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.

von Hippel-Lindau (VHL) disease is a genetic condition predisposing individuals to the development of benign and malignant tumors across various organs. This review explores the intricate genetic underpinnings of VHL disease, its clinical manifestations, and the associated malignancy risks. The latest diagnostic criteria, surveillance guidelines, and advancements in therapeutic strategies, including the Food and Drug Administration-approved hypoxia-inducible factor-2α inhibitor, belzutifan, are focused on. Through a multidisciplinary approach, tailored surveillance programs aim to improve patient outcomes while balancing intervention risks. Emerging technologies such as wholebody magnetic resonance imaging and liquid biopsies hold promises for enhancing non-invasive surveillance. This review underscores the significance of ongoing research and interdisciplinary care in managing this complex syndrome.

An understanding the natural history of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) is critical to the development of optimal clinical management approaches and interpretation of trial results for comparable populations and endpoints. Our aim was to describe the natural progression of disease in patients with VHL RCC.

This was a natural history study involving 244 patients with VHL with ≥10-mm renal tumor(s) who were evaluated and managed at the US National Cancer Institute between 2004 and 2020. We analyzed radiographic outcomes, renal surgeries, metastasis, sequalae of surgery, including chronic kidney disease (CKD), and mortality. Radiographic outcomes were assessed according to Response Evaluation Criteria in Solid Tumours v1.1. The primary analyses were descriptive in nature.

Among 178 patients with at least three serial tumor assessments and up to 5 yr of follow-up, the rate of spontaneous tumor regression (≥30% decrease) was 1.8% (95% confidence interval [CI] 0.4-5.2%). The probability of not having disease progression in the presence of competing risks at 5 yr was 37% (95% CI 30-44%). During follow-up, 186/244 patients had one or more renal surgeries, and 108/244 had two or more. RCC metastasis was reported for 12 patients. Among patients who underwent surgery, 41% developed postprocedure CKD. Potential limitations include selection bias and misclassification of outcomes.

Our study demonstrates that RCC is a significant burden for VHL patients, with high rates of disease progression, surgery, and metastasis development, even in a closely monitored, multidisciplinary clinical environment, and identifies CKD as an underappreciated aspect of VHL. These findings can provide a context for the antitumor activity of new treatments for RCC.

The von Hippel-Lindau (VHL) tumor suppressor is a substrate-defining component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by mutation or transcriptional silencing is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss in ccRCC leads to constitutive stabilization of E3 ligase substrates, including hypoxia inducible factor α (HIFα). HIFα stabilization upon VHL loss is known to contribute to ccRCC development through transactivation of hypoxia-responsive genes. HIF-independent VHL targets have been implicated in oncogenesis, although those mechanisms are less well-defined than for HIFα. Using proximity labeling to identify proteasomal-sensitive VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in a proteasomal-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, loss of pRb in ccRCC led to increased cell death, transcriptional changes, and loss of oncogenic properties in vitro and in vivo. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.

While papillary cystadenomas of the epididymis are relatively common, the occurrence of papillary cystadenomas in female individuals, particularly in the ovaries, remains exceedingly rare.

A 62-year-old white North African woman diagnosed with Von Hippel-Lindau disease in 2021 presented with multiple manifestations, including a left petrous bone tumor, left pheochromocytoma, left renal cell carcinoma, multi-cystic right kidney, and pancreatic masses. She underwent various treatments, including radiotherapy, adrenalectomy, nephrectomy, and cephalic duodenopancreatectomy. Ultrasonographic and magnetic resonance imaging examinations revealed a solid cystic mass in the left adnexal region. Laparoscopy identified cystic tumors in the right and left mesosalpinx. Following a hysterectomy with bilateral adnexectomy, histological examination revealed bilateral clear-cell papillary cystadenomas of the mesosalpinx and broad ligament, consistent with Von Hippel-Lindau disease.

This case highlights the rare occurrence of bilateral clear-cell papillary cystadenomas of the mesosalpinx and broad ligament in a woman with Von Hippel-Lindau disease, a condition typically associated with men. The comprehensive diagnostic and therapeutic approach, including imaging studies, laparoscopy, and histological examination, underscores the importance of vigilant monitoring and tailored management in patients with this complex, multisystem disorder.

