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.

BACKGROUND/AIM: The purpose of this study was to examine the prognostic value of Prostate imaging-reporting and data system (PI-RADS) v2.1 scoring system in patients who underwent radical prostatectomy (RP). PATIENTS AND METHODS: Clinical data of 294 patients who received RP between 2006 and 2018 were reviewed and multiple parameters including PI-RADS v2.1 score were employed to identify predictive factors for biochemical recurrence (BCR). Tumor volume was calculated from prostatectomy specimens. RESULTS: Median age at operation and initial PSA level were 67 years old and 7.68 ng/ml, respectively. 44.9 and 24.8% of patients were diagnosed with PI-RADS score 4 and 5 prior to biopsies, respectively. BCR was observed in 17% of patients and median observation period was 63.43 months. After multivariate analysis, PI-RADS v2.1 score 5 [hazard ratio (HR)=2.24, p=0.0124] was an independent predictive factor of BCR in addition to clinical T stage (≥2c) (HR=2.32, p=0.0093) and biopsy Gleason score (≥8) (HR=2.81, p=0.0007). Furthermore, PI-RADS score 5 significantly stratified the prognosis in D'Amico intermediate- and high-risk groups (p=0.0174 and p=0.0013, respectively). We established novel risk classifications including PI-RADS v2.1 score and found that prognostic capabilities were improved as compared to the D'Amico classification. CONCLUSION: The PI-RADS v2.1 score exhibited significant prognostic value in patients with localized prostate cancer following RP. Risk classifications based on PI-RADS v2.1 score might provide better ability for predicting oncological outcomes as compared to the D'Amico classification system.

Introduction Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing's syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery. Case presentation A 28‐year‐old woman presented with gradually worsening Cushing's signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38‐mm left adrenal tumor, which was the cause of the adrenal Cushing's syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing's syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted. Conclusion Adrenalectomy is considered safe in pregnant women with Cushing's syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications.

BACKGROUND: The prognostic nutritional index (PNI) based on the serum albumin level and the lymphocyte count has been investigated as a prognostic factor in patients with malignant tumors. However, it has been poorly studied in prostate cancer (PCa), and little is known about its clinical utility. METHODS: Clinical data of 353 patients with de novo, metastatic, hormone-sensitive PCa (mHSPC) who received androgen deprivation therapy (ADT) were obtained from multiple institutions between 2000 and 2019. The impacts of the pretreatment PNI level on treatment response and survival, together with clinical parameters, were examined. The Mann-Whitney U test, Cox proportional hazards models, and Kaplan-Meier methods were used to evaluate significance. RESULTS: The median age and initial prostate-specific antigen level were 73 and 266.18 ng/mL, respectively. Patients with a low PNI had shorter progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) (p < 0.0001). On multivariate analysis, low PNI was an independent prognostic factor for OS (p = 0.0027, HR = 1.65), as well as advanced age (p = 0.049, HR = 1.38), the International Society of Urological Pathology (ISUP) grade group (GG) 5 (p = 0.0027, HR = 1.69), and elevated lactate dehydrogenase (LDH) (p < 0.0001, HR = 2.08). A propensity score-matching analysis showed that the PNI level remained a significant prognostic biomarker for PFS (p = 0.0263), CSS (p = 0.0006), and OS (p = 0.0015). Furthermore, a novel risk classification using PNI, LDH, and the ISUP GG was established to stratify patients' prognosis. An increase in the number of risk factors was significantly correlated with poor outcomes. CONCLUSIONS: A low pretreatment PNI might be an effective biomarker of poor treatment response and survival in patients with mHSPC undergoing ADT.

Machine learning technology is expected to support diagnosis and prognosis prediction in medicine. We used machine learning to construct a new prognostic prediction model for prostate cancer patients based on longitudinal data obtained from age at diagnosis, peripheral blood and urine tests of 340 prostate cancer patients. Random survival forest (RSF) and survival tree were used for machine learning. In the time-series prognostic prediction model for metastatic prostate cancer patients, the RSF model showed better prediction accuracy than the conventional Cox proportional hazards model for almost all time periods of progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). Based on the RSF model, we created a clinically applicable prognostic prediction model using survival trees for OS and CSS by combining the values of lactate dehydrogenase (LDH) before starting treatment and alkaline phosphatase (ALP) at 120 days after treatment. Machine learning provides useful information for predicting the prognosis of metastatic prostate cancer prior to treatment intervention by considering the nonlinear and combined impacts of multiple features. The addition of data after the start of treatment would allow for more precise prognostic risk assessment of patients and would be beneficial for subsequent treatment selection.

(1) Objective: Our study investigated the prognostic value of tumor volume and location in prostate cancer patients who received radical prostatectomy (RP). (2) Methods: The prognostic significance of tumor volume and location, together with other clinical factors, was studied using 557 patients who received RP. (3) Results: The receiver operating characteristic (ROC) curve identified the optimal cutoff value of tumor volume as 2.8 cc for predicting biochemical recurrence (BCR). Cox regression analysis revealed that a tumor in the posterior area (p = 0.031), peripheral zone (p = 0.0472), and tumor volume ≥ 2.8 cc (p &lt; 0.0001) were predictive factors in univariate analysis. After multivariate analysis, tumor volume ≥ 2.8 cc (p = 0.0225) was an independent predictive factor for BCR. Among them, a novel risk model was established using tumor volume and location in the posterior area and peripheral zone. The progression-free survival (PFS) of patients who met the three criteria (unfavorable group) was significantly worse than other groups (p ≤ 0.001). Furthermore, multivariate analysis showed that the unfavorable risk was an independent prognostic factor for BCR. The prognostic significance of our risk model was observed in low- to intermediate-risk patients, although it was not observed in high-risk patients. (4) Conclusion: Tumor volume (≥2.8 cc) and localization (posterior/peripheral zone) may be a novel prognostic factor in patients undergoing RP.

