Journal of Kidney Cancer and VHL最新文献

{"title":"Visfatin Promotes Renal Cell Carcinoma Progression: Evidence from Clinical Samples and Cell Line Models.","authors":"Eiji Kashiwagi, Miho Ushijima, Shohei Ueda, Yoshihiro Sugita, Yui Mizushima, Takuo Matsukawa, Rieko Kimuro, Kazumasa Jojima, Katsuyoshi Higashijima, Yujiro Nagata, Akinori Minato, Ikko Tomisaki, Masatoshi Eto","doi":"10.15586/jkc.v12i3.427","DOIUrl":"10.15586/jkc.v12i3.427","url":null,"abstract":"<p><p>The kidney is enveloped by perirenal fat, which secretes various hormones and cytokines, known as adipokines. Adipokines have been demonstrated to influence the development and progression of tumors, including renal cell carcinoma (RCC). Visfatin, an adipokine secreted by the adipose tissue, has been implicated in RCC, but its precise role remains unclear. In this study, we investigated the expression of visfatin in perirenal fat from patients with RCC and its correlation with the RCC malignant phenotype, and we examined the role of visfatin in RCC cell lines in vitro. This study included adipose tissue samples from 57 Japanese patients with clear cell RCC who underwent partial or radical nephrectomy. We examined the mRNA expression level of visfatin using real-time PCR. In vitro MTT assay and western blot were performed using human RCC cell lines. The mRNA expression of visfatin in peri-tumor versus peri-normal fat was higher in Fuhrman grade ≥2 cases compared with Fuhrman grade 1 cases. Furthermore, the addition of visfatin to RCC cell lines promoted cell proliferation, which was accompanied by increased protein expression of HIF1α, p-Akt, and p-ERK. Conversely, the addition of FK866, a visfatin inhibitor, suppressed cell proliferation and reduced these proteins. Our findings suggest that visfatin from peri-tumor adipose tissue influences the malignancy of RCC and plays a role in promoting the growth of RCC. This indicates a potential mechanism by which adipose tissue contributes to the progression of RCC, providing a possible target for therapeutic intervention.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"58-65"},"PeriodicalIF":1.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Follicle-Stimulating Hormone Receptor in Von Hippel-Lindau Associated Tumors and Cysts: An Immunohistochemical Study.","authors":"Nicolae Ghinea, Maximilian Frosch, Anne Couvelard, Sefer Elezkurtaj, Vinciane Rebours, Philippe Camparo, Bertrand Guillonneau, Christine Julia Gizaw, Jan-Helge Klingler","doi":"10.15586/jkc.v12i3.409","DOIUrl":"10.15586/jkc.v12i3.409","url":null,"abstract":"<p><p>Von Hippel-Lindau (VHL) disease is a hereditary condition caused by mutations in the <i>VHL</i>-tumor suppressor gene leading to constitutive overproduction of HIF-1alpha and HIF-2alpha, two proangiogenic factors, involved in the development of highly vascular tumors. Published evidence has shown that FSH-receptor is expressed in endothelial cells of blood vessels (BV) in several types of tumors. Given that VHL-associated tumors are highly vascular, it is plausible that FSH-receptor could be expressed in their vasculature as well. This immunohistochemical study involved 71 patients diagnosed with VHL-associated tumors, who required surgical intervention. Tissue specimens from these patients included CNS-hemangioblastoma, pancreatic neuroendocrine tumors (panNET), and clear cell renal cell carcinoma (ccRCC). Immunohistochemical staining was performed using a highly specific monoclonal antibody against the human FSH-receptor to assess its expression in the endothelial cells and tumor cells. The distribution of FSH-receptor staining was analyzed using digital imaging techniques. FSHR-protein expression was detected in the BV endothelial cells in 100% of VHL-associated CNS-hemangioblastoma, panNET, and ccRCC cases. In CNS-hemangioblastoma, 96% of cases showed FSH-receptor positivity in tumor stromal cells. In panNET, 88% of the cases displayed FSH-receptor expression in tumor cells. No tumor cells showed FSH-receptor expression in ccRCC. This is the first study to demonstrate FSH-receptor expression by cells of VHL-associated tumors, with distinct expression patterns in different tumor types.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"47-57"},"PeriodicalIF":1.