Yu Ishizuya

Background: Belzutifan, a hypoxia‐inducible factor 2α (HIF‐2α) inhibitor, is effective for metastatic renal cell carcinoma (mRCC), although its cardiovascular safety profile remains unclear. Case Presentation: A 52‐year‐old woman with mRCC developed progressive dyspnea and a 6.7‐kg weight gain 27 days after initiating belzutifan as third‐line therapy. Chest radiography revealed marked cardiomegaly (cardiothoracic ratio 63.4%), and echocardiography showed preserved left ventricular ejection fraction (67.1%) with mild diastolic dysfunction and findings consistent with congestive heart failure. Intensive diuretic therapy led to rapid improvement, with the cardiothoracic ratio decreasing to 42.7% and NT‐proBNP declining from 912 to 203 pg/mL. After belzutifan rechallenge at a reduced dose, NT‐proBNP increased again and subsequently normalized after discontinuation due to disease progression. Conclusion: Belzutifan may be associated with reversible congestive heart failure with preserved ejection fraction. Cardiac evaluation should be considered in patients who develop dyspnea during belzutifan therapy.

Introduction: Enfortumab vedotin is a Nectin‐4‐directed antibody–drug conjugate approved for metastatic urothelial carcinoma. Cardiac adverse events such as pericardial effusion or tamponade associated with enfortumab vedotin are extremely rare. Case Presentation: A 50‐year‐old man with metastatic UC developed chest pain and dyspnea 3 days after the first EV infusion, followed by rapid progression to cardiac tamponade on Day 9. Emergency pericardiocentesis and thoracoscopic pericardial fenestration drained 2400 mL of pericardial and pleural fluid. Pericardial cytology revealed inflammatory cells without malignancy, while pleural nodules confirmed urothelial carcinoma. Infectious causes were excluded, and an acute EV‐related inflammatory reaction was suspected. EV was safely resumed on postoperative Day 20, achieving a sustained partial response for 8 months without recurrence of pericardial effusion. Conclusion: This rare case highlights the potential for acute, enfortumab vedotin‐related inflammatory pericardial effusion and emphasizes the importance of early recognition and prompt surgical intervention.

Purpose: Adjuvant chemotherapy (AC) improves survival after radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and adjuvant immunotherapy with nivolumab has shown beneficial effects. However, direct comparisons between these treatments in clinical practice are limited. This study evaluated the real-world outcomes of patients who received no adjuvant therapy, AC, or adjuvant immunotherapy after RC. Methods: This multicenter, retrospective study included 528 patients who underwent RC at Osaka University and its affiliated hospitals between 2010 and 2024. The patients were categorized into 3 groups: no adjuvant therapy, AC, and adjuvant immunotherapy. Propensity score matching (PSM) was used to minimize selection bias. Kaplan–Meier and Cox regression analyses were used to evaluate disease-free and cancer-specific survival. Results: Median disease-free survival (DFS) was 16.6, 22.3, and 26.4 months in the no-adjuvant therapy, AC, and adjuvant immunotherapy groups, respectively. Both adjuvant treatments significantly improved disease-free and cancer-specific survival in lymph node-positive patients. Multivariate analysis confirmed that AC ( P < .001) and immunotherapy ( P = .030) were independent prognostic factors for DFS. After PSM, adjuvant immunotherapy showed significantly improved disease-free ( P = .002) and cancer-specific survival ( P = .004) compared with no adjuvant therapy. No significant differences in survival outcomes were observed between AC and adjuvant immunotherapy groups. Conclusion: Adjuvant immunotherapy is an effective alternative to chemotherapy after RC, particularly in lymph node-positive patients. These findings support the use of immunotherapy as a postoperative treatment strategy for MIBC. Further research is needed to refine the optimal adjuvant treatment approaches.

