Citations

Abstract Background Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. Patients and Methods The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. Results In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. Conclusion Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

Abstract Background Red cell alloimmunization complicates sickle cell disease (SCD) management despite current widespread prophylactic Rh/K matching in the United States (US). Regional antibody patterns remain poorly characterized. Study Design and Methods We conducted a retrospective analysis of 2965 SCD patients from 9 US sites (2010–2022). All hospitals prophylactically match for Rh and K antigens. Each site collected demographics, antigen status, antibody histories, and antibody screen results from their laboratory information system. Results Overall antibody prevalence was 29.7% with dramatic institutional variation (17.9%–56.0%). Alloantibody prevalence was 27.5%. Most autoantibody‐positive patients (74.23%) also had alloantibodies, identifying a high‐risk population. A third of patients with positive antibody histories had negative screens. Pediatric patients showed markedly different antibody profiles than adults. Hospitals’ antibody patterns clustered by patient age rather than geography. Rh and K antibodies were the most common and also most likely to co‐occur, followed by S, Fya, and Jkb antibodies. Antibodies against Jsa (1.82%), V (1.75%), and Kpa (1.69%) were more prevalent than anti‐Jka (1.28%). Despite regional antibody variation, antigen frequencies remained overall consistent. In antigen–antibody pairwise comparisons, 3.15% were antigen‐negative and antibody‐positive reflecting alloimmunization; 0.47% were both antibody‐ and antigen‐positive, suggesting partial/variant antigens. Discussion Substantial institutional variation in antibody prevalence suggests need for site‐specific approaches to testing and prophylactic matching. High co‐occurrence of auto‐ and alloantibodies, antibody immunogenicity patterns, and antigen–antibody discordances support the need for further research and consideration of refined testing and/or matching strategies beyond the current Rh and K standard.

Abstract Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R ⁻ , drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 ⁺ and CD8 ⁺ T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 ⁺ T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 ⁺ T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive ‘viral-induced precursors’ (VIPs) and Timer-negative KLRG1 ⁺ ‘viral-induced terminal effectors’ (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 ⁺ T cell reprogramming, and durable regression of distant lesions in patients.

Background Psychiatric comorbidities are increasingly recognised in demyelinating diseases, yet their frequency and timing in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well defined. We aimed to characterise the spectrum and temporal pattern of psychiatric illness in MOGAD and compare to multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-IgG). Methods We conducted a cross-sectional study of patients with MOGAD (n=388), age-matched and sex-matched MS (n=257) and AQP4-IgG-positive NMOSD (n=58) evaluated at Mayo Clinic (1991–2025). Psychiatric diagnoses, timing relative to the first attack and patient-reported outcomes were extracted from electronic health records (EHRs). Complementary analyses were conducted using the NeuroBlu real-world EHR database. Results Among 388 patients with MOGAD, 54.8% had ≥1 psychiatric disorder, most commonly anxiety (47.7%), depression (36.6%) and attention-deficit/hyperactivity disorder (ADHD, 9%). After the first attack, 33.3% of patients with MOGAD developed a new psychiatric disorder, often within the first year. MOGAD showed a lower frequency of depression versus MS (36.6% vs 47.5%, p=0.02) but similar rates of anxiety and ADHD. Temporal patterns differed: psychiatric disorders often appeared years before onset in MS but clustered shortly after onset in MOGAD. NeuroBlu analyses supported high rates of psychiatric disorders across the three conditions. Conclusion Psychiatric comorbidities are common in MOGAD, particularly depression and anxiety, typically emerging close after onset, whereas in MS they often preceded onset by years. These findings underscore the need for routine psychiatric screening in MOGAD and highlight unresolved questions regarding whether, and to what extent, MOG-IgG-mediated inflammatory demyelination contributes to psychiatric vulnerability.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. They are intended to assist oncology teams to identify patients who require referral to psychosocial resources and to give oncology teams guidance on interventions for patients with significant distress. These guidelines also provide guidance for social workers, certified chaplains, and mental health professionals by describing treatments and interventions for various psychosocial problems as they relate to patients with cancer. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding standards of care for distress management in patients with cancer and implementation of these standards, including application of evidence-based care delivery models, such as the collaborative care model.

