Faculty Bibliography

Despite therapeutic progress, there has been little improvement in the outcome of the 15%-25% of newly diagnosed high-risk multiple myeloma (HRMM), which is characterized by early treatment resistance and very poor survival. HRMM is a substantial clinical problem both at presentation and later during the disease course with its prevalence increasing at each relapse. Although therapeutic interventions have substantially improved the outcome for standard- and intermediate-risk multiple myeloma, the survival for HRMM has not improved to the same extent. To address this poor outcome requires a strategy to define and identify HRMM in a standardized fashion, determine its biology, and identify novel strategies for treatment. A recognized driver of HR biology is loss of 17p and mutation of P53, but beyond this we are making significant inroads into breaking down the remaining monolith of HRMM into its component biologic subgroups. In this article, we provide a framework within which to understand the biology of HRMM and to clinically define it so that patients can be entered into clinical trial programs designed to systematically improve outcomes. We explore the evolving definitions of HRMM and investigate the role of personalized therapeutic strategies using conventional targeted agents and novel immunotherapies to address whether they can overcome adverse high-risk biology.

INTRODUCTION/BACKGROUND:with dysglycemia, it remains unknown if reducing air pollution exposure through air filtration can affect improvements in glucose. This study aims to test the hypothesis that short-term, in-home air pollution reduction using high efficiency particulate air (HEPA) filtration will improve blood sugar in adults with prediabetes. METHODS AND ANALYSIS/METHODS:as the independent variable. ETHICS AND DISSEMINATION/BACKGROUND:This study has undergone peer review; and the work was supported by Grant 2023-0214 from the Doris Duke Foundation, who had no other role in study design or implementation. The study was registered in ClinicalTrials.gov (NCT05994937) prior to recruitment.

IMPORTANCE/UNASSIGNED:Patients frequently forgo filling prescriptions due to high out-of-pocket costs. Real-time prescription benefit (RTPB) tools that recommend available lower-cost, clinically equivalent medications to prescribing clinicians may increase the likelihood that patients fill their prescriptions. OBJECTIVE/UNASSIGNED:To determine whether availability of an RTPB tool increases prescription fill rates. DESIGN AND SETTING/UNASSIGNED:This post hoc analysis of a cluster randomized clinical trial included medical practices within an urban ambulatory clinical network randomized to the RTPB tool between January and December 2021. Outpatient prescriptions that were eligible for an RTPB recommendation during the study period were analyzed. Data analyses were performed from October 18, 2022, to August 9, 2024. INTERVENTION/UNASSIGNED:An electronic health record-integrated RTPB tool that displays available lower-cost and clinically equivalent alternatives to the initiated prescription at the point of prescribing. MAIN OUTCOME AND MEASURE/UNASSIGNED:The primary outcome measured whether a prescription was filled. RESULTS/UNASSIGNED:Of 1 386 577 outpatient prescriptions at randomized practices during the trial period, 38 289 (2.8%) were included in the analytic sample. Across all orders, the availability of the RTPB tool did not impact the proportion of orders filled (54% and 55% in the control and RTPB groups, respectively; adjusted difference: 1.2 percentage points [pp]; 95% CI, -1.3 to 3.7 pp). However, in the quartile of drug classes with the highest out-of-pocket costs (average out-of-pocket cost for a 30-day fill of >$120.83), fill rates increased from 33% in the control group to 49% in the RTPB group (adjusted difference: 14.5 pp; 95% CI, 8.4-20.6 pp). Similar increases were not detected in lower-cost drug classes. Increases in fill rates within the highest out-of-pocket cost drug classes were largest for patients in the lowest-income communities served by the health system (30.3 pp; 95% CI, 19.5-41.1 pp) but not substantial in the highest-income communities (1.0 pp; 95% CI, -10.2 to 12.2 pp). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this post hoc analysis of a cluster randomized clinical trial, there was no change in overall prescription fill rates, but among high-cost drugs, the RTPB tool increased fill rates, particularly among patients from low-income communities. However, RTPB recommendations were made for a small proportion of orders, limiting the applicability of the findings to a narrow segment of the randomized population. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04940988.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Despite various therapeutic options, treatment resistance is common, underscoring the need for effective combination therapies and reliable pre-clinical models for patient-specific evaluation. Here, we describe strategies for reconstituting tumor immune microenvironment (TIME) components within patient-derived tumor organoid (PDTO) cultures. We established a tumor processing pipeline that enables concurrent expansion of tumor-infiltrating lymphocytes (TILs) and PDTO generation from the same resection. We optimized scalable assays to assess IFN-γ secretion and T cell cytotoxicity with immune checkpoint inhibitors (alone or in combination) and targeted inhibitors, capturing inter-patient heterogeneity and intra-patient variations between TILs and peripheral blood mononuclear cells (PBMCs). Additionally, we developed methods for differentiating PDTO-specific tumor-associated macrophages (TAMs) and established PDTO-TAM co-culture systems to evaluate TAM effects on PDTO growth and chemotherapy sensitivity. All approaches are scalable to high-throughput levels, highlighting the value of TIME-PDTO co-cultures for therapeutic modeling and precision medicine.

