Nesprin1 Deficiency Is Associated with Poor Prognosis of Renal Cell Carcinoma and Resistance to Sunitinib Treatment.

INTRODUCTION: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). METHODS: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. RESULTS: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. CONCLUSIONS: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment.

Comprehensive genomic profiling testing in Japanese castration-resistant prostate cancer patients: results of a single-center retrospective cohort study.

OBJECTIVE: Comprehensive genomic profiling testing using a hybrid-capture next-generation sequencing is commonly used in clinical practice to employ precision medicine in cancer treatment worldwide. In this study, we aimed to analyze the profiles obtained using comprehensive genomic profiling testing that was performed in Japanese castration-resistant prostate cancer patients and to discuss the genetic findings in a real-world setting. METHODS: A total of 60 cases and 57 castration-resistant prostate cancer patients underwent comprehensive genomic profiling testing between 1 January 2021 and 31 December 2022. Four types of comprehensive genomic profiling testing were selected, and clinically significant cancer-specific gene alterations were identified. RESULTS: The median age of patients was 74 years, and the median prostate-specific antigen value at the time of submission was 18.6 ng/ml. Fifty-seven (95%) of 60 cases were metastatic castration-resistant prostate cancers, and 3 cases (5%) were non-metastatic. Among all genetic alterations, androgen-receptor alteration was the most frequently detected in 17 cases (28.3%), followed by 15 cases of TP53 (25.0%), 14 cases of CDK12 (23.3%), 10 cases of phosphatase and tensin homolog (16.7%) and 9 cases of ATM (15.0%) mutations. A total of 13 patients (21.7%) received systemic therapy according to the comprehensive genomic profiling testing results. Overall, the survival rate was significantly greater in the group treated through systemic therapy based on comprehensive genomic profiling testing compared with the group without new therapeutic treatment (P = 0.041). CONCLUSIONS: Comprehensive genomic profiling testing is recommended in castration-resistant prostate cancer patients identified as resistant to standard therapy as this can provide a new therapeutic option.

Preoperative high serum total testosterone levels predict preserved postoperative sexual function in patients after nerve-sparing robot-assisted radical prostatectomy.

OBJECTIVE: To assess the association among preoperative total testosterone levels, postoperative sexual function, and prognosis after robot-assisted radical prostatectomy. METHODS: Patients who underwent robot-assisted radical prostatectomy in our institution were included in the study. Based on preoperative total testosterone levels, they were divided into low (<3.0 ng/mL) and high (≥3.0 ng/mL) total testosterone groups. Sexual function was evaluated using the International Index of Erectile Function scores, Expanded Prostate Cancer Index Composite scores, and the potency rate from preoperatively to 12 months after surgery. Oncological outcomes were evaluated based on biochemical recurrence. RESULTS: Out of 233 patients included, no significant difference in sexual function was found between the high (n = 183) and the low (n = 50) total testosterone groups at any point before or after surgery. However, in nerve-sparing cases, preservation in postoperative sexual function was observed only in the high total testosterone group (International Index of Erectile Function scores and Expanded Prostate Cancer Index Composite sexual function scores, at any point after surgery, p < 0.05; potency rate, at 3, 6, and 12 months after surgery; p < 0.05). Additionally, the high total testosterone group showed better biochemical recurrence-free survival than the low total testosterone group (p = 0.008). CONCLUSIONS: In the high total testosterone group, preservation in sexual function was observed after the nerve-sparing procedure, while the biochemical recurrence rate was low. Therefore, patients with high levels of total testosterone may be advised to consider nerve-sparing interventions.

Clinical characteristics and predictors of long-term postoperative urinary incontinence in patients treated with robot-assisted radical prostatectomy: A propensity-matched analysis.

