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Background: To investigate the impact of different urinary diversion (UD) techniques on the peri- and postoperative complications of robot-assisted radical cystectomy (RARC) with ileal conduit., Methods: We retrospectively analyzed 373 patients undergoing RARC with ileal conduit at 11 institutions in Japan between April 2018 and December 2021. Propensity score weighting was performed to adjust for confounding factors such as age, sex, body mass index, performance status, American Society of Anesthesiologists score, previous abdominal surgery, neoadjuvant chemotherapy, and preoperative high T stage (≥ cT3) and high N stage (≥ cN1). Perioperative complications were then compared among three groups: extracorporeal, intracorporeal, and hybrid urinary diversion (ECUD, ICUD, and HUD, respectively)., Results: A total of 150, 68, and 155 patients received ECUD, HUD, and ICUD, respectively. Bowel reconstruction time and UD time were significantly shorter in the ECUD group (p < 0.001), and console time was significantly longer and blood loss was significantly higher in the ICUD group (p < 0.001). For postoperative complications (Clavien-Dindo Classification grade ≥ 3), surgical site infection (p = 0.004), pelvic abscess (p = 0.013), anastomotic urine leak (p = 0.007), and pelvic organ prolapse (p = 0.011) significantly occurred in the ECUD group. For all grades, ileus was more common in the HUD group, whereas anastomotic stricture was more common in the ECUD group compared with the other groups (p < 0.05)., Conclusions: Severe complications did not increase after HUD and ICUD compared with ECUD; however, console time tended to be longer and blood loss was slightly higher during RARC., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Cabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment., Methods: Japanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses., Results: In total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1-131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1-40.6). Kaplan-Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4-18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6-85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline., Conclusions: Updated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219., (© 2023. The Author(s).)

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan., Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints., Results: The Japanese subgroup comprised 94 patients (pembrolizumab-axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6-37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab-axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab-axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab-axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab-axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred., Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population., (© 2021. The Author(s).)

Background: Based on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics., Methods: This non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs)., Results: In the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population., Conclusion: In a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.

Objectives: To determine risk factors influencing the incidence of parastomal hernia (PH) associated with ileal conduit (IC)., Methods: A total of 194 Japanese patients who underwent IC diversion followed by regular postoperative radiographic follow-up from 2005 through 2016 were enrolled. The diagnosis of PH was determined by computed tomography (CT) for patients with and without related symptoms. The cumulative incidence of PH was assessed by the Kaplan-Meier method. The log-rank test and a multivariate Cox proportional hazards model were used to evaluate risk factors associated with the incidence of PH., Results: PH was observed in 20 patients (10.3%) after a median follow-up of 25.5 months. Of the 20 patients, three were symptomatic. The cumulative incidences were 3.6%, 10.1% and 15.1% at 1, 2 and 5 years after operation, respectively. The median body mass index (BMI) was 23.1 kg/m 2 (IQR 20.4-24.6). The BMI and diameter of the passage through the rectus abdominis muscle for the IC (DPRAM) were significant predictors for PH (p = 0.04 and p < 0.001, respectively). In proportional hazards regression analysis, DPRAM ≥ 2.4 cm was the only independent risk factor for developing PH (HR 10.94, 95% CI 3.66-32.64)., Conclusions: The incidence of PH in the current Japanese series was relatively low. Even in the population with low BMI, higher BMI might have an impact on incidence of PH. Moreover, DPRAM was also significantly associated with the incidence, suggesting that the operative procedure for creation of the passage is critical for future development of PH.

Background: Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC., Methods: Patients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality., Results: Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5)., Conclusions: In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

