Association of the Model for End-Stage Liver Disease (MELD) Score With Spontaneous Bacterial Peritonitis in Patients With Liver Cirrhosis.

von Hippel-Lindau (VHL) disease is characterized by a propensity for the development of tumors in multiple organs and is caused by germline pathogenic variants in the VHL tumor suppressor gene. Manifestations of VHL disease in the eye include retinal hemangioblastoma (RH) and retinal vascular proliferation. Retinal hemangioblastomas represent one of the most common features of the disease, present in 1 or more eyes in 335 of 890 patients (38%) in a large cross-sectional cohort. These tumors can threaten vision by causing exudation, hemorrhage, scarring, and retinal detachment. Currently, they are treated primarily with ablative therapy if the location and size of the tumor are favorable, or in rare cases, with surgical removal. Juxtapapillary (associated with the optic nerve) RHs and RHs that involve a large proportion of the retina are not amenable to the available ablative therapies, although the latter sometimes can be removed with vitrectomy. von Hippel-Lindau protein (pVHL) plays a key role in regulating the cellular response to oxygen levels via its interaction with transcription factors known as hypoxia-inducible factors (HIFs). In normoxic conditions, HIF-α subunits (including HIF-2α) are targeted for proteasomal degradation by hydroxylation and binding with a ubiquitin ligase complex via pVHL. In the absence of functional pVHL, HIF-2α evades degradation, heterodimerizes with HIF-1β, and translocates into the nucleus to modulate the expression of hundreds of genes normally involved in the cellular response to hypoxia. Hypoxia-inducible factor 2α is present in the kidney, lung, liver, and endothelial cells, where it is known to exert effects on cell proliferation and angiogenesis. Hypoxia-inducible factor 2α over-expression is associated with the growth of clear cell renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors (pNETs), and paragangliomas or pheochromocytomas. Expression levels of HIF-2α in RHs are not known, but elevated HIF levels more generally have been documented. The location and the cell type responsible for the pathogenesis of RH have been investigated previously. Studies of surgical specimens from VHL disease-associated hemangioblastomas in the brain and spine indicated that the cell of origin is likely a mesoderm-derived, embryologically arrested hemangioblast. Other researchers found expression of stem cell markers in RH lesions associated with VHL disease in autopsied eyes, and subsequently developed a murine model of VHL disease-associated RH by inactivating VHL in a hemangioblast population in a transgenic mouse line. Thus, the hemangioblast is a likely candidate for cell of origin for hemangioblastomas in the CNS. Belzutifan (MK-6482; previously called PT-2977) is a first-in-class small-molecule inhibitor of HIF-2α approved in the United States, Great Britain, Canada, Australia, and several other countries for certain patients with VHL disease-associated RCC, CNS hemangioblastomas, or pNETs. The approval was based on the single-arm LITESPARK-004 study ( identifier, ), which evaluated oral belzutifan therapy in these patients. At a median follow-up of 37.8 months, 39 of 61 participants showed an objective response to belzutifan in RCC by Response Evaluation Criteria in Solid Tumors version 1.1 guidelines (objective response rate, 64%; 95% confidence interval [CI], 50.6%–75.8%). More recently, belzutifan was approved in the United States for patients with advanced RCC after a programmed death receptor-1 or ligand-1 inhibitor and a VEGF tyrosine kinase inhibitor, based on the phase 3 LITESPARK-005 study ( identifier, ).