OBJECTIVES: This study aimed to elucidate the clinical characteristics and predictors of long-term postoperative urinary incontinence (PUI) after robot-assisted radical prostatectomy (RARP). METHODS: This study included patients who underwent RARP at our institution and were stratified into PUI (≥1 pad/day) and continence (0 pad/day) groups at 60 months after RARP. A propensity score-matched analysis with multiple preoperative urinary status (Expanded Prostate Cancer Index Composite urinary subdomains, total International Prostate Symptom Score (IPSS), and IPSS-quality of life scores) was performed to match preoperative urinary status in these groups. Serial changes in urinary status and treatment satisfaction preoperatively and until 60 months after RARP were compared, and predictors of long-term PUI were assessed using multivariate logistic regression analysis. RESULTS: A total of 228 patients were included in the PUI and continence groups (114 patients each). Although no significant difference in preoperative urinary status was observed between the two groups, the postoperative urinary status significantly worsened overall in the PUI group than in the continence group. Treatment satisfaction was also significantly lower in the PUI group than in the continence group from 12 to 60 months postoperatively. Multivariate logistic regression analysis revealed that age (≥70 years) and biochemical recurrence (BCR) were significant predictors of the long-term PUI group (p < 0.05). CONCLUSIONS: Patients with long-term PUI had poor overall postoperative urinary status and lower treatment satisfaction than the continence group. Considering the age and risk of BCR is important for predicting long-term PUI when performing RARP.

Retrospective evaluation of the improvement in the urinary status-related quality of life after robot-assisted radical prostatectomy.

OBJECTIVES: This study aimed to investigate the characteristics of patients who report improvement in quality of life (QOL) related to urinary status after undergoing robot-assisted radical prostatectomy (RARP) for localized prostate cancer. METHODS: We retrospectively reviewed the patients who underwent RARP between May 2010 and May 2021 at our institution and were preoperatively unsatisfied with their urinary status. Patients were grouped as Group 1 (improved patients: "satisfied" with urinary status based on international prostate symptom score QOL [IPSS-QOL] = 0-2 at 12 months after RARP) and Group 2 (unimproved group: "unsatisfied"-IPSS-QOL 3-6). Additionally, the Expanded Prostate Cancer Index Composite (EPIC) urinary subdomains (urinary function, urinary bother [UB], urinary incontinence, and urinary irritation/obstruction [UIR]) and IPSS were evaluated preoperatively and till 12 months after RARP. RESULTS: Of the 237 patients, 72 (30.4%) were Group 1, and 165 (69.6%) were Group 2. Only UB and UIR improved at 12 months after RARP in Group 1, while other EPIC urinary subdomains remained unimproved at 12 months in both groups. On the other hand, IPSS improved at 12 months in both groups. Univariate and multivariate analysis revealed that the nerve-sparing, preoperative low IPSS (<11 vs. ≥11), and low IPSS-QOL (3 vs. 4-6) were associated with improvement in urinary status-related QOL (p < 0.05). CONCLUSIONS: Improvement in UB and UIR are important factors to ascertain improvement in urinary status-related QOL after RARP. Nerve-sparing and preoperative IPSS/IPSS-QOL values are useful predictors of this improvement.

[Postoperative Inguinal Hernia after Robot-Assisted Radical Prostatectomy with Prevention Technique Using Spermatic Cord Isolation].

We retrospectivelyevaluated postoperative inguinal hernias (PIHs) after robot-assisted radical prostatectomy(RARP) with a technique for preventing hernias byspermatic cord isolation. Among the RARPs performed from 2016 to 2018, 191 cases were evaluated 12 or more months after surgery. In all the cases, the peritoneum was isolated from the spermatic cord by5 cm or more as a hernia prevention technique during RARP. We compared the background factors between PIH-positive and PIH-negative groups. The PIH-positive group had a significantlylower bodymass index (BMI) than the PIH-negative group (20.6 kg/m2 vs 23.8 kg/m2, p＝0.0079), but there were no significant differences in other background factors. When patients were classified into three groups byBMI, low (＜21.9 kg/m2), intermediate (21.9 to 25.5 kg/m2), and high (＞25.5 kg/m2), the rate of PIH was 8.5% for the low group, 2.1% for the intermediate group, and 0% for the high group. Our findings suggest that incidences of inguinal hernias after the preventive technique of spermatic cord isolation in RARP, and the BMIs tended to be low in the hernia cases.