Pancreatic serous neoplasms can morphologically resemble metastatic clear cell renal cell carcinoma (ccRCC) and may present a diagnostic dilemma, particularly if the solid variant is in small biopsy specimens and/or in patients with von Hippel Lindau (VHL) syndrome. We investigate the utility of immunohistochemical staining in this differential diagnosis by performing head-to-head comparisons of commonly used immunohistochemical markers for these 2 tumor types. We examined 16 pancreatic serous neoplasms and 24 ccRCCs (12 metastatic to pancreas and 12 primaries in patients with VHL). All pancreatic serous neoplasms stained positive for CK7, and most were positive for CAIX (15/16) and GLUT1 (15/16), variable for alpha-inhibin and vimentin (each 8/16 weak/focal; and 7/16 and 8/16, respectively, positive), and weak/focal for synaptophysin (14/16). All pancreatic serous neoplasms were negative for PAX8 and Periodic acid-Schiff without diastase. In contrast, ccRCC, both metastatic and in VHL patients, were mostly positive for PAX8 (18/24; 6/24 were weak/focal), negative for CK7 (15/24; 8/24 were weak/focal, one case diffuse positive), and negative for alpha-inhibin (100%) and synaptophysin (22/24). Like pancreatic serous neoplasms, all ccRCC showed weak/focal or positive staining for GLUT1, CAIX, and vimentin, and were negative for PAS-D. In conclusion, CK7 and PAX8 are the most useful stains in distinguishing between pancreatic serous neoplasm and ccRCC; however, weak/focal CK7 or PAX8 staining can be seen in a minority of ccRCC, thereby presenting a diagnostic pitfall. Alpha-inhibin was at least weak/focal in most pancreatic serous neoplasms and negative in all ccRCC and may be useful as an adjunct stain in difficult cases.

To present new clinical features of juxtapapillary retinal capillary hemangiomas (JRCHs), assess the risk of von Hippel-Lindau (VHL) disease, and explore the genotype-phenotype correlations in patients with JRCH.

Fifty patients with JRCH were included. Multimodal retinal imaging including optical coherence tomography angiography (OCTA), visual acuity, presence of peripheral RCHs, affected lateralities, systemic evaluation for VHL disease, and underlying VHL variants were reviewed.

Of 59 eyes, 48 had classic JRCHs, whereas 11 had atypical JRCHs (type B, if it broke through the inner limiting membrane: 3 eyes; type A, if not: 8 eyes). Compared with atypical type A, which was indolent, type B might warrant surgical interventions. Better final visual acuity (P < 0.0001), fewer peripheral RCHs (P = 0.02), and lower prevalence of large peripheral RCHs (>1.5 mm) (P = 0.027) were observed in eyes with atypical JRCHs than classic JRCHs. VHL was diagnosed clinically in 72% of patients, and 22 VHL variants were identified, including 5 novel variants. Patients with truncating variants had a higher prevalence of atypical JRCHs than those with single amino acid substitution/deletion variants (P = 0.009). Patients with bilateral VHL-JRCHs were more likely to have large peripheral RCHs (P = 0.02) and less likely to harbor β-domain single amino acid substitution/deletion variants (P = 0.066) than those with unilateral VHL-JRCHs.

Atypical JRCHs, with distinctive OCTA characteristics and favorable visual outcomes, are less complicated by peripheral RCHs and more relevant to truncating variant genotypes. JRCH monitoring should incorporate OCTA classification and genotype analysis.

Von Hippel-Lindau disease (VHL) is a rare, autosomal-dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PVs) in the VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiple organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known.

The aim of this study was to identify prognostic factors associated with VHL-related PanNETs, notably the role of genotype-phenotype correlations.

Patients with both documented germline PV in the VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. The primary end point was the proportion of patients with PanNET-related metastases, and the secondary end point was overall survival (OS). Genotype/phenotype correlations were studied.

We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (P = .0089; best threshold 28 mm) and grade 2 PanNET (P = .048), and a pejorative prognostic impact (P = .043). Patients with PV in VHL exon 1 had larger PanNETs (P = .018), more often metastatic disease (48% vs 11.5%; P < .001) and a trend toward shorter OS (P = .16).

The risk of metastases associated with VHL-related PanNETs remains low (24%) but increases with tumor size greater than 28 mm, higher grade, and in case of PV, located in VHL exon 1. These data might help improve the management of these patients, who should be referred to an expert center.

