Search Results (127)

Pancreatic neuroendocrine neoplasms (PNENs) are a diverse group of rare tumor subtypes, representing less than 2% of all pancreatic tumors. Often detected late in the clinical course, they are associated with high rates of morbidity and mortality. Hereditary syndromes such as multiple endocrine neoplasia type-1 and von Hippel–Lindau are associated with the development of PNENs, although only a small portion of total tumors have a genetic basis. This review aims to explore the recent advances in laboratory diagnostics, imaging modalities, medical management, and surgical approaches to hormone-producing PNENs (including some common, less common, and some rare subtypes), with the goal of assisting physicians in the integration of evidence-based information into their practice. Full article

Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2α is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2α-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors. Despite being overall well tolerated, belzutifan has a distinct safety profile because of its unique mechanism of action. Anemia was the most common adverse event observed in clinical trials and is considered an on-target effect. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. This review summarizes the rates of hypoxia seen in clinical trials of belzutifan in ccRCC. As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2α inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients. Full article

Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5–10 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel–Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel–Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood–brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances. Full article

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT²GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT²GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT²GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article

Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation. Full article

The biological significance of sodium–glucose cotransporter 2 (SGLT2) in clear cell renal cell carcinoma (ccRCC) has yet to be elucidated. In this study, we aimed to determine the role of SGLT2 in ccRCC tumor progression. The human ccRCC line KMRC-1, which contains a von Hippel–Lindau (VHL) gene mutation, was used to assess the effects of the SGLT2 inhibitor (SGLT2i) dapagliflozin on proliferation and migration in media containing different glucose concentrations (25, 12.5, or 5 mM). Dapagliflozin significantly reduced cell proliferation and migration in 25 mM glucose medium. Similarly, SGLT2 knockdown involving short hairpin RNA lentiviral transfection significantly decreased cell viability, migration, and colony formation compared with the control subline in 25 mM glucose medium. Moreover, tumor progression was inhibited in the media with low glucose concentrations. Remarkably, 2 µM dapagliflozin inhibited the progression of ccRCC at concentrations as low as 5 mM (normoglycemic model) glucose medium as well as 25 mM (severe glycemia model) glucose medium. In addition, dapagliflozin treatment significantly enhanced the apoptosis of ccRCC cells. Our findings demonstrate that SGLT2 impacts the progression of ccRCC with the VHL mutation. In light of the above findings, SGLT2is, which exert the dual effects of SGLT2 blockade and glycemic control, may represent a novel therapeutic agent, particularly in patients with ccRCC who suffer from concurrent diabetes mellitus. To the best of our knowledge, this is the first preclinical study demonstrating the impact of SGLT2 inhibition on the progression of ccRCC with the VHL mutation. Full article

Background: Oral Submucous Fibrosis (OSMF) is a chronic, progressive condition characterized by the fibrosis of the oral mucosa, often associated with the habitual consumption of areca nut and tobacco, leading to significant morbidity. Despite its prevalent occurrence in many parts of the world, the underlying genetic and molecular mechanisms remain poorly understood, highlighting a critical need for research into its molecular genomics. The aim of this literature review is to investigate the molecular genomics of Oral Submucous Fibrosis by analyzing the relevant literature of the past decade. Methods: The search was conducted using MEDLINE (National Library of Medicine)-PubMed, focusing on the period 2015–2025 using the following keywords: Molecular Genomics AND Oral Submucous Fibrosis. This was followed by a manual search, and references were used to identify relevant articles. Results: A total of 12 articles were included in our review according to our inclusion criteria, which illustrated the importance of TGF-β, Wnt inhibitory factor-1, CypA, Hsp-70 1B, Calreticulin, Lumican, Enolase 1, MMP-2, IGF-1R, XIST, Epigallocatechin-3-gallate, Von Hippel-Lindau, and MUC1 and 4. Conclusions: Understanding the molecular pathogenesis of OSMF involves examining the molecular interactions and the roles of specific proteins. Advanced genomic technologies have opened new frontiers in the study of OSMF. As research in OSMF continues to evolve, emerging interdisciplinary approaches may provide therapeutic strategies, aiming to improve management outcomes for the patients. Full article

Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system (CNS-HBs). The standard treatment for these brain tumors is neurosurgical resection. However, multiple surgeries are often necessary due to tumor recurrence, which increases the risk of neurological sequelae. Thus, elucidation of the proliferative behavior of hemangioblastomas (with the aim of identifying biomarkers associated with tumor progression) and the development of pharmacological therapies could reduce the need for repeated surgical interventions and provide alternative treatment options for unresectable CNS-HBs. Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies. Results: In this study, primary cell cultures were successfully established from CNS-HB tissue samples of VHL patients, achieving a 75% success rate. These cultures were predominantly composed of stromal cells and pericytes. The proliferative patterns of patient-derived HB cell cultures significantly correlated with tumor burden and recurrence in VHL patients. Furthermore, flow cytometry, reverse transcription-PCR, and Western blot analyses revealed marked overexpression of both HIF-1α and HIF-2α isoforms in primary HB cells. In addition, evaluation of the therapeutic potential of acriflavine, a dual HIF-1α/HIF-2α inhibitor, demonstrated reduced HB cells viability, induced G2/M cell cycle arrest, and predominantly triggered necrotic cell death in patient-derived HB cultures. Conclusions: These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy. Full article

Introduction: Hemangioblastomas (HBs) are benign, highly vascular tumors that can be found intracranially or in the spinal region, representing around 2–15% of primary intramedullary tumors. They can occur sporadically or in association with Von Hipple–Lindau (VHL) disease. Despite recent of advancement of nonsurgical treatments, complete surgical resection remains the gold standard of care for the spinal HBs. Materials and Methods: We conducted an international multicenter retrospective analysis of adult patients surgically treated for spinal HBs in four European referral centers between January 2000 and September 2024, with a minimum post-operative follow-up duration of 6 months. Patients’ sex and age at surgical intervention, clinical presentation, and duration symptoms prior to clinical diagnosis were identified. The pre- and post-operative neurological status at 1 and 6 months and at the last visit was assessed using the modified McCormick score (MCS). The extent of surgical resection was divided into gross total resection (GTR) and subtotal resection (STR). Finally, post-operative complications were inspected as well, namely cerebrospinal fluid leaks, infections, hemorrhages and post-operative spinal stability. Results: A total of 35 patients were included in the cohort, with an age median of 52 years (34.5–60) and a slight male predominance (21/35, i.e., 60%). The median follow-up period was 37.5 months (12–75). More than half were located in the cervical region, making it the most common (54.3%). Syrinxes were observed in 23 cases (72%), and HBs were more commonly intramedullary (80%). GTR was achievable in around 88% of cases. Post-operative complications were observed in nine patients (25.7%). Nearly half of patients were discharged into rehabilitations centers (48.5%). Tumor recurrence was seen in 10.3% only. At the last follow-up, an excellent overall post-operative neurological status (positive ∆ McCormick) was observed in most of patients (88%) and was found to be associated with a relatively younger age group. Tumor location and presence of syrinxes did not show any statistical significance regarding clinical outcome. In patients having benefited from intra-operative monitoring, only D-wave changes showed statistical significance regarding post-operative outcome (p < 0.05). Conclusions: A large majority of patients operated for a spinal HB demonstrated favorable outcome after surgery, with unchanged or improved neurological status. Advanced age could have an impact on the post-operative neurological outcome. Other factors such as tumor size, location, and the presence of syrinx did not seem to significantly impact the neurological outcome. Finally, the surgery of these vascular lesions with no possibility of debulking or piece-meal removal and requiring “en bloc” resection is technically demanding and should be performed by experienced teams in spine and spinal cord surgery only. Full article

