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.

BACKGROUND:While payers and health systems are increasingly interested in addressing health-related social needs (HRSNs) to reduce health care use and align with value-based care incentives and regulatory requirements, limited evidence enables actionable strategies to manage and address social needs across population groups. OBJECTIVES/OBJECTIVE:To understand the relationship between HRSNs and health care access and use for adults with Medicare, Medicaid, and private health insurance coverage. RESEARCH DESIGN/METHODS:Survey data from adult participants from the All of Us Research Program (2017-2023; n=126,490) and logistic regression were used to examine the association between food insecurity and housing instability and having a usual source of care, seeing a health care provider, and forgoing care due to cost-stratified by payer type. RESULTS:The prevalence of HRSNs varied substantially by insurance: food insecurity affected 49.20% of Medicaid beneficiaries 18-64 years of age, 11.89% of privately insured adults 18-64 years of age, and 5.20% of Medicare beneficiaries 65 years of age and older; housing instability affected 54.61%, 25.18%, and 14.99%, respectively. Food insecurity was associated with lower odds of having a usual source of care for Medicaid and privately insured adults, lower odds of use for privately insured adults, and higher odds of forgone care for all 3 payer types. Housing instability was associated with lower odds of having a usual source of care for all 3 papers and with higher odds of forgone care for all groups. CONCLUSIONS:HRSNs like food insecurity and housing instability vary substantially by payer type and influence health care access and utilization in different ways. This can inform the design of payer-specific health management strategies that incorporate HRSNs.

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.

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.

BACKGROUND AND AIMS/OBJECTIVE:While inflammation and (auto-)immunity are modifiers of atherosclerosis, immunological determinants of cardiovascular risk beyond the established inflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) remain incompletely defined in humans. This exploratory proof-of-concept study aimed to detect immunological signals enriched in patients with increased cardiovascular risk. METHODS:A nested case-control study was performed within the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, a single-centre prospective study of 3316 patients. Forty-four individuals with and without angiographically confirmed coronary artery disease (CAD) and defined survival status were selected for comprehensive immunophenotyping employing bulk RNA, single-cell RNA (scRNA), single-cell T-cell receptor sequencing, mass cytometry, spatial imaging, and cytokine secretion in blood immune cells. Multi-omics factor analysis was applied to identify shared transcriptional programmes. Readouts were tested for their association with CAD status and cardiovascular mortality and validated in two independent cohorts. RESULTS:The integrated analysis strategy revealed immunological signals not detectable with conventional biomarkers, including a prominent signature of cellular proliferation, linked to activation, memory formation, clonal expansion, interferon signalling, and cytokine secretion in T cells. Cell types and transcriptional programmes associated with CAD status and poor long-term survival were identified. These associations were independent of established inflammatory markers, hsCRP and IL-6 that originated from myeloid cells. Key findings were replicated across independent cohorts using 136 scRNA sequencing datasets. Cellular proliferation was confirmed by protein validation in atherosclerotic plaques, and signatures were evaluated as stratification tools to predict short-term outcomes in acute coronary syndromes. CONCLUSIONS:Multi-omic profiling of blood immune cells revealed novel immune signatures associated with CAD, short- and long-term cardiovascular disease outcomes that are independent of systemic inflammation and may be used as risk stratification tools in the future.

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/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.

The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. Here, we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B cell stages to generate human-like lymphomas harboring the MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Genetically diverse lymphoma cells employ distinct immune evasion mechanisms that shape unique lymphoma microenvironment (LME) states. In this setting, clonally expanded T-cells function as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, the efficacy of standard-of-care and novel immunotherapies was determined using individual T-cell features. Furthermore, the experimental targeting of newly identified immune mechanisms has improved therapeutic responses in vivo. Our results elucidate that genetically driven LME landscapes influence therapeutic outcomes across distinct lymphoma subtypes, providing proof-of-concept for personalized treatment based on immune LME information.