Central nervous system (CNS) hemangioblastomas are rare, benign vascular tumors occurring sporadically or with von Hippel-Lindau (VHL) disease. While resection remains the primary treatment for symptomatic lesions, stereotactic radiosurgery (SRS) has emerged as an alternative where surgery is not feasible. This research aims to investigate the efficacy and safety of SRS for CNS hemangioblastomas, focusing on long-term outcomes and identifying key prognostic factors. A systematic search was conducted in PubMed, Scopus, Embase, Web of Science, and Cochrane Library till October 4th, 2024. Studies investigating the efficacy of SRS for CNS hemangioblastomas were included. The risk of bias was assessed using the ROBINS-I tool. Meta-analysis, subgroup analysis, and meta-regression were performed using the R programming language. A total of 28 studies with 627 patients and 1761 lesions were included. Our meta-analysis demonstrated pooled overall, 5- and 10-year local tumor control rates of 89% (95% CI: 85-92%), 87% (95% CI: 82-91%), and 80% (95% CI: 63-91%), respectively. Tumor response assessment revealed that 28% (95% CI: 19-40%) of lesions had regression, while 59% (95% CI: 46-70%) remained stable. VHL-associated lesions had a higher control than sporadic tumors at the 5-year follow-up (VHL: 94% (95% CI: 90-97%) vs. Sporadic: 82% (95% CI: 76-86%), P < 0.01). Pooled adverse events were 11% (95% CI: 8-15%). Meta-regression identified the female sex as a positive predictor for tumor control and lower adverse event rate (P < 0.01 and P = 0.02, respectively), while higher marginal and maximum radiation doses correlated with increased adverse events (P = 0.02 and P = 0.03, respectively). SRS represents a reasonably effective and safe treatment option for CNS hemangioblastomas, particularly in VHL-associated lesions. Patient demographics, VHL status, and tumor characteristics have been analyzed to identify factors potentially impacting treatment outcomes.

Patients with bilateral renal masses and an interaortocaval mass (IACM) present a complex scenario where, in addition to renal masses, management of the IACM adds to challenges in an already challenging case. A young man in his 30s presented with left flank pain, associated with loss of appetite, headache and sweating. The evaluation revealed multiple renal masses in the right kidney, a large mass in the left kidney and an IACM. Staged surgery revealed bilateral renal masses to be clear cell renal cell carcinoma (RCC) and the IACM as paraganglioma (PG). In bilateral RCC, should there be a retroperitoneal mass, PG should be strongly considered and ruled out in addition to the evaluation of Von Hippel-Lindau syndrome.

Pheochromocytomas and paragangliomas (PPGLs) are manifestations of von Hippel-Lindau (VHL) disease. This study aims to describe the clinical features of PPGLs in VHL patients and the distinctions between VHL disease-related PPGLs and sporadic PPGLs.

The study included all patients with VHL disease and PPGLs treated in a single centre from 2007 to 2023. A total of 145 patients were included in the sporadic PPGLs group. Their clinical data were retrospectively reviewed. Genetic testing for VHL mutation was conducted using Sanger sequencing. Statistical analysis was performed using SPSS 22.

Fifty-nine (65.6%) of the 90 VHL disease patients had PPGLs (male: female, 38:21; age at diagnosis, 25.0 ± 13.3 years). 42 (71.2%) patients had lesions only in the adrenal gland, and 16 (27.1%) patients had lesions both in and out of the adrenal gland. 45 (76.3%) patients had multiple lesions. Eighteen (45.0%) patients developed recurrence after surgery. Fifty-eight patients with PPGLs underwent genetic testing and had pathogenic or likely pathogenic mutations in the VHL gene. Fifty-three (91.4%) patients had missense mutations, 34 of which were located in the Elongin-C binding domain. The hotspot mutation sites were codon 161 and codon 167. Five novel mutations were identified. The clinical characteristics showed no significant differences between groups with different mutation sites. Compared to sporadic PPGLs, VHL disease-related PPGLs were more frequently located in the adrenal gland (71.2% vs. 49.0%, p < 0.001), had a higher prevalence of multiple lesions (76.3% vs. 11.0%, p < 0.001), and secreted noradrenaline (80.4% vs. 43.2%, p < 0.001). They were also more likely to relapse after surgery (45.0% vs. 15.3%, p < 0.001).

VHL disease-related PPGLs were often multifocal and noradrenergic, and more likely to relapse compared with sporadic PPGLs. No relationships were identified between the mutation sites and the clinical characteristics of PPGLs.

Systemic diseases, such as IgG4-related disease, sarcoidosis, and amyloidosis, usually involve multiple systems or organs simultaneously or sequentially. The gastrointestinal tract, hepatobiliary system, and genitourinary tract are commonly involved in many multisystem diseases and can also be the first sites with disease involvement. Cross-sectional imaging, such as CT and MR, plays an important role in the diagnosis and management of multisystem diseases by aiding in the evaluation of multiorgan involvement. Here, common imaging features of frequently affected organs are reviewed in multisystem diseases that we often encounter in the abdomen and pelvis, and the diagnostic roles of cross-sectional imaging for these diseases are also discussed.

