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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 Gliomas are rare and aggressive CNS tumors with limited survival, making clinical trial (CT) participation indispensable, particularly in progressive cases. Cross-national disparities in glioma CT access remain underexplored. This study investigates temporal trends and socioeconomic correlates of glioma CT activity across eight European countries, using lung cancer trials as a benchmark. MATERIAL AND METHODS Glioma CTs registered after 2004 and conducted in France, Germany, Italy, Denmark, Poland, Hungary, Greece, or Turkey were extracted from ClinicalTrials.gov. A comparable lung cancer dataset was created. National-level data on population, gross national income (GNI) per capita, human development index (HDI), and cancer incidence were obtained from public sources. Trial access was defined as active CTs per estimated annual new cases. RESULTS Of 3,292 glioma CTs globally, 640 involved at least one target country. France (n=287), Germany (n=192), Italy (n=151), and Denmark (n=61) hosted the most; Turkey (n=5), Hungary (n=13), Greece (n=10), and Poland (n=26) contributed minimally. Over time, France, Germany and Italy showed significant upward trends in glioma CT activity (p < 0.05). Denmark, despite lower absolute numbers, showed strong growth relative to population. Turkey remained the least active participant, with no significant increase in glioma trial activity. When adjusted for estimated glioma cases, Denmark had the highest trial access, followed by France and Germany. Trial access positively correlated with GNI per capita (ρ = 0.76, p = 0.028) and moderately with HDI (ρ = 0.69, p = 0.058). In contrast, lung cancer trials were more abundant and equitably distributed (p = 0.0078), without significant correlation with national socioeconomic indicators (ρ =0.14, p=0.7 gor GNI per capita and ρ =0.19 p=0.7 for HDI). Despite having similar or lower GDP per capita compared to other countries in the analysis, Poland and Hungary showed substantially higher lung cancer trial access than glioma trial access, highlighting the underrepresentation of glioma research in resource-limited settings. Notably, Turkey exhibited the lowest glioma CT access (0.0010 per patient), despite a moderate volume of lung cancer trials. CONCLUSION Glioma CT access varies widely across Europe and is closely tied to GNI and HDI, unlike lung cancer trials, which are more equitably distributed. These disparities may relate to differences in the availability of trained neuro-oncology professionals and structured care systems, warranting further study. Targeted policy efforts are needed to improve access and inclusion in glioma research across all regions.

Abstract BACKGROUND Volumetric analysis of brain metastatic lesions is of great relevance in neuro-oncology. Since manual annotation of a lesion is a laborious and time-consuming task, utilizing artificial intelligence (AI) tools for automated segmentation of brain metastases has shown promising potential, but published algorithms are not incorporated into clinical practice because of poor generalizability across institutions. Large publicly available and well-annotated datasets from across the world are critical for further clinical translation. MATERIAL AND METHODS The Brain Tumor Segmentation - Metastases (BraTS-METS) 2025 Lighthouse Challenge provides a competitive environment where scientists from various disciplines can benchmark their AI-based algorithms for automatic segmentation of pre- and post-treatment brain metastases on a well-curated publicly available brain metastasis dataset comprising 1,778 multiparametric brain MRI cases. Each case consists of T1-weighed, T1 post-contrast and FLAIR sequences. The cases were retrospectively obtained from 8 institutions in the USA and overseas, and underwent 3D nnU-Net pre-segmentation, followed by manual refinements performed by medical students and neuroradiologists, and a final approval by two independent board-certified neuroradiologists. A testing dataset was prepared through four rounds of annotation: two completed ‘from scratch’ and two following 3D nnU-Net pre-segmentation, all conducted by two independent neuroradiologists, with the segmentation process screen recorded for future analysis. This allowed us to establish inter- and intra-rater variability in brain metastases segmentation and create a reference standard dataset that will be publicly available after the conclusion of the challenge. The model performance of the participating teams in the challenge will be assessed via the following metrics: Dice Similarity Coefficient (DSC), Normalized Surface Distance (NSD), sensitivity, and precision of the model. RESULTS A multi-annotator testing dataset of 75 MRI cases of brain metastases and 300 segmentations (150 created ‘from scratch’ and 150 from 3D nnU-Net pre-segmentations of the cases) was developed as a new reference standard. The mean intra- and inter-rater DSC for the segmentations ‘from scratch’ were 0.68 and 0.59, respectively. The mean intra- and inter-rater DSC for the segmentations built upon 3D nnU-Net pre-segmentations were 0.88 and 0.77, respectively. CONCLUSION The BraTS-METS 2025 Lighthouse Challenge is a key initiative designed to advance the use of AI to improve characterization of brain metastases by providing algorithms for automatic segmentation of all lesions and peritumoral edema that are measured against a novel reference standard based on rigorous multi-annotator brain MRI segmentations.

