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Medical Sciences (Basel, Switzerland) Jun 2023Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased... (Review)
Review
Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 37489462
DOI: 10.3390/medsci11030046 -
Brain Tumor Research and Treatment Apr 2024Sleep has confirmed physical, psychological, and behavioral benefits, and disruptions can result in disturbances in these states. Moreover, it can be linked...
BACKGROUND
Sleep has confirmed physical, psychological, and behavioral benefits, and disruptions can result in disturbances in these states. Moreover, it can be linked bidirectionally with susceptibility to and the subsequent status of brain tumors. The current study examined mood disorders and sleep quality before and after surgery for hemangioblastoma brain tumors.
METHODS
Thirty-two patients diagnosed with hemangioblastoma brain tumors between 2017 and 2023 underwent surgical treatment. The Karnofsky Performance Status and ECOG performance status scales, the Brunel Mood Scale, the Morningness-Eveningness Questionnaire, and the Mini-Sleep Questionnaire were employed to assess the patients.
RESULTS
The findings indicate that after surgery, sleep quality and mood disorders, including tension, vigor, and depression, did not exhibit significant differences in these patients (>0.05). However, tension, vigor, depression, and sleep quality did have a significant impact on their functional status post-surgery (<0.05).
CONCLUSION
Depression is the significant mood factor in patients with brain tumors that impact their functional status. In this context, it is recommended that psychological therapies be considered for them, alongside conducting more comprehensive and in-depth studies on psychological disorders in patients with brain tumors.
PubMed: 38742256
DOI: 10.14791/btrt.2023.0040 -
Neurospine Sep 2023This study aimed to clarify the relationship between recurrence and the extent of resection in surgery for intramedullary spinal hemangioblastoma (sHB) and its impact on...
Comparison of the Recurrence and Surgical Outcome of Spinal Hemangioblastoma in Sporadic and Von Hippel-Lindau Diseases: A Subanalysis of a Nationwide Study by the Neurospinal Society of Japan.
OBJECTIVE
This study aimed to clarify the relationship between recurrence and the extent of resection in surgery for intramedullary spinal hemangioblastoma (sHB) and its impact on von Hippel-Lindau (vHL) disease.
METHODS
Data on sHB cases followed up for at least 6 months after surgery were extracted from a nationwide registry of 1,033 consecutive spinal intramedullary tumors surgically treated between 2009 and 2020, and were retrospectively categorized into a sporadic or vHL group. The diagnosis of vHL disease was made at each institution based on clinical findings.
RESULTS
A total of 168 patients (sporadic group, 101; vHL group, 67) were included in the study. Compared with the sporadic group, the vHL group had a younger onset (45.4 ± 16.8 years vs. 39.6 ± 14.1 years, p = 0.02), more preoperative motor (47.5% vs. 68.7%, p < 0.01) and gait (37.6% vs. 61.2%, p < 0.01) impairments, and more patients with worsening neurological symptoms at discharge (p = 0.02). The gross total resection (GTR) rates and the recurrence rates were not statistically different between the sporadic and the vHL groups. GTR significantly improved recurrence-free survival compared to non-GTR in all patient analysis (p < 0.01) but this trend was not observed in the sporadic group. Physical functional improvement from discharge to 6 months after surgery was observed in the sporadic group (p < 0.01) but not in the vHL group.
CONCLUSION
A high GTR rate may sufficiently decrease susceptibility to recurrence, especially in patients with sHB with vHL. In sporadic sHB, postoperative functional improvement can be expected, and the long-term functional prognosis is favorable.
PubMed: 37350167
DOI: 10.14245/ns.2346368.184 -
Clinical Cancer Research : An Official... Jun 2023Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL...
PURPOSE
Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL.
PATIENTS AND METHODS
We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002).
RESULTS
Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling.
CONCLUSIONS
We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
Topics: Humans; von Hippel-Lindau Disease; Hemangioblastoma; Vorinostat; Proteostasis; Von Hippel-Lindau Tumor Suppressor Protein; Central Nervous System Neoplasms; Biological Products
PubMed: 37018064
DOI: 10.1158/1078-0432.CCR-22-3651 -
Diagnostics (Basel, Switzerland) Jan 2024(1) Background: Hemangiomas in Von Hippel-Lindau (VHL) syndrome patients are typically benign but pose threats due to their vital locations involving the central nervous... (Review)
Review
(1) Background: Hemangiomas in Von Hippel-Lindau (VHL) syndrome patients are typically benign but pose threats due to their vital locations involving the central nervous system and the retina. An MRI is currently recommended as the gold standard for tumors associated with VHL in the head region. This narrative review aims to comprehensively outline current standards and recent findings related to imaging of retinal and CNS hemangiomas in Von Hippel-Lindau syndrome. (2) Material and Methods: A review in adherence to PRISMA guidelines using the search string "Von Hippel-Lindau hemangioblastoma imaging" was conducted on PUBMED and SCOPUS databases. (3) Results: After reviewing 455 titles and abstracts, 20 publications fulfilling the inclusion criteria were analyzed. The analysis included studies describing MRI, CT, optical coherence tomography, and PET/CT. (4) Conclusion: While MRI remains the gold standard for diagnosing head tumors in Von Hippel-Lindau syndrome, various PET/CT methods show promise as alternative imaging modalities.
PubMed: 38337825
DOI: 10.3390/diagnostics14030309