Nonstop extension or stop-loss mutations lead to the extension of a protein at its carboxyl terminus. Recently, nonstop mutations in the tumor suppressor SMAD Family Member 4 (SMAD4) have been discovered to lead to proteasomal SMAD4 degradation. However, this mutation type has not been studied in other cancer genes. Here, we explore somatic nonstop mutations in the tumor suppressor genes BRCA1 Associated Protein 1 (BAP1) and Von Hippel-Lindau (VHL) enriched in renal cell carcinoma. For BAP1, nonstop mutations generate an extremely long extension. Instead of proteasomal degradation, the extension decreases translation and depletes BAP1 messenger RNA from heavy polysomes. For VHL, the short extension leads to proteasomal degradation. Unexpectedly, the mutation alters the selection of the translational start site shifting VHL isoforms. We identify germline VHL nonstop mutations in patients leading to the early onset of severe disease manifestations. In summary, nonstop extension mutations inhibit the expression of renal tumor suppressor genes with pleiotropic effects on translation and protein stability.

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.

To evaluate the clinical features, surgical outcomes, and predictors of progression-free survival (PFS) in patients with endolymphatic sac tumors (ELSTs).

This retrospective study analyzed 15 cases from Beijing Tiantan Hospital and 237 from the literature (1988-2023), focusing on patients with pathologically confirmed intracranial or skull ELSTs who had comprehensive treatment and follow-up records. Univariate and multivariate Cox regression analyses were used to identify factors influencing PFS.

Patients from our institute comprised 10 males and 5 females, with an average age of 39.1 years. Among these patients, 86.7% underwent gross total resection (GTR). During the follow-up period, 2 patients (13.3%) were lost to follow-up. After a mean follow-up of 74.9 months, 1 patient experienced recurrence and another died from unrelated causes. A review of the literature identified 237 additional patients, including 134 females (56.5%), with an average age of 39.8 years; 22.8% of these patients had von Hippel-Lindau disease. The GTR rate was 69.2%. After a mean follow-up of 53.2 months, 33 recurrences occurred, and the median PFS was 48 months. In addition, 8 patients died during the follow-up period; none of the deaths was attributed to ELSTs. Multivariate analysis identified GTR (hazard ratio, 0.279; 95% confidence interval, 0.086-0.903; P = 0.033) as a significant protective factor against recurrence among the pooled cases.

GTR is crucial for improving PFS in patients with ELST, emphasizing the need for advanced surgical techniques and long-term follow-up because of potential recurrences.

Renal cell carcinoma (RCC) constitutes the most frequent kidney cancer of the adult population and one of the most lethal malignant tumors worldwide. RCC often presents without early symptoms, leading to late diagnosis. Prognosis varies widely based on the stage of cancer at diagnosis. In the early-stage, localized RCC has a relatively good prognosis, while advanced or metastatic RCC has a poor outcome. Obesity, smoking, genetic mutations and family history are all considered risk factors for RCC, while inherited disorders, such as Tuberous Sclerosis and von Hippel-Lindau syndrome, are causally associated with RCC development. Genetic screening, deep sequencing analysis, quantitative proteomics and immunostaining analysis on RCC tissues, biological fluids and blood samples have been employed to identify novel biomarkers, predisposing factors and therapeutic targets for RCC with important clinical implications for patient treatment. Combined approaches of gene-targeting strategies coupled to a deep functional analysis of cancer cell biology, both in vitro and in appropriate animal models of RCC, significantly contributed to identify and characterize relevant pathogenic mechanisms underlying development and progression of RCC. These studies provided also important cues for the generation of novel target-specific therapeutics that selectively restore deranged cancer cell signalling and dysfunctional immune checkpoints, positively impacting on the survival rate of treated RCC patients. In this review, we will describe the recent discoveries concerning the most relevant pathogenic mechanisms of RCC and will highlight novel therapeutic strategies that interrupt oncogenic pathways and restore immune defences in RCC patients.

Hemangioblastomas (HBs) occurring in the cervical spinal region are infrequently reported. Surgical resection of cervical HBs poses a significant challenge, and the long-term therapeutic outcomes remain unclear.

A comprehensive retrospective analysis was conducted to review the treatment outcomes of patients with cervical HBs from 2011 to 2021. Patients with detailed preoperative clinical and radiological information, as well as follow-up data, were included in this study.

