Citations

Introduction/Background: Despite numerous medical advances, 30% of patients with Fontan circulation require heart transplantation by 21. Current risk stratification relies on clinical metrics that lack strong correlations to patient outcomes, leading to a high waitlist mortality. Hypothesis: Integration of physics-based hemodynamic modeling with interpretable machine learning will improve prediction of patient outcomes (listing for heart transplant and/or cardiac death) by quantifying physiologic mechanisms inaccessible through clinical measures alone. Goals/Aims: 1. Develop a lumped-parameter mechanistic model (LPMM) of Fontan circulation 2. Identify patient clusters and predictors of patient outcomes 3. Validate model-informed classifiers against clinical-only approaches Methods/Approach: A LPMM incorporating ventricular sarcomere mechanics, atrial hemodynamics, and vascular viscoelastic effects was optimized to cardiac catheterization and echocardiography data from 51 patients (age 25±8 years). Thirty-eight parameters (ventricular inotropy, atrial stiffness, pulmonary elastance, etc.) were calibrated via surrogate optimization, minimizing least-squares error versus 11 clinical targets. Partial least-squares regression with leave-one-out cross-validation compared clinical-only versus model-informed classifiers of outcomes. Results/Data: The LPMM achieved 2% mean error across hemodynamic targets, with CVP and pulmonary pressures matching clinical measurements within 1%. Model-derived minimum atrial pressure (4.46±1.78 vs 2.68±0.87 mmHg, p<0.05) outperformed all clinical variables in discriminating patient outcomes. Integration of LPMM parameters increased AUROC from 0.67 to 0.78 for patient outcome prediction. Conclusions: Physics-based modeling identifies ventricular passive stiffness, atrial end-diastolic volume, and minimum atrial pressure, along with patient age (a clinical value) as critical determinants of Fontan failure. Combined mechanistic-machine learning approaches enable phenotype-specific risk stratification, supporting earlier referral for advanced therapies. This methodology establishes a framework for precision management of complex congenital circulations.

Lacking effective therapeutics, cholangiocarcinoma (CCA) remains a deadly malignancy of the biliary tract. The Hippo pathway effector protein Yes-associated protein (YAP) is implicated in CCA pathogenesis and chemotherapeutic resistance; however, the oncogenic mechanisms underlying YAP regulation remain incompletely understood. An enhanced understanding of YAP and its role in CCA may uncover novel therapeutic targets and better define resistance pathways. Human CCA cells and murine syngeneic CCA models were utilized to explore the molecular relationship of YAP and protein tyrosine phosphatase 1B (PTP1B). Previous work in CCA has demonstrated that YAP interacts with multiple protein tyrosine phosphatases, including SHP2 and PTP1B. We observed that PTP1B pharmacologic inhibition was associated with increased cell proliferation and YAP target gene expression, while genetically enforced overexpression of PTP1B was associated with a decrease in YAP activation. Treatment of CCA cells in vitro and syngeneic, orthotopically implanted CCA murine tumors in vivo with standard cytotoxic chemotherapy, gemcitabine/cisplatin, had enhanced efficacy in the setting of PTP1B overexpression. These findings demonstrate that pYAPY357 can be modulated through protein tyrosine 1B phosphatase activity, and reducing pYAPY357 through enhanced phosphatase levels can sensitize CCA to chemotherapy.

Abstract BACKGROUND IDH-mutant gliomas are diffusely infiltrating, slow-growing brain tumors that inevitably undergo malignant progression to grade IV astrocytoma - a highly aggressive and uniformly fatal disease with dismal prognosis. Despite extensive research, the molecular mechanisms underlying this transformation remain poorly understood. While alterations in canonical driver genes such as CDKN2A, PTEN, and PDGFRA have been implicated, the broader landscape of genetic drivers involved in IDH-mutant glioma progression is largely uncharacterized. In contrast to many other malignancies, IDH-mutant gliomas acquire relatively few somatic point mutations during progression - typically in the range of 30 to 40 - suggesting that alternative mechanisms may be driving tumor evolution. Notably, these tumors exhibit widespread chromosomal instability, resulting in a heterogeneous and highly prevalent pattern of copy number alterations (CNAs). This observation raises the possibility that gene dosage changes due to CNAs play a critical role in tumor progression. MATERIAL AND METHODS To investigate this hypothesis, we performed integrative analysis of IDH-mutant glioma cohorts from the Mayo Clinic and TCGA datasets (~1,500 patients), identifying twelve highly recurrent CNAs significantly associated with patient outcomes. We refer to these as malignant IDH-associated CNAs (mIDH CNAs). We hypothesized that these recurrent CNAs harbor driver genes that confer selective growth advantages, thereby contributing to their recurrence and prognostic relevance. To systematically assess the functional impact of genes within these regions, we developed a novel in vivo CRISPR-based screening platform, termed CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA). This approach utilizes stereotaxic delivery of lentiviral gRNA libraries - targeting mouse orthologs of ~1,800 genes within recurrently deleted regions and ~1,200 genes within amplified regions - into the brains of a genetically engineered mouse model of IDH-mutant glioma (rs557mut;IDHmut;P53KO;AtrxKO;Cas9GFP: Yanchus et. al Science 2022). RESULTS Mice injected with mIDH CNA-targeting libraries developed tumors significantly more rapidly than control cohorts. Deconvolution of the CRISPR-KOALA screen identified several putative driver genes, including regulators of the NOTCH signaling pathway, lipid metabolism modulators such as THEM6, and the NMDA receptor modulator GRINA - implicating dysregulation of metabolism, immune response, and glutamatergic signaling in the malignant transformation of IDH-mutant gliomas. CONCLUSION Together, these findings provide critical insights into the genetic mechanisms driving the progression of IDH-mutant gliomas and identify new candidate genes and pathways for potential therapeutic targeting.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (&gt;124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.

