Shinichi Sakamoto

Objectives: To characterize mid‐term oncological outcomes after nephrectomy for renal cell carcinoma (RCC) in Japan using the National Clinical Database (NCD). Methods: We retrospectively analyzed patients with RCC who underwent nephrectomy between April and December 2018 and had at least 5 years of follow‐up recorded in the NCD. Age, sex, nephrectomy type, operative approach, and pathological T category were evaluated. Disease‐free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared with the log‐rank test. Results: Of 16 786 patients registered at 759 institutions, 9065 with available 5‐year follow‐up were analyzed. Patients aged ≥ 75 years comprised 24.7% of the cohort. Radical and partial nephrectomy were performed in 55.0% and 45.0% of patients, respectively. Median DFS and OS were not reached. Older age and male sex were associated with shorter DFS and OS. Radical nephrectomy and open surgery were also associated with shorter survival. Both DFS and OS decreased significantly with advancing pathological stage, with earlier recurrence in pT3–4 disease. Conclusions: This nationwide NCD‐based study provides descriptive mid‐term survival data for patients with RCC undergoing nephrectomy in Japan. Age, sex, nephrectomy type, operative approach, and pathological stage were associated with survival differences. These findings provide real‐world outcome data for patients with available long‐term follow‐up and a basis for future risk‐adjusted analyses.

Objectives: To evaluate the effect of neoadjuvant chemotherapy (NAC) on pathological response and oncologic outcomes in patients with high‐risk upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) in a real‐world multicenter setting. Methods: We retrospectively analyzed data from 184 patients with high‐risk UTUC who underwent RNU across six institutions and were divided into NAC and non‐NAC groups. The primary endpoint was pathological downstaging. Secondary endpoints were non‐urinary‐tract recurrence‐free survival (NUT‐RFS) and overall survival (OS). We also compared the NAC group with the combined non‐NAC and adjuvant chemotherapy (AC) group. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: 34.2% and 14.1% of 184 patients (median age, 75 years; men, 70.7%) received NAC and AC, respectively. NAC was not significantly associated with pathological downstaging. On multivariable analysis, positive urine cytology (bladder) was independently associated with a lower likelihood of downstaging, whereas a higher baseline eGFR was independently associated with a higher likelihood of downstaging. Neither NUT‐RFS nor OS differed significantly between the NAC and non‐NAC groups or between the NAC and non‐NAC plus AC groups, either in the overall cohort or after PSM. Conclusions: In this real‐world cohort, NAC did not significantly improve pathological or survival outcomes in patients with high‐risk UTUC. Oncological outcomes did not differ significantly between NAC and AC administered after pathological confirmation of risk, although this comparison is susceptible to selection and guarantee‐time bias. Pathology‐guided AC may be a reasonable perioperative strategy, but its relative benefit remains uncertain and warrants prospective validation.

Objectives: To investigate active surveillance (AS) continuation rates and associated clinical and institutional factors in Japanese patients with localized prostate cancer. Methods: We retrospectively analyzed 989 patients with localized prostate cancer from 92 institutions who initiated AS between 2016 and 2018. Institutions were categorized into three groups based on AS uptake for low‐risk disease. Discontinuation triggers and subsequent treatments were examined. Results: Median age was 70 years; 66.2%, 26.0%, and 7.8% of patients had low‐, intermediate‐, and high‐risk disease, respectively. Over a median follow‐up of 3.4 years, 47.0% discontinued AS (median AS continuation time: 3.0 years; 5‐year AS continuation rate: 33.7%). Multivariable analysis showed that ≥ 2 comorbidities, ≥ 3 positive biopsy cores, and T2b–c stage were associated with restricted mean continuation time differences (RMCTDs) of −0.6, −0.6, and −0.8 years, respectively (all p < 0.05). Conversely, intermediate‐ and high‐AS uptake institutions had significantly longer adjusted RMCTD (1.0 and 1.1 years, respectively; both p < 0.001). Triggers for discontinuation were more often multifaceted in high‐AS uptake institutions (39.1%) compared with low‐ or intermediate‐AS uptake institutions (16.2% and 15.1%, respectively). After discontinuation, 36.5%, 39.2%, and 24.3% of patients received prostatectomy, radiotherapy, and hormonal therapy, respectively. With advancing age, the proportion of patients whose AS was discontinued due to PSA elevation increased, as did the rate of subsequent hormonal therapy. Conclusions: In Japanese real‐world practice, AS continuation was limited. Beyond clinicopathological factors, institutional strategies for localized prostate cancer played a significant role in treatment choices following AS.

