Combination of PARPi and NAMPTi lead to unresolved double stranded breaks NAPRT silenced models.

The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence‐based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus‐building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3–pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum‐based chemotherapy postprogression in biomarker‐negative UTC. For RCC, there was consensus on the role of single‐agent vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence‐informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.

PURPOSE:To determine the technical success, long-term overall survival (OS), cancer-specific survival (CSS), and local tumor progression-free survival (LTPFS) of patients who underwent percutaneous microwave ablation (MWA) of renal cell carcinoma (RCC). MATERIALS AND METHODS:This institutional review board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study cohort included patients who underwent CT and contrast-enhanced ultrasound (US) guided percutaneous MWA between 2013 and 2017 of biopsy-proven RCC. Patient demographics, tumor characteristics, and technical outcomes were compiled, and the OS, CSS, and LTPFS were derived with Kaplan-Meier analysis and log-rank test to evaluate differences. Complications were classified per the Clavien-Dindo system. Logistic regression was used for categorical outcomes, the χ2 test was used for categorical outcomes excluding repeated measures at the patient level, and the paired t test was used for evaluating differences in preablative and postablative estimated glomerular filtration rate. RESULTS:The study cohort comprised 86 biopsy-proven RCCs from 81 patients (mean age, 67.6 years [SD ± 16.9]), with a median follow-up of 76.8 months. Overall, primary, and secondary technical success were 100% (86/86), 98% (84/86), and 100% (10/10), respectively. The 10-year OS, CSS, and LTPFS rates were 76%, 85%, and 83%, respectively. The T1b subcohort 8-year LTPFS rate was lower than the T1a subcohort (P = .003). The preablative and 2- to 3-year postablative estimated glomerular filtration rate (58.5 vs 58.4 mL/min/1.73 m2) were stable (P = .932). There was a 2% overall incidence of complications, all Grade I. CONCLUSIONS:Percutaneous image-guided MWA of T1 RCC was associated with excellent long-term OS, CSS, and LTPFS, supporting MWA as an effective treatment option.

Combination of FK866 and olaparib leads to sustained cell cycle arrest in G2.

Detailed pathology and FH mutation information for HLRCC patients' samples.

Combination of PARPi and NAMPTi lead to unresolved double stranded breaks NAPRT silenced models.

Immunotherapy has been a pillar of the renal cell carcinoma (RCC) treatment landscape for over three decades. Some of the earliest cancer immunotherapies available, such as interleukin 2 and interferon-alpha, have resulted in complete responses, but only in a small number of patients. Immune checkpoint inhibitors (ICIs), however, have demonstrated improved response rates and prolonged survival for a greater number of patients, fully transforming the standard of care in first-line and subsequent-line settings. More recently, ICIs are also being used in the adjuvant setting for high-risk patients. However, treatment with ICIs requires a nuanced understanding of topics such as patient selection, histology and risk considerations, and integration with local therapies. As such, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline (CPG) on immunotherapy for the treatment of RCC. Drawing from published data and clinical experience, the Expert Panel developed evidence-based and consensus-based recommendations. Topics include therapy selection in the adjuvant and metastatic settings, considerations for special patient populations, response monitoring, and patient education and quality of life considerations, among others, with the goal of improving patient care by providing guidance to the oncology community.

Carbonic anhydrase IX (CAIX) is a cell surface protein expressed in over 90% of clear cell renal cell carcinoma (ccRCC), driven by hypoxia or Von-Hippel Lindau (VHL) loss. The phase 3 ZIRCON trial evaluated [89Zr]girentuximab, a CAIX-targeted positron emission tomography (PET) radiotracer, and met its primary endpoint for the accurate detection of ccRCC in patients with renal masses. Many aggressive forms of non-ccRCC (nccRCC) can express CAIX, which is linked to a hypoxic state. A reanalysis of the trial was performed demonstrating the tracer also identified nccRCC, particularly in forms of papillary RCC (pRCC) with higher CAIX expression (H score) and PET avidity (SUVmax). The positive predictive value for any renal malignancy was 98%, with sensitivity/specificity of 82% and 87%, respectively. This suggests [89Zr]girentuximab has applications beyond the detection of ccRCC in primary renal masses and may have implications to management of nccRCC. Patient summary The ZIRCON phase 3 trial used an imaging agent ([89Zr]girentuximab) with a primary focus to detect the most common kidney cancer, clear cell renal cell carcinoma. Other forms of kidney cancer can express the marker that the imaging agent can identify. The additional analysis showed that when positive, 98% of cases were correctly identified as any form of cancer.

Background 17-alpha hydroxylase deficiency is a rare autosomal recessive disorder characterized by impaired cortisol and sex steroid synthesis due to a deficiency in the 17-alpha hydroxylase enzyme. This enzymatic defect, when accompanied by bilateral adrenal hyperplasia, presents a rare and complex clinical scenario. Case Presentation: We describe a 45-year-old woman with congenital adrenal hyperplasia due to 17-alpha hydroxylase deficiency who developed massive bilateral adrenal enlargement. Despite lifelong glucocorticoid therapy, chronic nonadherence led to persistently elevated adrenocorticotropic hormone levels and progressive abdominal distention, early satiety, and dyspnea. Imaging demonstrated giant, fat-containing adrenal masses: the left measuring 27.6 × 21.8 × 7.9 cm (2,510 g) and the right measuring 19.5 × 11.5 × 6.3 cm (718 g), displacing abdominal organs and kidneys. A trial of optimized medical therapy failed to reduce gland size. Given worsening symptoms and mass effect, she underwent open bilateral adrenalectomy, umbilical hernia repair, and nephropexy. Histopathology confirmed bilateral myelolipomas with cortical hyperplasia and no evidence of malignancy. She recovered well postoperatively and was transitioned to physiologic steroid replacement. Conclusion This case presents a rare but clinically significant complication of 17-alpha hydroxylase deficiency: massive bilateral adrenal myelolipomas driven by chronic adrenocorticotropic hormone excess. While myelolipomas are typically benign and nonfunctional, progressive enlargement can produce disabling mass effect requiring surgical intervention. Bilateral adrenalectomy is effective for symptom control but carries lifelong risks, underscoring the importance of medical adherence, multidisciplinary evaluation, and individualized risk–benefit assessment when surgery becomes necessary.