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.

Abstract BACKGROUND Ovarian cancer rarely metastasises to the brain, thus studies reporting the outcomes of affected patients are lacking. Stereotactic radiosurgery (SRS) is now the mainstay of management for patients with brain metastases (BM) from most primary sites, but little evidence of its efficacy in ovarian cancer is available. The current study was undertaken to provide guidance for SRS management using pooled data from multiple institutions. MATERIAL AND METHODS Centers participating in the IRRF (International Radiosurgery Research Foundation) were asked to provide outcome data for patients who had SRS for ovarian cancer brain metastases between 2020 and 2024 and at least one clinical and imaging follow-up after the procedure. Primary endpoints included survival from SRS, local tumor response according to RANO-BM criteria and occurrence of adverse radiation effects (ARE). Cox regression analyses were performed to identify variables impact each endpoint. RESULTS 128 patients had SRS for a total of 532 BM treated. Epithelial histology was the most common (91%). Median age at SRS was 62 years (IQR 56-70). Median KPS was 80% (IQR 80-90%) and 71.9% of patients had neurological symptoms at presentation. Other active systemic metastases were present in 41.4%. The median number of treated BM was 2 (IQR1-3) and the median cumulative treatment volume was 6 cc (IQR 2-12.9). The median margin dose was 18 Gy (IQR 16-20). At last follow-up, 19.5% of patients were still alive. The median overall survival (OS) after SRS was 27 months, and 6-, 12- and 24-month OS was 83.8%, 74.2% and 52.2%, respectively. Multivariate analyses revealed that increasing age at SRS (HR 1.02, p=0.05), active systemic metastases (HR 2, p=0.005) and increasing number of brain metastases (HR 1.05, p=0.04) were associated with worse survival, while repeating SRS (HR 0.4, p=0.002) led to improved survival. Local failure occurred in 12.8% of treated BM. Actuarial progression-free survival (PFS) at 6, 12 and 24 months was 92.3%, 86.6% and 70.3%, respectively. Only prior WBRT (HR 4.36, p=0.03) led to worse local control on multivariate analyses. New remote BM appeared in 49.5% of patients and 14.5% suffered from leptomeningeal dissemination. ARE were seen in 12.1% of BM but were symptomatic in only 3.2%. On multivariate analyses, prior SRS (HR 3.13, p=0.002) was associated with increased risk of ARE. CONCLUSION Ovarian cancer brain metastases can be safely and effectively managed with SRS as the primary treatment modality in most patients.

Abstract Introduction This study investigated the impact of visual editing of sleep recordings for use in predicting neurodegenerative disorder (NDD) risk. Methods All participants underwent in-home Sleep Profiler studies. Forty-four were diagnosed with mild cognitive impartment (MCI = 40) or Alzheimer’s disease (AD = 4)(MCI/AD: 55% women, 72.6+/-8.6 years), 26 with REM sleep behavior disorder (RBD: women = 27%, age = 67+/-9.8), and 29 were controls (NC: women = 69%, age = 63+/-11.5). A 4-class machine learning algorithm used age plus eight sleep biomarkers to assign NDD risk probabilities. Records with CG-assigned probabilities &gt;70% were labeled Probably-Normal, and from 45-70% Likely-Normal. Similar thresholds were used to assign Likely- or Probably-Abnormal. NDD risk characterizations were generated based on auto-scoring (“auto”), and again after the recordings were visually edited for accuracy (“edited”). Results Comparing the auto- vs. edited-NDD classifications in the MCI/AD group, the same NDD risk classifications were observed in 91% (39/43), with 2 cases shifting from Likely-Normal to Probably-Normal, one shifted from Likely-AD to Likely-Normal with AD Indications, and one changed from Probably-AD to Likely-AD. The same NDD risk classifications were observed in 81% (21/26) of the RBD cases, 3 shifted from Probably-Abnormal to Likely-Abnormal, one shifted from Likely-Normal to Probably-Normal, and one changed from Likely-Abnormal to Likely-Normal. The same NDD risk classifications were observed in 86% of the NC group, with 4 cases shifting from Likely-Normal to Probably-Normal. Conclusions These findings suggest that the likelihood of a gross misclassification of NDD risk resulting from auto-detected sleep biomarkers is relatively low with inconsistencies directed toward slightly increased NDD risk classifications.

Abstract Introduction This study investigated differences in opinions about neurodegenerative disorders (NDD) in countries with large populations and expanded access to healthcare. Methods A 5-point Likert scale survey assessed opinions of 30–59-year-olds, pertaining to their parents and NDD conditions. 100 surveys, translated into native languages, were acquired in eight developed countries. Positive (somewhat- or strongly-agree) vs. other responses, sex, and country were submitted to logistic regression and Chi-squared analyses. Results “It is important for me to know if my parent has a risk for developing a NDD condition in the future, even if nothing can be currently done to prevent or cure those diseases” had higher positive responses in Australia (92%) compared to Germany (74%) and the USA (78%). “I believe that knowing about my parent’s risk for developing a NDD condition will help me assist in the planning of their future” had higher number of positive responses in Australia (91%) versus Japan (70%), Germany (76%), Italy (80%) and UK (80%). “If my parent(s) was found to be at risk for a NDD condition, I would want to learn more about medications and adaptive therapies that could delay onset” was responded to more positively in Australia (92%), Canada (78%), France (87%), Germany (78%), Italy (88%), UK (88%), and USA (81%) versus Japan (60%). Conclusions Australians responded more positively to questions related to care of a parent with a NDD disorder. These findings suggest cultural differences that could influence education and support systems requirements for sleep medicine providers and NDD patients.