Objectives: To evaluate real‐world biochemical recurrence‐free survival (BCRFS) after radical prostatectomy (RP) for prostate cancer in Japan using nationwide data from the National Clinical Database (NCD). Methods: This study included patients who underwent RP between April and December 2018 and were registered in the NCD from 647 participating institutions. BCRFS was estimated using the Kaplan–Meier method. Outcomes were evaluated according to surgical approach and clinicopathological factors without adjustment for baseline characteristics. Results: A total of 14 992 patients with available 5‐year postoperative follow‐up data were included in the analysis. Robot‐assisted RP accounted for the majority of procedures (73.2%), followed by open RP (16.0%) and laparoscopic RP (10.8%). The overall 5‐year BCRFS rate was 81%. BCRFS was comparable across age groups and surgical approaches. In contrast, pathological factors strongly influenced prognosis. Five‐year BCRFS decreased with increasing pathological stage (pT2, 86%; pT3, 65%; pT4, 41%) and was lower in patients with nodal metastasis (pN0, 81%; pN1, 59%). The International Society of Urological Pathology (ISUP) Grade Group demonstrated a stepwise association with prognosis, with 5‐year BCRFS declining from 92% in grade group 1 to 60% in grade group 5. Five‐year BCRFS was lowest in the extended lymph node dissection group (73%), followed by the obturator lymph node dissection group (80%) and the no‐dissection group (87%). Conclusions: Current nationwide data delineate the real‐world oncological outcomes following RP in Japan. Pathological tumor characteristics—rather than patient age or surgical approach—were the predominant determinants of postoperative prognosis. These findings may provide essential benchmarks to guide clinical decision‐making.

Glutamine supports biosynthesis and redox homeostasis in cancer cells. The glutamine transporter ASCT2 is highly expressed in prostate cancer and is associated with higher Gleason grade. Although ASCT2 inhibition induces reactive oxygen species (ROS) accumulation and apoptosis, cancer cells may activate antioxidant adaptive mechanisms that limit therapeutic efficacy. Here, we identified an NRF2/xCT‐dependent redox‐adaptive response following ASCT2 inhibition in prostate cancer. Mechanistically, ASCT2 inhibition induced ROS accumulation, promoted nuclear translocation of NRF2, and upregulated xCT together with other NRF2‐associated antioxidant genes. Functional redox analysis showed that ASCT2 inhibition reduced glutathione‐dependent redox capacity, whereas combined ASCT2 and xCT inhibition further increased GSSG accumulation and markedly decreased GSH levels and the GSH/GSSG ratio. These fin\dings were further validated in C4‐2 cells as an additional prostate cancer model. Cell death discrimination assays showed that combined ASCT2 and xCT inhibition induced lipid peroxidation that was partially rescued by ferrostatin‐1, whereas z‐VAD produced a stronger rescue effect and Annexin V/PI staining confirmed prominent apoptotic cell death. In castrated 22Rv1 xenograft models, combined treatment with V‐9302 and erastin produced the strongest inhibition of tumor growth without significant body weight loss during treatment. Collectively, these findings demonstrate that NRF2/xCT‐mediated residual glutathione redox buffering functions as an adaptive survival mechanism following ASCT2 inhibition and provide a mechanistic rationale for combined targeting of ASCT2 and xCT to overcome redox‐adaptive resistance in prostate cancer.

Prostate cancer (PCa) exhibits a unique propensity to metastasize to bone, where it predominantly generates osteoblastic lesions. The formation of these lesions is a complex and dynamic process driven by reciprocal interactions between tumor cells and the bone microenvironment. Emerging evidence indicates that extracellular vesicles (EVs) play pivotal roles in the establishment of metastatic colonies and disease progression, as well as in local tumor–bone interactions. Through their diverse cargos, including proteins, lipids, and non-coding RNAs, EVs mediate bidirectional communication that regulates osteoclastogenesis, osteoblast activation, and osteocyte function, ultimately reshaping the bone niche to favor tumor growth. Importantly, EVs exhibit dual and context-dependent functions, acting either as promoters or suppressors of malignancy depending on the cellular source and microenvironmental context. These insights highlight EVs not only as mechanistic drivers of PCa bone metastases but also as promising therapeutic targets. Approaches aimed at modulating EV biogenesis, eliminating deleterious EVs, or harnessing EVs as drug delivery vehicles hold significant potential for advancing treatment strategies against PCa bone metastases.

Unmet challenges in systemic therapy persist for advanced renal cell carcinoma (RCC) despite the widespread use of anti‐angiogenetic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We previously showed that dipeptidyl peptidase 4 inhibitor (DPP4i) improved TKI sensitivity using patient‐derived RCC cells and experimental TKI‐resistant models. To address whether DPP4i is clinically useful for the enhancement of RCC systemic therapy, including ICIs, we analyzed 320 cases with RCC who underwent systemic therapy. Patients with DPP4i treatment exhibited longer overall survival (hazard ratio: 0.50, 95% confidence interval: 0.30–0.82, p = 0.0060). In the Cox proportional hazards model, the use of DPP4is, along with BMI ≥ 25, no metastasis, low serum lactate dehydrogenase (LDH), and low serum C‐reactive protein (CRP), was a favorable prognostic factor. Additionally, more pronounced tumor shrinkage was observed in a within‐subgroup comparison of patients receiving TKI or ICI as first‐line therapies. Consistently, we found that DPP4 high RCC tumors exhibit reduced immune infiltration and lower scores for effector T cell infiltration‐related signatures based on the RNA sequencing data from the CheckMate‐009, 010, and 025 studies. These findings can potentially change the interpretation of the prognostic impact of type 2 diabetes mellitus on RCC and bolster the rationale for initiating a prospective clinical trial to evaluate concurrent use of DPP4i with RCC therapeutic strategies.