Clear-cell renal cell carcinoma (ccRCC) is associated with the mutated von Hippel–Lindau (VHL) gene leading to the activation of hypoxia-inducible factor 1A (HIF1A) and subsequent overexpression of erythropoietin (EPO). We analyzed tumor and healthy tissues from 43 ccRCC patients after radical nephrectomy and cultured 786-O (biallelic VHL inactivation) and Caki-1 (wild-type VHL) cells in normal (21% O₂) and low oxygen (3% O₂) with 10% and 2% fetal bovine serum (FBS). DNA sequencing, including Sanger sequencing, MLPA and LOH, revealed 27 somatic mutations of VHL in ccRCC. HIF1A protein showed decreased or no expression in tumors compared to healthy tissue, independent of VHL alteration. The 786-O cells showed increased HIF1A protein expression after 48 h under low oxygen and 10% FBS. EPO and erythropoietin receptor (EPOR) were significantly decreased in ccRCC without HIF1A expression. EPO mRNA increased in the 786-O cells at 3% O₂ after 48 h, while the Caki-1 cells had low or no EPO expression. Hypoxia increased EPOR mRNA in the Caki-1 cells at 10% FBS, but decreased in the 786-O cells at 2% FBS after 48 h. JAK2/STAT5A activity was increased only in HIF1A-positive tumors. These results suggest that EPO/EPOR activation in ccRCC is mainly driven by low oxygen, not VHL regulation of hypoxia-related responses. Full article

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers. Full article

Background and Objectives: Von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and can develop various cancers. Hypoxia-inducible factors 1 and 2 alphas, regulated by the VHL gene, can increase the levels of vascular endothelial growth factor, thereby activating cancer progression. Here, we demonstrated clinical and prognostic values of VHL expression in rectal cancer (RC). Materials and Methods: Von Hippel–Lindau mRNA expression was examined in 60 patients with RC. Furthermore, we evaluated survival to determine the prognostic significance of VHL mRNA expression levels in RC using the Cancer Genome Atlas (TCGA) data. Results: Lower VHL expression was correlated with the recurrence (p = 0.058) and lymphatic invasion (p = 0.078), although it was not statistically significant. In TCGA data, VHL expression level was correlated with the M stage (p = 0.044); however, it had a possible association with lymphatic invasion (p = 0.068) and N stage (p = 0.104). Survival analysis showed that lower VHL gene expression predicted poorer survival in both patients with RC and TCGA data. Conclusions: This study identified a significant correlation between VHL gene expression and RC for the first time using patient tissues and TCGA data, suggesting that the VHL gene expression level could be a potential biomarker or candidate for the treatment of RC. Further studies are required to identify the molecular pathogenesis and clinical characteristics of VHL disease in RC. Full article

Belzutifan is a new HIF-α inhibitor mainly used in two different indications: von Hippel–Lindau syndrome-associated renal cell carcinoma, haemangioblastomas and pancreatic neuroendocrine tumours, as well as sporadic advanced pre-treated renal cell carcinoma. Although efficacy has been demonstrated in phase II and III studies, belzutifan is still not approved in many countries. In addition, von Hippel–Lindau syndrome is a rare disease. Therefore, there is virtually no real-world experience data of belzutifan efficacy available. We aim to determine the real-world efficacy and tolerability of belzutifan in patients with von Hippel–Lindau syndrome-associated tumours and in patients with sporadic advanced tyrosine kinase- and immune checkpoint inhibitors pre-treated for renal cell carcinoma. A retrospective analysis of five patients treated with belzutifan between 2023 and 2024 at a Swiss cancer centre was conducted. In this case series, all patients consistently benefitted from belzutifan with response to treatment. This case series provides real-world evidence that belzutifan is an effective and well-tolerated treatment option for patients with von Hippel–Lindau syndrome-associated renal cell carcinoma, haemangioblastomas and sporadic advanced pre-treated renal cell carcinoma. Full article

Mutations of the von Hippel–Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4–6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance. Full article

Clear cell renal cell carcinoma is the most common form of kidney cancer, accounting for 75% of malignant kidney tumors, and is generally associated with poor patient outcomes. With risk factors including smoking, obesity, and hypertension, all of which have a high prevalence in the United States and Europe, as well as genetic factors including tuberous sclerosis complex and Von Hippel–Lindau syndrome, there is an increasing need to expand our present understanding. The current clear cell renal cell carcinoma knowledge is outdated, with obsolete diagnostic criteria and moderately invasive surgical treatments still prevailing, partially ascribed to its resistance to chemotherapy and radiation therapy. The standard of treatment relies on surgical intervention, including radical nephrectomy and partial nephrectomy, while more recent treatments target neoplastic growth pathways and immune regulation checkpoints. Full article