One hundred six adult patients were enrolled, with a mean age of 37.4 ± 15.6 years (range: 18-68 years), and a male predominance of 58.5 %. Thirty-two patients (30.2 %) had von Hippel-Lindau (VHL) disease. VHL-associated patients were younger (p = 0.023), had a shorter duration of symptoms (p = 0.004), and had smaller lesion size (p = 0.039) compared to the sporadic group. Fourteen patients (13.2 %) experienced immediate postoperative deterioration. During long-term follow-up, 35 patients (33.0 %) improved, 57 patients (53.8 %) remained stable. 8 patients (7.5 %) worsened compared to baseline, and 6 patients (5.7 %) died. A recurrent HBs (p = 0.027), ventral location (p = 0.046), and worsened immediately after surgery (p = 0.001) were statistically significant indicators for unfavorable outcomes in multivariate analysis.

Surgical resection of cervical spinal HBs can achieve favorable long-term outcomes in most cases, although neurological deterioration may occur immediately after surgery. Postoperative deficits occur in 13.2 % patients, and the incidence of respiratory insufficiency is relatively low. A recurrent HBs, ventral location, and worsened immediately after surgery were indicators for unfavorable outcomes.

To enhance the understanding of familial erythrocytosis type 2 (ECYT2) resulting from compound heterozygous mutations in the VHL gene. Methods: We conducted a retrospective analysis of the case data from a patient with ECYT2 to investigate its pathogenesis, clinical features, diagnosis and treatment options, as well as prognosis, while also reviewing the relevant literature. Results: A 31-year-old man was admitted to the hospital due to facial and hand flushing that had persisted for 29 years. Whole exome sequencing revealed compound heterozygous mutations in VHL p.P81L and p.N90T. Both of his parents were found to carry only one of these heterozygous mutations, yet they exhibited normal phenotypes. Based on the patient's hematological tests, a clear diagnosis of ECYT2 was established. Following treatment with erythrocytapheresis and daily administration of aspirin at a dosage of 100 mg, the patient experienced relief from dizziness and headaches associated with blood hyperviscosity, without any thrombotic or bleeding complications during this period. Conclusions: ECYT2 is a rare group of autosomal recessive genetic disorders. This case of ECYT2, resulting from compound heterozygous mutations in the VHL gene, represents the first report in China. Clinically, it is characterized by elevated red cell mass, normal or increased serum erythropoietin levels, and normal hemoglobin oxygen affinity levels. These factors contribute to thrombotic and bleeding complications that can lead to early mortality.

Proteasomes are the catalytic complexes in eukaryotic cells that decide the fate of proteins involved in various cellular processes in an energy-dependent manner. The proteasomal system performs its function by selectively destroying the proteins labelled with the small protein ubiquitin. Dysfunctional proteasomal activity is allegedly involved in various clinical disorders such as cancer, neurodegenerative disorders, ageing, and so forth, making it an important therapeutic target. Notably, compared to healthy cells, cancer cells have a higher protein homeostasis requirement and a faster protein turnover rate. The ubiquitin-proteasome system (UPS) helps cancer cells increase rapidly and experience less apoptotic cell death. Therefore, understanding UPS is essential to design and discover some effective inhibitors for cancer therapy. Hereby, we have focused on the role of the 26S proteasome complex, mainly the UPS, in carcinogenesis and seeking potential therapeutic targets in treating numerous cancers.

Hemangioblastoma is the most common tumor associated with von Hippel-Lindau (VHL), and are a leading cause of mortality. We present five pediatric patients with VHL-associated hemangioblastomas treated with belzutifan, a hypoxia-inducible factor 2a (HIF2a) inhibitor. Three patients were started on belzutifan due to vision loss from progressive retinal hemangioblastomas. Within one year of treatment, all three patients had improvement in hemangioblastoma size and visual acuity. For patients with intracranial lesions, belzutifan resulted in an improvement in neurologic symptoms and hemangioblastoma size. Four patients experienced grade 1-2 anemia and two patients required a dose reduction. Our report suggests that belzutifan can be an effective therapy for pediatric, adolescent, and young adult patients with VHL-associated hemangioblastomas.

