, 538 (3.8%) likely because of an incomplete RT course. χ 2 testing suggested differences in anomalous data prevalence by reporting facility type ( P = .0007), geographic region ( P < .001), distance from participants' homes ( P < .001), diagnosis year ( P < .001), and location of RT relative to reporting facility ( P = .0038). Five-year OS in those with one or more anomalous data entry was 51.3% versus 58.0% for those without anomalous data ( P < .001), and anomalous data remained significantly associated with OS on multivariable analysis. After excluding insufficient, excessive, or unknown total RT dose, anomalous data were no longer significant on multivariable analysis., Conclusion: The overwhelming majority of RT data within the NCDB seem to be appropriate for the clinical scenario. Nevertheless, approximately one eighth of participants in this test clinical scenario had adjuvant RT data that were internally inconsistent or outside generously defined norms. The presence of anomalous RT data was significantly associated with compromised OS, an effect not observed after correcting for total RT dose.

Defining adaptive immunity with the complex structures of the human gastrointestinal (GI) tract over life is essential for understanding immune responses to ingested antigens, commensal and pathogenic microorganisms, and dysfunctions in disease. We present here an analysis of lymphocyte localization and T cell subset composition across the human GI tract including mucosal sites (jejunum, ileum, colon), gut-associated lymphoid tissues (isolated lymphoid follicles (ILFs), Peyer's patches (PPs), appendix), and mesenteric lymph nodes (MLNs) from a total of 68 donors spanning eight decades of life. In pediatric donors, ILFs and PP containing naïve T cells and regulatory T cells (Tregs) are prevalent in the jejunum and ileum, respectively; these decline in frequency with age, contrasting stable frequencies of ILFs and T cell subsets in the colon. In the mucosa, tissue resident memory T cells develop during childhood, and persist in high frequencies into advanced ages, while T cell composition changes with age in GALT and MLN. These spatial and temporal features of human intestinal T cell immunity define signatures that can be used to train predictive machine learning algorithms. Our findings demonstrate an anatomic basis for age-associated alterations in immune responses, and establish a quantitative baseline for intestinal immunity to define disease pathologies.

Importance: Because of the recurrent nature of idiopathic subglottic stenosis, routine follow-up is necessary for monitoring progression of stenosis. However, no easily accessible, standardized objective measure exists to monitor disease progression., Objective: To determine whether peak expiratory flow (PEF) can be used as a reliable and easily accessible biometric indicator of disease progression relative to other validated spirometry measures in patients with idiopathic subglottic stenosis., Design, Setting, and Participants: Prospectively collected data on PEF, expiratory disproportion index (EDI), and total peak flow (TPF) from 42 women with idiopathic subglottic stenosis without comorbid lower airway or parenchymal lung disease who were treated at a single tertiary referral center between 2014 and 2018 were analyzed. The mean follow-up period was 18.2 months (range, 2-40 months). Ten patients initially screened were not included in the analysis owing to comorbid glottic or supraglottic stenosis or nonidiopathic etiology., Main Outcomes and Measures: Measurements of PEF, EDI, and TPF were taken at preoperative visits and at all other visits., Results: Forty-two women (mean age, 51.5 years; 98% white [n = 41]) met the inclusion criteria. The area under the curve for PEF was 0.855 (95% CI, 0.784-0.926). The optimal cutoff value was 4.4 liters per second (264 L/min), with a sensitivity and specificity of 84.4% and 82.0%, respectively. The area under the curve for EDI was 0.853 (95% CI, 0.782-0.925). For TPF, this was 0.836 (95% CI, 0.757-0.916)., Conclusions and Relevance: This study provides evidence supporting the use of PEF as a simple, efficient, and accessible way of monitoring progression of idiopathic subglottic stenosis and predicting receipt of surgical intervention. Sensitivity and specificity of PEF were comparable to those of the more complex measures of TPF and EDI.

Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-γ and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function.

