The outcome of central nervous system hemangioblastomas in Von Hippel-Lindau (VHL) disease treated with belzutifan: a single-institution retrospective experience.

PURPOSE: Belzutifan is a Hypoxia Inducible Factor 2-alpha inhibitor approved in 2021 by the FDA for the treatment of renal cell carcinoma (RCC) in patients with Von-Hippel Landau (VHL) disease. These patients can also present with central nervous system (CNS) hemangioblastomas (HBs). We aim to study the effectiveness and adverse effects of belzutifan for CNS HBs, by reporting our preliminary institutional experience. METHODS: We present a series of VHL patients with CNS HBs undergoing treatment with belzutifan for RCC. All the included patients met the RECIST inclusion criteria. The clinical and radiological outcome measures included: Objective response rate (ORR), time-to-response (TTR), adverse events (AE), and patient response. Patient response was classified as partial response (PR), complete response (CR), progressive disease (PD), or stable disease (SD). RESULTS: Seven patients with 25 HBs were included in our study. A belzutifan dose of 120 mg/day PO was administered for a median of 13 months (range 10-17). Median follow up time was 15 months (range 10-24). An ORR of 71% was observed. The median TTR was 5 months (range: 1-10). None of the patients showed CR, while 5 patients (71.4%) showed PR and 2 (28.5%) showed SD. Among patients with SD the maximum tumor response was 20% [increase/decrease] of the lesion diameter. All the patients experienced decreased hemoglobin concentration, fatigue, and dizziness. None of the patients experienced severe anemia (grade 3-4 CTCAE). CONCLUSION: Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required.

Neurological applications of belzutifan in von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a tumor predisposition syndrome caused by mutations in the VHL gene that presents with visceral neoplasms and growths, including clear cell renal cell carcinoma, and central nervous system manifestations, such as hemangioblastomas of the brain and spine. The pathophysiology involves dysregulation of oxygen sensing caused by the inability to degrade HIFα, leading to the overactivation of hypoxic pathways. Hemangioblastomas are the most common tumors in patients with VHL and cause significant morbidity. Until recently, there were no systemic therapies available for patients that could effectively reduce the size of these lesions. Belzutifan, the first approved HIF-2α inhibitor, has demonstrated benefit in VHL-associated tumors, with a 30% response rate in hemangioblastomas and ~30%-50% reduction in their sizes over the course of treatment. Anemia is the most prominent adverse effect, affecting 76%-90% of participants and sometimes requiring dose reduction or transfusion. Other significant adverse events include hypoxia and fatigue. Overall, belzutifan is well tolerated; however, long-term data on dosing regimens, safety, and fertility are not yet available. Belzutifan holds promise for the treatment of neurological manifestations of VHL and its utility may influence the clinical management paradigms for this patient population.

Assessment of Retinal Changes Following Intravitreal Aflibercept in 2 Patients With Von Hippel-Lindau Disease-Related Retinal Capillary Hemangioblastoma.

This case report of 2 patients describes peripheral Von Hippel-Lindau disease associated with a series of aflibercept injections.

Blockade of ß2-Adrenergic Receptor Reduces Inflammation and Oxidative Stress in Clear Cell Renal Cell Carcinoma.

Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the ß2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.

Photodynamic Therapy for Retinal Hemangioblastoma: Treatment Outcomes of 17 Consecutive Patients.

PURPOSE: To report the efficacy of photodynamic therapy (PDT) for management of retinal hemangioblastoma. DESIGN: Retrospective case series. PARTICIPANTS: Seventeen patients with retinal hemangioblastoma treated with PDT. METHODS: The medical records of 17 patients with retinal hemangioblastoma treated with PDT were reviewed, and treatment outcomes were assessed. Photodynamic therapy was performed with 6 mg/m2 body surface area of verteporfin infused intravenously over 10 minutes activated by 50 J/cm2 laser light at 689 nm for 83 or 166 seconds. MAIN OUTCOME MEASURES: Tumor control, subretinal and intraretinal fluid resolution, and visual outcome. RESULTS: Eighteen retinal hemangioblastomas in 17 eyes were treated with PDT. Median patient age was 31 years (mean, 36 years; range, 7-66 years), and median follow-up was 51 months (mean, 61 months; range, 2-144 months). Genetic testing confirmed von Hippel-Lindau disease in 8 of 17 patients (47%). The tumors were unilateral in all patients and unifocal in most patients (n = 13/17 [76%]). The tumor median basal diameter was 3.5 mm (mean, 3.4 mm; range, 1.5-6.0 mm) and median thickness was 2.1 mm (mean, 2.3 mm; range, 1.0-5.0 mm). The tumor location was juxtapapillary in 9 of 18 cases (50%). Associated findings included subretinal fluid (n = 14/17 [82%]) and macular edema (n = 12/17 [71%]). The median number of PDT sessions was 1.5 (mean, 1.8; range, 1.0-4.0). Standard duration of PDT (83 seconds) was used in all cases except 2, in which double duration (166 seconds) was used. Outcomes revealed tumor control in 13 of 18 tumors (72%), partial or complete resolution of subretinal fluid in 10 of 14 eyes (71%), and partial or complete resolution of macular edema in 7 of 12 eyes (58%), and stable or improved visual acuity in 12 of 17 eyes (71%). Photodynamic therapy-related transient exudative response was noted in 4 of 17 eyes (24%). CONCLUSIONS: Photodynamic therapy is an effective treatment for both juxtapapillary and peripheral retinal hemangioblastomas, providing satisfactory rates of tumor control and visual stabilization and improvement. Patients should be monitored for PDT-related transient exudative response.