Gastroenteropancreatic neuroendocrine tumors (NET) often metastasize to the liver. Although curative liver resection provides a favorable prognosis for patients with neuroendocrine liver metastasis (NELM), with a 5-year survival rate of 70-80%, recurrence is almost inevitable, mainly in the remnant liver. In Western countries, liver transplantation (LT) has been performed in patients with NELM, with the objective of complete removal of macro- and micro-NELMs. However, prognosis had been unsatisfactory, with 5-year overall survival and recurrence-free survival rates of approximately 50 and 30%, respectively. In 2007, the Milan criteria were proposed as indications for LT for NELM. The criteria included: (1) confirmed histology of NET-G1 or G2; (2) a primary tumor drained by the portal system and all extrahepatic diseases removed with curative resection before LT; (3) liver involvement ≤50%; (4) good response or stable disease for at least 6 months before LT; (5) age ≤ 55 years. A subsequent report demonstrated outstanding LT outcomes for NELM within the Milan criteria, with 5-year overall survival and recurrence rates of 97 and 13%, respectively. In Japan, living donor LT (LDLT) for NELM has been performed sporadically in only 16 patients by 2021 in Japan; however, no consensus has been reached on the indications or perioperative management of LDLT. This article presents the outcomes of these 16 patients who underwent LDLT in Japan and reviews the literature to clarify optimal indications and perioperative management of LDLT for NELM in the era of novel multimodal treatments.

A thorough study of Clear Cell Renal Cell Carcinoma (ccRCC) shows that combining tyrosine kinase inhibitors (TKI) with immune checkpoint inhibitors (ICI) shows promising results in addressing the tumor-promoting influences of abnormal immunological and molecular biomarkers in metastatic Clear Cell Renal Cell Carcinoma (ccRCC). These abnormal biomarkers enhance drug resistance, support tumor growth, and trigger cancer-related genes. Ongoing clinical trials are testing new treatment options that appear more effective than earlier ones. However, more research is needed to confirm their long-term safety use and potential side effects. This study highlights vital molecular and immunological biomarkers associated with drug resistance in Clear Cell Renal Cell Carcinoma (ccRCC). Furthermore, this study identifies a number of promising drug candidates and biomarkers that serve as significant contributors to the enhancement of the overall survival of ccRCC patients. Consequently, this article offers pertinent insights on both recently completed and ongoing clinical trials, recommending further toxicity study for the prolonged use of this treatment strategy for patients with metastatic ccRCC, while equipping researchers with invaluable information for the progression of current treatment strategies.

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common pancreatic malignancy. While most cases are sporadic, a small proportion is associated with genetic syndromes, such as Multiple Endocrine Neoplasia (MEN), Von Hippel-Lindau Syndrome (VHL), Neurofibromatosis Type 1 (NF1), and Tuberous Sclerosis Complex (TSC). This review aims to use pNENs as a clue to reveal the full spectrum of disease, providing a comprehensive understanding of diagnosis. It aids in promptly identifying abnormalities in other organs, recognizing familial genetic mutations, and achieving personalized treatment.

Von Hippel-Lindau disease (e.g. VHL) is an autosomal dominant multi-organ cancer syndrome caused by a mutation in the VHL tumour suppressor gene. In this study, we introduce a novel genetic variant found in 11 family members diagnosed initially with isolated Pheochromocytoma. Subsequent findings revealed its association with VHL syndrome and corresponds to the Type 2 C phenotype.

The VHL gene was amplified through the utilisation of the polymerase chain reaction (PCR). PCR fragments were sequenced using bidirectional Sanger sequencing, using BigDye™ Terminator v3.1 Cycle Sequencing Kit, running on the 3500 genetic analyser. Results were assembled and analysed Using Software SeqA and chromas pro.

A heterozygous in-frame duplication of three nucleotides, specifically ATG, c.377_379dup; p.Asp126dup in exon 2, was identified in all the patients tested within the pedigree.

In this study, we disclose the identification of a novel genetic variant in a Jordanian family, affecting eleven family members with pheochromocytoma associated with VHL disease. This finding underscores the importance of screening family members and contemplating genetic testing for individuals newly diagnosed with pheochromocytoma and could enhance our comprehension of the potential adverse consequences associated with VHL germline mutations.

Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WES and poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.

 Spinal cord hemangioblastomas are rare benign and highly vascular tumors that develop either sporadically or as part of von Hippel-Lindau (VHL) disease. Generally, complete resection without significant neurologic deficit remains considerably challenging due to the risk of massive bleeding. The current study therefore aimed to describe en bloc resection of spinal cord hemangioblastomas according to the typical anatomical structures of peripheral lesions and evaluate the neurofunctional prognosis of this technique.

