Citations

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.

ABSTRACTSurgical biopsy of brainstem tumors carries a risk of neurological injury. We performed magnetic resonance spectroscopy (MRS) of 2‐hydroxyglutarate (2HG) and glycine in patients with brainstem tumors to assess the feasibility of detecting and quantifying 2HG in the brainstem to obviate the need for a diagnostic biopsy and to establish the clinical significance of glycine MRS in brainstem tumors in vivo. Twenty adult patients with radiographically identified presumed brainstem gliomas were prospectively enrolled in the study. Proton MRS was obtained at 3T with a protocol tailored for detection of 2HG and glycine (TE 97‐ms PRESS). Spectra were fit using LCModel software and in‐house basis signals of metabolites and lipids. The metabolite concentrations were quantified with reference to water and examined with respect to clinical outcomes, including postgadolinium MRI and overall survival time. MRS data from 19 patients were included in subsequent analysis, excluding suboptimal data from one patient. Tumors with elevated 2HG (> 1.9 mM, N = 8) and undetectable 2HG (< 0.3 mM, N = 11) were clearly distinguishable. Tumors with elevated glycine (> 1.5 mM, N = 4) showed rapid progression. Kaplan–Meier survival analyses with metabolite measures demonstrated that tumors with 2HG higher than 1.0 mM were significantly associated with a favorable prognosis (p = 0.01). In contrast, tumors with glycine higher than 2.5 mM showed a strong association with poor survival (p = 0.0005). The data confirm detection of 2HG in brainstem tumors at a concentration that is consistent with an IDH mutation and expected good prognosis, whereas elevated glycine in brainstem tumors portends rapid tumor progression and a worse prognosis.

Abstract BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) is one of the two most common precursor lesions leading to the development of pancreatic ductal adenocarcinoma (PDA). IPMNs comprise a heterogeneous group of tumors with a wide range of grades and histotypes, and the emergence of single-cell RNA sequencing (RNA-seq) and multiplex digital spatial profiling have characterized unique cell populations, including dysplastic epithelial and immune cells, within the heterogeneous tumor microenvironment that carry signature gene expressions, which could be used as markers for disease progression. However, it is not clear on the heterogeneity of the epithelial and immune response of the evolution during progression of IPMN to PDA. OBJECTIVE Combining nuclear GSK-3β with oncogenic KRas mice (referred to as KNGC – KRas, nuclear GSK-3β, Cre) resulted in the development of IPMN. We have found that 4-week-old KNGC mice show progressive desmoplasia and ductal lesion development with increased M2-like macrophage infiltration. Interestingly, CX3CL1 (fractalkine), a chemokine involved in the recruitment of CX3CR1-expressing monocytes and M2-like macrophage conversion in various disease models is expressed by IPMN progenitor ductal cells. We aim to investigate expression and contribution of CX3CL1-CX3CL1 axis in the development and progression of IPMN. METHODS We utilized a newly generated CX3CL1-mCherry and well-established CX3CR1-GFP knockin/knockout mouse for crossbreeding with KNGC and KGC (KRas, GNas, Cre) for lineage tracing and function analysis by immunofluorescent staining, flow cytometry and CyTOF. RESULTS Both KNGC- and KGC-3LmCherry/+ mice harbor a large population of CX3CL1-mCherry/EPCAM+ epithelial cells as compared to 3LmCherry/+ and wildtype (WT) control mice. In KNGC and KGC mice, we show that there was a unique population of macrophages (CD45+ CD11b+ Ly6G- F4/80+ Ly6c- ) with significantly higher expression of CX3CR1 (CX3CR1Hi) that was not seen in WT mice. Significantly, Knockout of CX3CR1 in KNGC-3RGFP/GFP animals had a paucity of M2-like macrophages, reduced T regulatory cells (Tregs), substantially reduced desmoplasia and impaired development of IPMN. CONCLUSIONS The study provides important knowledge regarding the role of CX3CL1-CX3CR1 axis in recruitment and generation of M2-like macrophages, and their impact on the initiation of the immune/stroma microenvironment facilitating IPMN development. Further investigations using these models have the potential to identify new biomarkers for risk stratification and therapeutic intervention. Citation Format: Li Ding, Kaely Roeck, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Esther Rodman, Mark Maynes, Bibo Zhu, Aaron Johnson, Jie Sun, Li Hu, Daniel Billadeau. Uncoupling CX3CL1-CX3CR1 Axis in IPMN Development Through Transgenic Mouse Models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A064.

