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ABSTRACT Patient outcomes in advanced renal cell carcinoma (RCC) remain poor, with five‐year survival rates ranging from ~10% to 30%. Early projections of therapeutic outcomes could optimize precision medicine and accelerate drug development. While machine learning (ML) models integrating tumor growth inhibition (TGI) metrics have improved survival predictions over traditional models, their application in RCC remains unexplored. Herein, we used TGI metrics and baseline data to evaluate parametric (PM) and semi‐parametric (SPM) survival models alongside ML approaches for predicting progression‐free (PFS) and overall survival (OS) in 1839 RCC patients from four trials (evaluating sunitinib, axitinib, sorafenib, interferon‐alpha, and avelumab + axitinib). Data were split into training (70%) and testing (30%), and feature selection was used to determine parsimonious and robust models. Bootstrap resampling ( n = 100) was employed for models' validation, and performance was assessed using C‐index and Integrated Brier Score. In brief, training data results demonstrated that tree‐based ML models (random survival forest (RSF) and XGBoost) outperformed PM and SPM models in predicting PFS (C‐index: 0.783–0.785 vs. 0.725–0.738 for PM and SPM; p < 0.05) and OS (C‐index: 0.77–0.867 vs. 0.750–0.758 for PM and SPM; p < 0.05), with RSF achieving better prediction of PFS and OS using only 3–5 covariates, compared to 9–35 with other tested methods. Tree‐based methods were also superior in the testing data. SHapley Additive exPlanations revealed nonlinear relationships among top predictors, including TGI metrics, underscoring the ability of tree‐based methods to capture complex prognostic interactions. Further validation is required to confirm models' generalizability to additional therapies and patients with differing tumor severity.

BACKGROUND: Significant disparities persist in timely, guideline-concordant breast cancer treatment across the US, impacting cancer outcomes. The influence of both patient-level and facility-level socioeconomic status (SES) on adherence to Commission on Cancer quality measures remains incompletely understood. STUDY DESIGN: We conducted a retrospective cohort study using the National Cancer Database to assess associations between patient and facility SES and concordance with timeliness of 3 Commission on Cancer breast cancer quality measures: surgery, multiagent chemotherapy, and radiotherapy, among patients diagnosed from 2018 to 2022. Multivariable logistic regression models were used to evaluate predictors of concordant care, including a composite measure of facility-level social risk. RESULTS: The analytic cohorts included 471,425 patients for surgery, 82,734 for chemotherapy, and 311,523 for radiotherapy. Black race, uninsured status, and lower educational attainment were each independently associated with lower odds of receiving guideline-concordant care across all measures. Patients treated at low-SES facilities had higher odds of receiving timely surgery (adjusted odds ratio [OR] 1.27, 95% CI 1.24 to 1.31) but lower odds of receiving timely chemotherapy (OR 0.85, 95% CI 0.79 to 0.91) and radiotherapy (OR 0.95, 95% CI 0.92 to 0.97) compared with those at other institutions. Facility type, fragmented care, and comorbidities also contributed to variation in concordance. CONCLUSIONS: Significant disparities in guideline-concordant breast cancer care persist by race, insurance, education, and facility-level social risk, highlighting intervention opportunities to improve outcomes for these already vulnerable populations. These findings highlight the importance of policy and institutional strategies that address both patient- and facility-level barriers to ensure equitable access to high-quality multidisciplinary treatment.

Key Points We studied the link between brachial-ankle pulse wave velocity (baPWV) and CKD risk in adults undergoing cardiovascular disease screening. A higher baseline baPWV was predictive of an increased annualized rate of creatinine-based eGFR (eGFR Cr ) decline. Compared with normal baPWV, higher baseline baPWV was associated with increased risk of developing CKD and lower CKD-free survival time. Background CKD affects 35 million adults in the United States and is associated with high morbidity and mortality. We investigated whether brachial-ankle pulse wave velocity (baPWV), a noninvasive measure of arterial stiffness, was associated with kidney function decline in adults undergoing cardiovascular disease (CVD) screening. Methods In 1862 patients referred for an exercise electrocardiogram test between 2007 and 2009, baPWV was measured using an Omron Colin oscillometric device. Creatinine-based GFR was estimated (eGFR Cr ) for participants with available baseline and follow-up creatinine values using the CKD Epidemiology Collaboration formula. We performed multivariable linear regression analyses to assess whether baseline baPWV was associated with annualized change in eGFR Cr , after adjustment for age, sex, body mass index, baseline eGFR Cr , and traditional CVD risk factors, including mean arterial pressure, diabetes and hypertension diagnoses, nephroprotective medication use, smoking status, and total cholesterol. To determine risk of developing CKD and CKD-free survival time by arterial stiffness subgroups, we performed covariable-adjusted Cox proportional hazards modeling and a Kaplan-Meier survival analysis, respectively. Results After exclusion of participants with missing covariable data and adjustment for covariables, one SD increase in baPWV was associated with a 0.18 ml/min per 1.73 m 2 BSA greater yearly decrease in eGFR Cr ( P = 0.023) over a median follow-up time of 13.2 years. Participants with higher baseline baPWV had increased risk of CKD (hazard ratio [95% confidence interval], P value; elevated baPWV: 2.4 [1.1 to 5.4], P = 0.037; borderline-elevated baPWV: 1.8 [1.1 to 3.1], P = 0.028) and had a shorter CKD-free survival time (median CKD-free survival time [years]; normal baPWV: 16.2; borderline-elevated baPWV: 16.0; elevated baPWV: 15.6 [ P < 0.001]). Conclusions Elevated baPWV, a noninvasive measure of arterial stiffness that can be obtained in the office setting, was associated with decline in kidney function, risk of CKD development, and CKD-free survival in individuals undergoing CVD screening.