 A total of 39 spinal cord hemangioblastomas from a series of 19 patients who underwent en bloc resection were retrospectively analyzed. In all cases, clinical and radiologic characteristics, as well as surgical tenets, were retrospectively determined and analyzed. Short- and long-term outcomes were analyzed using the McCormick grade and Odom's criteria. Factors significantly associated with poor neurologic function after en bloc resection were also determined.

 All 39 spinal cord hemangioblastomas, including 28 intramedullary, 2 intramedullary-extramedullary, and 9 extramedullary lesions, were located dorsally or dorsolaterally (100.0%). The most common lesion location was the thoracic segment (53.8%), with most of the lesions being accompanied by syringomyelia (94.7%). Long-term follow-up (mean: 103 ± 50.4 months) for prognosis determination revealed that 88.2% (15/17) of all cases had stable or improved neurofunctional outcomes according to the McCormick grade and Odom's criteria. Only one case with VHL disease developed recurrence 4 years after surgery. Additionally, statistical analysis showed that VHL disease was an independent prognostic factor associated with deteriorating neurologic function (p = 0.015).

 En bloc resection facilitated satisfactory long-term functional outcomes in patients with spinal cord hemangioblastomas. Given that VHL disease was identified as a predictor of poor long-term outcomes, regular long-term follow-up of patients with VHL-associated spinal cord hemangioblastoma seems necessary.

Spinal intramedullary hemangioblastoma is a rare and highly vascularized benign tumor. The characteristics of the tumor, its corresponding location, and surgical outcomes remain unknown. The purpose of this study was to identify risk factors and strategies for neurologic deterioration following hemangioblastoma surgery.

A comprehensive retrospective analysis was undertaken to evaluate patients who underwent surgical intervention for intramedullary hemangioblastoma at our institution from 1993 to 2022. Patients with at least 1 year of follow-up data were included. The analysis covered patient demographics, pre- and post-operative modified McCormick scale (MMCS), tumor location, and tumor size.

This study included 25 cases. One-year after surgery, neurological deterioration was observed in five cases (20.0%), and neurological improvement was found in nine cases (36.0%). Five cases were ventrally located, and twelve cases were dorsally located. Ventrally located cases were larger in tumor axial size (p=0.029) than dorsal location tumors, resulting in poorer follow-up MMCS and a higher prevalence of von Hippel-Lindau syndrome (VHL) (p=0.042). Three of them were confirmed to be supplied by the anterior spinal artery. In the case of dorsally located cases, there was no neurologic deterioration.

In intramedullary spinal cord hemangioblastomas, cases located ventrally had a higher incidence of neurological deterioration following surgery than those located dorsally or in intramedullary extramedullary cases. Ventrally located hemangioblastomas were larger than those in other locations. They were mainly supplied by the anterior spinal artery in VHL patients.

This scientific report aims to investigate the genotype-phenotype correlations of retinal hemangioblastoma (RH) in von Hippel-Lindau (VHL) disease. The study included 77 patients with genetically confirmed VHL disease who visited an ophthalmology clinic for the evaluation of RH. The presence, location, and size of RH were evaluated, Patients were categorized into three groups based on variants: HIF-1α binding site missense (HM), non-HIF-1α binding site missense (nHM), and truncating (TR) mutations. Fifty-six patients (72.7%) had RH in either eye, and 24 had bilateral RH. Sixteen patients (20.8%) had juxtapapillary RH in either eye. Nine patients had RH ≥ 2.0 disc diameters in size. VHL c.208G>A variant was the most frequent single mutation. Compared with patients having nHM mutations (15 patients) in VHL gene, patients with HM mutations (33 patients) or TR mutations (26 patients) presented a greater number of eyes affected (p = 0.007 and 0.004, respectively), a greater number of RH (p = 0.012 and 0.003, respectively), and more frequent presentation of large RH ≥ 2.0 disc diameters (p = 0.012, and 0.013, respectively). In conclusion, this study provides a deeper understanding of the genetic spectrum of VHL disease in Korean VHL disease and highlights the importance of the location of missense mutations regarding the risk of RH.

von Hippel-Lindau disease (VHL) is an autosomal dominant familial neoplasia syndrome. The most common manifestation of VHL is central nervous system hemangioblastomas. VHL patients will often develop multiple hemangioblastomas along their craniospinal axis over their lifetime. Spinal cord hemangioblastomas account for nearly half of all nervous system hemangioblastomas in VHL.

The authors conducted a literature review and summation of available articles on spinal cord hemangioblastomas associated with VHL.