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires 'fit-for-purpose' formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH. This phenomenon is known to result in potential risk of variable and decreased exposure in vivo. Combination of citrate buffer at pH 3.0 and hydroxypropylbetadex enabled formulation of DNS-7801 solutions that were stable as formulated and up on manipulation for oral administration. The solutions were compatible with apple juice, used to mask (blind) the potential taste differences between the placebo and DNS-7801 solutions when dosing study subjects. The oral administration of the solutions resulted in dose proportional C max , AUC 0-24 , and AUC 0-∞ of DNS-7801 in non-elderly and elderly subjects. A key advantage of the use of an EP approach with DNS-7801 was the flexibility in dose selection that this approach offered because DNS-7801 concentration in the preparation and/or volume could be readily adjusted based on real-time cohort data., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes [LN]) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. In this study, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors and identify a subset of memory CD8 + T cells in LN, which maintain a distinct differentiation and functional profile compared with memory CD8 + T cells in blood, spleen, bone marrow, and lungs. Whole-transcriptome and high-dimensional cytometry by time-of-flight profiling reveals that LN memory CD8 + T cells express signatures of quiescence and self-renewal compared with corresponding populations in blood, spleen, bone marrow, and lung. LN memory T cells exhibit a distinct transcriptional signature, including expression of stem cell-associated transcription factors TCF-1 and LEF-1, T follicular helper cell markers CXCR5 and CXCR4, and reduced expression of effector molecules. LN memory T cells display high homology to a subset of mouse CD8 + T cells identified in chronic infection models that respond to checkpoint blockade immunotherapy. Functionally, human LN memory T cells exhibit increased proliferation to TCR-mediated stimulation and maintain higher TCR clonal diversity compared with memory T cells from blood and other sites. These findings establish human LN as reservoirs for memory T cells with high capacities for expansion and diverse recognition and important targets for immunotherapies., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The proportion of deceased donor kidneys procured for transplant but subsequently discarded has been growing steadily in the United States, but factors contributing to the rising discard rate remain unclear. To assess the reasons for and probability of organ discard we assembled a cohort of 212,305 deceased donor kidneys recovered for transplant from 2000-2015 in the SRTR registry that included 36,700 kidneys that were discarded. 'Biopsy Findings' (38.2%) was the most commonly reported reason for discard. The median Kidney Donor Risk Index of discarded kidneys was significantly higher than transplanted organs (1.78 vs 1.12), but a large overlap in the quality of discarded and transplanted kidneys was observed. Kidneys of donors who were older, female, Black, obese, diabetic, hypertensive or HCV-positive experienced a significantly increased odds of discard. Kidneys from donors with multiple unfavorable characteristics were more likely to be discarded, whereas unilaterally discarded kidneys had the most desirable donor characteristics and the recipients of their partner kidneys experienced a one-year death-censored graft survival rate over 90%. There was considerable geographic variation in the odds of discard across the United States, which further supports the notion that factors beyond organ quality contributed to kidney discard. Thus, while the discard of a small fraction of organs procured from donors may be inevitable, the discard of potentially transplantable kidneys needs to be avoided. This will require a better understanding of the factors contributing to organ discard in order to remove the disincentives to utilize less-than-ideal organs for transplantation., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: Head and neck radiotherapy (RT) is a risk factor for cerebrovascular disease. We performed a retrospective cohort study to evaluate carotid artery stenosis (CAS) incidence in head and neck cancer (HNC) patients undergoing RT, characterizing associated risk factors., Materials and Methods: Records were retrospectively reviewed for HNC patients undergoing carotid ultrasound screening after definitive or adjuvant RT between January 2000 and May 2016. CAS was defined as ≥50% stenosis on imaging, stroke, or transient ischemic attack. Actuarial CAS rates were calculated by Kaplan-Meier method. Univariate and multivariate analyses predicted CAS risk based on carotid dosimetric and clinical parameters., Results: 366 patients met inclusion criteria. Median time from RT completion to last follow-up was 4.1 yr. Actuarial risk for CAS was 29% (95% CI 22-36%) at 8 years. Univariate analysis showed that smoking (HR 1.7; 95% CI 1.1-2.7), hyperlipidemia (HR 1.6; 95% CI 1.03-2.6), diabetes (HR 2.8; 95% CI 1.6-4.8), coronary artery disease (HR 2.4; 95% CI 1.4-4.2), and peripheral artery disease (HR 3.6; 95% CI 1.1-11.6) were significantly associated with increased CAS. In multivariate analysis, diabetes was predictive of time to CAS (HR 1.9; 95% CI 1.1-3.4). Carotid dose parameters were not significantly associated with CAS., Conclusions: CAS incidence is high after head and neck radiotherapy, gradually rising over time. No clear dose-response effect between carotid dose and CAS was identified for HNC patients. Carotid artery screening and preventative strategies should be employed in this high-risk patient population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Optical spectroscopy offers a noninvasive alternative to biopsy as a first-line screening tool for suspicious skin lesions. This study sought to define several optical parameters across malignant and benign tissue types., Study Design: Prospective pilot trial utilizing the Zenalux IM1 optical spectroscopy device from April 2016 to February 2017. For each skin lesion, provider pre-biopsy probability of malignancy was compared to histolopathologic diagnosis. Optical data were characterized across basal cell carcinoma (BCC; n = 9), squamous cell carcinoma (SCC; n = 5), actinic keratosis (AK; n = 4), scar tissue (n = 6), nevus (n = 2), and neurofibroma (NF; n = 1). Across all patients, agreement was determined between control measurements collected adjacent to the lesion and from the upper extremity., Methods: Prospective single center pilot study. The optical properties of 27 cutaneous lesions were collected from 18 adult patients presenting to Otolaryngology and Dermatology clinics with suspicious skin lesions warranting biopsy. Spectroscopy measurements were recorded for each lesion: two at the lesion site, two at an adjacent site (internal control), and one at the central medial upper extremity (arm control). Variables of interest included absolute oxygenated hemoglobin (Hb), Hb saturation, total Hb concentration, and Eumelanin concentration. For each lesion, internal control averages were subtracted from lesion averages to provide delta parameter values, and lesion averages were divided by internal control averages to provide ratio parameter values., Results: Mean percent difference between pre-biopsy probability of malignancy and histology was 29%, with a difference of 75% or greater seen in 5 of 25 lesions. Mean values for BCC, SCC, AK, and scar tissue varied most between extracted mean reduced scatter estimate (μa'; cm - ) delta values (BCC: -2.2 ± 3.8; SCC: -3.9 ± 2.0; AK: -3.3 ± 4.2, Scar: -1.7 ± 1.2) and total Hb (µM) ratio (BCC: 2.0 ± 3.3; SCC: 3.0 ± 1.3; AK: 1.1 ± 0.6; Scar: 1.4 ± 1.1). Agreement between local and arm controls was poor., Conclusion: This pilot trial utilizes optical spectroscopy as a noninvasive method for determining cutaneous lesion histology. Effect sizes observed across optical parameters for benign and malignant tissue types will guide larger prospective studies that may ultimately lead to prediction of lesional histology without need for invasive biopsy. Lasers Surg. Med. 50:246-252, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Superior semicircular canal dehiscence (SCD) remains difficult to diagnose despite advances in high-resolution computed tomography (HRCT) imaging. We hypothesize possible associations between gross temporal bone anatomy and sub-millimeter pathology of the semicircular canals, which may supplement imaging and clinical suspicion. This pilot study investigates differences in gross temporal bone anatomic parameters between temporal bones with and without SCD., Methods: Records were reviewed for 18 patients referred to an otology clinic complaining of dizziness with normal caloric stimulation results indicative of non-vestibular findings. Eleven patients had normal temporal bone anatomy while seven had SCD. Three-dimensional reconstruction of every patient's temporal bone anatomy was created from patient-specific computational tomography images. Surface area (SA), volume (V), and SA to V ratios (SA:V) were computed across temporal bone anatomical parameters., Results: SCD temporal bones have significantly smaller V, and larger temporal bone SA. Mean (±SD) V was 21,484 ± 3,921 mm 3 in temporal bones without SCD and 16,343 ± 34,471 mm 3 for those with SCD. Their respective SA were 13,733 ± 1,603 mm 2 and 18,073 ± 3,002 mm 2 . Temporal bone airspaces and lateral semicircular canals did not demonstrate significant differences where SCD was and was not present. Plots of MV warm response against computed SCD temporal bone anatomic parameters (SA, V and SA:V) showed moderate to strong correlations: temporal bone SA:V (r = 0.64), temporal bone airspace V (r = 0.60), temporal bone airspace SA (r = 0.55), LSCC SA (r = 0.51), and LSCC-to-TM Distance (r = 0.65)., Conclusions: This analysis demonstrated that SCD is associated with decreased temporal bone volume and density. The defect in SCD does not appear to influence caloric responses.

