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.

TPS6126 Background: Oral cavity cancers (OCC) are a rare subtype of head and neck cancer (HNC) with poor outcomes and limited second-line treatment options in the recurrent or metastatic (R/M) setting. Treatment-related morbidity and repeated local recurrences in OCC result in significant impairment of function and quality of life. Rural OCC patients comprise a sizable portion (50%) of our practice and are usually of lower socioeconomic status with lack of access to specialist care. They also have multiple barriers to treatment access and ancillary services, translating to poorer clinical outcomes. There is a critical need for effective and accessible therapies for R/M OCC in rural patients. Triple oral metronomic chemotherapy (TOMC) with Methotrexate, Erlotinib and Celecoxib (MEC) suppresses angiogenesis and activates antitumor microenvironment in HNC. Studies using TOMC in R/M OCC outside the US show reasonable efficacy (6-month OS 52.9%), better safety and lower cost compared to standard second line options. We hypothesize that a decentralized clinical trial with TOMC in R/M OCC is feasible, safe and effective in addition to being economical and accessible for rural patients. Methods: MC240701 is a single institution, open label, decentralized, single arm pilot study of MEC in patients with R/M OCC. Eligible pts must be ≥18 years old, have pathologically confirmed R/M OCC not amenable to curative-intent therapy, ECOG 0-2 and adequate organ function. At least 1 measurable lesion by RECIST 1.1 OR non-measurable disease (evident mucosal lesions, CNS/bone disease, lesions not meeting RECIST criteria) is permitted. Patients must have received standard first line immunotherapy with or without chemotherapy OR should be unable/unwilling to receive first line treatment. Key exclusion criteria include patients unable to take pills by mouth, serious medical co-morbidity or autoimmune disease, immunocompromised patients and other active malignancy. Primary endpoint is to demonstrate feasibility of decentralized clinical trials, secondary outcomes include overall response rate, progression free and overall survival and toxicity. Additional goals are to evaluate patient impact of decentralized treatment through surveys and interviews After initial screening and evaluation, patients are remotely consented and will receive study drugs by mail. All patients will receive the same treatment of Methotrexate 9mg/m 2 PO weekly, Erlotinib 150 mg PO daily, and Celecoxib 200 mg PO BID, each cycle will be 28 days. Treatment will continue until disease progression or treatment tolerance, study duration is for 2 years. All subsequent clinical and laboratory monitoring and response assessments (every 3 cycles) will be remotely performed or have an option for local testing. Enrollment began July 2025 and 4 out of planned 25 patients have been accrued. FDA IND:174540. Clinical trial information: NCT06997068 .

