Citations

ABSTRACT Surgery after response to first‐line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real‐world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first‐line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression‐free survival (PFS), disease‐free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow‐up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty‐four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic‐net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism‐corrected AUC of 0.65. First‐line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

Stem cell-derived β (SC-β) cells are a promising therapy for type 1 diabetes (T1D), but their long-term efficacy is limited by immune-mediated graft rejection. Platelet-derived exosome product (PEP) has emerged as a novel immunomodulatory agent, although its effect on SC-β cell xenograft rejection remains unclear. Here, we evaluated PEP in stimulated human peripheral blood mononuclear cells (PBMCs) and in an immunocompetent mouse model of SC-β cell transplantation under the kidney capsule. Immune-related gene expression was assessed by quantitative PCR, immune cell infiltration by immunofluorescence, and graft function by circulating human insulin. In vitro, PEP reduced NK-cell-associated gene expression, including NK1.1, EOMES, and KLRK1, and increased IL-10 expression. In vivo, untreated SC-β cell xenografts showed progressive immune infiltration and loss of detectable human insulin by day 14, whereas PEP-treated grafts retained detectable insulin through day 14 across co-transplantation, pretreatment, and systemic administration strategies. PEP co-transplantation delayed, but did not prevent, xenograft rejection, with graft loss observed by day 21. This delay was associated with reduced NK1.1+ cell infiltration and lower expression of selected inflammatory and rejection-associated markers, including NK1.1, Nos2, and Nlrp3. These findings suggest that PEP modulates graft-associated immune responses and may serve as an adjunct immunomodulatory strategy for stem cell-based therapies for type 1 diabetes. Further studies are needed to evaluate sustained graft durability, safety, and translational efficacy.

ABSTRACT Background Data on the global prevalence of alarm features in the general population and among individuals with disorders of gut–brain interaction (DGBI) are limited. Methods We analysed data from the Rome Foundation Global Epidemiology Study to estimate the prevalence of fourteen self‐reported alarm features in the global population and among individuals with Rome IV defined DGBI, including 54,127 participants from 26 countries. Differences between participants with and without DGBI were evaluated in a sample excluding those with self‐reported organic gastrointestinal disease, using univariable logistic regression. Analyses were stratified by age (< 50 vs. ≥ 50 years). Results Alarm features were reported by 63.1% of participants aged < 50 years and 51.8% of those aged ≥ 50 years. Individual self‐reported alarm features ranged from 0.9% to 18.3% in younger participants to 0.3%–13.3% in older participants. Haematemesis was the least frequently reported feature, while a major change in bowel movements was the most frequent in both age groups. Self‐reported alarm features were more frequent among participants with than without DGBI (< 50 years: 75.3% vs. 50.7%; OR 3.0 [2.8–3.1]; ≥ 50 years: 67.5% vs. 38.8%; OR 3.3 [3.1–3.5]). Participants with DGBI were also more likely to report multiple alarm features. Discussion Self‐reported alarm features are common in the general population and more prevalent among individuals with DGBI. These findings underscore the importance of interpreting alarm features within a broader clinical context rather than in isolation. Further studies are needed to clarify the diagnostic utility of alarm features in unselected populations, particularly among individuals with DGBI.

Introduction/Objectives The rise in screening for social drivers of health (SDoH) in primary care settings has led to questions about effective intervention design. A large primary care practice at Mayo Clinic developed a model centered on a full-time Health Equity Coordinator (HEC) to facilitate clinic-community partnerships in 2022. The goal of this analysis was to assess the model on process outcomes, resolution of SDoH needs, and changes in healthcare utilization. Methods Using a cohort study design, we identified primary care patients with unmet SDoH needs at the intervention clinic and two comparator clinics from March 2022 to December 2023. We assessed process outcomes descriptively and resolution of SDoH needs and healthcare utilization using multivariable regression. Results The HEC contacted 348 patients and conducted 748 meetings with community-based organization staff. While there were decreases for SDoH needs and missed or late cancelled appointments in intervention group, there were no significant difference in resolution of SDoH and healthcare utilization relative to comparator groups. Conclusions The HEC model for multi-stakeholder coordination showed promise in referring patients to services and engaging key stakeholders in a primary care setting. Longer term follow up may be needed to identify changes in SDoH needs and healthcare utilization.

Hospital medicine offers diverse career opportunities, yet formal guidance for residents pursuing hospitalist careers is often lacking. To address this gap, the Hospital Internal Medicine Interest Group (HIMIG) was launched at an academic institution in the Southeastern United States to provide structured mentorship and professional development. Residents expressing interest completed an entry survey to identify career goals and areas of focus, informing a longitudinal curriculum that included education, leadership, research, quality improvement, and networking. Seventeen residents (≈25% of the IM residency program) joined HIMIG, and 88% completed the initial survey. Education, leadership, and quality improvement were top interests, while mentorship and career guidance were primary motivators. A post-implementation survey revealed all participants met mentors and felt HIMIG supported their career goals. HIMIG demonstrates a flexible, personalized approach to hospitalist career development that may serve as a model for other programs.

Abstract Introduction Germinal center (GC) formation in lymph node (LN) follicles is essential for generating high-affinity antibodies following infection or vaccination. This response in aging is impaired, resulting in smaller and fewer GCs that generate less abundant antibodies with reduced antigen affinities as compared to young adults. Early GC formation depends on dendritic cell (DC)-mediated activation of naïve CD4+ T cells, which differentiate into CD4+ T follicular helper (TFH) cells that drive B cell responses. Antigen-specific TFH induction is mediated by type 2 conventional DCs, which localize to the T:B cell interfollicular boundaries. Live-cell 2-photon microscopy has previously revealed that T cell priming by DCs occurs in distinct phases of lasting versus intermittent interactions, though the quality and duration of DC:CD4+ T cell interactions has not been characterized in aged hosts. We hypothesize that age-associated alterations in LN microenvironments disrupt these interactions, leading to impaired GC formation. Methods Young and aged mice were subcutaneously immunized in the flank with nitrophenyl hapten conjugated to ovalbumin in alum adjuvant, and naïve OT-II CD4+ T cells were adoptively transferred via retroorbital injection. 48 hours after immunization, draining LNs and naïve controls were analyzed by multiplex immunofluorescence microscopy to map the spatial organization of DCs and stromal elements. Results Structural mapping showed disrupted alignment of stromal networks, suggesting impaired spatial compartmentalization of the aged microenvironment. Moreover, within aged immunized mice the localization of DCs within the interfollicular region and T:B cell zone borders of the LNs were altered. Conclusion Our findings suggest age-associated disruption of the LN microarchitecture diminishes the quality of DC:CD4+ T cell interactions essential for initiating GCs. These insights highlight tissue microenvironmental remodeling as a key contributor to age-related immune decline. Funding Source NIH Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Background High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

ABSTRACT Background Genetic testing for cardiomyopathy and arrhythmia (CM/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM/ARRH genetic testing. Methods This was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results. Results Among 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives’ care. Of these, 75 (55.1%) received recommendations for the patient’s own care, most frequently additional diagnostic tests/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66/138, 47.8% vs 9/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009). Conclusions The results from CM/ARRH genetic testing on affected patients influenced cardiologists’ medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM/ARRH impact health outcomes.

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.