Compared with cancers of other organs, precursor lesions of renal cell neoplasms are rarely discussed. However, there are specific scenarios where cysts or microscopic solid lesions are thought to precede tumor formation. In 2024, the International Society of Urological Pathology (ISUP) held a consensus meeting on precursor lesions of urologic neoplasms in Florence, Italy. This report details the findings of Working Group 3-Precursor Lesions of the Kidney. Papillary adenoma is likely the best-established precursor lesion in the kidney, thought to be an incipient form of papillary renal cell carcinoma (RCC) with shared morphology, immunohistochemistry, and genetics. Likewise, in patients with VHL disease, the kidney often contains multiple small nodules of clear cells and/or cysts lined by one or more layers of clear cells, likely representing early tumor or precursor lesions. Interestingly, a precursor counterpart for clear cell RCC in the sporadic setting is not well established. In other scenarios, cysts are considered potential precursors of neoplasia, such as those in acquired cystic kidney disease (ACKD) and possibly in some hereditary renal tumor syndromes. The consensus panel proposes the following terms "cyst with epithelial proliferation" for tufted/hyperplastic/cribriform cyst lining in ACKD without solid tumor, and "papillary hyperplasia" for tufting of cyst lining in autosomal dominant polycystic kidney. Terms such as "tumorlet," "microtumor," or "incipient tumor" are acceptable for incidental unencapsulated microscopic lesions in hereditary syndrome patients. There is insufficient evidence for the diagnosis of "tubular dysplasia" as a precursor to RCC at the present time.

NAMPTis and PARPis synergize in IDH1/2 NAPRT-deficient tumor models.

Compared with cancers of other organs, precursor lesions of renal cell neoplasms are rarely discussed. However, there are specific scenarios where cysts or microscopic solid lesions are thought to precede tumor formation. In 2024, the International Society of Urological Pathology (ISUP) held a consensus meeting on precursor lesions of urologic neoplasms in Florence, Italy. This report details the findings of Working Group 3—Precursor Lesions of the Kidney. Papillary adenoma is likely the best-established precursor lesion in the kidney, thought to be an incipient form of papillary renal cell carcinoma (RCC) with shared morphology, immunohistochemistry, and genetics. Likewise, in patients with VHL disease, the kidney often contains multiple small nodules of clear cells and/or cysts lined by one or more layers of clear cells, likely representing early tumor or precursor lesions. Interestingly, a precursor counterpart for clear cell RCC in the sporadic setting is not well established. In other scenarios, cysts are considered potential precursors of neoplasia, such as those in acquired cystic kidney disease (ACKD) and possibly in some hereditary renal tumor syndromes. The consensus panel proposes the following terms “cyst with epithelial proliferation” for tufted/hyperplastic/cribriform cyst lining in ACKD without solid tumor, and “papillary hyperplasia” for tufting of cyst lining in autosomal dominant polycystic kidney. Terms such as “tumorlet,” “microtumor,” or “incipient tumor” are acceptable for incidental unencapsulated microscopic lesions in hereditary syndrome patients. There is insufficient evidence for the diagnosis of “tubular dysplasia” as a precursor to RCC at the present time.

Recently, a structured approach to renal mass characterization known as the Kidney Imaging Reporting and Data System (KI-RADS) was proposed. In that proposal, the authors noted the need for imaging characteristics to be rooted in the biological underpinnings of the tumors in order to optimally risk stratify patients with indeterminate renal masses. Although multi-parametric magnetic resonance imaging may be an important initial modality for locoregional staging and lesion characterization, molecular imaging may provide more fundamental biological insight. To date, the mitochondrial imaging agent 99mTc-sestamibi for single-photon emission computed tomography/computed tomography and the carbonic anhydrase IX-targeted monoclonal antibody 89Zr-girentuximab for positron emission tomography/computed tomography are the best characterized radiotracers that can potentially be incorporated into indeterminate renal mass risk stratification. Both have been studied in large, prospective, scan-and-resect trials against a surgical histopathology gold standard. In this manuscript, we review the current imaging approaches to renal mass characterization; discuss the evidence for molecular imaging in this setting; explore the potential synergy among anatomic imaging, molecular imaging, and biopsy; and propose a molecular imaging-focused companion KI-RADS framework. We also outline future directions for integrating diverse sources of data with potential application of artificial intelligence. The molecular imaging perspective on KI-RADS translates summarized biological insights from imaging into a five-point Likert scale based on the potential for an aggressive histology for an indeterminate renal mass. Going forward, we believe that the strong correlations between molecular imaging findings and underlying tumor biology will warrant incorporation of molecular imaging techniques into any final form of KI-RADS.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications, the vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and the potential for early metastatic spread. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland and Leydig cell tumours. The aggressive behaviour of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining predisposition for de novo primary renal tumours in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. Vascular endothelial growth factor/epidermal growth factor receptor-directed treatment regimes, such as erlotinib/bevacizumab, demonstrate efficacy against HLRCC-associated RCC. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 World Health Organization classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to discuss this impact and raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.

Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.

Supplementary Table S1: FH variants with population frequencies, interpretations of pathogenicity, catalytic efficiencies, and multimerization states