BACKGROUND:Older adults who are homebound, defined as those who rarely or never leave home without assistance or difficulty, experience high levels of multimorbidity, functional impairment, and mortality. Yet their needs remain poorly served by current care delivery models. While research on homebound older adults implies that these individuals are universally frail, this assumption has never been tested empirically. We aimed to better characterize the non-frail homebound older adult population. METHODS:Using nationally representative data from the National Health and Aging Trends study (NHATS), years 2011-2019 and 2021-2023, we identified the persistently homebound population (n = 3851 unique older adults). Frailty status was determined using the Fried physical frailty phenotype. We identified socio-demographic, health-related, functional and environmental characteristics associated with the absence of frailty among the homebound using multivariable logistic regression. RESULTS:Among the homebound, 8.1% were non-frail, 47.9% were pre-frail, and 44.0% were frail. Characteristics associated with not being frail included being female (70% non-frail), married (47%), and Hispanic (15%). Non-frail homebound older adults had fewer mental health symptoms (12.4% depression, 8.3% anxiety non-frail; vs. 40.2% and 33.0% frail), were less likely to be socially isolated (25.3% non-frail vs. 37.7% frail), and more likely to be functionally independent (72.1% non-frail vs. 36.7% frail). Robust homebound older adults self-reported better health (79.0% non-frail vs. 34.6% frail), fewer hospitalizations (22.0% non-frail vs. 51.4% frail), and had lower mortality rates (6.4% non-frail vs. 20.5% frail) compared to frail/pre-frail older adults. CONCLUSION/CONCLUSIONS:While the vast majority of the homebound population is frail or pre-frail, a considerable portion are not frail. Efforts to manage high-need, high-cost populations such as homebound older adults must account for the heterogeneity of the population with efforts to better understand the non-frail subpopulation and target interventions tailored to their needs with the goal of potentially reversing their homebound status.