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).

Continuous angiogenesis inhibition in the treatment for von Hippel-Lindau-related hemangioblastomas of retina and spinal cord.

Hemangioblastomas of central nervous system are rare and indolent. Twenty-five percent of cases are in association with von Hippel-Lindau disease. Surgery is the standard therapy but un-resectable or recurrent cases need radiation or systemic therapy. Defective von Hippel-Lindau tumor suppressor gene leads to vascular endothelial growth factor overexpression and enhance angiogenesis. Here we report a 19-year-old male, diagnosed at pediatric age, who had retinal and spinal cord hemangioblastomas. He was treated 34 months with bevacizumab, afterwards 12 months with thalidomide and tertiary therapy with pazopanib for 9 months which still goes on. In case of need, radiation and surgical procedures were performed. Vascular endothelial growth factor inhibition continuity is a good therapeutic option, which improves outcomes of von Hippel-Lindau-related hemangioblastomas.

Von Hippel-Lindau with early onset of hemangioblastoma and multiple drop-metastases like spinal lesions: A case report.

RATIONALE: Hemangioblastoma is a rare tumor of the central nervous system (CNS). It is usually observed in patients with von-Hippel Lindau (VHL). The peak age for hemangioblastoma is between 20 and 50 years of age with very few cases over 65 or below 18 years of age. PATIENT CONCERNS: We report a female with a rare VHL mutation (c.337C>T) who was diagnosed with multifocal CNS hemangioblastoma at a very young age. DIAGNOSIS: At 17-years of age, she presented with obstructive hydrocephalus due to large cystic cerebellar mass. Imaging showed multiple lesions resembling drop metastases throughout her spinal cord. Immunohistochemistry of the resected tumor confirmed the pathological diagnosis of hemangioblastoma (World Health Organization Grade 1). INTERVENTIONS AND OUTCOME: She was treated with multi-stage resection of her primary and drop- metastasis like disease. She presented six months later with retinal hemangioblastoma while her other lesions were stable. She presented with multiple CNS and eye hemangioblastomas after failing to follow up for 2 years. Subsequently, Everolimus was started to treat her systemic disease. LESSONS: The unique feature of our case is the presence of multiple drop-metastases like spinal lesions, which has not been reported in the literature to be associated with hemangioblastoma.

Variable response of CNS hemangioblastomas to Pazopanib in a single patient with von Hippel-Lindau disease: Case report.

Von Hippel-Lindau (VHL) disease is a multisystem genetic disease, the cardinal manifestations of which include central nervous system hemangioblastomas (CNS HB), renal cell carcinomas (RCC), and pheochromocytoma. Tumorigenesis in VHL of both RCC and CNS HB occurs secondary to downstream effects of a mutated or absent VHL protein. Treatment of RCCs with tyrosine kinase inhibitors (TKIs) such as Pazopanib is now first line therapy, but their effect on VHL-associated CNS HBs remains unknown. We report the use of Pazopanib in a patient with VHL disease for treatment of RCC who also harbored multiple CNS HBs. Following initiation of treatment, a large cervical and a lumbar spinal HB regressed in size while the remaining CNS HBs exhibited stable or progressive disease. These findings highlight the multiplicity of factors contributing to hemangioblastoma development, even among tumors with a common germline mutation, and the potential limitations of TKIs, but additionally this report supports the conservative management of asymptomatic VHL patients with spinal HBs whereby tumor response to TKI treatment may alleviate or postpone the need for surgery.

Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a ß-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL). METHODS: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments. RESULTS: Propranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment. CONCLUSIONS: Although more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity. TRIAL REGISTRATION: The study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014-003671-30 . Registered 2 September 2014.

Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target.

Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX - caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat 68Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.

Verteporfin photodynamic therapy for the treatment of sporadic retinal capillary haemangioblastoma.

