Citations

Abstract Renal cell carcinoma (RCC) is the most common form of kidney cancer, with 435 000 patients newly diagnosed worldwide each year. In addition to morphology and histology, molecular subtyping has advanced the diagnostic classification of RCC. Contemporary diagnosis relies on cross sectional imaging in the form of computed tomography or magnetic resonance imaging and selective biopsy. For localised disease, nephrectomy remains the standard of care, with partial nephrectomy being an option for smaller tumours. Ablation or stereotactic radiation is appropriate for selected patients. Adjuvant pembrolizumab provides improved disease-free and overall survival in high risk clear cell RCC. In metastatic disease, the introduction of immune checkpoint inhibitor based combinations has extended overall survival, providing a durable response in some patients. Despite these advances, primary and secondary resistance, along with the lack of predictive and prognostic biomarkers, remain a challenge.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCAs) and angina with nonobstructive coronary arteries (ANOCAs) present diagnostic and therapeutic challenges. We assessed the frequency of coronary microvascular disease (CMD) and its subtypes in MINOCA compared with ANOCA and evaluated long-term cardiovascular outcomes. METHODS: Patients with nonobstructive coronary arteries undergoing invasive coronary function testing from 2012 to 2022 were prospectively enrolled and retrospectively classified as MINOCA or ANOCA (reference group). Myocardial infarction due to atherothrombosis, myocarditis, and Takotsubo syndrome were excluded. Invasive provocation testing was performed. CMD was classified as endothelium-independent (coronary flow reserve <2.5 with adenosine) and endothelium-dependent (<50% increase in coronary blood flow with acetylcholine). Major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, heart failure hospitalization, urgent revascularization, stroke) were recorded over 8 years. RESULTS: Of 622 patients, 73 (12%) had MINOCA (69% female, median age 56 years) and 549 (88%) ANOCA (72% female, median age 53 years). CMD was common in both groups (71% versus 64%; P =0.271), while endothelium-independent CMD was more frequent in MINOCA (41% versus 21%; P <0.001). Over a median follow-up of 4.5 years, major adverse cardiovascular events occurred more often in MINOCA (40% versus 11%; adjusted hazard ratio, 2.4; P =0.001). CMD predicted higher major adverse cardiovascular events in both MINOCA (hazard ratio, 3.6 [95% CI, 1.1–12.0]; P =0.038) and ANOCA (hazard ratio, 7.9 [95% CI, 2.9–21.8]; P <0.001). CONCLUSIONS: CMD is common in both MINOCA and ANOCA. The higher prevalence of endothelium-independent CMD in MINOCA suggests a potential mechanistic role in infarction. Patients with MINOCA have a worse prognosis than ANOCA, particularly when CMD is present.

Introduction Pluripotent stem cell-derived alpha cells (SC-α cells) represent a promising component of next-generation cell therapies designed to more fully recapitulate human islet function; however, heterogeneity and the presence of undesired side populations limit their functional maturity and therapeutic potential. Here, we identify the cell surface protein CD98hc (SLC3A2), that when highly expressed in precursor cells, is associated with differentiation toward a more transcriptionally and functionally mature population of human SC-α cells. Methods Directed differentiation was used to generate SC-α cells from pluripotent stem cells, which were assessed via single cell RNA sequencing, flow cytometry, and immunofluorescence imaging. Following magnetic activated cell sorting (MACS) of CD98hc enriched precursors, SC-α cell function was assessed using glucose stimulated glucagon secretion (GSGS). Results We show that CD98hc is upregulated in SC-α cells expressing high levels of genes known to play important roles in α cell identity and function, and that CD98hc expression is elevated at the pre-α precursor stage relative to non–α cell populations. We demonstrate that magnetic enrichment of CD98hc⁺ pre-α cells derived from multiple pluripotent stem cell lines selectively increases the proportion of the highest CD98hc expressing glucagon-copositive precursors while depleting multiple undesired side populations, including somatostatin-positive and SOX9-positive cells. Although total α cell yield equalizes following complete differentiation, SC-α cells derived from high-CD98hc enriched precursors exhibit significantly enhanced glucose-responsive glucagon secretion compared to sham-sorted controls, indicating improved functional maturation of this precursor population. Discussion Together, these findings establish that high expression levels of CD98hc marks a functionally superior α cell precursor, that enrichment at the precursor stage can bias differentiation toward higher functional α cell output, that stem cell-derived α cell populations harbor intrinsic functional heterogeneity, and that selective targeting of precursor populations represents a generalizable strategy to improve the quality and performance of stem cell-derived endocrine cell products.