Purpose: As the incidence of prostate cancer rises in Asian countries, notable disparities in life expectancy, economic status, and education levels are observed. This study aimed to use the Human Development Index (HDI), which reflects these factors, to explore differences in prostate cancer diagnosis, staging, and initial treatment across various Asian nations and areas, and uncover the impact of socioeconomic factors on patient outcomes. Methods: We analyzed patients diagnosed with prostate cancer between January 2016 and December 2018 who were enrolled in the Asian Prostate Cancer Study Group (A‐CaP). Patients were grouped into three HDI categories (medium, high, very high). A statistical comparison was conducted to evaluate differences in diagnostic methods and initial treatments across 12 Asian countries and areas based on HDI classification. Results: In total, 35,776 prostate cancer patients were included. Patients in the very high HDI group had lower PSA levels, fewer ISUP Grade 5 cases, and reduced metastatic disease (M1) compared to the other groups. Advanced diagnostic modalities (e.g., CT, MRI, and bone scintigraphy) were more commonly used in the very high HDI group. Imaging modalities were less frequently used in medium HDI countries with low PSA, and in high HDI countries with high PSA. Regarding treatment, patients in very high HDI countries and areas were more likely to receive radiation therapy or active surveillance. Surgical treatment was more common for metastatic patients in high and medium HDI countries and areas. Conclusion: This study highlights significant differences in prostate cancer management across 12 Asian countries and areas, emphasizing the influence of HDI on diagnostic and treatment outcomes.

Cystinuria is the most common genetic cause of urinary stones. Defects in SLC3A1/SLC7A9 genes coding cystine transporter proteins rBAT/b^0,+AT will cause Cystinuria. The current work analyzed the clinical and genetic characteristics of Japanese Cystinuria patients. In total, 101 Cystinuria patients were studied. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 was performed by next-generation sequencing. Excretion of cystine was determined by 24 h urine analysis. The median age of presentation was 17 years. In total, 51 different mutant variant alleles were identified (22 and 29 mutant variants in SLC3A1 and SLC7A9, respectively), including 25 novel variants. The p.(Pro482Leu) (c.1445C > T) variant in SCL7A9 was predominantly found in 73 patients. Variants in exon–intron boundaries were identified in 6 cases. The patient with a homozygote intron (exon–intron boundary) variant in SCL7A9 presented a severe phenotype with a significant loss of mRNA expression. Including exon and exon–intron boundary variants reduced the number of cases that did not fit autosomal recessive inheritance from 14 to 9%. Current data revealed a specific genotype of Japanese cystinuria through the analysis of exon and exon–intron boundaries.

Introduction: Maintaining a castration level of testosterone (TST) during radiation therapy combined with androgen deprivation therapy (ADT) is an essential strategy in the treatment of prostate cancer; however, hypogonadism can cause various complications. The aim was to compare serum TST recovery between LHRH agonists and LHRH antagonists.Methods: A total of 131 patients who underwent radiation therapy with ADT for prostate cancer were retrospectively analyzed. Serum TST levels after termination of ADT including LHRH agonists and antagonists were compared. Cox proportional hazards model and the Kaplan–Meier method were used for statistical analysis.Results: Median age, baseline TST, nadir TST, and duration of ADT were 71 years, 535 ng/dL, 10.92 ng/dL, and 12 months, respectively. Multivariate analysis identified significant associations of initial PSA ≥ 10.92 ng/mL (p = 0.0366), ADT ≥ 360 days (p = 0.0408), nadir TST ≤ 19 ng/dL (p = 0.0003), and LHRH agonist (p = 0.0027) with delayed TST recovery to castration level (50 ng/dL). We created a risk model based on these four independent risk factors (Low: 0–1 factor/Intermediate: 2 factors/High Risk: 3–4 factors). Each risk group significantly differentiated the TST recovery to castration level. Even after propensity score matching, recovery of TST to castration level and therapeutic level (200 ng/dL) was significantly delayed in the LHRH agonist group compared with the LHRH antagonist group (p = 0.0016, p = 0.0389, respectively).Conclusion: LHRH antagonists restored serum TST to castration and therapeutic levels faster than LHRH agonists in prostate cancer patients undergoing radiation therapy with ADT.