Abstract Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett’s esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett’s esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82–0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86–0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66–0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7–0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett’s esophagus surveillance. Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett’s esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Abstract Background In the current Canadian treatment landscape for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), eligibility for autologous stem cell transplantation (ASCT) guides the choice of salvage treatment. CD19 chimeric antigen receptor T-cell (CAR-T) therapies have improved outcomes in patients with chemorefractory DLBCL, but access is limited to eligible patients. This subanalysis of the RE-MIND2 observational retrospective cohort study investigated treatment patterns for R/R DLBCL in Canada. Patients and methods Data from patients enrolled in RE-MIND2 treated between 2010 and 2020 at 2 Canadian centers were retrospectively collected from health records. Descriptive statistics were used to analyze baseline characteristics, treatment initiated, and duration of treatment by line of therapy. Results One hundred and nine patients were included; 74.2% of patients were eligible for ASCT as 2L therapy, and 45.4% received transplants. ASCT eligibility for third- (3L) and fourth-line (4L) therapy declined to 17.1% and 5.9%, respectively. Patients received a wide variety of treatments in 3 and 4L. CAR-T therapy became available in 3 and 4L by the end of 2019. Median durations of treatment were &lt;2.6 months in all lines of therapy; median time to next treatment ranged from 3.4 months in 4L to 5.3 months in 2L. Conclusion Results of our study support that ASCT-ineligible patients have a poor prognosis with conventional salvage chemotherapy. Before the availability of novel immunotherapies, no apparent standard of care was observed for Canadian patients with R/R DLBCL who were ineligible for or did not receive ASCT, especially after 2L treatment.

ABSTRACT Transgender and gender diverse (TGD) individuals face minority stress and often avoid the emergency department (ED) due to previous negative experiences. The goal of this review is to prepare the emergency medicine pharmacist to care for TGD patients, with the ultimate goal of improving the care TGD patients receive. This review summarizes interactions with TGD patients, trauma‐informed considerations, physical exam and organ inventory sensitivities, and gender‐affirming hormone therapy and complications that may arise and be seen in the ED. Additionally, this review discusses common complaints and considerations that may commonly arise when caring for TGD patients.

Abstract Background Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity. Methods Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests. Results In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC. Conclusions Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options and poor survival. This study explores how a medically supervised ketogenic diet (MSKD) impacts the gut microbiome and treatment response in patients with newly diagnosed metastatic PDAC receiving gemcitabine, nab-paclitaxel, and cisplatin chemotherapy. Methods: As part of a randomized Phase II trial, 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to either MSKD or standard diet (SD) combined with chemotherapy. Stool samples were collected from 4 patients in the MSKD group (13 samples) and 8 patients in the SD group (23 samples). Deep shotgun metagenomic sequencing was conducted using NovaSeq (Illumina). Taxonomical and functional microbiome characterization was performed using MetaPhlAn 4.0 and HUMAnN 3.6 (The Huttenhower Lab, Harvard). Comprehensive bioinformatics analyses, using QIIME2, were performed to analyze microbiome composition and function over time. Results: Patients in the MSKD group showed better treatment responses overall. Microbiome profiles between the two groups remained distinct throughout therapy. Though not statistically significant due to sample size, MSKD patients showed lower alpha diversity (Shannon diversity; p-value=0.1339), likely reflecting reduced intake of fermentable fiber. Differential abundance analysis using the ANCOM-BC method revealed a significant enrichment of beneficial taxa in the MSKD group compared to the SD group (p&lt;0.05, log-fold change [lfc]≥2), including Akkermansia muciniphila (linked to improved response to immune checkpoint inhibitors; p=0.017931, q=1), Intestinimonas butyriciproducens (a short-chain fatty acid [SCFA] and butyrate producer; p=3.09E-05, q=0.017), and Streptococcus thermophilus (a supporter of gut mucosal health; p=1.15E-05, q=0.006). During the course of the study, only MSKD patients showed sustained increases in Roseburia hominis (SFCA/butyrate producer; p=3.94E-05, q=0.021) and Lacticaseibacillus rhamnosus (with anti-inflammatory and immune-modulating properties; p=7.28E-19, q=3.98E-16), along with a marked reduction in potentially pro-inflammatory Actinomyces spp.(p≤4.47E-05, q≤0.024). Functional profiling showed increased abundance of cancer-relevant microbial pathways in MSKD patients, including phosphatidate metabolism (PWY-7039; involved in lipid signaling and immune regulation; p=4.36E-04, q=0.20) and allantoin degradation (PWY-5705; linked to redox balance; p=9.16E-06, q=0.004). Conversely, L-ascorbate biosynthesis V (PWY-6415) was reduced (p=3.80E-04, q=0.17), likely due to decreased D-galacturonate substrate availability from fiber restriction. Conclusion: These findings suggest that an MSKD may beneficially modulate the gut microbiome in ways that support and enhance therapeutic response in patients with PDAC. Further validation in a larger cohort is warranted to confirm these results and improve analytical resolution. Citation Format: Keehoon Lee, Derek Cridebring, Gayle S. Jameson, Denis J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G.P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela T. Alistar, Alan M. Miller, J. Erin Wiedmeier-Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Drew W. Rasco, Daniel D. Von Hoff. Ketogenic Diet Modulates Gut Microbiome Composition and Enhances Treatment Response in Patients with Advanced Pancreatic Cancer: A Phase II Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B094.