Lachance, Daniel Honore

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.

Background: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. Objective: A GWAS was performed to identify variants associated with TD. Methods: The case–control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p -value threshold of 5 × 10 −8 was GWAS significant and 5 × 10 −6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. Results: Variants on chromosome 14 (rs117797734, p = 2.06 × 10 −11 , odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10 −7 , OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. Conclusion: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

Abstract Background The CCDC26 germline variant rs55705857 is causal for development of IDH mutant (IDHmut) adult glioma. However, ~60% of IDHmut patients do not carry the rs55705857 risk allele. We aimed to identify variants associated with developing IDHmut glioma among patients that do not have the rs55705857 risk allele and to further understand development of IDHwt glioma. Methods We used three datasets that included 1216 IDHmut and 1442 IDHwt glioma patients and a case–case design to perform genome-wide association (GWAS) analyses comparing IDHmut versus IDHwt glioma. Analyses were performed overall and stratified by rs55705857 genotype and sex. Multivariable logistic regression and regression trees were used to develop models to predict IDH status using germline variants, age, and contrast enhancement on MRI. Results Three regions were identified comparing IDHmut versus IDHwt: rs55705857 (meta P-value [P] = 1.35 × 10−43), PHLDB1 (rs7125115, P = 3.46 × 10−17), and D2HGDH (rs71430382, P = 2.43 × 10−12). When analyzing only patients that do not have the rs55705857 risk allele, PHLDB1 (rs7125115, P = 1.73 × 10−13) and D2HGDH (rs71430382, P = 8.86 × 10−10) were identified. Among patients who have the rs55705857 risk allele, four variants between ROBO1 and ROBO2 (rs4680975, P = 4.65 × 10−7) increased the likelihood of having an IDHwt tumor. Tumor expression of ROBO1 was associated with rs4680975 genotype in IDHwt patients that have the rs55705857 risk allele (P = 0.034). Multivariable logistic analysis demonstrated that rs55705857, rs71430382 (D2HGDH), and age predicted IDH mutation status. Conclusions To understand the development of adult glioma, we demonstrate that D2HGDH and PHLDB1 should be prioritized for functional studies in IDHmut tumors. The ROBO1 region warrants further investigation in IDHwt tumors.

e13893 Background: For individuals with CNS tumors who have experience difficulties with in-person (IP) evaluations due to disease-related neurologic disability or the costs associated with travel, telehealth (TH) offers a convenient and timely alternative for accessing specialized neuro-oncology care. We report our institution’s experience with telehealth utilization in neuro-oncology. Methods: We conducted a retrospective review of patients who had at least one neuro-oncology telehealth visit between August 2021 and May 2024 at Mayo Clinic in Rochester, Minnesota. Reasons for visits, outcomes of appointments, acute care utilization following visits was reviewed. Results: A total of 660 patients who had at least one TH visit between August 2021 and May 2024 were included in the analysis. Median age was 56 (range 20-98), 49% were female, and 92% were white. Most patients resided in the US Midwest (84%), followed by the South (8%), West (5%), Northeast (1%), and US Territories (< 1%). Less than two percent were international patients. The most common primary visit diagnosis was glioblastoma (GBM, 26%), followed by astrocytoma, IDH-mutant (17%), meningioma (17%), oligodendroglioma, IDH-mutant, 1p/19q codeleted (7%). Of 6657 visits reviewed, 2745 (41%) were conducted via TH. Telehealth visits served various purposes, including consultation for newly diagnosed tumors or abnormal MRIs (n = 26), second opinion for an established tumor diagnosis (n = 119), discussion about clinical trial participation (n = 108), tumor-related treatment discussions (n = 719), chemotherapy education (n = 161), new symptom assessment (n = 117), symptom management (n = 366), and tumor surveillance (n = 1694). Outcomes from telehealth visits included enrollment in clinical trials (n = 28), proceeding with tumor-directed surgery (n = 46), initiation of radiation therapy (n = 88), starting or changing systemic therapy (n = 377), continuing existing systemic therapy (n = 932), transition to supportive care (n = 45), tumor diagnostic workup (n = 28), continuation of tumor surveillance (n = 1254). Acute care utilization, defined as an emergency department visit or hospitalization within one month of an appointment, was the same following telehealth visits compared to in-person visits (6.9% for IP vs 5% for TH, p = 0.507). Conclusions: Our findings demonstrate that telehealth can effectively support all aspects of neuro-oncology care, ranging from initial diagnosis discussions to systemic therapy management and transitions to supportive care. Telehealth offers a convenient and accessible method of care delivery option for patients faced with neurologic illness. Additionally, THs do not lead to increased acute care utilization compared to IP evaluations.