BACKGROUND: To identify the real high-risk group among Japanese de novo metastatic prostate cancer patients who fit CHAARTED or LATITUDE criteria. METHODS: We retrospectively studied patients who fitted CHAARTED (292 patients) and LATITUDE (294 patients) criteria from Japanese multi-institutions. All patients received androgen deprivation therapy with bicalutamide as an initial treatment. Factors related to overall survival (OS) and progression-free survival were statistically analyzed. RESULTS: The median OS was 55.5 months and 60.0 months in patients who met the CHAARTED and the LATITUDE criteria, respectively. In patients who met CHAARTED criteria, lactate dehydrogenase (LDH) (hazard ratio (HR) 2.63, P < 0.0001) and C-reactive protein (CRP) (HR 1.65, P = 0.042) were independent risk factors for OS. In patients who met the LATITUDE criteria, Gleason score (GS) ≥9 (HR 1.77, P = 0.0326) and LDH (HR 2.62, P < 0.0001) were independent risk factors for OS. Modified CHAARTED criteria by adding LDH and CRP showed a significant difference in OS (HR 2.55, P < 0.0001) with a comparative median OS (31.8 months) to placebo of CHAARTED trial (32.2 months). Modified LATITUDE criteria by adding GS ≥9 and LDH showed a significant difference in OS (HR 2.66, P < 0.0001) with a comparative median OS (32.7 months) to placebo of LATITUDE trial (34.7 months). CONCLUSION: Modified criteria may potentially elucidate the true "high volume" and "high risk" patients in the Japanese cohort who require early intensive therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued. PATIENTS AND METHODS: Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed. RESULTS: A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p<0.0001). The eGFR decreased with the duration of ADT treatment. At 12 months, renal function had started to recover in group 1, while it had continued to decrease in group 2. CONCLUSION: Discontinuation of ADT tended to result in improvements in renal function. Furthermore, this study indicated that renal dysfunction caused by 6 months of ADT is transient. Normalization of the serum testosterone level seen after the discontinuation of ADT may be associated with improvements in renal function. Thus, intermittent ADT may be a useful treatment for PCa, as it would help to preserve renal function.

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.

Prostate cancer is a major cause of cancer-related deaths among men worldwide. In addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. While aberrant deoxyribonucleic acid hypermethylation in promoter CpG islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. Acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. Deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone H3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. In this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.

Introduction: 123I-metaiodobenzylguanidine scanning has high sensitivity and specificity for the diagnosis of tumors derived from sympathetic nerves or the adrenal medulla. We report the rare case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. Case presentation: The patient was referred to our hospital with an incidental left renal mass during evaluation for hypertension. An ovarian tumor and prominent ascites were also observed. Serum and urine catecholamine levels were high to suspect a catecholamine-producing tumor of the kidney. 123I-metaiodobenzylguanidine scintigraphy showed increased 123I-metaiodobenzylguanidine intake in the tumor. Laparoscopic radical left nephrectomy was performed. The pathologic diagnosis was an oncocytic variant of chromophobe renal cell carcinoma. No pheochromocytoma features were found. Conclusion: We report the first case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. This case was diagnosed with primary aldosteronism and Meigs' syndrome, which made the clinical course more complicated.

Objectives: The aim of this study was to investigate the clinical usefulness for prediction of outcome of laparoscopic partial nephrectomy (LPN) using the R.E.N.A.L nephrometry scoring system (RNS) and centrality index score (C-index). Materials and Methods: We retrospectively reviewed 64 patients who underwent LPN from 2010 to 2014 in our institution. The RNS and C-index scores were assigned according to the described protocols for their systems. The relationships between the patients' scores before surgery and the outcomes of LPN, warm ischemia time (WIT), operative time (ORT), estimated blood loss (EBL), and percent change in estimated glomerular filtration rate (eGFR) were analyzed retrospectively. Results: Mean tumor size was 3.1cm, mean WIT was 27.6 minutes, mean ORT was 189.0 minutes, and mean EBL was 187mL. Although the RNS had statistically significant correlations with WIT, ORT, and percent change in eGFR, these correlations were not score-dependent. For WIT, a statistically significant difference was observed between the low-risk group and the middle-risk group. For percent change in eGFR, a statistically significant difference was observed between the low-risk group and the high-risk group only. For the C-index, statistically significant correlations between complexity categories and WIT, ORT, EBL, and percent change in eGFR were observed. Regarding the raw C-index scores, linear correlations were observed between the scores and each outcome of LPN. Conclusions: The RNS and C-index are useful for predicting the complexity of LPN. The C-index may be more suitable than the RNS for predicting postoperative renal function.