Background. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising noninvasive biomarker for detecting allograft rejection in solid organ transplantation. However, its diagnostic utility in pancreas transplantation, including in multiorgan recipients, remains underexplored. Methods. We conducted a retrospective analysis of 42 pancreas transplant recipients (38 simultaneous pancreas-kidney, 4 pancreas transplant alone) who underwent for-cause organ biopsy and dd-cfDNA testing between April 2020 and December 2024. dd-cfDNA was measured using the Prospera assay, with a threshold of ≥1% considered high risk and <1% low-risk. Biopsy results were correlated with dd-cfDNA to assess test performance. Results. A total of 50 dd-cfDNA tests and 45 organ biopsies were analyzed. Among simultaneous pancreas-kidney recipients, dd-cfDNA demonstrated a sensitivity of 86.7%, specificity of 52.2%, positive predictive value (PPV) of 54.2%, and negative predictive value (NPV) of 85.7% for rejection. In pancreas transplant alone recipients, all high-risk dd-cfDNA results corresponded to biopsy-proven rejection, yielding 100% sensitivity, specificity, PPV, and NPV. When combining both cohorts, dd-cfDNA testing achieved an overall sensitivity of 88.2%, specificity of 57.7%, PPV of 57.7%, and NPV of 88.2%. Additionally, dd-cfDNA kinetics suggested its potential utility as a surveillance tool posttreatment, potentially reducing the need for closure biopsies. Conclusions. dd-cfDNA is a valuable noninvasive adjunct for monitoring of rejection in pancreas transplant recipients. Further prospective studies are needed to validate these findings and define the optimal role of dd-cfDNA in posttransplant care.

Management of locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV(+) OPSCC) can include induction chemotherapy followed by definitive chemoradiation. The standard induction regimen of cisplatin, docetaxel, and 5-fluorouracil (TPF) is associated with high toxicity. Given the chemosensitivity of HPV(+) OPSCC, platinum doublets are frequently used as induction therapy with potentially less toxicity. This retrospective study aimed to compare outcomes between treatment-naive HPV(+) OPSCC patients receiving induction TPF and those receiving an induction platinum doublet. Data collected included tumor characteristics, response after chemoradiation, hospitalization rates, and overall survival (OS). Fifty-five patients (18 TPF and 37 platinum doublet) were included. There was no significant difference in response after completion of definitive chemoradiation (TPF: CR 83.3%, PR 5.6%, progression or metastasis 11.1% vs. platinum doublet: CR 75.7%, PR 16.2%, progression or metastasis 8.1%; p = 0.5241). There were also no differences in hospitalizations for adverse events (38.9% in TPF vs. 40.5% in platinum doublet, p = 0.907) or recurrence (11.1% in TPF vs. 2.7% in platinum doublet, p = 0.198). The 5-year OS was 84.6% in the TPF group and 81.5% in the platinum doublet group (p = 0.581). Induction platinum doublet regimens offer comparable OS, response, and hospitalization rates to TPF in locally advanced HPV(+) OPSCC. Induction with a platinum doublet may be a viable de-escalation strategy for patients who are not candidates for TPF.

