Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course.

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.

EXERT-BC: A pilot study of an exercise regimen designed to improve functional mobility, body composition, and strength after the treatment for breast cancer.

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.

Nutritional epigenetics education improves diet and attitude of parents of children with autism or attention deficit/hyperactivity disorder.

BACKGROUND: Unhealthy maternal diet leads to heavy metal exposures from the consumption of ultra-processed foods that may impact gene behavior across generations, creating conditions for the neurodevelopmental disorders known as autism and attention deficit/hyperactivity disorder (ADHD). Children with these disorders have difficulty metabolizing and excreting heavy metals from their bloodstream, and the severity of their symptoms correlates with the heavy metal levels measured in their blood. Psychiatrists may play a key role in helping parents reduce their ultra-processed food and dietary heavy metal intake by providing access to effective nutritional epigenetics education. AIM: To test the efficacy of nutritional epigenetics instruction in reducing parental ultra-processed food intake. METHODS: The study utilized a semi-randomized test and control group pretest-posttest pilot study design with participants recruited from parents having a learning-disabled child with autism or ADHD. Twenty-two parents who met the inclusion criteria were randomly selected to serve in the test (n = 11) or control (n = 11) group. The test group participated in the six-week online nutritional epigenetics tutorial, while the control group did not. The efficacy of the nutritional epigenetics instruction was determined by measuring changes in parent diet and attitude using data derived from an online diet survey administered to the participants during the pre and post intervention periods. Diet intake scores were derived for both ultra-processed and whole/organic foods. Paired sample t-tests were conducted to determine any differences in mean diet scores within each group. RESULTS: There was a significant difference in the diet scores of the test group between the pre- and post-intervention periods. The parents in the test group significantly reduced their intake of ultra-processed foods with a pre-intervention diet score of 70 (mean = 5.385, SD = 2.534) and a post-intervention diet score of 113 (mean = 8.692, SD = 1.750) and the paired t-test analysis showing a significance of P < 0.001. The test group also significantly increased their consumption of whole and/or organic foods with a pre-intervention diet score of 100 (mean = 5.882, SD = 2.472) and post-intervention diet score of 121 (mean = 7.118, SD = 2.390) and the paired t-test analysis showing a significance of P < 0.05. CONCLUSION: Here we show nutritional epigenetics education can be used to reduce ultra-processed food intake and improve attitude among parents having learning-disabled children with autism or ADHD.

Automatic data-driven design and 3D printing of custom ocular prostheses.

Millions of people require custom ocular prostheses due to eye loss or congenital defects. The current fully manual manufacturing processes used by highly skilled ocularists are time-consuming with varying quality. Additive manufacturing technology has the potential to simplify the manufacture of ocular prosthetics, but existing approaches just replace to various degrees craftsmanship by manual digital design and still require substantial expertise and time. Here we present an automatic digital end-to-end process for producing custom ocular prostheses that uses image data from an anterior segment optical coherence tomography device and considers both shape and appearance. Our approach uses a statistical shape model to predict, based on incomplete surface information of the eye socket, a best fitting prosthesis shape. We use a colour characterized image of the healthy fellow eye to determine and procedurally generate the prosthesis's appearance that matches the fellow eye. The prosthesis is manufactured using a multi-material full-colour 3D printer and postprocessed to satisfy regulatory compliance. We demonstrate the effectiveness of our approach by presenting results for 10 clinic patients who received a 3D printed prosthesis. Compared to a current manual process, our approach requires five times less labour of the ocularist and produces reproducible output.

Society of Critical Care Medicine Guidelines on Glycemic Control for Critically Ill Children and Adults 2024.