Objectives: Nerve‐sparing techniques are commonly used in retroperitoneal lymph node dissection (RPLND) for patients with testicular cancer to preserve postoperative ejaculation. Laparoscopic RPLND is applicable to small residual masses; however, nerve‐sparing techniques remain challenging. This study aimed to establish a safe, bilateral nerve‐sparing laparoscopic RPLND via the transperitoneal approach. The technique was developed through cadaveric surgical training (CST) and applied clinically. Methods: Thiel‐fixed human cadavers were used for CST. In patients with testicular cancer after chemotherapy, laparoscopic RPLND was performed based on normalized tumor markers, typically with a residual mass of 5 cm or less. Patients were placed in the lateral position, and four to six ports were used, including the umbilical port; central ports were shared bilaterally. The dissection extent followed a bilateral full‐template approach. Results: In CST, lumbar splanchnic nerves were identified and preserved, supporting the clinical feasibility of laparoscopic RPLND. The bilateral nerve‐sparing laparoscopic RPLND was performed in 10 patients: 6 with non‐seminoma and 4 with seminoma. The mean pre‐chemotherapy tumor diameter was 2.7 cm (range, 1.2–5.6 cm). The mean blood loss was 165 mL (range, 0–540 mL). The bilateral lumbar splanchnic nerves were preserved in all cases, and postoperative ejaculatory function was confirmed to be preserved in 9 cases. Surgical complications included Grade 1 chyle leakage in 5 patients, all of whom improved with conservative management. Conclusions: A laparoscopic bilateral nerve‐sparing RPLND technique was developed to achieve both minimal invasiveness and preservation of ejaculatory function. Long‐term follow‐up is necessary to confirm oncological outcomes.

Alterations in the homologous recombination repair genes, such as BRCA1 and BRCA2, are prevalent in various cancers, presenting a unique opportunity to develop synthetic lethal strategies that target homologous recombination deficiency (HRD). Poly ADP‐ribose polymerase inhibitors (PARPis) have been developed to induce synthetic lethality in tumors with HRD by inhibiting the repair of single‐strand DNA breaks. Beyond the initial approach to target cancers associated with HRD, the utility of PARPis has expanded to combination therapy with immune checkpoint inhibitors, anti‐angiogenic drugs, or anti‐androgen drugs based on the molecular biological rationale. In the field of genitourinary (GU) cancer, PARPis, such as olaparib, rucaparib, and talazoparib, are approved by the Food and Drug Administration in metastatic prostate cancer patients with BRCA1 / 2 mutations, sometimes in combination with other agents (e.g., olaparib plus abiraterone acetate, or talazoparib plus enzalutamide). More recently, pivotal clinical trials have broadened the potential of PARPis to the other GU cancers, including urothelial carcinoma and renal cell carcinoma. In this review, we examine the biomarkers for the response to PARPis beyond mutations in BRCA1 / 2 and discuss the current state and future perspectives of PARPis in GU cancers.

Telomerase reverse transcriptase (TERT) promoter mutations are frequently found in tumors or urine from patients with urothelial carcinoma (UC). TERT promoter mutations are also detected in urine from patients with no evidence of cancer but are associated with subsequent UC development. Mutations in the TERT promoter are thought to be present in nonmalignant urothelium (NMU) during early stages of tumor formation prior to pathological change, but this has not been proven directly. In this proof‐of‐concept study, we investigated the clinical utility of TERT promoter mutation analysis in NMU of patients with non‐muscle‐invasive bladder cancer (NMIBC). This single‐institute study included 53 primary tumors and 428 systematic bladder biopsy specimens from 54 patients with NMIBC. All patients underwent systematic random biopsy and transurethral resection of the bladder tumor. Genomic DNA was analyzed for TERT C228T and C250T mutations using droplet digital PCR (ddPCR). The association between TERT promoter mutation of NMU and bladder recurrence was examined by the Kaplan–Meier method and Cox proportional hazards model. Of the 54 patients, 16 (29.6%) had a TERT C228T mutation and three (5.6%) had a TERT C250T mutation in NMU. Of 428 biopsy specimens, the TERT C228T mutation was detected in 9% (31/364) of normal urothelium, 27% (4/15) of urothelial dysplasia (UD), 50% (9/18) of UD suspicious for carcinoma in situ (CIS), and 58% (18/31) of CIS. During follow‐up (median: 3.7 years), 22 (40.7%) patients experienced bladder recurrence and five (9.3%) experienced disease progression. Cox proportional hazard analysis showed that TERT C228T mutation in NMU was significantly associated with bladder recurrence after adjustment for cofounding factors (P = 0.0128). Thus, TERT C228T mutation was detected in NMU, which was a reliable independent prognostic factor of bladder tumor recurrence.