6123 Background: Pemetrexed (PTX) is safe and tolerable with responses reported in pts with R/M SGC. Given enhanced responses with PTX and pembrolizumab (PMB) for lung cancer, we hypothesized that PTX and PMB will have activity for SGC. Herein we present the efficacy results in pts with adenoid cystic carcinoma (ACC). Methods: MC200708 is a single arm phase II study of PTX and PMB in pts with R/M SGC (NCT04895735) with 2 cohorts: ACC (cohort A) and non-ACC (cohort B). Key eligibility criteria: ≥18 years, ECOG 0-1, measurable disease. Prior ICI and/or PTX was allowed. Key exclusion criteria: serious comorbidities, autoimmune disease and brain metastases. Simon’s 2-stage design was used for each cohort. Primary endpoint was overall response rate (ORR) for Cohort A but was amended to clinical benefit rate (CBR=SD+PR+CR) due to prolonged SD in several pts. Secondary endpoints: progression free survival (PFS), overall survival (OS), and toxicity. Exploratory analyses in Cohort A1 (post-amendment pts) included PSMA PET imaging and circulating PSMA extravesicles (EVs) as a biomarker. All pts received PTX 500 mg/m2 IV + PMB 200 mg IV q3 weeks until progression or treatment intolerance. Imaging was q3 cycles. Results: 20 pts (11 Cohort A + 9 Cohort A1) were enrolled from August 2021-Feb 2025. All 20 patients were eligible and received ≥ 1 cycle of treatment. Median age was 60.5 yrs, 50% male, performance status 0 (80%) or 1 (20%). 11 pts had no prior therapies (55.0%). The remaining pts had 1 (35%) or 2 (10%) prior lines of therapy. 75% of pts had no prior ICI. In Cohort A, the ORR was 0% (0 of 11). Cohort A1 met criteria for success based on CBR with 1 PR (12.5%) and 5 SD (62.5%) in the first 8 pts. For the whole cohort of 20 patients, the ORR was 5% (95% CI: 0.1-24.9) and the CBR rate was 75% (95% CI: 51-91) with 1 PR and 14 pts with SD. The duration of response for the 1 PR patient was 12.4 months. The median duration of response for the 15 pts with SD was 7.5 (2.0-29.7) months. 3 pts (15%) had PD and 2 pts (10%) went off prior to response assessment. Median cycles of treatment was 4 (2-30). In the 17 pts who discontinued, treatment was stopped in 9 (53%) for PD, 4 (23.5%) due to adverse events (AE), and 4 (23.5%) due to physician/patient preference. With a median follow-up of 14.5 months (1.5-39.2), the 1-year PFS rate is 52.1% (32.6 – 83.2%) and the OS rate is 82.1% (95% CI: 65.6 – 100%). The overall grade 3+ AE rate regardless of attribution was 80% (16/20). The most common grade 3 AEs were lymphocyte count decrease (40%), hypertension (20%), fatigue (10%), and pneumonitis (10%). 2 pts had a grade 4 AE (lymphocyte count decrease and thrombotic thrombocytopenic purpura). There were no treatment-related deaths. Analysis of correlative studies for Cohort A1 with PSMA imaging and EV biomarker ongoing. Conclusions: PTX and PMB has modest activity in pts with R/M ACC with CBR of 75% and prolonged benefit for some patients. Clinical trial information: NCT04895735 .

560 Background: Patients (pts) with early stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) remain at both short and long term risk of recurrence. While clinico-pathological and gene-based biomarkers provide insight into early and late recurrence risk, additional prognostic tools are needed. We previously developed (Saha et al. Clin Cancer Res , 2025) a new breast MRI image-based artificial intelligence prognostic tool (TumorSight Risk) composed of both radiographic and clinical information. Here we sought to validate this tool in an independent cohort. Methods: In this multi-center, blinded, prospective/retrospective validation study, we sought to validate the 5-year recurrence-free survival (RFS) according to pre-defined risk scores (0-100) and categories (“high” or “low”) via pre-specified cutoff (≥47) for pts with HR+/HER2- BC. Kaplan-Meier and Cox regression analyses were then used to assess the unadjusted and adjusted association between risk category/score and the 5-year RFS. Results: 2,129 pts with HR+/HER2- BC diagnosed between January 1, 2010, and December 31, 2024, who underwent breast MRI prior to surgery (no neoadjuvant therapy) were included from four institutions. Median age was 57 years, 16% were Black, 15% had grade 3 disease, 93% were clinical T1 or T2, and 85%/15% were clinical N0/N1. At a median follow up of 6.24 years, the unadjusted hazard ratio (HR) for RFS comparing low (n=1808) and high risk (n=321) pts was 2.71 (95% CI = 1.95 – 3.76, p = 3x10 -9 ). The estimated 5 year RFS rate according to risk score (low and high) was 95.5% (95% CI: 94.63 – 96.3%) and 89.6% (95% CI = 86.4 – 92.6%) while the 10 year RFS estimates were 88.9% (95% CI = 86.5 - 90.9%) and 69.6% (95% CI = 59.1 – 77.9%). Univariate subgroup analysis demonstrated that the risk score was prognostic by age (< 50 vs. ≥50 years), pathologic nodal status, grade, and surgery type, regardless of chemo-, endocrine, or radiation therapy administration. The observed continuous risk score was strongly associated with risk of recurrence, with a 22% increase in relative risk per 10-unit change in risk score (0-100), translating to a 2.4% (95% CI = 1.2 – 4.5%) and 25.5% (95% CI = 15.4 – 40.4%) risk of recurrence at 5-years for pts at the lowest (0-9) versus highest (90-100) risk score. The prognostic association between risk score and RFS remained after adjusting for pathologic T- and N-stage, grade, age, race, and treatment (p = 0.002). Conclusions: TumorSight Risk is a new image-based biomarker for HR+/HER2- BC that provides prognostic information independent of standard clinico-pathological parameters. Given the ready availability of breast MRI in most pts with BC, TumorSight Risk may be a convenient tool for estimating risk for recurrence.