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VHL Syndrome with Diabetes Mellitus, and Pulmonary and Thyroid Nodules: A Case Report.","authors":"Zhiyuan Peng, Chuan Hua, Wenze Liu, Mingrui Zhou, Xiulan Yu, Yong Zhao, Xinhe Zuo","doi":"10.15586/jkc.v12i3.412","DOIUrl":"10.15586/jkc.v12i3.412","url":null,"abstract":"<p><p>Von Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary tumor syndrome caused by mutations in the <i>VHL</i> gene. It is characterized by the occurrence of tumors in multiple organs. Pancreatic involvement in VHL syndrome can present as pancreatic cysts or neuroendocrine tumors, which may interfere with both pancreatic exocrine and endocrine pancreatic functions. To our knowledge, no patients with VHL syndrome complicated by diabetes mellitus, pulmonary nodules, and thyroid nodules are reported in the literature. This study aims to explore the pathogenesis of diabetes, pulmonary nodules, and thyroid nodules in VHL syndrome through the analysis of a patient with VHL syndrome and to review relevant literature.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"37-46"},"PeriodicalIF":1.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12451314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Partial Nephrectomy as Management of Oligometastatic Cancer with Limited Systemic Treatment Options: A Case Report.","authors":"Chibuzor Victor Nwachukwu, Christopher Michael Brede, Gerald Paul Wright, Brian Robert Lane","doi":"10.15586/jkc.v12i3.414","DOIUrl":"10.15586/jkc.v12i3.414","url":null,"abstract":"<p><p>Ocular melanoma is a form of melanoma that rarely offers actionable mutations for treatment with systemic therapy and is relatively radioresistant. As such, surgery is the mainstay of treatment for localized disease and can be considered for oligometastatic disease. We present a case of ocular melanoma that recurred with a solitary renal metastasis 9 years after initial diagnosis and treatment with intraocular brachytherapy. After multidisciplinary discussion, the patient underwent a partial nephrectomy for her solitary renal metastasis. The patient continued in follow-up 3.5 years after partial nephrectomy. She was treated again surgically for a solitary metastasis to the breast before initiation of systemic therapy once multifocal disease was identified. We suggest interdisciplinary management of patients with metastatic involvement of target organs, given the rapidly changing treatment landscape for melanoma and other forms of cancer.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"32-36"},"PeriodicalIF":1.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term Safety and Efficacy of Belzutifan in Von Hippel-Lindau Syndrome: A VHL Coordinating Care Center Experience.","authors":"Paulo Siqueira do Amaral, Ricardo Borges Fonseca, Breanne Reisen, Aaron Winer, Gabriel Berlingieri Polho, Robin Tumlinson, Morgan Lambrecht, Elizabeth Kaiser, Patrick David Kelly, Robert Ramirez, Daniel Barocas, Alan Tan, Kelvin Alexander Moses, Alexander Mohler, Brian Ignatius Rini, Kathryn Beckermann","doi":"10.15586/jkc.v12i3.425","DOIUrl":"10.15586/jkc.v12i3.425","url":null,"abstract":"<p><p>Von Hippel-Lindau (VHL) disease is a rare inherited syndrome characterized by benign and malignant neoplasms. Belzutifan, a HIF-2α inhibitor, was approved for the treatment of VHL-associated neoplasms. As a first-in-class agent, understanding tolerability and efficacy outside of a clinical trial setting and optimizing the management of adverse events (AEs) is important. We conducted a retrospective analysis of VHL patients ≥18 years old, treated with belzutifan at Vanderbilt University Medical Center, between November 2018 and December 2024. Clinical data and AEs were collected. Primary endpoint was safety; secondary endpoints included dose reduction, treatment interruption, treatment discontinuation, time to anemia onset, time to dose reduction, tumor shrinkage, objective response (per RECIST 1.1), and need for subsequent VHL-related procedures. Among 25 patients, with a median follow-up of 35.0 months, any-grade AEs occurred in 23 (92%) patients; anemia was the most frequent (64%, no grade ≥ 3). The median time to anemia onset was 3.7 months. Treatment interruption happened in 80% of the patients. The dose reduction was needed in 15 (60%) patients, with a median time of 6.8 months, and the median final dose was 80 mg. Tumor shrinkage occurred in 89% of RCC patients, 80% of CNS hemangioblastoma, and 80% of pancreatic neuroendocrine tumors (pNET). Overall, four (20%) patients experienced the progression of the disease. During follow-up, three (12%) patients required new VHL-related procedures. These findings support the long-term safety and efficacy of belzutifan in VHL disease, underscore the utility of dose reduction for AE management while demonstrating durable disease control, and a low incidence of interventional procedures.