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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.

Background and Objective: This review aims to provide an overview of novel diagnostic and therapeutic radiopharmaceuticals tested recently or used currently in genitourinary cancers within prospective phase 1-2 clinical trials, summarizing progresses and future directions., Methods: A systematic search was conducted using the PubMed/MEDLINE and ClinicalTrials.gov databases for original prospective research studies following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines., Key Findings and Limitations: Forty-six papers were systematically reviewed; 74 ongoing clinical trials were identified. The results of 27 novel radiopharmaceuticals (ie, not approved by the Food and Drug Administration/European Medicines Agency and not listed in the Pharmacopeia) prospectively investigated in genitourinary cancers, mostly prostate, for diagnostic, theranostic, or therapeutic purposes (21, one, and five of the 27 radiopharmaceuticals, respectively) over the past 5 yr were presented. Most were prostate-specific membrane antigen-targeting agents (17/27); other targets included gastrin-releasing peptide receptor, carbonic anhydrase IX, Cu, six transmembrane epithelial antigen of the prostate 1, tumor-associated glycoprotein 42, and urokinase-type plasminogen activator receptor. Ongoing research confirms the same trend. Fibroblast activation protein inhibitor, PD-L1, CD8, nectin-4, and HER2 are other targets under investigation. Among the 22 ongoing therapeutic trials (out of the 74 ongoing clinical trials), targeted alpha therapy is being explored in 12, and five are evaluating combinations of radioligand therapy with other treatments. We confirmed the safety of radiopharmaceuticals (regardless of the diagnostic/therapeutic purpose) and showed promising results in terms of diagnostic accuracy and therapeutic efficacy in genitourinary cancers., Conclusions and Clinical Implications: There continues to be expansion in radiopharmaceutical approaches to genitourinary cancers, reflecting a strong emphasis on improving tumor detection and treatment, which will likely impact future management across the disease spectrum, with the potential for improved patient care and outcomes., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with the silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis, in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi). NAPRT silencing was also associated with synergistic tumor cell killing with PARP inhibitors and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite-associated hypermethylation can impact diverse cellular processes and lead to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARP inhibitors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89 Zr-labelled monoclonal antibody ([ 89 Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [ 89 Zr]Zr-girentuximab PET-CT imaging for detection and characterisation of clear-cell renal cell carcinoma., Methods: ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [ 89 Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET-CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [ 89 Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [ 89 Zr]Zr-girentuximab PET-CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET-CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment., Findings: Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [ 89 Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5-89·6) and mean specificity was 87·0% (81·0-93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [ 89 Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths., Interpretation: Our results suggest that [ 89 Zr]Zr-girentuximab PET-CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing., Funding: Telix Pharmaceuticals., Competing Interests: Declaration of interests BS has served as a consultant for Telix Pharmaceuticals, Veracyte, Merck, and Johnson & Johnson; has served as a speaker for Merck; and received travel support from Histosonics. AJP has received institutional funding and medical writing support from Telix Pharmaceuticals for this trial. J-CB has served as a consultant or advisor, and received honoraria and research funding from Bristol Myers Squibb, Conmed, Ipsen Pharmaceuticals, Merck Sharp and Dohme, Pfizer, and Intuitive Surgical. MAM has received institutional funding from Telix Pharmaceuticals; served as a board member for Oranomed, RayzeBio, Fusion, Advanced Molecular Imaging and Therapy, American College of Nuclear Medicine, and Society for Nuclear Medicine and Molecular Imaging; and holds stock or stock options from Advanced Molecular Imaging and Therapy, Gentem Health, and SoftThread. VM has received honoraria from Ethicon and Exelixis. AMS has received institutional research funding from Telix Pharmaceuticals, National Health and Medical Research Council, National Imaging Facility, National Breast Cancer Foundation, Medical Research Future Fund, Australian Cancer Research Foundation, and Victorian Cancer Agency; holds intellectual property licensing with Humanigen, AbbVie, and Life Science Pharmaceuticals; served as an advisory board member and consultant for ImmunOs and Imagion Bio; served as a board member, committee member, or chair for Fusion, Telix Pharmaceuticals, Australian and New Zealand Society of Nuclear Medicine, Australian and New Zealand Urogenital and Prostate Cancer trials group, Cooperative Trials Group for Neuro-Oncology, National Imaging Facility Molecular Imaging Theme, Australian Academy of Health and Medical Sciences, Melbourne Academic Centre for Health Molecular Imaging Theme, World Federation of Nuclear Medicine and Biology, Victorian Comprehensive Cancer Centre, Australian Nuclear Science and Technology Organisation External Advisory Board, and International Centers for Precision Oncology Foundation. CvP has served as consultant or advisor for Astellas and Merck; received honoraria from Astellas; and received travel funding from Ipsen. CBa has served as a data safety monitoring board or advisory board member for Telix Pharmaceuticals. BO