RATIONALE: Maintaining glycemic control of critically ill patients may impact outcomes such as survival, infection, and neuromuscular recovery, but there is equipoise on the target blood levels, monitoring frequency, and methods. OBJECTIVES: The purpose was to update the 2012 Society of Critical Care Medicine and American College of Critical Care Medicine (ACCM) guidelines with a new systematic review of the literature and provide actionable guidance for clinicians. PANEL DESIGN: The total multiprofessional task force of 22, consisting of clinicians and patient/family advocates, and a methodologist applied the processes described in the ACCM guidelines standard operating procedure manual to develop evidence-based recommendations in alignment with the Grading of Recommendations Assessment, Development, and Evaluation Approach (GRADE) methodology. Conflict of interest policies were strictly followed in all phases of the guidelines, including panel selection and voting. METHODS: We conducted a systematic review for each Population, Intervention, Comparator, and Outcomes question related to glycemic management in critically ill children (≥ 42 wk old adjusted gestational age to 18 yr old) and adults, including triggers for initiation of insulin therapy, route of administration, monitoring frequency, role of an explicit decision support tool for protocol maintenance, and methodology for glucose testing. We identified the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the GRADE approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak or as a good practice statement. In addition, "In our practice" statements were included when the available evidence was insufficient to support a recommendation, but the panel felt that describing their practice patterns may be appropriate. Additional topics were identified for future research. RESULTS: This guideline is an update of the guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. It is intended for adult and pediatric practitioners to reassess current practices and direct research into areas with inadequate literature. The panel issued seven statements related to glycemic control in unselected adults (two good practice statements, four conditional recommendations, one research statement) and seven statements for pediatric patients (two good practice statements, one strong recommendation, one conditional recommendation, two "In our practice" statements, and one research statement), with additional detail on specific subset populations where available. CONCLUSIONS: The guidelines panel achieved consensus for adults and children regarding a preference for an insulin infusion for the acute management of hyperglycemia with titration guided by an explicit clinical decision support tool and frequent (≤ 1 hr) monitoring intervals during glycemic instability to minimize hypoglycemia and against targeting intensive glucose levels. These recommendations are intended for consideration within the framework of the patient's existing clinical status. Further research is required to evaluate the role of individualized glycemic targets, continuous glucose monitoring systems, explicit decision support tools, and standardized glycemic control metrics.

Effects of Ataxia-Telangiectasia Mutated Variants on Radionecrosis and Local Control After Stereotactic Radiation Surgery for Non-Small Cell Lung Cancer Brain Metastases.

Purpose: Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials: Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status. Results: A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months (P = .46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months (P = .26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP. Conclusions: We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS.

Genomic classifiers and prognosis of localized prostate cancer: a systematic review.

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.

Radiation technique and outcomes following moderately hypofractionated treatment of low risk prostate cancer: a secondary analysis of RTOG 0415.

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.

Differential gene expression and developmental pathologies associated with persistent organic pollutants in sentinel fish in Troutman Lake, Sivuqaq, Alaska.

Persistent organic pollutants (POPs) are lipophilic compounds that bioaccumulate in animals and biomagnify within food webs. Many POPs are endocrine disrupting compounds that impact vertebrate development. POPs accumulate in the Arctic via global distillation and thereby impact high trophic level vertebrates as well as people who live a subsistence lifestyle. The Arctic also contains thousands of point sources of pollution, such as formerly used defense (FUD) sites. Sivuqaq (St. Lawrence Island), Alaska was used by the U.S. military during the Cold War and FUD sites on the island remain point sources of POP contamination. We examined the effects of POP exposure on ninespine stickleback (Pungitius pungitius) collected from Troutman Lake in the village of Gambell as a model for human exposure and disease. During the Cold War, Troutman Lake was used as a dump site by the U.S. military. We found that PCB concentrations in stickleback exceeded the U.S. Environmental Protection Agency's guideline for unlimited consumption despite these fish being low trophic level organisms. We examined effects at three levels of biological organization: gene expression, endocrinology, and histomorphology. We found that ninespine stickleback from Troutman Lake exhibited suppressed gonadal development compared to threespine stickleback (Gasterosteus aculeatus) studied elsewhere. Troutman Lake stickleback also displayed two distinct hepatic phenotypes, one with lipid accumulation and one with glycogen-type vacuolation. We compared the transcriptomic profiles of these liver phenotypes using RNA sequencing and found significant upregulation of genes involved in ribosomal and metabolic pathways in the lipid accumulation group. Additionally, stickleback displaying liver lipid accumulation had significantly fewer thyroid follicles than the vacuolated phenotype. Our study and previous work highlight health concerns for people and wildlife due to pollution hotspots in the Arctic, and the need for health-protective remediation.

