Journal of Kidney Cancer and VHL最新文献

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary tumor syndrome caused by mutations in the VHL 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.

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.

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.

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.

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 VEGF, PDGF, CAIX, and Oct4. VHL disease caused by the deficiency of VHL gene product results in decreased degradation of HIF-2α, leading to increased activation of these transcription factors. Tumors driven by the deficiency of VHL 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.

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, LRRC75A 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 LRRC75A expression was significantly associated with decreased tumor response and less robust reduction of VEGF expression. LRRC75A 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.

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.

To assess the surgical outcomes and techniques in managing renal cell carcinoma (RCC) with inferior vena cava (IVC) thrombus and bilateral renal tumors with a focus on the role of autotransplantation in complex cases, this retrospective study analyzed 58 patients treated at our center between 2013 and 2023 for RCC with tumor thrombus extending into the IVC and, in some cases, the right atrium (RA). Surgical management included radical nephrectomy and thrombectomy with techniques adapted to thrombus level. For level I and II thrombi, innovative occluding maneuvers were used to control the contralateral renal vein. For level IV thrombi, a beating heart technique combined with cardiopulmonary bypass (CPB) was employed. Of the 10 patients with bilateral renal tumors, 2 underwent autotransplantation and 8 underwent bilateral partial nephrectomy. In this 10-year retrospective study of 58 patients with either RCC with venous tumor extension or bilateral RCC, 40 males and 18 females, with a mean age of 66 ± 8 years. Tumor involvement was predominantly right-sided (72.4%). Thrombus levels included 53.44% Level I, 25.9% Level II, and 3.4% Level IV. Intraoperative and postoperative complications were minimal, affecting 10 patients; patients with Level I thrombus had a better survival rate; and one patient with Level IV thrombus died postoperatively. The mean blood loss was 360 mL and the mean operative time was 195 minutes. Histopathology revealed clear cell carcinoma in 65.5% of cases. Among the 10 patients with bilateral renal tumors, autotransplantation and partial nephrectomies resulted in excellent renal preservation and favorable outcomes. This study demonstrates the effectiveness of radical nephrectomy and thrombectomy for RCC with venous tumor extension. Tailored surgical techniques, including autotransplantation for bilateral tumors, resulted in excellent outcomes with minimal complications. Personalized surgical strategies were key to preserving renal function and improving survival in complex RCC cases.

This article is a case report of a 62-year-old male with a left-sided renal cell carcinoma (RCC) with a level II inferior vena cava (IVC) thrombus and caval occlusion. He was managed with open left radical nephrectomy and juxtarenal cavectomy. To preserve right renal venous drainage, the right renal vein was anastomosed to the right gonadal vein. He has not had any renal functional decline or disease recurrence with 3 years of follow-up. The focus of this article is to discuss this distinctive method for vascular reconstruction as an option for right renal venous drainage following left nephrectomy and juxtarenal cavectomy.