Prognostic Impact of the Modified 5-Item Frailty Index After Radical Nephroureterectomy in Patients With Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: The modified 5-item frailty index can be used to evaluate frailty using 5 routinely encountered clinical variables. This study aimed to assess the impact of the modified 5-item frailty index in patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma. PATIENTS AND METHODS: In this multicenter retrospective study, we calculated the modified 5-item frailty index scores of patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma between 2010 and 2022. Patients were categorized into the high (≥2) and low (≤1) modified 5-item frailty index score groups. To assess the prognostic influence of the preoperative modified 5-item frailty index, we conducted Cox proportional regression analyses concerning progression-free, overall, and cancer-specific survival. RESULTS: Of 434 patients, 82, and 352 were classified into the high and low modified 5-item frailty index score groups, respectively. The high modified 5-item frailty index score group had significantly higher rates of severe surgical complications (P = .038) and ≥30 days of hospitalization (P = .049) and significantly worse progression-free (P = .012) and overall survival (P = .002) than the low modified 5-item frailty index score group. The multivariable Cox proportional hazard analysis revealed that a high modified 5-item frailty index score was independently associated with poor progression-free (P = .044), overall (P = .017), and cancer-specific survival (P = .005). CONCLUSION: The modified 5-item frailty index emerged as a significant predictive indicator of severe surgical complications and postoperative survival outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy.

Centrality angle is a novel nephrometry score to predict tumor complexity and perioperative outcomes for partial nephrectomy.

To propose the centrality angle (C-angle) as a novel simple nephrometry score for the evaluation of tumor complexity and prediction of perioperative outcomes in nephron-sparing surgery (NSS) for renal tumors. The analysis was based on 174 patients who underwent robot-assisted partial nephrectomy retrospectively. C-angle was defined as the angle occupied by the tumor from the center of the kidney in the coronal CT images. Other nephrometry scores were calculated and compared with C-angle. Associations between C-angle and perioperative outcomes were examined. Significant differences were found in C-angle between tumors greater and less than 4 cm, exophytic and endophytic tumors, and hilar and non-hilar tumors. C-angle was correlated with other nephrometry scores, including RENAL, PADUA, and C-index. Significant positive correlations with WIT, operation time, and EBL, and significant negative correlations with preserved eGFR. C-angle could predict perioperative complications. Patients with a C-angle > 45° had worse perioperative outcomes, including longer operative time, longer WIT, lower rate of preserved eGFR, and complications. C-angle can be used to evaluate the complexity of renal tumors and predict perioperative outcomes. C-angle can potentially be used for decision-making in the treatment of patients and to guide surgical planning of NSS.

Muscle-Invasive Bladder Cancer With Hydronephrosis Exhibits a High Frequency of Mutations in Fibroblast Growth Factor Receptor 3 Gene.

BACKGROUND/AIM: Recent studies have reported conflicting findings regarding the significance of hydronephrosis (HN) in muscle-invasive bladder cancer (MIBC). The molecular characteristics of MIBC with HN are unclear, therefore, we aimed to address the gaps in previous research and elucidate HN's molecular significance in patients with MIBC. MATERIALS AND METHODS: Clinical, genetic, and imaging information on bladder cancer patients enrolled in The Cancer Genome Atlas were obtained from public databases to analyze the association between the presence of hydronephrosis and genetic alterations and molecular subtyping. A total of 108 patients who underwent total cystectomy for MIBC at the Hiroshima University Hospital were enrolled in the study to verify the association between HN and renal function with patient prognosis. RESULTS: We observed a statistically significant difference in the distribution of molecular subtypes (p=0.0146). The proportion of patients with the luminal papillary subtype was approximately twice as high in patients with HN (48.8%) than in those without HN (25.0%). The mutation frequency of fibroblast growth factor receptor (FGFR) 3 was approximately three-fold higher in patients with HN (20.9%) than in those without HN (7.1%). Multivariate analysis, which considered HN and estimated glomerular filtration rate as confounding factors in our MIBC cohort, revealed that reduced renal function, but not HN, was an independent predictor for overall survival. CONCLUSION: MIBC presenting HN exhibits a high frequency of mutations in the FGFR3 gene. In addition, not HN itself, but reduced renal function due to HN may worsen the prognosis for MIBC.