PURPOSE: To assess the effectivity of photodynamic therapy (PDT) for the treatment of retinal capillary haemangiomas METHOD: Retrospective case note analysis of all patients with retinal angiomas treated with PDT between 2003 and 2010. RESULTS: Six eyes of 6 patients (3 male, 3 female) with a mean age of 50 years (range, 23-78) were identified in our database. The follow up period was between 24 and 60 months (mean, 36). Tumor regression was evident in two patients; three tumors showed no demonstrable response to treatment on ophthalmoscopy or ultrasonography and one tumor progressed despite PDT and subsequent cryotherapy. One patient developed retinal neovascularisations following a period of inattendence to our clinic. Visual acuity improved in two patients following PDT, deteriorated in three patients and remained stable in a one patient. CONCLUSION: The response of retinal haemangioblastomas to PDT is inconsistent. Other treatment modalities ought to be utilized for peripheral lesions, however PDT may be tried in juxtapapillary lesions where radiotherapy or cryotherapy is likely to result in concurrent visual loss.

Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review.

Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-ß pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.

Intradural-extramedullary haemangioblastoma with paraspinal extension in a dog.

CASE REPORT: An 8-year-old spayed female cross-breed dog was evaluated following a 2-month history of thoracic limb weakness. Neurological examination revealed a spinal cord lesion between C1 and C5 segments. Magnetic resonance imaging (MRI) revealed that almost 70% of the spinal canal between C1 and C2 was occupied by an intradural extramedullary mass that was connected to a paraspinal mass from the cranial aspect of C2 to the cranial aspect of C3. The dog was anaesthetised and a dorsal, right-sided hemilaminectomy was performed. A durotomy was performed to expose a multilobular mass located principally along the right dorsal-lateral aspect of the spinal cord. The mass did not appear to infiltrate the cord parenchyma. The abnormal tissue was removed as completely as possible using gentle dissection and submitted for histological evaluation. The histological findings were consistent with an intradural-extramedullary haemangioblastoma with paraspinal extension. Following surgery, no neurological deterioration was detected. A metronomic-dosing chemotherapy protocol was administered to prevent progression or recurrence of the tumour. Follow-up MRI studies were performed 3, 6 and 12 months after the surgery, confirming complete tumour removal and the absence of recurrence. CONCLUSION: Haemangioblastoma is an extremely rare neoplasm in animals and only two cases of this tumour have been reported, but in other anatomical locations. Haemangioblastomas in human patients are more commonly located in the cerebellum and intradural-extramedullary growth is extremely rare. The dog in this study responded favourably to combined surgery and metronomic chemotherapy and was clinically normal 1 year after surgery.

Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumors: hemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma, pheochromocytomas, pancreatic serous cystadenoma, and endolymphatic sac tumors. These tumors do not express VHL protein (pVHL). pVHL ubiquitinates hypoxia inducible factor (HIF) protein for degradation by the proteasome; in the absence of VHL, HIF translocates to the nucleus to activate the expression of its target genes. Targeting VHL-derived tumors with drugs that have reduced side effects is urgent to avoid repeat CNS surgeries. Recent reports have shown that propranolol, a ß-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control hemangioblastoma growth in VHL disease because of its antiangiogenic effects demonstrated in IH and the hypothetical impact on HIF levels. METHODS: HeLa 9X (HRE) hypoxia responsive element cell line and primary hemangioblastoma-derived cells were subjected to propranolol treatment and cell viability and apoptosis were evaluated. HIF1-α and Hif-2α expression after propranolol treatment was analyzed by western blotting. Quantitative PCR was performed to study the mRNA expression of HIF target genes. Vascular endothelial growth factor (VEGF) was measured in culture supernatants by immunoassay. RESULTS: Propranolol downregulated HIF-dependent transcription in HeLa 9XHRE cells. Under hypoxic conditions, propranolol decreased the expression of HIF target genes in hemangioblastoma cells, which stopped proliferating and died following long-term treatment. These results suggests that propranolol treatment promoted reduced HIF protein expression and corresponding downregulation of HIF target genes, and inhibited cell proliferation in parallel with induction of cell death by apoptosis. CONCLUSIONS: Our results suggest that propranolol could reduce the growth of HIF-dependent tumors and may thus be a promising treatment to delay surgery in VHL patients.

Neuropathological characteristics of progression after prolonged response to bevacizumab in multifocal hemangioblastoma.

BACKGROUND: Antiangiogenic treatment has been explored in few patients with hemangioblastoma after failure of surgery and radiotherapy. CASE REPORT: We present the first histopathological follow-up study of a bevacizumab-responsive hemangioblastoma that eventually progressed. For a period of 12 months, therapy with bevacizumab achieved a clinical response and radiological stabilization in a patient with progressive multifocal central nervous system (CNS) hemangioblastoma. Subsequently, selected tumor sites showed radiological progression, in particular, the formation of an intramedullary lesion of the initially predominantly leptomeningeal disease. Histology showed diffuse dural invasion by the hemangioblastoma accompanied with a relatively reduced cell density compared to the preserved vessel structures. CONCLUSION: The pattern of progression upon vascular endothelial growth factor (VEGF)-targeting antiangiogenic treatment in hemangioblastoma may involve increased tumor invasiveness.