Citations

Abstract Exposure to asbestos is the primary cause of mesothelioma, however the processes underpinning its initiation and evolutionary trajectory remain elusive. To address this knowledge gap, we conducted whole exome sequencing and phylogenetic analysis of 277 mesotheliomas. Using multidimensional Dirichlet process clustering we inferred phylogenies, uncovering mutation order dominated by early 13q,1p, 8p, 6q and 22q somatic copy number alterations. Mesotheliomas exhibit a spectrum of genomic intra-tumor heterogeneity spanning linear (L) to highly branched (B) tree topologies, quantifiable by the Weighted Shannon Entropy (WSE). Somatic copy number alterations emerge earlier than single nucleotide variants (SNVs), and at a much faster relative rate in L-mesotheliomas. BAP1 is the only positively selected driver in L-mesotheliomas, whereas, B-mesotheliomas harbor multiple positively selected drivers and an aggressive phenotype, including a bias of loss of RPL5, and MTAP deletion linked to breakpoint enriched with long interspersed nuclear elements. L-trees had lower WSE, but greater T-cell inflammation and tertiary lymphoid structures, despite having a lower neoantigen burden. WSE is higher in larger volume, immunologically cold mesotheliomas, and is associated with shorter survival. In summary, progressive genomic heterogeneity is a defining feature of more aggressive mesothelioma yet illuminates opportunities for precision therapeutic intervention.

Prehabilitation with Impella 5.5 offers hemodynamic support while allowing early mobilization, yet its overall effect on post-transplant recovery remains unclear. The aim was to assess recovery during Impella 5.5–supported prehabilitation and determine its association with early post-heart transplant outcomes, including a potential dose–response relationship with ambulatory activity. We conducted a single-center retrospective cohort study of adults bridged to transplant with Impella 5.5 between April 1, 2022 and September 30, 2024. Daily walking distance, recorded by nursing staff, served as the intervention. Primary outcome was postoperative hospital length of stay (LOS); the secondary outcome was time to extubation. Fine–Gray competing-risk models, adjusted for age, Sequential Organ Failure Assessment (SOFA) score, New York Heart Association (NYHA) class, and days of Impella support, assessed associations. Longitudinal recovery trajectories were analyzed with linear mixed-effects models incorporating restricted cubic splines. Among 82 eligible patients, 65 met the inclusion criteria. Patients who walked farther during Impella 5.5 support in the intensive care unit (ICU) had shorter hospital stays and were taken off the ventilator sooner after transplantation. The overall recovery peaked during the first 2–3 weeks of support, with smaller recovery thereafter, indicating that most functional recovery occurred early during prehabilitation.

Graph neural networks (GNNs) are increasingly used for medical imaging analysis and biological data modeling, where the integration of radiomics, topology, geometry, and generative artificial intelligence (AI) may improve representation learning from medical images and related biomedical data. Across the reviewed literature, GNNs show particular value for modeling spatial relationships, multimodal interactions, graph-structured biological networks, and non-Euclidean imaging features that are difficult to capture using conventional convolutional architectures alone. Topology- and geometry-aware approaches further expand this capability by encoding multi-scale structure, higher-order relationships, curvature, geodesic organization, and equivariant spatial priors. Hybrid graph–transformer models and generative graph methods represent emerging directions for modeling long-range dependencies, augmenting scarce datasets, supporting synthetic pretraining, and improving representation learning in low-label or heterogeneous biomedical settings. However, clinical translation remains limited by variability in graph construction, limited external validation, computational cost, scalability constraints, interpretability challenges, and uncertainty regarding the biological realism of synthetic data. Overall, this review highlights that GNN-based medical imaging analysis is most likely to advance when graph construction is biologically justified, model performance is evaluated across diverse clinical cohorts, and technical gains are paired with transparent validation, interpretability, and implementation strategies.

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

ABSTRACT Purpose To explore the opioid decision‐making process of prescribers in primary care, surgery, and subspecialty pain management. Methods This was a multistage qualitative‐qualitative study with clinicians involved in opioid prescribing and management from a single healthcare organization with locations in Minnesota, Florida, Arizona, and Wisconsin. Clinicians in this study included physicians, nurse practitioners (NPs), and physician assistants (PAs) practicing in primary care, surgery, or pain medicine. The interview guide was organized in three domains of a conceptual model for opioid use: (1) prescriber characteristics, (2) patient characteristics, and (3) practice environment characteristics. Individual interviews ( N = 20) were performed first, and data were summarized using a rapid template‐based approach. Subsequently, focus groups (FGs) ( N = 4) were conducted with an additional 21 clinicians to confirm and explore interview results. Data from interviews and FGs were analyzed using a common codebook. Results Findings were organized as decision factors into the three domains. Factors in the prescriber domain included characteristics such as formal pain management training, as well as factors that influenced knowledge and beliefs (e.g., advice from or observation of supervising clinicians and expert colleagues). Decision factors in the patient domain included patient pain etiology, comorbid medical or mental health conditions, and demographic characteristics. Clinicians' perceptions of these factors, such as viewing older age as having lesser risk for opioid misuse, influenced prescribing decisions. Clinicians also described challenges associated with “legacy patients” whose therapy was previously managed by a different clinician. Primary care clinicians, in particular, expressed difficulties managing post‐surgical or trauma‐related pain after care transition. Relevant decision factors reported by prescribers in the practice environment domain included guidelines and practice oversight. Most participants reported practicing in an environment that promoted conservative opioid use and having access to standardized institutional guidelines that reduced perceived decision‐making burden. Clinicians described how they used prescribing guidelines to help them communicate with patients about opioid use and prescribing decisions. Conclusions Intersecting prescriber, patient, and practice environment factors shape opioid analgesic prescribing decisions. Available resources in the practice environment, including peer input and institutional guidelines, may support clinician decision‐making and conversations with patients at the point of care, including in cases where patients have complex histories or personal characteristics that influence decision making.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

