金坂 学斗

OBJECTIVES: Renal cell carcinoma (RCC) is shown to have a tendency for late recurrence, occurring 5 or more years after curative surgery. Imaging diagnosis is required for follow-up, and there is no definitive answer as to how long this should continue. Some patients discontinue follow-up visits at their own discretion. How best to predict late recurrence and loss to follow-up (LF) remains unclear. PATIENTS AND METHODS: This study targeted patients diagnosed with non-metastatic RCC who underwent either radical or partial nephrectomy at Chiba University Hospital between 1988 and 2021. Follow-up for patients with RCC is typically lifelong. We used random survival forests (RSFs), a machine learning-based survival analysis method, to predict late recurrence and LF. For verification of prediction accuracy, we applied the time-dependent area under the receiver operating characteristic curve (t-AUC). To analyse the risks of late recurrence and LF, SurvSHAP(t) and partial dependence plots were used. RESULTS: We analysed 1051 cases in this study. Median follow-up was 58.5 (range: 0-376) months. The predictive accuracy of recurrence using RSF was t-AUC 0.806, 0.761, 0.674 and 0.566 at 60, 120, 180 and 240 months postoperatively, respectively. The recurrence risk impact showed a time-dependent increase up to approximately 50 months postoperatively. Beyond 50 months, there were no distinct risk factors characteristic of late recurrence. The predictive accuracy of LF using RSF was t-AUC 0.542, 0.699, 0.685, 0.628 and 0.674 at 60, 120, 180, 240 and 300 months postoperatively, respectively. The risk of LF increased with advancing age beyond 70 years. CONCLUSION: It is difficult to identify factors that predict late recurrence. For long-term follow-up observation, it is essential to pay particular attention to patients with RCC aged 70 years and above. Establishing frameworks to facilitate collaboration with local hospitals near patients' residences and providing care within the community is necessary.

The prognostic significance of unconventional histology (UH) subtypes including intraductal carcinoma of the prostate (IDC-P), ductal adenocarcinoma, and cribriform pattern has been investigated for prostate cancer (PCa). However, little is known about magnetic resonance imaging (MRI) features and the oncological impact of tumor localization in localized PCa with UH. Clinical data of 211 patients with acinar adenocarcinoma (conventional histology [CH]) and 82 patients with UH who underwent robotic-assisted radical prostatectomy (RARP) were reviewed. Patients with UH are more likely to be older and have higher Gleason grade group, higher Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score, and larger tumor volume (TV) than those with CH. Multivariate analysis identified the presence of UH as an independent prognostic factor for progression-free survival (PFS) (hazard ration (HR) 2.41, 95% confidence interval (CI) 0.22-0.79, P = 0.0073). No significant difference in PFS was seen regarding tumor localization (transition zone [TZ] or peripheral zone [PZ]) in patients with UH (P = 0.8949), whereas PZ cancer showed shorter PFS in patients with CH (P = 0.0174). PCa with UH was associated with higher progression than PCa with CH among resection margin (RM)-negative cases (P < 0.0001). Further, increased PI-RADS v2.1 score did not correlate with larger TV in UH (P = 0.991), whereas a significant difference in TV was observed in CH (P < 0.0001). The prognostic significance of UH tumor was independent of tumor localization, and shorter PFS was observed even in RM-negative cases, indicating an aggressive subtype with micro-metastatic potential. Furthermore, UH tumors are more likely to harbor a large TV despite PI-RADS v2.1 score ≤ 3. These findings will help optimal perioperative management for PCa with UH.

Non-muscle-invasive bladder carcinoma often occurs in older adults, who often also have urinary dysfunction. The residual urine volume is an important indicator of urinary dysfunction. However, the impact of the residual urine volume on intravesical recurrence remains unclear. In the present study, we analyzed the data of 372 patients at high or very high risk of cancer progression according to the Japanese Urological Association classification who had undergone transurethral resection of a bladder tumor. In univariate analysis, postoperative absence of intravesical Bacillus Calmette-Guérin (BCG) induction was an independent risk factor for intravesical recurrence (hazard ratio 1.94, absence versus presence, p = 0.0019). The incidence of intravesical recurrence did not significantly differ between the mild, intermediate, and severe residual urine groups in the total cohort. Among the BCG-treated cohort, the three groups showed similar trends. Among the non-BCG-treated cohort, although the patients with more than 100 ml of residual urine tended to have more intravesical recurrence than patients with a smaller residual urine volume, this difference did not reach statistical significance. BCG treatment is recommended for patients at high risk of bladder carcinoma. Patients with a large residual urine volume without BCG treatment may be at high risk of intravesical recurrence.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/β-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.