Abstract BACKGROUND Primary Central Nervous System histiocytic sarcoma is rare aggressive malignant neoplasm with less that 50 cases reported in the literature. They usually harbor variable genetic alteration including MAPK and PI3K pathways as well as tumor suppressor genes TP53 and CDKN2A/B, among others. Herein, two additional two cases of Primary CNS histiocytic sarcoma are reported. MATERIAL AND METHODS N/A. RESULTS Case 1: 78-year-old man with past medical history significant for renal cell carcinoma (25 years ago), and chronic kidney disease, presented with gait instability and multiple falls. Magnetic resonance imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET/CT) scan revealed prominent intraventricular dissemination with multiple enhancing masses along the ventricular system and periventricular areas that were enlarging over time. In addition, there were multiple intramedullary, central canal and pial surface lesions in the cervical spine. Also left adreanal adenoma was seen and small indeterminate lesions in the liver and left kidney. Overall findings were suspicious for primary CNS malignancy. Biopsy revealed histiocytic sarcoma. Given the advanced stage of disease the patient opted for palliative therapy and eventually passed away 14 days after the diagnosis. Case 2: 56-year-old woman with medical history of breast carcinoma (2021) and hypertension presented with one year history of bilateral feet and calf paresthesia, followed by repeated falls and eventually becoming wheelchair-bound. She also developed hearing impairment, dysarthria, dysphagia and abnormal extraocular movements. Multiple brain MRIs revealed extensive extra-axial and leptomeningeal enhancement involving bilateral cavernous sinuses, optic chiasm and tracts, prepontine cistern and adjacent temporal regions. Nodular enhancement along cranial nerves and brainstem was also noted. Excisional biopsy revealed histiocytic sarcoma. Patient clinically deteriorated rapidly and passed away 10 days after the diagnosis. Pathology: Both cases revealed high-grade malignancy composed of sheets of large cells with ample cytoplasm. Significant nuclear pleomorphism and multinucleation was seen. Background chronic inflammation was present. Large neoplastic cell were positive for histiocytic markers, including CD68, CD163, CD4, PU.1 and S100, while all other lymphoma, epithelial, melanocytic and sarcoma markers were negative. MayoComplete Histiocytic Neoplasm panel was negative for all 8 mutations tested. CONCLUSION Primary CNS histiocytic sarcoma is a very rare entity. These two cases support the previously reported aggressive clinical course of primary CNS histiocytic sarcoma. Histiocytic sarcoma can involved any area of central nervous system, but prominent intraventricular dissemination as seen in case 1 has been previously reported in only case.