Enzalutamide versus Abiraterone Plus Prednisolone for Nonmetastatic Castration-Resistant Prostate Cancer: A Sub-Analysis from the ENABLE Study for PCa.

Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22-2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35-1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19-2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC.

Long-term efficacy of penile rehabilitation with low-intensity extracorporeal shock wave therapy for sexual and erectile function recovery following robotic-assisted radical prostatectomy: a single-cohort pilot study.

Background: The long-term efficacy of low-intensity extracorporeal shock wave therapy (LIESWT) for penile rehabilitation after robot-assisted radical prostatectomy (RARP) has not yet been reported. Aim: To assess the long-term efficacy of LIESWT for penile rehabilitation after RARP by evaluating the postoperative recovery of sexual and erectile functions following RARP. Methods: Patients who underwent RARP at our institution were categorized into 2 groups: those who received LIESWT and those who underwent penile rehabilitation with a phosphodiesterase type 5 inhibitor (PDE5i). The control group included patients who did not undergo penile rehabilitation. Potency and scores on the Expanded Prostate Cancer Index Composite for sexual function and 5-item International Index of Erectile Function (IIEF-5) were evaluated preoperatively and over 60 months after RARP. Outcomes: The LIESWT group had significantly higher postoperative sexual function and total IIEF-5 scores and potency than the control group over the long term, and its results were not inferior to those of the PDE5i group. Results: The LIESWT, PDE5i, and control groups comprised 16, 13, and 139 patients, respectively. As compared with the control group, the LIESWT group had significantly higher sexual function scores at 6, 12, and 60 months after surgery (P < .05) and total IIEF-5 scores at 24 and 60 months (P < .05). The LIESWT group also had a significantly higher potency rate than the control group at 60 months (P < .05). For all time points after surgery, there were no significant differences between the LIESWT and PDE5i groups in terms of sexual function and total IIEF-5 scores and potency. Clinical Implications: LIESWT may be a new option for penile rehabilitation in patients with erectile dysfunction after RARP. Strengths and Limitations: This pilot study was performed at a single center and involved relatively few patients, which may have led to selection bias. Furthermore, the selection of this study for penile rehabilitation was not made randomly but by the patient's choice. Despite these limitations, our results provide evidence in support of LIESWT for penile rehabilitation after RARP because this is the first study to assess the long-term efficacy of LIESWT. Conclusion: LIESWT can improve sexual and erectile functions in patients with erectile dysfunction after RARP, and its efficacy can be maintained over a long period after surgery.

Comparison of surgical outcomes and split renal function between laparoscopic and robot-assisted partial nephrectomy: a propensity score-matched analysis.