e13635 Background: Melanoma is an aggressive skin malignancy with rising global incidence, for which checkpoint inhibitors (CPI) and BRAF-targeted therapies are standard of care in advanced disease. However, access to molecular diagnostics and CPI remains limited in conflict-affected regions such as Syria. Real-world data describing melanoma management in this setting are scarce. Methods: We conducted a retrospective study of all patients diagnosed with melanoma between 2022 and 2024 at Al-Bairouni University Hospital (ABUH), Syria’s primary oncology referral center. Demographic and clinical characteristics were analyzed for the entire cohort, and patients with advanced disease were evaluated for molecular testing and treatment patterns. Semi-structured interviews were conducted in a mixed advanced cancer subset (N = 35) to explore barriers to immunotherapy access. Results: Among 115 patients with melanoma, the median age at diagnosis was 57 years (IQR 44.5–67), and 54.7% were male. At presentation, 18.3% had stage I disease, 1.7% stage II, 2.6% stage III, and 40.9% stage IV disease; staging was unavailable in 36.5%. Among patients with advanced melanoma (n = 47), BRAF testing was performed in 17 (36.2%), with targeted therapy administered to 5/16 BRAF-positive patients. Only 7/47 patients (14.9%) received CPI, primarily as monotherapy. In the qualitative subset (predominantly lung cancer), five major barriers to immunotherapy access emerged: financial toxicity (n = 22), limited drug availability (n = 9), limited patient awareness (n = 8), geographic/logistical challenges (n = 5), and system delays (n = 4). Conclusions: Despite a substantial burden of advanced melanoma, access to molecular testing, targeted therapy and CPI in Syria remains limited. Qualitative findings highlight financial and structural barriers as primary drivers of limited access, underscoring the need for improved drug availability, diagnostic infrastructure, and patient education in conflict-affected settings.

Abstract Context Limited data are available on quality of life (QoL) and adrenal crises in patients with immune checkpoint inhibitor–induced secondary adrenal insufficiency (ICI-SAI). Objective To (1) characterize the presentation, management, and outcomes of patients with ICI-SAI; (2) compare outcomes of ICI-SAI with other etiologies of secondary adrenal insufficiency (oSAI); and (3) identify variables associated with QoL and adrenal crisis. Methods In this single-center cross-sectional study, adults with ICI-SAI or oSAI (2018-2025) completed questionnaires assessing symptoms, management, adrenal crises, and the Addison’s Disease–Specific QoL survey (AddiQoL); outcomes included AddiQoL score and adrenal crisis events. Results Patients with ICI-SAI (n = 109) were older (median age 66 vs 60 years), more often women (59% vs 43%), and more frequently diagnosed within 1 year of symptom onset (88% vs 42%, P < .001), compared to patients with oSAI (n = 139). Patients with ICI-SAI had higher AddiQoL scores (median 87 vs 85, P = .020). In a multivariable analysis of age, sex, glucocorticoid dose and type, insurance support, and duration of SAI, ICI-SAI remained independently associated with higher AddiQoL (estimate 5.4, P = .010). The prevalence of reported adrenal crises within the prior year was similar between groups (15% vs 14%, P = .782). In a multivariable analysis, higher AddiQoL scores were independently associated with lower odds of adrenal crisis (OR 0.57; 95% CI 0.42-0.76). Conclusion Patients with ICI-SAI report better QoL compared with patients with other causes of SAI, despite similar adrenal crisis rates. These differences may be related to earlier diagnosis and differing clinical contexts, underscoring the importance of timeline recognition and patient-centered management.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly conceptualized as multisystem neurodevelopmental conditions involving behavioral, gastrointestinal, immune, and metabolic alterations. The microbiota–gut–brain axis (MGBA) has been proposed as a key framework linking these systems, although evidence from human studies remains heterogeneous and inconclusive. We conducted a structured narrative review of pediatric human studies investigating the microbiota-gut-brain axis (MGBA) in ASD and ADHD, excluding preclinical and animal studies. PRISMA 2020 principles were used as a transparency framework to support reporting of study identification, screening, and eligibility. Observational, cohort, and interventional studies were synthesized with particular attention to study design, methodology, associations with standardized clinical scales, dietary factors, and therapeutic implications. Across ASD ( n = 90), most studies were observational, predominantly cross-sectional or case-control in designs, reporting consistent associations between ASD symptom severity and gastrointestinal symptoms, intestinal permeability, immune activation, and dietary selectivity. Evidence in ADHD ( n = 21) was substantially more limited and largely observational. Diet emerged as a major modulating and confounding factor in microbiota–behavior associations. Interventional studies involving probiotics, microbiota transfer therapy, and other gut-directed approaches showed more consistent improved gastrointestinal outcomes but showed modest and heterogeneous effects on core ASD symptoms, often limited to subgroups with prominent gastrointestinal comorbidities. To strengthen interpretation of interventional findings, randomized trial reports and non-randomized interventional studies were appraised according to study design, whereas the predominantly heterogeneous observational literature was interpreted narratively. Overall, this review suggests that MGBA alterations may be better conceptualized as modifiers of symptom expression, particularly in ASD and with only emerging relevance in ADHD, rather than as disorder-specific causal mechanisms. This interpretation underscores the need for stratified, longitudinal, and clinically informed research frameworks, in line with the focus of the present research topic.

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.