Abstract BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are rare, partially cystic central nervous system tumors driven by the WNT/β-catenin pathway. As they grow, ACPs compress the surrounding pituitary gland, optic chiasm, and third ventricle. ACPs are highly morbid tumors with enormous quality of life impact on patients, often early in life. Thus, better treatments are needed. Current ACP treatment consists of maximally safe surgical resection with radiation for residual disease. Complete surgical resection is challenging, and recurrence is common. Targeted systemic chemotherapy is not routinely used for ACP treatment. Interleukin-6 (IL-6) levels are elevated within ACPs compared to normal brain tissue, making IL-6 an intriguing therapeutic target. Treatment response of ACP to tocilizumab alone or in combination with bevacizumab has been reported in children. MATERIAL AND METHODS We retrospectively reviewed the medical records of three adults with recurrent ACP who received combination treatment with bevacizumab and tocilizumab on a compassionate basis between June 2022 and April 2025 at Mayo Clinic in Rochester, MN. We collected demographic, clinical, treatment, radiologic, and outcome data. RESULTS All three patients were male and median age at initial ACP diagnosis was 38 years (range: 32-42 years). All patients underwent subtotal resection followed by radiation therapy. One patient had repeat surgical resection and two patients required interventions for hydrocephalus. At the time of ACP recurrence, all patients had visual impairment, endocrine dysfunction, and headaches. All patients received bevacizumab (7.5 mg/kg q3 weeks) and tocilizumab (8 mg/kg q3 weeks [n=2] or 4 mg/kg q4 weeks [n=1]). While receiving combination therapy, ACP tumor volume decreased on magnetic resonance imaging for all three patients (64%, 68%, and 29% reduction). None exhibited tumor growth since starting combination therapy. One patient had a small intraparenchymal hemorrhage, suspected secondary to radiation-induced cavernous malformation, so bevacizumab was discontinued, and he remains on tocilizumab alone. The other two patients continue combination therapy (for 344 and 351 days). Two patients experienced improvement in vision, and one had improvement in cognition. Possible adverse effects of treatment included sinus infections, fatigue, neutropenia, and hypertension. CONCLUSION Treatment with combination bevacizumab and tocilizumab was associated with shrinkage of ACP tumors and clinical improvements and obviated the need for further surgery or radiation in all three patients. This combination of medications may reprogram the tumor microenvironment, leading to ACP involution. This well-tolerated regimen provides a noninvasive option for treatment of recurrent ACP, and potentially initial ACP treatment, and may improve quality of life for patients.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract BACKGROUND Glioblastoma (GBM) is a highly aggressive brain tumour with limited prognostic tools that are broadly implementable in routine clinical settings. Current models often depend on molecular platforms not universally accessible. We aimed to develop and validate a clinically practical prognostic model for GBM that integrates ICAM1 protein expression, imaging-derived tumor morphometrics, and clinical features. MATERIAL AND METHODS We analyzed ICAM1 expression in GBM at the DNA methylation, RNA, and protein levels using public datasets and institutional cohorts, confirming its association with tumor grade and poor survival. ICAM1 protein levels were then quantified via digital pathology in a multi-institutional cohort of 197 newly diagnosed, treatment-naïve GBM patients. Tumor surface irregularity (SIR) was calculated from pre-operative contrast-enhanced MRI using open-source imaging tools. Age at diagnosis was also recorded. These three variables—ICAM1 expression, SIR, and age—were integrated into a Clinical-Imaging-Molecular (CIM) model using multivariable Cox regression. The model was validated in an independent external GBM cohort (n = 20). Survival prediction was assessed using Kaplan-Meier curves, ROC analysis, and concordance index (c-index). RESULTS ICAM1 expression was associated with DNA hypomethylation and significantly correlated with reduced survival at transcriptomic and proteomic levels. Pathway analysis identified associations with immune activation and angiogenesis. In the clinical cohort, high ICAM1 expression, elevated tumor SIR, and older age independently predicted worse survival. The CIM model combining these factors stratified patients into distinct prognostic groups, achieving strong performance (c-index = 0.779, AUC = 0.778). External validation confirmed the model’s predictive utility (median survival difference: 9.1 months, P = 0.009). CONCLUSION We present a validated and clinically applicable prognostic model for GBM that integrates ICAM1 expression, imaging features, and age. The CIM model is scalable, interpretable, and feasible for implementation across academic and community settings, providing a robust tool for patient stratification, treatment planning, and trial design.

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.

Context.— Though numerous quality assurance (QA) measures are in place for the practice of gynecologic cytopathology, many of them are not clearly defined and may be variably used by laboratories worldwide. Objective.— To assess current practice patterns regarding the implementation of selected gynecologic cytology QA metrics to help develop guidance for laboratories. Design.— A supplemental questionnaire was mailed to laboratories participating in the 2022 College of American Pathologists (CAP) Gynecologic Cytopathology (PAP Education) Program requesting data regarding their QA measures in gynecologic cytology. Results.— A total of 562 laboratories responded to the supplemental questionnaire; responses from 511 laboratories were analyzed further. Of 492 laboratories, most considered Papanicolaou (Pap) tests from patients with untreated abnormal cytology in the previous year (386; 78.5%) or with an abnormal gynecologic biopsy finding (concurrent or within the past year) (331; 67.3%) as high-risk for negative rescreening. Many laboratories (436 of 511; 85.3%) required pathologist review of Pap tests for indications other than reactive/abnormal cells (eg, endometrial cells in women 45 years of age and older). For assessing cytologists’ performance, 88.5% (399 of 451) of respondents recorded the discrepancy rate between cytologist’s and pathologist’s interpretations. For monitoring pathologists’ performance, most laboratories (243 of 389; 62.5%) evaluated cases with significant cytologic-histologic discrepancy. Conclusions.— The CAP survey provided a detailed assessment of current QA practices regarding gynecologic cytology, which can aid laboratories in making decisions related to enhancement of QA in their setting. As the guidelines and tools for cervical cancer screening evolve, QA metrics will need to be accordingly refined.

ABSTRACT The deep inferior epigastric perforator (DIEP) flap remains the preferred flap option for autologous breast reconstruction following mastectomy. This case report presents the novel use of the cephalic vein (CV) as an interposition graft to alleviate venous congestion in a patient undergoing DIEP flap reconstruction. A 42‐year‐old woman experienced venous congestion following her initial autologous reconstruction, attributed to thrombus formation from kinking of the vascular pedicle. Despite initial attempts to resolve the congestion, the condition persisted. Since the flap was based on a single perforator, we decided to attempt a CV turndown. The CV was noted to be attenuated and not feasible for use in turndown; therefore, venous salvage was completed by using the CV as an interposition graft to bypass the affected flap vena comitans. The procedure successfully restored venous flow, allowing for flap salvage and subsequent healing. This case underscores the potential of CV as an interposition graft in autologous breast reconstruction, particularly when traditional CV turndown is not possible due to vessel attenuation.