Abstract Clinical management of IDH wildtype glioblastoma (GBM) and tumefactive multiple sclerosis (tMS) is drastically different. GBM requires maximal safe resection followed by chemoradiation, while tMS outcome is worsened by surgery and radiotherapy. Noninvasive methods are needed to help with accurate diagnosis of tumor and non-tumor etiologies. To develop an MRI-based classification model, tMS subjects diagnosed prior to January 1, 2020, were matched to tMS by age at diagnosis, sex, index MRI date, and 2D/3D acquisition. Inclusion criteria included one cm minimal lesion size and pre-operative post-contrast T1 and T2 images available for analysis. A 3D-DenseNet121 was used to develop a classification model using prespecified parameters: 650 epochs, batch size 16, learning rate 10-3, cross-entropy loss, and AdamW optimizer. The stopping rule was defined as three sequential differences in epoch cross-entropy loss &lt;0.02. Models were developed using both T1gd and T2, as well as from only T1gd and only T2. Training included 220 subjects (110 GBM, 110 tMS). A 2-stage validation design was used, which included both retrospective and prospective cohorts. Stage 1 consisted of 272 retrospective GBM (diagnosed prior to January 1, 2020). Stage 2 consisted of 69 and 34 prospective (diagnosed after January 1, 2020) GBM and tMS, respectively. External validation on the 272 retrospective GBM demonstrated accuracy of 91%, 84%, and 78% for T1gd+T2, T1gd only, and T2 only, respectively. External validation on the 69 prospective GBM demonstrated an accuracy of 87%, 64%, and 67% for T1gd+T2, T1gd only, and T2 only, respectively. The 34 prospective tMS demonstrated accuracy of 76%, 76%, and 82% for T1gd+T2, T1gd only, and T2 only, respectively. This shows the feasibility of deep learning to aid in differential diagnosis of brain lesions. Future work entails the integration of germline variants into the classification model, including variants associated with the risk of glioma or MS.

Abstract Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Abstract Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.

Abstract BACKGROUND Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors. METHODS We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide. RESULTS Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2). CONCLUSION In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.

Abstract Histologic features, presence of CDKN2A/B homozygous deletion and methylation subtype are strong determinants of outcome and of therapy in IDH-mutant gliomas. We were interested in learning if there are additional markers of outcome in these tumors. To address this question, we assembled a cohort of 963 IDH-mutant gliomas with overall survival data (median follow-up alive 2.7 years, median follow-up deceased 3.9 years). Array-based copy number data, targeted NGS, germline genotyping data and Illumina EPIC array methylation data were available on 872, 226, 542, and 401 patients, respectively. Morphologic type (oligodendroglioma versus astrocytoma, grade (2/3 vs 4) and methylation subtype (A_IDH_LG vs A_IDH_HG) were all significantly associated with survival (p &lt;0.001). There was no significant difference in survival between grade 2 vs 3 IDH-mutant astrocytomas (p=0.53 adjusting for age and sex). However, subjects with the risk allele (G) for rs55705857 had a better overall survival than subjects with the non-risk allele (A) in IDH-mutant oligodendroglioma (AG/GG vs AA, median overall survival 21.6 vs 15.7 years, p=0.048 after adjusting for grade, age, and sex). Conversely, rs55705857 was associated with a markedly worse survival in grade 2 IDH-mutant astrocytomas (AG/GG vs AA, median overall survival 8.6 vs 19.6 years, p=0.007 after adjusting for age and sex). Despite similar sample sizes and number of deaths, there was no significant difference in overall survival by rs55705857 genotype in grade 3 or 4 IDH-mutant astrocytomas. Upon further functional analyses, TLX1 and GALNT17 were found to be differentially methylated in IDH1-mutant astrocytomas and oligodendrogliomas, respectively, when stratified by rs55705857 risk allele. This is the first observation of a germline characteristic (e.g. rs55705857) predicting survival in low-grade IDH-mutant astrocytoma. While this observation requires validation, it suggests that germline genotype may be practice changing and inform results of trials such as CATNON and CODEL.