Journal of Kidney Cancer and VHL (JKCVHL)
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Partial Nephrectomy as Management of Oligometastatic Cancer with Limited Systemic Treatment Options: A Case Report
Full text linkOcular melanoma is a form of melanoma that rarely offers actionable mutations for treatment with systemic therapy and is relatively radioresis-tant. 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
Patient Perspective on Medical Conditions Post Immune Checkpoint Therapy in Advanced Renal Carcinoma
Full text linkImmune checkpoint therapy (ICI) has enabled induction of remission in advanced renal cell carcinoma RCC. ICI toxicities can persist as chronic health conditions. We developed a patient survey to assess changes in medical comorbidities after ICI. The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists, and patient advocates. The survey was broadcast between July 2022 and September 2022 to patients via website, mailing lists, and social media platforms. Patient perspective on changes to any medical conditions were evaluated in the survey questionnaire. Of 1062 patients that responded, 399 were self-identified as being metastatic and 289 reported to be treated with ICI. Eighty-five percent of respondents were from the United States. The most common conditions noted were thyroid dysfunction in 80 patients, hypertension in 50 patients, chronic kidney disease in 23 patients, heart disease in 10 patients, and diabetes mellitus (DM) in 13 patients. Immune disorders developed in 26 (9%) patients. The limitations are the survey had minimal participation from minority populations. Multiple medical conditions were noted to either emerge or worsen as a result of ICI-based therapies in RCC. Awareness of this information as a starting point should stimulate the development of survivorship programs for renal cancer. A survey of patients with advanced kidney cancer showed that some medical conditions such as thyroid dysfunction, hypertension, heart and kidney disease, DM, and immune conditions were newly diagnosed and/or persisted after immune therapy
Hypoxia Inducible Factor-2α (HIF-2α) Pathway Inhibitors
Full text linkHypoxia 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.
Long-term Safety and Efficacy of Belzutifan in Von Hippel–Lindau Syndrome: A VHL Coordinating Care Center Experience
Full text linkVon Hippel–Lindau (VHL) disease is a rare inherited syndrome characterized by benign and malignant neoplasms. Belzutifan, a HIF-2α inhib-itor, 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
Visfatin Promotes Renal Cell Carcinoma Progression: Evidence from Clinical Samples and Cell Line Models
Full text linkThe 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 perire-nal 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
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
Full text linkIpilimumab 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
Identification of BCL11A, NTN5, and OGN as Diagnosis Biomarker of Papillary Renal Cell Carcinomas by Bioinformatic Analysis
Full text linkThe prevalence of papillary renal cell carcinomas (PRCCs) is estimated to be between 10% and 15%. At present, there is no effective therapeutic approach available for patients with advanced PRCCs. The molecular biomarkers associated with PRCC diagnoses have been rarely studied compared to renal clear cell carcinomas; therefore, the necessity for the identification of novel molecular biomarkers to aid in the early identification of this disease. Bioinformatics and artificial intelligence technologies have become increasingly important in the search for diagnostic biomarkers for early cancer detection. In this study, three genes—BCL11A, NTN5, and OGN—were identified as diagnostic biomarkers using the Cancer Genome Atlas (TCGA) database and deep learning techniques. To identify the differential expression genes (DEGs), ribonucleic acid (RNA) expression profiles of PRCC patients were analyzed using a machine learning approach. A number of molecular pathways and coexpressions of DEGs have been analyzed and a correlation between DEGs and clinical data has been determined. Diagnostic markers were then determined via machine learning analysis. The 10 genes selected with the highest variable importance value (more than 0.9) were further investigated, with six upregulated (BCL11A, NTN5, SEL1L3, SKA3, TAPBP, SEMA6A) and four downregulated (OGN, ADCY4, SMOC2, CCL23). A combined receiver operating characteristic (ROC) curve analysis revealed that the BCL11A-NTN5-OGN genes, which have specificity and sensitivity values of 0.968 and 0.901, respectively, can be used as a diagnostic biomarker for PRCC. In general, the genes introduced in this study may be used as diagnostic biomarkers for the early diagnosis of PRCC, thus providing the possibility of early treatment and preventing the progression of the disease
Zinc as a Dual-Condition Inhibitor of HIF-1α/VEGF-α–Mediated Angiogenesis in Clear Cell Renal Carcinoma
Full text linkClear cell renal cell carcinoma (ccRCC) is marked by aberrant hypoxia-driven signaling and enhanced angiogenesis mediated by hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor alpha (VEGF-α). Zinc (Zn), an essential trace element with emerging anticancer potential, was evaluated for its ability to modulate angiogenesis in von Hippel–Lindau (VHL)-deficient 786-0 cells under normoxic and hypoxic conditions. Using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence, we observed that Zn treatment reduced HIF-1α expression and VEGF-α secretion across both oxygenation states. Notably, Zn inhibited the hypoxia-induced nuclear accumulation of HIF-1α and attenuated paracrine endothelial activation, as shown by reduced human umbilical vein endothelial cell (HUVEC) viability in conditioned media assays. These effects likely involve transcrip-tional repression, enhanced proteasomal degradation of HIF-1α, and interference with VEGF-α–dependent signaling. Overall, our findings suggest that zinc may function as a multifunctional modulator of tumor angiogenesis and holds potential as an adjuvant in antiangiogenic strategies, particularly under hypoxic conditions
Renal Cell Carcinoma Masquerading as Pyonephrosis — A Case Report of A Rare Presentation
Full text linkWe describe here an atypical case of pyonephrosis which on further evaluation turned out to be a renal cell carcinoma (RCC). The clinical presentation of the patient was that of an infective etiology. However, the renal mass associated with renal vein thrombus and lung metastasis was later diagnosed based on the clinical deterioration of the patient even after insertion of percutaneous nephrostomy. In this case, an underlying renal cancer was probably complicated secondarily leading to pyonephrosis which was the initial presenting manifestation which led to a delay in diagnosis. Pyonephrosis is usually associated with Xanthogranulomatous pyelonephritis. Association of RCC with pyonephrosis is extremely rare and hence seldom reported. Our patient later on underwent radical nephrectomy and the histopathology report was suggestive of RCC. We have described here the clinical manifestations and diagnostic issues of such a case. This case provides evidence that RCC should be kept as one of the differentials in such patients