Fish consumption and omega-3 polyunsaturated fatty acids from diet are positively associated with cognitive function in older adults even in the presence of exposure to lead, cadmium, selenium, and methylmercury: a cross-sectional study using NHANES 2011-2014 data.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are reported to be beneficial for cognition, but limited consumption of some fish is recommended due to high concentrations of heavy metals and persistent organics. OBJECTIVE: We aimed to determine whether dietary ω-3 PUFAs from fish consumption are associated with higher cognitive scores in older adults and explored the associations of mixtures of ω-3 PUFAs and blood concentrations of lead, cadmium, selenium, and methylmercury on cognitive performance. METHODS: We conducted a cross-sectional study with data from the NHANES 2011-2014, assessing cognitive scores of immediate recall, delayed recall, and executive function in adults ≥60 y (n = 3123). We performed multivariate linear regressions and mixture models utilizing the quantile-based g-computation method to identify associations between monthly fish consumption or dietary ω-3 PUFAs with blood concentrations of lead, cadmium, methyl mercury, and selenium on cognitive scores. RESULTS: Fish consumption had significant positive associations with all 3 cognitive scores, whereas dietary ω-3 PUFAs were only significantly associated with the Digit Symbol Substitution Test (DSST) scores. Mixture analysis showed significant positive associations with DSST scores for fish consumption (ß: 0.88; 95% CI: 0.48, 1.29) and dietary ω-3 PUFAs (ß: 0.41; 95% CI: 0.03, 0.78) with positive component weights for fish consumption, dietary ω-3 PUFAs, and blood selenium and negative component weight for blood cadmium concentrations. CONCLUSIONS: Our findings support dietary recommendations for older adults to consume fish to maintain cognitive function, likely due to biomolecular actions of ω-3 PUFAs that increase neuronal membrane fluidity, have antioxidation activity, and restore cell damage. The combination of selenium and fish consumption or ω-3 PUFAs was associated with reduced decline in cognitive scores and less negative associations from exposures to lead, cadmium, and mercury compounds.

Long-term risk of carotid stenosis and cerebrovascular disease after radiation therapy for head and neck cancer.

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.

Different volatile organic compounds in local point source air pollution pose distinctive elevated risks for respiratory disease-associated emergency room visits.

Air pollution increases risk of respiratory disease but prior research has focused on particulate matter and criteria air pollutants, and there are few studies on respiratory effects of volatile organic compounds (VOC). We examined zip code level relationships between emergency room (ER) visits for respiratory illness and VOC pollution in New York State from 2010 to 2018. Detailed information on VOC pollution was derived from the National Emissions Inventory, which provides point source information on VOC emissions at the zip code level. We considered four respiratory diseases: asthma, acute upper respiratory infections, chronic obstructive pulmonary disease (COPD), and lower respiratory disease, using mixed effects regression with a random intercept to account for county level variability in single pollutant models, and Random Forest Regression (RFR) to assess relative importance of VOC exposures when considered together in multipollutant models. Single pollutant models show associations between respiratory-related ER visits with all pollutants of interest across all study years, even after adjusting for poverty and smoking by zip code. The largest relative single pollutant effect sizes considered included benzene, ethylbenzene, and total (summed) VOCs. Results from RFR including all VOC exposures indicate that ethylbenzene has the greatest variable importance for asthma, acute upper respiratory infections, and COPD, with toluene and benzene most important for lower respiratory ailments. RFR results also demonstrate presence of pairwise interactive effects between VOC pollutants. Our findings show that local VOC pollution may offer a significant contribution to the risk of respiratory disease-related ER visits, and that effects vary by illness and by VOC compound. ER visit rates for respiratory illness were elevated in high poverty zip codes, although this may be attributable to the fact that the poor lack basic access to health care and use ERs more frequently for routine care.

Effects of mixtures of polychlorinated biphenyls (PCBs) and three organochlorine pesticides on cognitive function differ between older Mohawks at Akwesasne and older adults in NHANES.