has received research funding from Telix Pharmaceuticals. TA has received honoraria and research funding from Telix Pharmaceuticals. RM has received research funding from Telix Pharmaceuticals. DMS has received institutional research funding from Telix Pharmaceuticals; served as a consultant for Global Medical Solutions Taiwan, Progenics Pharmaceuticals, Heidelberg University, and DuChemBio; received payments or honoraria from the School of Breast Oncology, PrecisCa, and US Department of Justice; and served as an associate chair of Society for Nuclear Medicine and Molecular Imaging Scientific Program Committee. STL has received research funding from Telix Pharmaceuticals. NP-T has received honoraria from Actinium Pharmaceuticals; served as a consultant and advisor for Illumina, Imaginab, Actinium, and Progenics/Lantheus; a speaker for Actinium Pharmaceuticals and Telix Pharmaceuticals; and received institutional research funding from Actinium Pharmaceuticals, Imaginab, Regeneron Pharmaceuticals, Bristol Myers Squibb, Janssen, Clarity, Bayer Health, Telix Pharmaceuticals, and Ymabs. ACF is a board member of Molecular Decisions; a consultant or advisor for Verily; has received research funding from Earli, Filtricine, MagARRAY, and Calithera; and holds founders stock at Molecular Decisions, ACF's spouse is an employee or owner of Silverado Hospice and Antelope Valley Hospice. PA is an employee of Premier Research, and a consultant for Premier Research. KS is an employee of ABX-CRO advanced pharmaceutical services Forschungsgesellschaft. LT is an employee of Telix Pharmaceuticals and holds stock from Novartis. MW is an employee and holds patents and stock from Telix Pharmaceuticals. CBe is an employee of Telix Pharmaceuticals. CRWH was an employee of Telix Pharmaceuticals at the time of the trial. PM has received research funding from Telix Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To meet the increasing demands of genetic risk assessment for genitourinary cancers due to expanded clinical guidelines, we established an academic/industry partnership to create a streamlined workflow to overcome the barriers to access to care., Materials and Methods: Genome Medical offers multilingual genetic counseling. A pilot program evaluated patients at risk for hereditary genitourinary syndromes. Between January 1, 2020 and January 07, 2022, all patients in need of germline testing were offered hybrid in-clinic telehealth pre-test counseling and when indicated, genetic testing. Post-test counseling was offered based on results and encouraged if positive. Testing results, patient satisfaction, and costs were evaluated., Results: A total of 146 of 182 (80.0%) patients agreed to participate, with 130 (89.0%) completing pre-test counseling. Median age was 65 (range 22-95), with 91% being male and approximately 60% having prostate cancer. The median time from referral to pre-test counseling was 11 days (IQR 7-20). After assessment, testing was recommended for 127 (97.7%) of which 123 (96.8%) completed testing. The median time from testing to result release was 15 days (IQR 10-20.8). Forty (32.5%) had post-test counseling. Reimbursement by private insurers increased annually from $17.2 to $52.4. Patient satisfaction was high with a mean Genetic Counselor Satisfaction Scale of 27.9 out of 30., Conclusion: Our program provided high patient satisfaction, rapid access to genetic counseling, prompt genetic testing, timely release of results, and was cost-effective compared to traditional models. This approach is scalable across community and academic settings and across cancer types., Competing Interests: Declaration of Competing Interest Josu Yurasits, Joanna Mercado, and Megan Meyes are employees of Genome Medical and assisted with designing a workflow to integrate with their system. They reviewed the final manuscript and provided input on factual content. The remaining authors declare they have no relevant conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only., Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or T any N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual., Findings: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related., Interpretation: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma., Funding: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb., Competing Interests: Declaration of interests VM reports support for attending meetings or travel from American College of Surgeons; and participation on the Advisory Board on Diversity, Equity, and Inclusion at Exelixis. VM also reports a leadership role (unpaid) on Society of Urologic Oncology Clinical Trials Consortia. DFM received payment or honoraria from Bristol Myers Squibb, Pfizer, Merck, Eisai, Xilio, Aveo, Genentech, Cullinan, and Exelixis; and support for attending meetings or travel from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. LCH reports ownership of stock in Coherus and previous employment at Surface Oncology. SS reports grants or contracts from Bristol Myers Squibb and Exelixis to their institution; and royalties or licenses from Biogenex. SS also reports consulting fees from AstraZeneca, Merck, and CRISPR Therapeutics; and a leadership or fiduciary role at American Association for Cancer Research as Senior Editor at Clinical Cancer Research and at the NCI National Cancer Institute as Renal Task Force Co-Chair. HE reports consulting fees for Janssen and Aveo advisory boards. NA reports grants or contracts from Exelixis, Genentech, Merck, and Bristol Myers Squibb; and consulting fees from Exelixis, Bristol Myers Squibb, Aveo, Merck, EMD Serono, and Sanofi. MAB reports institutional grants from Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer; and payment or honoraria for Advisory Board participation from Exelixis, Bayer, Bristol Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi. TMM reports payment to their institution for clinical trials from Merck, Curium, and ECOG; consulting fees from Impact Network and Aptitude Health; and honoraria from Exelixis and Blue Earth Diagnostics. TC reports support from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports institutional research funding related to clinical trials from AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda. TC also reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports payment or honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports support for attending meetings or travel in relation to meetings, lectures, and advisory boards; and participates in the Aravive Data and Safety Monitoring Board or advisory board. TC also reports a patent related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of current date). TC also reports a leadership or fiduciary role in KidneyCan (unpaid) and committees for American Society of Clinical Oncology, European Society of Medical Oncology, National Comprehensive Cancer Network, and Genitourinary Steering Committee of the NCI. TC also reports stock ownership (for being an advisor) of Pionyr, Tempest, Precede Bio, Osel, Curesponse, Immdura, and Primium. TC also reports no receipt of equipment, materials, drugs, medical writing, gifts, or other services, except for travel and accommodation (flights, hotel, and meals) related to advisory or consulting when travel needed. TC also reports to be supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE(2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at Dana Farber Cancer Institute. MDD reports participation on the Scientific Advisory Boards (honoraria received) at Merck, Eisai, Exelixis, and Janssen. DYH reports compensation from consulting work from Bristol Myers Squibb, Merck, Ipsen, Exelixis, Pfizer, and Eisai. BS reports consulting fees from Merck, Veracyte, Telix, and Johnson and Johnson; payment or honoraria from Merck; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Telix. BCL reports a leadership or fiduciary role at Kidney Cancer Association as Chair of Board of Directors. JM reports participation on the NCI Central Institutional Review Board and has been recused from all discussions of this study. RU reports participation and financial support on a Data Safety Monitoring Board at Pfizer and other financial support on a steering committee at Merck. RU also reports a leadership or fiduciary role (non-financial support) at Haymarket Media as a board member. GB reports a leadership role during the study as President of the Society of Urologic Oncology–Clinical Trial Consortium. NBH reports participation in the Data and Safety Monitoring Committee atezolizumab at Roche Genentech and advisory boards at Bristol Myers Squibb and Eisai. NBH also reports a non-financial leadership role as ECOG ACRIN Genitourinary Committee Co-Chair. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: To evaluate the effectiveness of cryoablation compared to partial nephrectomy in patients with stage IA papillary and chromophobe renal cell carcinoma (pRCC; chRCC)., Material and Methods: The 2004-2016 National Cancer Database was queried for adult patients with stage IA pRCC or chRCC treated with cryoablation or partial nephrectomy. Patients receiving systemic therapy or radiotherapy, as well as those with bilateral RCC or prior malignant disease were excluded. Overall survival (OS) was assessed using Kaplan-Meier plots and Cox proportional hazard regression models. Nearest neighbor propensity matching (1:1 cryoablation:partial nephrectomy, stratified for pRCC and chRCC) was used to account for potential confounders., Results: A total of 11122 stage IA renal cell carcinoma patients were included (pRCC 8030; chRCC 3092). Cryoablation was performed in 607 (5.5%) patients, and partial nephrectomy in 10515 (94.5%) patients. A higher likelihood of cryoablation treatment was observed in older patients with non-private healthcare insurance, as well as in those with smaller diameter low-grade pRCC treated at non-academic centers in specific US geographic regions. After propensity score matching to account for confounders, there was no statistically significant difference in OS comparing cryoablation vs partial nephrectomy in patients with pRCC (HR = 1.3, 95% CI: 0.96-1.75, p = 0.09) and those with chRCC (HR = 1.38, 95% CI: 0.67-2.82, p = 0.38)., Conclusion: After accounting for confounders, cryoablation, and partial nephrectomy demonstrated comparable OS in patients with stage IA papillary and chromophobe RCC. Cryoablation is a reasonable treatment alternative to partial nephrectomy for these histological RCC subtypes when radiologically suspected or diagnosed after biopsy., Critical Relevance Statement: Cryoablation might be considered as an upfront treatment alternative to partial nephrectomy in patients with papillary and chromophobe stage IA renal cell carcinoma, as both treatment approaches yield comparable oncological outcomes., Key Points: The utilization of cryoablation for stage IA papillary and chromophobe RCC increases. In the National Cancer Database, we found specific patterns of use of cryoablation. Cryoablation and partial nephrectomy demonstrate comparable outcomes after accounting for confounders., (© 2024. The Author(s).)

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established., Materials and Methods: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors., Results: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%., Conclusion: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Approximately 65% of renal cell carcinomas (RCC) are diagnosed at a localized stage. We investigated the chromosome 5q gain impact on disease-free survival (DFS) in RCC patients. Overall, 676 patients with stages 1-2 RCC and having cytogenetic analysis were included. Gain of 5q was observed in 108 patients, more frequently in clear cell (ccRCC) than non-clear cell tumors. Gain of 5q is likely an independent prognostic factor since the concerned patients had a decreased recurrence risk in stages 1-2 RCC, confirmed in multivariable analysis. Detecting 5q gain could enhance recurrence risk assessment, allowing tailored post-surgery surveillance, and reducing unnecessary treatments.

Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors., Significance: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 American Association for Cancer Research.)