Background: Distinguishing eosinophilic nasal polyps (NP) from noneosinophilic NP will impact prognosis and therapeutic responsiveness., Objective: To investigate the ability of clinical history and biomarkers to distinguish these conditions., Methods: A total of 74 consecutive patients undergoing surgery for NP were enrolled. Clinical presentations were evaluated using the 22-item sinonasal outcome test (SNOT-22). Biomarkers included absolute eosinophil count, IgE, and extent of tissue hyperplasia on sinus computed tomography scan. Tissue eosinophilia was quantified in 10 random hpf and data analyzed addressing both peak and average results., Results: No component of the SNOT-22 was predictive of tissue eosinophilia. Similarly, a medical history of allergic rhinitis, asthma, or aspirin-exacerbated respiratory disease was not predictive. An absolute eosinophil count of more than 300 was associated with NP tissue eosinophilia. In contrast, neither IgE nor extent of sinus computed tomography hyperplasia was predictive., Conclusions: The ability to individualize therapies for NP is dependent on identifying clinical features or biomarkers of eosinophilia. However, with the exception of circulating eosinophilia, we could not identify a clinical feature or biomarker that robustly predicted the presence of tissue eosinophilia. Even more problematic, even the seeming "criterion standard" determination of tissue pathology was of limited value, as our cohort displayed a continuous spectrum of tissue eosinophil expression, making arbitrary any definitive cutoff distinguishing these conditions., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69 + subset of memory CD4 + and CD8 + T cells in lung and spleen that is distinct from that of CD69 - TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8 + TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks-one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