BACKGROUND: Akwesasne Mohawks has been exposed to high concentrations of polychlorinated biphenyls (PCBs) and background levels of organochlorine pesticides, hexachlorobenzene (HCB), dichlorodiphenyl dichloroethylene (DDE), and mirex. We have previously reported relative contributions to the mixture of low- and high-chlorinated PCBs, HCB, and DDE on cognitive decrements in Mohawks of various ages. OBJECTIVE: This study examines differences in the mixture effects of PCB congener groups, HCB, DDE, and mirex on cognitive function in older Mohawks and less PCB-exposed older adults from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 cycles. METHODS: We used Bayesian kernel machine regression (BKMR) to evaluate the mixture effects of different PCB congener groups, HCB, DDE, and mirex on cognitive function in both populations. Models were adjusted for age, sex, education levels, and race/ethnicity focusing on individuals 60 years and older. RESULTS: Older Mohawks had 3-fold higher mean total PCB concentrations and 1.8-fold higher mirex, but slightly lower mean DDE and HCB levels than NHANES older adults. Higher mixture concentrations were significantly associated with greater cognitive decline. In older Mohawks, low- and high-chlorinated PCBs, HCB, and DDE contributed to the cognitive score decline. In contrast, score decline in older NHANES adults were primarily from high-chlorinated PCBs and DDE with a threshold dose of approximately 2.08-2.27 ng/g and 2.02-2.40 ng/g, respectively. CONCLUSION: Mixtures of PCBs and organochlorine pesticides increase the risk of cognitive decline in both older Mohawks and NHANES older adults. However, contributions to these mixture effects show significant differences. In older Mohawks, high- and low-chlorinated PCBs, DDE, and HCB are the primary contributors, while high-chlorinated PCBs and DDE are important contributors in NHANES older adults. Due to chronic heavy exposures to PCBs, older Mohawks had a significantly increased risk of cognitive decline compared to general older adults from NHANES.

Toxicity and Outcomes of Moderately Hypofractionated Radiation for Prostate Cancer With Seminal Vesicle Involvement.

Purpose: The aim of this study was to assess the toxicity and outcomes following treatment of prostate cancer with seminal vesicle involvement (SVI) evident on magnetic resonance imaging or clinical examination with moderately hypofractionated radiation therapy (MHRT). Methods and Materials: Forty-one patients treated with MHRT to the prostate and 1 or both seminal vesicles from 2013 to 2021 at a single institution were identified and propensity score matched to 82 patients treated during the same period with prescription dose given to the prostate alone. Dosimetry of the planning target volume, bladder, and rectum were compared. Urinary and bowel toxicity were scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Clinical outcomes including freedom from biochemical recurrence, prostate cancer-specific survival, and overall survival were assessed. Results: Of the 41 patients identified with SVI, 26.8% had SVI by clinical examination and 95.1% had high-risk prostate cancer. Compared with the cohort without SVI, treatment plans to include SVI had a larger planning target volume (152.2 vs 109.9 cc; P < .001), maximum point dose (107.9% vs 105.8%; P < .001), and volume receiving 100% of the prescription dose (143.1 vs 95.9 cc; P < .001). No difference in bladder dosimetric variables between cohorts was observed, but there was an increase in the rectal maximum point dose (103.9% vs 102.8%; P = .030) and rectal volume receiving 100% of the prescription dose (1.8 vs 1.2 cc; P = .016). Despite these differences, there was no difference in the cumulative incidence of grade 2+ urinary (hazard ratio [HR], 0.73; 95% CI, 0.39-1.35; P = .31) or bowel (HR, 0.35; 95% CI, 0.04-3.03; P = .34) toxicity. Freedom from biochemical recurrence (HR, 0.47; 95% CI, 0.16-1.38; P = .17), prostate cancer-specific survival (HR, 0.31; 95% CI, 0.04-2.49; P = .31), and overall survival (HR, 0.35; 95% CI, 0.10-1.16; P = .09) also did not differ with or without SVI, respectively. Conclusions: Treatment of SVI to prescription dose with MHRT for localized prostate cancer does not increase bowel or urinary toxicity. Similar clinical outcomes were also observed with or without SVI.

Clinical Factors Associated With 30-Day Mortality Among Patients Undergoing Radiation Therapy for Brain Metastases.

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.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases.

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.

Outcomes in Patients with Intact and Resected Brain Metastasis Treated with 5-Fraction Stereotactic Radiosurgery.

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.