ABSTRACT Background/Objectives Prospective applicants for pediatric dermatology fellowships often use program websites as a source of information. This study evaluated the content of pediatric dermatology fellowship websites to identify potential areas of improvement including website accessibility and information found on websites. In addition, this study also surveyed current pediatric dermatology fellows and program directors (PDs) to determine priorities in website content across different stakeholders. Methods Using the Society for Pediatric Dermatology's (SPD) list of fellowship programs, two independent evaluators assessed the same 40 total programs, with 29 of the same websites included for analysis, against 27 criteria across four domains. In addition, an electronic survey was disseminated via the SPD's mailing list to current pediatric dermatology fellows and fellowship PDs. Results On average between both evaluators, of the 29 included fellowship websites, 9 educational criteria were included 47.8% of the time across the websites, compared to 46.0% of 10 recruitment criteria, 30.7% of 5 social criteria, and 31.6% of 3 other criteria. Fellows were significantly more likely than PDs to consider several website components as highly valuable. Conclusions These findings reveal variable and incomplete content across pediatric dermatology fellowship websites, as well as differing expectations for fellowship websites between pediatric dermatology fellowship applicants and PDs, which may help provide suggestions to optimize future website development to enhance applicant engagement.

OBJECTIVE Intramedullary spinal cord tumors (IMSCTs) are typically treated with maximal safe resection, during which neurosurgeons often monitor for neurological injury using muscle motor evoked potential (mMEP) and direct wave (D-wave) neuromonitoring. The predictive value of changes in D-waves for identifying motor outcomes is underexplored. This study evaluated the utility of D-waves for predicting postoperative motor deficits. METHODS Patients who underwent resection of a primary IMSCT with mMEP neuromonitoring from 2003 to 2023 at a tertiary care hospital were identified. Patients who underwent D-wave monitoring in addition to mMEP monitoring were compared to those who underwent mMEP monitoring alone using the Mann-Whitney U-test, chi-square test, and Fisher’s exact test. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of D-wave and mMEP monitoring for identifying new neurological deficits immediately postoperatively and at 1 month, 6 months, and last follow-up were calculated. RESULTS After matching, 125 patients were included (median age 42.0 years; 57.6% male; median follow-up 34.0 months), of whom 88 had both mMEP and D-wave data. The most common pathologies were ependymoma (64.0%) and astrocytoma (17.6%). Patients who did and did not undergo D-wave neuromonitoring had similar preoperative neurological function, primary pathology, tumor grade, and tumor location. D-wave use was associated with increased gross-total resection (88.6% vs 64.9%, p = 0.002) and reduced mortality (5.7% vs 24.3%, p = 0.007), length of stay (5.0 vs 6.0 days, p = 0.033), and 30-day readmission (2.3% vs 13.5%, p = 0.013) and reoperation (1.1% vs 10.8%, p = 0.012). At the 6-month follow-up, D-wave monitoring alone was superior to mMEP and combination monitoring for detecting new motor deficits. D-wave monitoring had peak sensitivity (77.8%) and NPV (96.5%) at 6 months and peak specificity (95.8%) and PPV (76.9%) in the immediate postoperative period. CONCLUSIONS D-wave monitoring was associated with reduced mortality and was more accurate than mMEP monitoring alone or combination monitoring for detecting new postoperative neurological deficits. Further prospective studies are needed to validate these results.