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"25-31"},"PeriodicalIF":1.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Narrative Review of Von Hippel-Lindau Syndrome: From Discovery to Modern Medical and Surgical Therapies.","authors":"Danilo Coco, Silvana Leanza","doi":"10.15586/jkc.v12i3.396","DOIUrl":"10.15586/jkc.v12i3.396","url":null,"abstract":"<p><p>The von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene, leading to the development of benign and malignant tumors in multiple organs, including the kidneys, brain, spine, retina, and pancreas. Since its initial description in the early 20th century, significant progress has been made in understanding its pathogenesis, genetic basis, and clinical management. This narrative review provides a comprehensive overview of VHL syndrome, from its discovery to the latest medical and surgical therapies. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating the Egger test to assess publication bias. The review highlights the evolution of diagnostic criteria, the role of genetic testing, and the development of targeted therapies such as hypoxia-inducible factor 2-alpha (HIF-2α) inhibitors. Surgical interventions, including nephron-sparing surgery and minimally invasive techniques, are also discussed. This review emphasizes the importance of a multidisciplinary approach to managing VHL syndrome and explores emerging therapies that hold promise for improving patient outcomes.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"16-24"},"PeriodicalIF":1.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia Inducible Factor-2α (HIF-2α) Pathway Inhibitors.","authors":"Ratika Dogra, Ulka Vaishampayan","doi":"10.15586/jkc.v12i3.413","DOIUrl":"10.15586/jkc.v12i3.413","url":null,"abstract":"<p><p>Hypoxia creates a stressful environment for the cells triggering adaptive changes in the transcription factors called hypoxia inducible factors (HIF), which help to meet the metabolic and angiogenic requirements of cells. HIF-2 is one such factor that is implicated in the progression of various cancers, especially the ones associated with Von Hippel-Lindau (VHL) disease. HIF-2 factor has an unstable component alpha and a stable component beta. HIF-2α detects hypoxia and dimerizes with HIF-beta (Aryl hydrocarbon receptor nuclear translocator [ARNT]) through per-ARNT-sim (PAS)-mediated signaling domains. These domain sites are recognized as targets for HIF-2 inhibitors. HIF-2 inhibitors block this heterodimerization and prevent the expression of target genes which are oncogenic, including <i>VEGF, PDGF, CAIX</i>, and <i>Oct4</i>. VHL disease caused by the deficiency of <i>VHL</i> gene product results in decreased degradation of HIF-2α, leading to increased activation of these transcription factors. Tumors driven by the deficiency of <i>VHL</i> gene product are natural candidates for HIF-2 inhibitor therapy. These inhibitors have emerged as a promising class of targeted therapies for renal cell carcinoma (RCC), particularly in cases resistant to conventional treatments. In this review, we explore the role of hypoxia and HIF transcription factors in tumor formation and progression, highlighting the role and development of HIF-2 pathway inhibitors as potential cancer therapies. We discuss the major key inhibitors, with focus on belzutifan and review the various trials investigating its efficacy in monotherapy as well as in combination therapies in RCC. Additionally, we explore its development in pheochromocytoma, hemangioblastoma, and pancreatic neuroendocrine tumors. We also highlight emerging HIF-2α inhibitors currently in clinical trials, namely casdatifan, NKT-2152, and DFF332. Finally, we address the major toxicities and management of these inhibitors.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 3","pages":"1-15"},"PeriodicalIF":1.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Data as Real Evidence Showing Real-World Outcomes.","authors":"Ulka Vaishampayan","doi":"10.15586/jkc.v12i2.404","DOIUrl":"10.15586/jkc.v12i2.404","url":null,"abstract":"","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 2","pages":"46-47"},"PeriodicalIF":1.