The embryological origins, epidemiology, natural history, surgical outcomes, nonsurgical treatments, and future directions in spinal cord hemangioblastomas are discussed.

Hemangioblastomas in VHL are optimally managed with a multidisciplinary approach that includes surgical resection of symptomatic lesions. Novel treatments are gaining traction, but must be studied further for efficacy and safety.

To highlight the neurosurgical implications of the hypoxia-inducible factor-2α- targeting agent belzutifan in the management of both von-Hippel Lindau (VHL)-associated and sporadic hemangioblastomas (HBLs).

The literature was queried for VHL, HBLs, and belzutifan. A summary of recent uses of belzutifan and currently ongoing clinical trials that are investigating the use of belzutifan in the treatment of HBLs is presented.

VHL disease occurs as a result of germline mutations in the VHL tumor suppressor gene on chromosome 3p25-p26, leading to growth of benign and malignant tumors such as HBLs. The possibility of intermittent growth in HBLs indicates that it is important to avoid hasty surgical interventions. Belzutifan is the first nonsurgical food and drug administration-approved treatment for VHL disease-related tumors that may delay or circumvent the need for surgery or radiation therapy by inhibiting HIF-2α, an important component of cellular hypoxic response. There is limited real-world experience of belzutifan in patients with HBLs as a primary indication, though there are 2 phase II clinical trials investigating the use of belzutifan in the treatment of HBLs.

There is limited experience regarding the use of belzutifan for CNS hemangioblastoma. While its application has been limited to a small group of clinical cases, it has exhibited significant efficacy in reducing the size and consequences of HBLs. Based on the promising outcomes observed in individual patient experiences and ongoing clinical trials, we infer that further exploration and integration of belzutifan into neurosurgical treatment plans for both sporadic and VHL-associated HBLs are warranted.

Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.

Approximately 40% of pheochromocytoma and paraganglioma (PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical characteristics and perioperative care for PPGL. Pheochromocytoma in von Hippel-Lindau (VHL) disease exhibits heightened secretion activity without significant perioperative hemodynamic changes. Tumors in multiple endocrine neoplasia type 2 (MEN2) have a stronger endocrine function, which may induce hemodynamic fluctuations during surgery. Therefore, pheochromocytoma screening is essential at all stages of MEN2. Neurofibromatosis type 1 (NF1) often presents multisystem lesions and can result in difficult airway. Pheochromocytoma should be evaluated when NF1 patients present hypertension. Pheochromocytoma and paraganglioma type 5 may present multiple lesions of pheochromocytoma or paraganglioma. In summary, hereditary PPGLs may present with severe lesions in other systems, beyond tumor function. A multi-disciplinary team (MDT) approach is often invaluable in perioperative management.

This study investigates the intricate mechanisms underlying the correlation between elevated consumption of harmful fats and the onset of kidney malignancies. The rise in global obesity rates has been accompanied by an increased prevalence of renal cancers, prompting an exploration into the molecular pathways and biological processes linking these phenomena. Through an extensive review of current literature and clinical studies, we identify potential key factors contributing to the carcinogenic influence of harmful fats on renal tissues. Our analysis highlights the role of adipose tissue-derived factors, inflammatory mediators, and lipid metabolism dysregulation in fostering a microenvironment conducive to renal tumorigenesis. Furthermore, we delve into the impact of harmful fats on signaling pathways associated with cell proliferation, apoptosis evasion, and angiogenesis within the renal parenchyma. This review underscores the importance of elucidating the molecular intricacies linking lipid metabolism and kidney malignancies, offering a foundation for future research and the development of targeted preventive and therapeutic interventions. The findings discussed herein contribute to our understanding of the complex relationship between lipid mediators and renal cancer, providing a basis for public health strategies aimed at mitigating the impact of harmful fats on kidney health.

Renal cell carcinoma (RCC) is a heterogenous disease which the incidence is increasing worldwide. The identification and understanding of the role of the Von Hipple Lindau (VHP) in regulating the hypoxia-inducible factor signaling pathway has revolutionized the treatment of this disease. Belzutifan is an oral hypoxia-inducible factor (HIF)-2α inhibitor, which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease and for the treatment of adults with RCC who experienced disease progression after PD-1/PD-L1- and VEGFR-targeted therapies. One of the most common adverse effect of this drug is anemia; however, it is treatment is not well known. This review summarizes role of the VHL-HIF pathway in ccRCC aroused the interest of targeting HIF activity, the history of belzutifan development and their relationship to anemia as well as propose a management algorithm.

Von Hippel-Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general.