Foundation models are reshaping computational pathology by enabling scalable task-agnostic representations of histopathological whole-slide images (WSIs). Unlike earlier task-specific deep learning systems, pathology foundation models (PFMs) leverage massive whole-slide image repositories and self-supervised Vision Transformer architectures to achieve broad generalization and few-shot adaptability. Their evolution reflects a shift from weakly supervised approaches such as Clustering-Constrained Attention Multiple Instance Learning (CLAM) and hierarchical architectures such as Hierarchical Image Pyramid Transformer (HIPT) to large-scale efforts including foundation models, UNI, Virchow, Phikon, CONtrastive learning from Captions for Histopathology (CONCH), GigaPath, H-Optimus, Transformer-Based Pathology Image and Text Alignment Network (TITAN), and the Mayo Clinic Atlas. These models demonstrate impressive performance across diagnostic and prognostic benchmarks while also opening pathways for multimodal integration with genomics and clinical data. Yet significant barriers remain including inconsistent generalization across institutions, interpretability lagging behind clinical needs, and slow integration into routine laboratory workflows. Certain domains of anatomic pathology such as cytopathology, transplant pathology, frozen sections, and rare tumor subtypes remain particularly resistant to current models. Here, we review the development of PFMs, critically evaluate their strengths and limitations, and outline priorities for their safe and effective clinical translation. We argue that the next phase of PFM development will depend on rigorous benchmarking, pathologist-in-the-loop deployment, and multimodal fusion ensuring these models evolve from research tools into clinically robust systems.

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.

Abstract Background and Aims Burnout affects millions of healthcare workers worldwide, from food service and nurses to physicians and leaders, impairing worklives and threatening health system stability. Methods An international collaborative, PREVAIL, was created to reduce burnout globally. Leaders from six continents shared structured insights into the local state of wellness and burnout contributors and mitigators, which were then subjected to a formal thematic (qualitative) analysis to identify common and region-specific themes. Results Across continents, findings showed the global state of well-being was in danger, though threats varied by region: long shifts in Africa, heavy workloads in Asia, austerity-prone environments in Europe and financially driven care in North America. Vulnerable worker groups included women, nurses, and primary care. Mitigators included workload and schedule adjustments (Africa), shift policies with fair pay (Asia), leader support and regular well-being assessments (Australia), improved psychosocial services (Europe), organizational wellness support and career development (North America), and trainee support (South America). Conclusions A proposed “common pathway” framework explains shared drivers of poor workforce well-being and provides actionable steps for promoting compassionate, supportive environments worldwide. Implications/Learning Points Adopting a coordinated international approach may prevent devastating workforce shortages over the comingdecades. Burnout assessment and reduction in the global workforce is a high priority.

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are increasingly associated with cardiovascular toxicities, including myocarditis and accelerated atherosclerosis. While ICI myocarditis has received substantial attention, thrombotic complications remain underrecognized and may be difficult to distinguish from immune-mediated cardiac inflammation and cancer-related hypercoagulable state. We present a case of non-bacterial thrombotic endocarditis (NBTE) and myocardial microthrombi mimicking ICI myocarditis. Case summary A 76-year-old woman with metastatic adenosquamous lung carcinoma presented with progressive dyspnoea 3 weeks after initiating pembrolizumab. Pulmonary arterial and coronary imaging were unremarkable, but cardiac magnetic resonance imaging (MRI) showed late gadolinium enhancement (LGE) and myocardial oedema suggestive of ICI myocarditis. Chest computed tomography revealed inflammatory lung changes, and empirical corticosteroids were initiated with initial clinical improvement. One week later, brain MRI showed multifocal infarcts, and Doppler ultrasound identified bilateral lower extremity deep vein thromboses. Transoesophageal echocardiography showed thickened mitral and aortic valves with moderate regurgitation. Non-bacterial thrombotic endocarditis with embolic phenomena was suspected. Anticoagulation was escalated from apixaban to therapeutic enoxaparin, followed by warfarin. Despite initial stabilization, the patient died 2 months later. Post-mortem examination revealed fibrin-rich valvular vegetations consistent with NBTE, widespread intramyocardial thrombi, and no histopathologic evidence of myocarditis. Discussion This case underscores how microthrombotic complications of ICI therapy may closely mimic myocarditis on imaging. Nonspecific cardiac MRI findings, such as LGE and T2 signal elevation, can result from thrombotic or ischaemic injury alike. Histopathologic confirmation may be required for accurate diagnosis, as misclassification can lead to suboptimal treatment.