INTRODUCTION/BACKGROUND:Adjuvant chemotherapy can improve recurrence-free survival (RFS) in gastrointestinal malignancies. Previous review of phase III randomized controlled trials (RCTs) for colorectal cancer observed that RFS improvements were driven by early divergences during active chemotherapy; late recurrences were not influenced by adjuvant therapy. The broader applicability of this finding is unknown. METHODS:PubMed, Cochrane Library (CENTRAL), Embase, Scopus, and Web of Science were queried from database inception to December 31, 2025, for phase III RCTs including pancreatic, gastroesophageal, hepatocellular, and biliary tract malignancies. Trials where significant differences in RFS were observed between experimental (adjuvant chemotherapy) and control (resection alone) arms were included. Summary data were extracted from Kaplan-Meier curves using DigitizeIT, and absolute differences in RFS were compared at matched intervals using Wilcoxon matched-pairs signed rank tests. RESULTS:A total of 14 RCTs were identified, investigating periampullary (n = 4), gastroesophageal (n = 5), hepatocellular (n = 4), and biliary tract (n = 1) carcinomas. Across pooled RCTs, the highest rates of recurrence were observed in the first year following resection. Median RFS event rate was significantly higher with resection alone (0-0.5 y: resection alone 44.9 [IQR 14.2-84.1] versus adjuvant chemotherapy 26.4 [IQR 7.7-41.9], P < 0.001; 0.5-1 y: resection alone 33.2 [22.7-42.1] versus adjuvant chemotherapy 25.0 [13.8-44.5]; P = 0.007). No difference was observed during later intervals from postoperative randomization (1-2 y: P = 0.952; 2-3 y: P = 0.191; 3-4 y: P = 0.999; 4-5 y: P = 0.110). For the subset of trials where ≤6 mo of adjuvant chemotherapy was used (n = 10), improvements in RFS event rates were observed only during and immediately following the treatment interval (0-6 mo: P = 0.001; 6-12 mo: P = 0.037). CONCLUSIONS:Across multiple gastrointestinal malignancies, improvements in RFS associated with active adjuvant chemotherapy regimens are driven by early changes in recurrence dynamics. These data may provide in vivo understanding of residual tumor cell populations after curative-intent resection and how chemotherapy can be best used to prevent recurrence.

BACKGROUND/UNASSIGNED:The transition from hospital discharge to home is a critical period prone to gaps in care. Telemedicine has potential to smooth this transition; however, few educational interventions assess the unique skills required for high-quality telemedicine care at this critical juncture. OBJECTIVE/UNASSIGNED:standardized patient (SP) encounters in internal medicine residents' actual clinics to assess telemedicine skills in the post-discharge period. METHODS/UNASSIGNED:We developed 2 cases portraying recently discharged patients, designed behaviorally anchored assessment checklists, created mock electronic health record entries, and scheduled telemedicine visits in residents' clinics throughout the 2023-2024 academic year. SPs assessed skills as "not done," "partly done," or "well done" across 5 skill domains: Information Gathering, Relationship Development, Education and Counseling, Telemedicine-Specific Skills, and Care Transition Skills. We analyzed differences in the percentage of "well done" items, fit an ordinal mixed-effects model to assess for performance by case and postgraduate year (PGY) level, and surveyed residents. RESULTS/UNASSIGNED:All 42 (100%) PGY-1s and PGY-2s in our program participated in 79 total encounters. Residents performed well in core communication domains but struggled with Telemedicine-Specific Skills, Care Transition Skills, and Education and Counseling skills. PGY-2 performance was stronger than PGY-1 performance in these domains. Among residents who completed both cases, performance in case 2, which took place 6 months after case 1, was stronger; this effect was driven by PGY-1 performance. Twenty-nine of 31 residents (94%) reported this intervention improved their telemedicine skills. CONCLUSIONS/UNASSIGNED:We report a high-fidelity strategy that captures telemedicine skill development in the context of patient care.

Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.

PURPOSE/OBJECTIVE:The objective of this study was to evaluate cross-sectional and longitudinal associations between contact with the criminal legal system (CCLS) and substance use among transgender women of color in New York City. METHODS:= 311). CCLS included arrest and incarceration and was measured at baseline, 6 months, and 12 months. Substance use included recreational substance use (any), alcohol use (any), and specific substance use (cannabis, cocaine, and methamphetamine). Generalized estimating equations were used to assess longitudinal associations between baseline CCLS and substance use over time. RESULTS:At baseline, 50.5% of participants reported having been arrested, and 28.0% reported experiencing incarceration. In multivariable analyses, CCLS was associated with substance use after controlling for confounders. In particular, at baseline, incarceration was associated with a 1.73 times (95% confidence interval: 1.06-2.81) likelihood of recreational substance use. We found no significant associations between CCLS and alcohol or specific substance use. CONCLUSION/CONCLUSIONS:The findings suggest that CCLS was associated with recreational substance use among transgender women of color at baseline. Substance use prevention and treatment programs should consider screening for substance use during reentry after incarceration and providing additional support for individuals with criminal legal system involvement.