Toshiharu Morikawa

Introduction: We report a case of de novo prostatic adenosquamous carcinoma with a minute squamous component in the initial biopsy and early liver metastasis despite a marked prostate‐specific antigen response. Case Presentation: A 72‐year‐old man was diagnosed with locally advanced prostate cancer with nodal and multiple bone metastases. Prostate biopsy initially showed adenocarcinoma with a Gleason score of 4 + 5. After leuprolide and abiraterone plus radiotherapy, prostate‐specific antigen decreased from 13.0 to 0.22 ng/mL; however, a liver metastasis developed. Re‐evaluation of the prostate biopsy revealed minute squamous differentiation, and liver biopsy showed metastatic squamous cell carcinoma. Immunohistochemistry showed retained MLH1 and PMS2 expression with loss of MSH2 and MSH6 in both specimens. Genomic profiling showed microsatellite instability‐high status. Conclusion: Repeat biopsy and molecular‐pathological reassessment may be important when radiographic progression is discordant with prostate‐specific antigen kinetics.

Enfortumab vedotin (EV) is a crucial treatment for patients with metastatic urothelial carcinoma (mUC). However, a significant proportion of patients experience adverse events (AEs). The identification of biomarkers for AEs is imperative for the detection and treatment of AEs at an early stage. In this exploratory study, we aimed to identify biomarkers of AEs in patients with mUC treated with EV. We retrospectively examined 10 factors identified from the data of 116 patients with mUC treated with EV to identify biomarkers (age, body mass index, C‐reactive protein level, Eastern Cooperative Oncology Group performance status, eosinophil proportion, history of diabetes, lymphocyte proportion, neutrophil proportion, neutrophil‐to‐lymphocyte ratio, and platelet count) associated with the occurrence of AEs of any grade. The candidate biomarkers were measured at the start of EV treatment. The least absolute shrinkage and selection operator method was used to select the most useful parameters for predicting AE occurrence. Among the 10 factors, eosinophil proportion was identified as the only potential biomarker. The optimal cutoff value for eosinophil proportion against the occurrence of AEs of any grade was 2.5% (area under the curve = 0.625). Univariable logistic regression analyses showed that an eosinophil proportion of ≥ 2.5% was a risk factor for AE development (odds ratio = 4.35, 95% confidence interval = 1.35–14.0). Therefore, the results of this exploratory study indicated that an eosinophil proportion of ≥ 2.5% at the start of EV treatment may be a candidate biomarker for the occurrence of AEs of any grade.

There is an unmet need to predict immune‐related adverse events (irAEs) in patients receiving immune checkpoint inhibitors. This study aimed to examine whether eosinophils can predict irAEs in metastatic urothelial carcinoma (mUC). In this multicenter cohort study, we retrospectively examined eosinophil before (baseline sample) and 3 weeks after treatment (3‐week sample) in 124 patients with mUC treated with pembrolizumab between January 2018 and October 2024. We divided the patients into two groups depending on whether they had experienced an irAE (irAE group) or not (non‐irAE group). The variation in eosinophil proportion from baseline to 3 weeks was significantly higher in the irAE group than in the non‐irAE group (non‐irAE, 2.4%–3.1%; irAE, 2.2%–4.3%; p < 0.05). Notably, the variation in eosinophils from baseline to 3 weeks in patients with bladder cancer was significantly higher in the irAE group than in the non‐irAE group (non‐irAE, 2.5%–2.8%; irAE, 1.9%–4.1%; p < 0.05), but not in upper urinary tract urothelial cancer (non‐irAE, 2.2%–3.7%; irAE, 2.8%–4.4%; p = 0.97). The optimal cutoff value for eosinophils in patients with bladder cancer against the occurrence of any‐grade irAEs was 5.0% (area under the curve = 0.655). Multivariable analyses showed that eosinophil levels ≥ 5.0% increased the risk of any‐grade irAEs in patients with bladder cancer (odds ratio 3.61, 95% confidence interval, 1.00–13.0). An eosinophil proportion ≥ 5.0% may be an effective biomarker for evaluating pembrolizumab‐induced irAEs in patients with mUC, particularly those with bladder cancer.