PURPOSE: The objective of this study was to compare perioperative outcomes and total and split renal function between laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN). Predictive risk factors of preservation of operated renal function were also assessed. METHODS: We retrospectively analyzed 173 patients who underwent LPN (n = 84) or RAPN (n = 89) between 2010 and 2020. After propensity score matching (1:1), perioperative outcomes and total and split renal function were assessed. Logistic regression analysis was used to evaluate predictive risk factors of preservation of operated renal function. Trifecta criteria were defined as negative surgical margins, warm ischemia time (WIT) < 25 min, and no complications more than Clavien-Dindo grade II within 4 weeks after surgery. Split renal function was evaluated by mercaptoacetyltriglycine renal scan. RESULTS: After propensity score matching, 42 patients were allocated to each group. RAPN was associated with significantly shorter WIT (RAPN vs LPN: 12 vs 22 min; p < 0.0001) and higher trifecta achievement rate (93.3 vs 64.2%; p < 0.0001). Other perioperative outcomes and total and split renal function were not significantly different between LPN and RAPN. The R.E.N.A.L. nephrometry score (RNS) was a predictive risk factor of preservation of operated renal function in the multivariable logistic regression analysis (odds ratio 1.68, 95% confidence interval 1.29-2.20, p < 0.0001). CONCLUSIONS: RAPN improved WIT and trifecta achievement rate, but it did not improve the preservation of operated renal function, for which RNS was found to be a strong predictive risk factor.

Complexity in radiological morphology predicts worse prognosis and is associated with an increase in proteasome component levels in clear cell renal cell carcinoma.

Background: We previously reported preoperative radiological morphology (RM) as an independent predictor for pathological upstaging after partial nephrectomy in patients with T1 renal cell carcinoma (RCC). Purpose: To investigate the prognostic importance of RM in all stages and the molecular characteristics underlying the differences between each type of RM in patients with clear cell RCC (ccRCC). Design setting and participants: The Cancer Imaging Archive datasets (TCIA), comprising CT images and RNA-sequencing data, were used (n = 163). Specimens from 63 patients with ccRCC at our institution and their CT images were used. All images were divided into three types according to RM classification. Outcome measurements and statistical analysis: Relationships with outcome were analyzed using Cox regression analysis and log-rank test. Results and limitations: The irregular type was a significant independent predictor of worse disease-free survival (odds ratio: 2.22, p = 0.037) compared to round and lobular types in TCIA datasets. The irregular type showed a significant increase in both mRNA and protein expression of proteasome components, PSMB1 and PSMB3. Moreover, high expression of their coding genes shortened the progression-free survival of the patients with ccRCC who received sunitinib or avelumab plus axitinib therapy. The study limitations include the qualitative classification of RM and the need for novel radiomics and texture analysis techniques. Conclusions: Investigating RM on pre-treatment CT scans can effectively predict worse prognosis. Increased RM complexity may indirectly predict drug sensitivity via increased expression of PSMB1 and PSMB3 in patients with ccRCC. Specific targeting of the ubiquitin-proteasome system might be a novel treatment strategy for ccRCC with increased RM complexity. Patient summary: The clinical and morphological characteristics of patients with ccRCC vary greatly according to cancer staging. In this study, we built upon our prior findings of the prognostic importance of RM in T1 RCC and expanded it to encompass all stages of RCC, using a series of patients from a Japanese hospital.

[ROBOT-ASSISTED RADICAL CYSTECTOMY AT HIROSHIMA CITY ASA HOSPITAL -COMPARISON WITH LAPAROSCOPIC RADICAL CYSTECTOMY].

(Objective) We compared the perioperative parameters of robot-assisted radical cystectomy (RARC) and laparoscopic radical cystectomy (LRC) to evaluate the utility of RARC. (Patients and methods) At Hiroshima City Asa Hospital, 25 patients underwent RARC from July 2018 to May 2020 (R group) and 79 patients underwent LRC from July 2012 to June 2018 (L group). We retrospectively compared the patient characteristics, perioperative outcomes, and pathological outcomes between the R group and the L group. (Results) Regarding the patient characteristics, the R group had significantly more neo-adjuvant chemotherapy than the L group (64.0% vs. 32.9%, P=0.009), but the other characteristics did not differ. Between the R group and the L group, there were no significant differences in the total operating time (R group = 400 minutes vs. L group = 421 minutes), estimated blood loss (R group = 228 ml vs. L group = 318 ml), or pathological outcomes. However, there were significantly less postoperative complications in the R group than in the L group (24.0% vs. 52.6%, P=0.020). (Conclusion) This study showed that there might be benefits to introducing RARC into medical centers that perform LRC.