Transcranial magnetic stimulation can provide noninvasive measures of cortical excitability and plasticity, but relationships between these measures and clinically observable features of autism are not fully characterized. Nineteen autistic participants aged 15 to 40 years were included in the analysis of a left primary motor cortex continuous theta-burst stimulation (cTBS) biomarker protocol. Motor evoked potentials were measured at baseline and at seven assessments from 5 to 60 min after stimulation. Linear mixed-effects models evaluated whether clinical measures moderated the post-stimulation motor evoked potential log-response ratio over time. Aberrant Behavior Checklist (ABC) and Attenuated Behavior Questionnaire (ABQ) analyses were restricted to the same 15 participants with caregiver-informant assessments. Catatonia severity, social impairment, ABQ Motor Total, ABQ Total, and cognitive ability did not significantly moderate the post-stimulation response. ABC Inappropriate Speech was associated with progressively greater post-stimulation facilitation (standardized Time-by-Inappropriate Speech interaction: beta = +0.688, SE = 0.210, 95% CI +0.276 to +1.099; Holm-adjusted P = .008 across eight informant-rated models). Two individual speech-related items ("Talks excessively" and "Talks to self loudly") survived false-discovery-rate correction. An exploratory eight-item ABC phenotype showed a large descriptive in-sample association (beta = +0.904, SE = 0.200, P less than .001) and directionally positive held-out performance. However, full-pipeline permutation tests were nonsignificant for both Pearson (r = .357, two-sided empirical P = .360) and Spearman correlations (rho = .446, two-sided empirical P = .261). Caregiver-rated inappropriate speech may be associated with altered post-cTBS motor cortical facilitation in autism. The candidate phenotype remains hypothesis-generating and requires independent validation.

Background/Objectives: Hospital-at-home (HaH) programs have emerged as an alternative model to brick-and-mortar (BaM) hospital management of acute conditions such as heart failure, pneumonia, pyelonephritis, and chronic obstructive pulmonary disease exacerbation among the others. However, the clinical management of acute pancreatitis in the HaH setting has never been described in the literature. The primary objective of this study was to describe the demographic and clinical characteristics of patients with acute pancreatitis managed in a Mayo Clinic Advanced Care at home (ACH) program. The secondary objective was to describe feasibility and short-term clinical outcomes. Methods: This multistate, multicenter, retrospective descriptive study included 40 unique patients with acute pancreatitis managed at ACH between 13 October 2020 and 1 June 2024. Repeat admissions were excluded from the primary analysis. Results: The most common etiologies were idiopathic (42.5%), gallstone-related (22.5%), and alcohol-related (12.5%). Peripancreatic fluid collections occurred in 17.5%, necrotizing pancreatitis in 10.0%, pleural effusion in 12.5%, and infected pancreatitis in 7.5%. Intravenous antiemetics were administered to 22.5%, intravenous fluids to 62.5%, and intravenous opioids to 7.5%. Median total hospital length of stay was 5.0 days (IQR, 3.0–8.25), including a median of 3.0 days (IQR, 2.0–4.0) in ACH. Four patients (10.0%; exact 95% CI, 2.8–23.7%) were transferred from ACH to BaM care. Seven-day and 30-day readmission rates were 10% (95% CI: 2.8%, 23.7%) and 5% (95%CI: 0.6%, 16.9%), respectively. The 30-day emergency department visit was 0%. Although 30-day mortality was 2.5% (95% CI: 0.0%, 13.2%), in-program mortality was 0%. Conclusions: Among a highly selected group of clinically stable patients meeting the program’s eligibility criteria, management of acute pancreatitis in ACH was feasible and was associated with low observed rates of unplanned escalations and short-term adverse outcomes.

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

ABSTRACT Introduction Composite indolent B‐cell lymphomas may remain unrecognized when one component dominates the clinical presentation. Apparent relapse after therapy may, therefore, represent the emergence of a biologically distinct lymphoma rather than the recurrence of the original disease. Case Presentation An 82‐year‐old woman presented with systemic low‐grade B‐cell lymphoma that was most consistent with marginal zone lymphoma (MZL). Staging demonstrated peripheral blood involvement and multifocal FDG‐avid disease. Treatment with the CD20×CD3‐bispecific antibody mosunetuzumab resulted in complete metabolic remission. During surveillance, a new, isolated cervical lymph node developed despite sustained systemic response. Biopsy revealed follicular lymphoma (Grade 1–2) with a germinal center phenotype and a BCL2 rearrangement, findings discordant with recurrence of MZL. Retrospective review of the original specimen identified in situ follicular neoplasia within the initial biopsy. The disease course was, therefore, reinterpreted as a synchronous composite lymphoma in which treatment of the dominant MZL unmasked a previously clinically silent B‐cell neoplasm with follicular lineage. Local radiotherapy achieved remission of the follicular component. Conclusions New disease following treatment of an indolent lymphoma should not automatically be interpreted as relapse. Discordant clinical behavior, particularly focal progression after systemic response, warrants repeat biopsy and integrated pathologic reassessment. This case illustrates how therapy may reveal preexisting clonal heterogeneity and emphasizes the importance of temporality in distinguishing relapse from composite lymphoma. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.