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC.

Bladder cancer (BC) often arises in an immunosuppressive tumor microenvironment that limits responses to immune checkpoint inhibitors. Magnetic hyperthermia therapy (MHT) can induce immunogenic cell death, but its value as an immunotherapeutic remains insufficient. We conjugated anti-programmed death-ligand 1 (PD-L1) antibody (αPD-L1) with magnetite cationic liposomes (MCL) and developed αPD-L1@MCL for MHT in an MB49 murine subcutaneous BC model. Mice received a single or triple exposure of αPD-L1@MCL-mediated MHT (P-MHT) at 43 °C or 46 °C (n = 5 per group), then we assessed tumor growth and CD8⁺ T-cell infiltration. Without αPD-L1, triple MHT at 46 °C induced complete tumor regression, whereas a single exposure 43 °C was insufficient. A single exposure 43 °C P-MHT achieved complete regression in four out of five mice. Flow cytometry revealed an increase in CD8⁺ T cells in tumors treated with P-MHT. Our αPD-L1@MCL enables hyperthermia with magnetic nanoparticles and immunotherapy with an anti-PD-L1 antibody. These findings support further development of hyperthermia mediated by anti-PD-L1 antibody-conjugated magnetic nanoparticles as a promising therapeutic strategy for BC.

Introduction: Open radical cystectomy is the current standard treatment for bladder cancer. However, it is associated with high morbidity and mortality, particularly in the elderly. Recently, robotic surgery has become a minimally invasive approach. To this end, we aimed to evaluate the safety and complications of robot‐assisted radical cystectomy (RARC) in elderly patients with urothelial carcinoma. Methods: We performed a retrospective single‐center analysis of 103 patients who underwent RARC between May 2018 and May 2024. The patients were divided into an elderly group (age, ≥ 80 years; n = 24) and a younger group ( n = 79). Results: The American Society of Anesthesiologists Physical Status Classification System scores were significantly lower in the elderly group than in the younger group. No significant differences were observed between the two groups in terms of demography. Operative time was shorter in the elderly group than in the younger group. Conversely, the postoperative hospital stay was shorter in the younger group than in the elderly group. There were no significant differences in the frequency or severity of complications between the two groups; however, the incidence of ileus was significantly higher in the elderly group. In addition, higher age, ileus, and days to drain removal were identified as independent factors that prolonged hospitalization. Conclusions: RARC is a safe treatment option for elderly patients with bladder cancer, with complication profiles comparable to those in younger patients. However, the increased risk of ileus and prolonged hospitalization in elderly patients highlights the need for cautious perioperative management to optimize outcomes in this growing population.

We have established a highly stable and reproducible patient derived xenograft model that exclusively and robustly retains the morphological, functional, and proliferative characteristics of human yolk sac tumor of the testis. This model might provide an invaluable in vivo platform for accelerating the discovery and validation of novel therapeutic strategies for this aggressive malignancy, with the ultimate aim of improving the prognosis for affected patients.

Introduction: Patients with metastatic renal cell carcinoma have a poor prognosis and its specific pathogenesis remains unelucidated.Case presentation: At 78 years of age, a Japanese male patient was diagnosed with metastatic renal cell carcinoma (cT3N2M1 stage) and multiple brain metastases that were responsive to stereotactic radiation therapy followed by systemic combination induction therapy of pembrolizumab plus lenvatinib. Adverse events, including grade 3 hypertension, grade 2 eruption, and elevated grade 2 fever, were controlled by a dose reduction or suspension of drugs. The patient eventually showed a tolerance for continuing with 8 mg lenvatinib. Fourteen months after the initiation of treatment, and on 8 mg lenvatinib, this patient showed no sign of disease progression at the last follow‐up.Conclusion: We detail the absence of disease progression in a metastatic renal cell carcinoma case with multiple brain metastases more than 1 year after stereotactic radiation therapy followed by first‐line pembrolizumab plus lenvatinib.

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.