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cabozantinib-Exposed Renal Cell Carcinoma Organoids Suggest Transcriptomic Associations with Treatment Resistance in Clear Cell and Nonclear Cell Tumors.","authors":"Wesley H Chou, Nicholas H Chakiryan, George V Thomas","doi":"10.15586/jkc.v12i2.386","DOIUrl":"10.15586/jkc.v12i2.386","url":null,"abstract":"<p><p>While vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a mainstay of treatment for advanced renal cell carcinoma (RCC), mechanisms of resistance to VEGF-TKIs remain under ongoing investigation. To assess transcriptomic changes in clear-cell RCC (ccRCC) and non-ccRCC exposed to a VEGF-TKI, we analyzed differential single-cell gene expression in RCC tumor-organoids exposed to cabozantinib versus control solvent. In ccRCC organoid cells, <i>LRRC75A</i> was notably highly associated with cabozantinib exposure (log2 fold-change 2.18, detected proportion 0.52 vs. 0.23, false-detection rate adjusted p<0.001). Importantly, our findings were independently validated in a recent study of advanced ccRCC patients treated with cabozantinib, which demonstrated that higher <i>LRRC75A</i> expression was significantly associated with decreased tumor response and less robust reduction of VEGF expression. <i>LRRC75A</i> has been shown to mediate VEGF secretion in a separate study and may potentiate compensatory angiogenesis after cabozantinib exposure. Gene expression scores were then developed based on transcriptomic changes associated with cabozantinib exposure and applied to stage IV patients in several independent cohorts. Higher scores were significant predictors of worse overall survival in TCGA non-RCC patients and worse progression-free survival in JAVELIN Renal 101 ccRCC patients. Overall, this experiment represents an incremental step in a larger effort to elucidate resistance mechanisms to VEGF-TKIs.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 2","pages":"37-45"},"PeriodicalIF":1.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-Line Ipilimumab with Nivolumab versus Immune Checkpoint Inhibitors with Tyrosine Kinase Inhibitors in Patients with Intermediate- or Poor-Risk Metastatic Clear Cell Renal Cell Carcinoma.","authors":"Micah Ostrowski, Yeonjung Jo, Georges Gebrael, Chadi Hage Chehade, Zeynep Irem Ozay, Blake Nordblad, Ayana Srivastava, Diya Garg, Richard Ji, Gliceida Galarza Fortuna, Vinay Mathew Thomas, Beverly Chigarira, Ethan Anderson, Neeraj Agarwal, Benjamin L Maughan, Umang Swami","doi":"10.15586/jkc.v12i2.387","DOIUrl":"https://doi.org/10.15586/jkc.v12i2.387","url":null,"abstract":"<p><p>Ipilimumab with nivolumab (Ipi + Nivo) and immune checkpoint inhibitors with tyrosine kinase inhibitors (ICI + TKI) are the first-line approved treatments for intermediate- and poor-risk metastatic clear cell renal cell carcinoma (mccRCC); however, they have not been compared head-to-head in prospective trials to guide treatment selection. Thereupon, we sought to compare survival outcomes of patients receiving first-line Ipi + Nivo versus ICI + TKI, using a large, real-world database among patients with intermediate- and poor-risk mccRCC. This retrospective cohort study used a nationwide electronic health record-derived deidentified database, where patients with mccRCC with intermediate- or poor-risk who received first-line Ipi + Nivo or ICI + TKI between 20 June, 2016, and 26 January, 2023, were included. Primary outcomes were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS), summarized via Kaplan-Meier survival estimates with 95% confidence intervals (CIs) and compared in the context of propensity score (PS) matching weighted analysis. Of the 12,707 patients in the dataset, 1,438 with mccRCC met eligibility and were included. After PS matching weighted analysis, no significant difference in rwOS was noted between both groups (HR 1.01, 95% CI 0.86-1.19; p = 0.91); however, rwTTNT was significantly shorter with Ipi + Nivo than with ICI + TKI (HR 0.78, 95% CI 0.68-0.89; p < 0.001). In this large real-world study, there was evidence that rwOS was comparable, while rwTTNT was superior in patients receiving ICI + TKI compared to those receiving Ipi + Nivo. These real-world data offer important guidance for clinicians in choosing between Ipi + Nivo and ICI + TKI as frontline treatment.</p>","PeriodicalId":44291,"journal":{"name":"Journal of Kidney Cancer and VHL","volume":"12 2","pages":"27-36"},"PeriodicalIF":1.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}