Objectives: Recent studies have introduced middle ear volume (MEV) as a novel determinant of perforation-induced conductive hearing loss (CHL) in a mechanism driven by trans-tympanic membrane pressure differences. The primary aims of this preliminary report are to: 1) correlate CHL with perforation size; 2) describe the relationship between CHL and MEV; and 3) compare CHL across a range of cholesteatoma involvement., Design: A retrospective pilot study was performed in 31 subjects with audiometry indicative of conductive hearing loss, temporal bone CT scans, and no prior middle ear surgery. Perforation size and MEV were analyzed with respect to CHL in a cohort of 10 perforated ears with no cholesteatoma. CHLs were compared in 3 groups defined by extent of cholesteatoma involvement., Results: Ears with large and small perforations showed mean ABG values of 32.0 ± 15.7 dB and 16.0 ± 16.4 dB, respectively. A direct relationship was observed between MEV and CHL for ears with large perforations across all frequencies, whereas this relationship for small perforations was frequency-dependent. Finally, a statistically significant increase in CHL was found across ears with increasing cholesteatoma involvement at 1000 Hz (χ 2 (2) = 9.786, p = 0.008), 2000 Hz (χ 2 (2) = 8.455, p = 0.015), and 4000 Hz (χ 2 (2) = 8.253, p = 0.016)., Conclusions: These pilot data suggest that greater perforation-induced conductive hearing losses may be associated with larger perforation sizes and cholesteatoma. The correlation between MEV and CHL may require additional study.

Introduction: Middle ear volume (MEV) is a clinically relevant parameter across middle ear diseases. MEV values between these techniques have never before been tested for agreement in ears with perforated tympanic membranes (TMs)., Methods: Middle ears were identified from 36 patients ranging 18-89 years of age with TM perforations who underwent tympanometry and temporal bone computed tomography (CT) between 2005 and 2015. MEVs calculated by both tympanometry and three-dimensional volume reconstruction (3DVR) were analyzed for agreement using Bland Altman plots. The differences between tympanometric and 3DVR MEV values for each given middle ear were characterized across MEV quartiles (1 = smallest; 4 = largest) and across increasing states of middle ear disease using Kruskal-Wallis and Wilcoxon testing with Bonferroni correction., Results: Bland Altman plots demonstrated significant disagreement between MEV measurement techniques. Differences between tympanometric (T) and 3DVR MEV values were significantly greater with increasing average (i.e. (T+3DVR)/2)) MEV per linear regression (p < 0.0001). Significance was demonstrated between fourth and first average MEV quartiles (p = 0.0024), fourth and second quartiles (p = 0.0024), third and first quartiles (p = 0.0048), and third and second quartiles (p = 0.048). Absolute MEV difference was not significantly different across varying states of middle ear disease (p = 0.44)., Conclusion: Statistically and clinically significant disagreement was demonstrated between tympanometric and 3DVR MEV values. Studies that vary in MEV estimation techniques may be expected to demonstrate significantly different results. These preliminary results suggest that clinicians should endeavor to seek further confirmation when interpreting high tympanometric MEV values.

Renal artery stenosis is the most common vascular complication following renal transplantation. Percutaneous endovascular transluminal angioplasty with stenting is the treatment of choice for clinically significant renal artery stenosis. The authors present a case describing a novel combined transrenal parenchyma and transfemoral approach to repairing a disrupted transplant renal artery stent. The patient's allograft renal artery stenosis was initially managed via the standard percutaneous approach, but during follow-up the stent became disrupted and crushed, causing partial occlusion of the renal artery. This was manifested by persistently elevated serum creatinine values, lower extremity edema, and four-medication hypertension. After a failed traditional percutaneous transfemoral attempt, the authors were able to successfully access the renal arterial system via a combined transrenal and transfemoral approach, using an upper-pole artery through the renal parenchyma. This transrenal approach used a 3 Fr system, allowing the authors to get a wire across the stent, which they were previously unable to do. With wire access, they performed a balloon angioplastic reconstruction to restore the stent's patency, resulting in a reduction in serum creatinine, lower extremity edema, and blood pressure. This technique avoided a potentially difficult reoperative repair without immediate complication and provides a method for vascular access to the renal arterial system in select patients., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)