Objectives: Value based decision making regarding nonoperative management vs. early surgical stabilization for first-time anterior shoulder instability (ASI) events remains controversial. Thus, the purpose of this study was to perform 1) a systematic review of the current literature and 2) a Markov model-based cost-effectiveness analysis comparing an initial trial of nonoperative management to arthroscopic Bankart repair (ABR) for first-time ASI. Methods: A Markov Chain Monte Carlo probabilistic model (Figure 1) was developed to evaluate the outcomes and costs of 1,000 simulated patients (average age » 20 years old) with first-time ASI undergoing nonoperative management vs. ABR. Utility values, recurrence rates, and transition probabilities were derived from the published literature. Costs were determined based on the typical patient undergoing each treatment strategy at our institution. Outcome measures included costs, quality-adjust life-years (QALYs), and the incremental cost-effectiveness ratio (ICER). Probabilities of recurrence as well as the utility of each treatment strategy were obtained from the literature search as described above. Probabilities were pooled across studies to obtain a weighted average for both nonoperative treatment and ABR. Similarly, studies reporting scores on the Western Ontario Shoulder Instability Index (WOSI) scale were utilized to approximate shoulder-related quality of life after each treatment strategy and outcome. Costs for each treatment strategy and transition state in the model were considered from the payer perspective (commercial or government) and obtained from institutional data at a large, academic medical center. Results: The Markov model with Monte Carlo microsimulation demonstrated average (± standard deviation) costs for nonoperative management and ABR of $38,649 ± 10,521 and $43,052 ± 9,352, respectively. Total QALYS acquired over the 10-year time horizon were 7.7 ± 0.4 and 8.4 ± 0.5 for nonoperative management and ABR, respectively. The ICER comparing ABR to nonoperative management was found to be just $5,725/QALY, which falls substantially below the $50,000 willingness-to-pay (WTP) threshold (Figure 2). The mean number of recurrences were 2.6 ± 0.3 and 1.2 ± 0.2 for patients initially assigned to the nonoperative and ABR treatment groups, respectively. Out of 1,000 samples run over 1,000 trials, ABR was the optimal strategy in 98.7% of cases, with nonoperative management the optimal strategy in 1.3% of cases (Figure 3). Conclusions: The primary findings of this systematic review and cost-effectiveness analysis were as follows: 1) when compared to nonoperative management, arthroscopic Bankart repair (ABR) substantially reduces the risk of recurrent dislocations, 2) ABR results in greater shoulder function and higher WOSI scores than does nonoperative management, and 3) despite substantially higher upfront costs, ABR proved to be more cost-effective than an initial trial of nonoperative management, which can be attributed to both fewer recurrent dislocations and greater utility over the long-term.

Background: Spasticity is common in spinal cord injury (SCI) and multiple sclerosis (MS), and it can manifest as repeated, rhythmic muscle contractions called clonus. The spontaneous nature of clonus can disrupt independent performance of activities of daily living and negatively impact overall health and quality of life. Objectives: To quantify biomarkers of clonus and explore management of clonus in individuals with SCI or progressive MS using epidural spinal cord stimulation (ES) or dorsal root stimulation (DRS). Methods: Four male participants were included in this case series study: 3 with SCI and 1 with MS. All participants underwent temporary percutaneous ES lead placement over the dorsolateral thoracolumbar region of the spinal cord. Participants with SCI were also implanted with DRS leads at the L4 dorsal root. Clonus was elicited mechanically at the ankle while recording electromyography of the soleus muscle synchronized to direct spinal cord field potential recordings from ES and DRS percutaneous leads. Results: Clonus was evident as a prominent band (5-8 Hz) in recordings from ES leads, DRS leads, soleus muscle, and accelerometry. In 4 participants, percutaneous spinal stimulation reduced median clonus duration and cycle count. Clonus was immediately suppressed upon activation of spinal cord stimulation, and the suppression persisted even when clonus was reinitiated after turning off the stimulation. Conclusion: The use of objective biomarkers, including spinal cord potentials, to quantify clonus in real time combined with the immediate and reversible effects of stimulation highlight the potential of neuromodulation as a therapeutic tool for managing clonus. These data demonstrate preliminary efficacy of ES and DRS for clonus monitoring and treatment in 4 participants.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin &amp;lt;3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

Abstract Error analysis is a critical step in evaluating and improving clinical concept extraction models, the most common clinical natural language processing (NLP) task. Unlike corpus annotation, which follows standardized protocols for creating gold-standard datasets, error analysis requires nuanced judgment grounded in both clinical expertise and NLP knowledge. This is especially important given the heterogeneity of clinical text, where variations in documentation style, note structure, and terminology can substantially influence model behavior. Despite its importance, there is currently no standardized, user-level framework to support systematic error analysis in clinical concept extraction task. In this study, we developed and validated MedError, a machine-assisted, human-in-the-loop framework designed to standardize and enhance error analysis for clinical concept extraction tasks. We collected and manually curated a corpus of 1,187 unique errors from a total of 4,237 notes across three different distinct hospitals. The error categories were defined using our previously validated error taxonomy and included 480 false negatives and 707 false positives across 25 error types and 48 clinical concept categories. We evaluated the performance of three proprietary and three open-source large language models (LLMs) in automatically classifying these errors into 26 and 15 predefined categories. We further developed a machine-assisted framework, MedError, which integrates best practices in error analysis, LLM-assisted classification and reasoning, and a user-friendly interface to enable more efficient, reproducible, and context-aware error analysis. The framework supports both single-site and federated multisite error analysis, facilitating the effective translation of clinical NLP systems into real-world settings.