2026-07-09 | Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel–Lindau disease: a case report
Purpose To report a case of retinal capillary hemangioblastoma (RCH) regression in a patient with von Hippel–Lindau (VHL) disease following treatment with systemic belzutifan. Case presentation A 49-year-old female with VHL disease presented with a retinal capillary hemangioblastoma in the left eye that had been previously treated with laser therapy. She subsequently developed a new retinal lesion and interval growth of a renal intraparenchymal mass, for which systemic belzutifan was initiated. Four months after treatment initiation, a reduction in the size of the retinal lesions was observed, along with decreased perfusion and vascularity. Conclusion Systemic belzutifan therapy for VHL disease may induce regression of retinal capillary hemangioblastomas and can be effective as either a primary or an adjunctive treatment modality.
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2026-07-01 | Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) plays an essential role in ccRCC initiation and progression. The VHL-HIF2α axis as the main driver for ccRCC may present specific opportunities to control the disease by cotargeting HIF2α with belzutifan and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC. Upregulated in ccRCC in a VHL-HIF2α-dependent manner, TRAIL is selectively essential in ccRCC cells, promoting cell proliferation by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cell and tumor models to recombinant TRAIL, presenting a promising avenue for combination therapy in ccRCC.
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2026-06-23 | ID #700 NTRK2-Altered Pilocytic Astrocytoma in a patient with Von Hippel-Lindau Syndrome
Abstract Background Von Hippel–Lindau (VHL) disease is a rare autosomal dominant tumor predisposition disorder caused by pathogenic germline variants in the VHL gene. Individuals with VHL are at increased risk for central nervous system hemangioblastomas, retinal angiomas, renal cell carcinoma, and other neoplasms. Pilocytic astrocytomas represent the most common type of pediatric low-grade glioma and are typically associated with fusions or mutations in the BRAF gene, though other oncogenic drivers such as FGFR, MYB,and NTRK have been identified. The coexistence of VHL syndrome and pilocytic astrocytoma is exceedingly rare. Case Presentation We report the case of a two-year-old male with known VHL who presented with progressive peripheral vision loss and nystagmus. Neuroimaging revealed an expansile mass involving the optic chiasm and hypothalamus. Comprehensive histo-molecular characterization, including targeted next-generation sequencing and methylation profiling, resulted in an integrated diagnosis of pilocytic astrocytoma harboring a KCTD16::NTRK2 fusion. The tumor was negative for BRAF alterations or any high-grade features. He has responded favorably both radiographically and ophthalmologically to targeted therapy with the TRK inhibitor, Larotrectinib. Discussion To our knowledge, there is only one other documented case of concurrent VHL and low-grade glioma. This finding expands the molecular spectrum of VHL-associated central nervous system tumors and highlights the importance of broad molecular profiling, even in tumors with classic histology and/or known cancer predisposition. Identification of an NTRK fusion is clinically significant, as it introduces the potential role of targeted TRK inhibitor therapy, particularly in cases of inoperable tumors or in the setting of tumor progression or recurrence. Conclusion This case underscores the complexity of tumor biology in hereditary cancer predisposition syndromes and supports the integration of molecular diagnostics into the evaluation of pediatric brain tumors. Recognition of actionable alterations such as NTRK fusions may inform precision treatment strategies and improve patient outcomes.
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