ABSTRACT Importance Rural-urban disparities in chronic disease prevalence are well established; however, the extent to which individual-level socioeconomic status (SES) contributes to these disparities remains unclear. Objective To examine the associations of rurality and SES with the prevalence of five most burdensome chronic diseases among adults. Design We conducted a retrospective cross-sectional study of adults across 27 Upper Midwest counties using the Expanded Rochester Epidemiology Project (E-REP) medical record data linkage system to evaluate associations between rurality, SES and chronic disease prevalence. Prevalence of clinically diagnosed asthma, diabetes, hypertension, coronary heart disease, and mood disorders was identified from International Classification of Diseases ICD9/10 codes over a five-year period (2014-2019). Setting Population based Participants Adults over 18 years residing in the 27 E-REP counties, excluding those missing rural-urban residence status. Exposure HOUSES index, an individual-level measure of SES, served as the primary measure, while rurality based on Rural Urban Commuting Area (RUCA) codes 4-10 was the secondary measure. Main Outcome Prevalence of the five clinically diagnosed chronic diseases was identified using ICD9/10 codes from 2014–2019. Mixed effect logistic regression models were used and adjusted for demographics and general medical examination receipt, to assess rural-urban and SES differences for prevalence of each chronic disease. Results Among 455,802 adults with available HOUSES index, 42.8% lived in rural areas, 53.8% were female and 87.4% were non-Hispanic White. In the unadjusted analysis, rural and urban populations showed comparable asthma and CHD prevalence, while mood disorders, hypertension, and diabetes were more common in urban areas. After adjusting for demographic factors and healthcare utilization, rural-urban differences were no longer statistically significant, whereas SES remained strongly associated with all diseases in a dose response manner (e.g., adjusted Odds Ratio for hypertension (ref: HOUSES index Q4): 1.14, 1.27, and 1.42 for HOUSES index Q3, Q2, and Q1, respectively). Conclusions and Relevance Individual-level SES measured by the HOUSES index, was more strongly associated with chronic disease prevalence than rurality, supporting its integration into population health assessment and risk stratification.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with limited treatment options. CCA exhibits a distinct desmoplastic and tolerogenic tumor immune microenvironment (TIME) characterized by elevated bile acid concentrations resulting from obstructive cholestasis and dysregulated bile acid metabolism. TGR5 is an essential component of bile acid signaling. We hypothesize that bile acids promote CCA progression by establishing an immunosuppressive TIME through TGR5 signaling, which can be therapeutically targeted using SBI-364, a novel potent small molecule TGR5 inhibitor. Methods: Single-cell RNA sequencing (scRNA-seq) of immune cells from human intrahepatic (iCCA) and perihilar (pCCA) CCA tumors were conducted. Therapeutic studies were performed using syngeneic murine models of iCCA (PMID: 38458319), a novel syngeneic model of pCCA, and patient-derived xenograft (PDX) models. In collaboration with Sanford Burnham Prebys, SBI-364, a first in-class competitive TGR5 antagonist, was assessed in vivo. Additionally, we performed co-culture experiments with bile acid +/- SBI-364-treated murine bone marrow-derived monocytic myeloid-derived suppressor cells (M-MDSCs) and CD8+ T cells to assess functional immunosuppressive effects. Results: Human scRNA-seq revealed significantly increased TGR5 (GPBAR1) expression predominantly in myeloid cell populations within the CCA TIME. SBI-364 treatment significantly reduced tumor burden in both syngeneic orthotopic iCCA models and a novel pCCA model that recapitulates the anatomic characteristics of perihilar CCA. In contrast, NOD/SCID mice bearing PDX535 (predicted sensitive) and PDX136 (predicted resistant), SBI-364 treatment did not achieve tumor reduction, suggesting that TGR5 inhibition predominantly attenuates tumor progression through modulation of bile acid-immune cell interactions. SBI-364 treated murine tumors had a significant reduction in immunosuppressive macrophages expressing interleukin-10 and M-MDSCs compared to vehicle treated tumors. Furthermore, bile acid-treated M-MDSCs exhibited enhanced suppression of CD8+ T cell proliferation and function, an effect that was abrogated by SBI-364 co-treatment. Conclusion: We demonstrate that TGR5 inhibition represents a promising therapeutic strategy across multiple immunocompetent preclinical CCA models. We demonstrate that the bile-acid TGR5 axis promotes CCA progression via immunosuppressive myeloid cells. Specifically, TGR5 signaling potentiates the immunosuppressive capacity of M-MDSCs, contributing to an immunosuppressive niche that facilitates tumor progression. These results establish TGR5 as a rational therapeutic target for overcoming immune evasion in cholangiocarcinoma. Citation Format: Enis Hikmet Ozmert, Binbin Li, Jingchun Yang, Hannah Elizabeth Stumpf, Jessica R. Willhite, Danielle Carlson, Jennifer L. Tomlinson, Jon Covel, Raghuveer Ramachandra, Steven Olson, Rory L. Smoot, Sumera Ilyas. Therapeutic targeting of TGR5 abrogates bile acid driven myeloid cell immunosuppression in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2896.