Purpose: We prospectively evaluated the 90-day postoperative mortality and morbidity of open radical cystectomy by using a standardized reporting methodology. Additionally, we assessed the preoperative characteristics to determine risk factors for major complications., Methods: This multicenter prospective study included 185 consecutive patients undergoing open radical cystectomy from October 2010 through March 2014. Postoperative complications within 90 days were recorded and graded according to the modified Clavien-Dindo classification., Results: Totally, 328 postoperative complications were observed in 149 patients (80.5%). Of these events, 73 (22.2%) were high grade (≥ Grade III), and developed in 46 patients (24.9%). Three patients (1.6%) died postoperatively. Urinary tract infection, wound complications, and paralytic ileus were common complications that occurred in 55 (29.7%), 42 (22.7%) and 41 (22.2%) patients, respectively. Ureteroenteric stricture was diagnosed in 13 of the 151 patients (8.6%) undergoing intestinal urinary diversion. Emergency room visits were required for 13 patients (7.0%) and readmission after discharge was needed for 36 (19.5%). A body mass index ≥ 25 kg/m 2 , smoking history and Charlson Comorbidity Index ≥ 2 were independent risk factors for high-grade complications, and their odds ratios (95% confidence intervals) were 2.357 (1.123-4.948), 2.843 (1.225-6.596) and 3.025 (1.390-6.596), respectively., Conclusions: Open radical cystectomy is associated with a high incidence of postoperative complications. Most, however, are of low grade. Our results suggest that obesity, a smoking history, and increasing comorbidity are risk factors for major complications.

Background: Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases., Methods: In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period., Results: Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was -19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%)., Conclusions: Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial., Clinical Trial Registration: ClinicalTrials.gov NCT01929655.

Objective: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis., Methods: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months., Results: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups., Conclusions: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Objectives: The aims of this study were to clarify the frequency and prognosis of febrile neutropenia (FN) in patients who received urological anticancer chemotherapy., Methods: Between May 2005 and January 2010, 141 patients underwent urological anticancer chemotherapy at the Sapporo Medical University Hospital, Sapporo, Japan. They consisted of 124 men and 17 women aged 62 (range 16-80) years. The patients underwent a total of 626 treatment courses of urological anticancer chemotherapy., Results: Of the 626 urological anticancer chemotherapy courses, grades 3 and 4 neutropenia occurred in 451 (72.0 %) courses. FN developed in 57 (9.1 %) courses in which 7 (12.3 %) and 50 (87.7 %) patients were classified as high risk and low risk, respectively, according to the Multinational Association for Supportive Care in Cancer (MASCC) risk index scoring system. There was no anticancer chemotherapy-related death in either the high- or low-risk group. The frequencies of bacteria isolated from courses with FN were 0 and 10.0 % for the high- and low-risk groups, respectively., Conclusions: According to the MASCC scoring system, there were fewer patients in the high-risk group than in the low-risk group in this study. There were no cases of anticancer chemotherapy-related death in either group. Therefore, urological anticancer chemotherapy can be conducted safely with the proper management of neutropenia and FN.

Background: To evaluate the clinical outcomes of urothelial carcinoma of the prostate (UCP)., Materials and Methods: This retrospective study included a total of 46 patients with UCP detected in radical cystectomy specimens from 1990 to 2006. All patients were stratified by patterns for extension of UC from the bladder and invasion of the prostatic stroma. The overall survival rates of patients were determined by pathological variables of radical cystectomy specimens., Results: Of the 46 patients with UCP, 34 (74 %) and 12 (26 %) had prostatic stromal and no stromal involvement, respectively. Of 34 patients with UC having prostatic stromal involvement, 22 had contiguous involvement from bladder cancer. Twenty-four patients (52.1 %) had non-contiguous UCP, and of these, 12 (50 %) had UC of the prostatic stroma. UCP patients with prostatic stromal invasion showed a significantly worse prognosis than those without stromal invasion (P = 0.0108). There was no significant difference in survival between patients with contiguous and non-contiguous involvement (P = 0.0877). Patients with non-contiguous UCP (prostatic urethral cancer) showed poor prognosis if the UC invaded into the prostatic stroma and lymph node metastasis was present. Multivariate analysis revealed that these 2 variables were factors that significantly affected the clinical outcome of these patients., Conclusions: Patients having UCP with stromal invasion of the prostatic urethra showed much worse prognosis than those without stromal invasion regardless of extension patterns from UC of the bladder. In prostatic urethral cancer, prostatic stromal invasion and lymph node metastasis were significant prognostic factors.

Objective: We evaluated the outcome of renal cell carcinoma (RCC) after surgery in a long-term follow-up study to elucidate the specific biological behaviors of RCC, such as late recurrence and late cancer-specific death., Materials and Methods: We retrospectively reviewed the clinical and pathological features of 625 patients who were diagnosed as having renal cell carcinoma at our institution from 1975 to 2006. We analyzed the parameters and outcomes for the patients who had received radical or partial nephrectomy. Pathological staging was reviewed again by two pathologists., Results: The median age of the patients was 61 years (range 16-87). The median follow-up was 7.0 years (range 0.1-30.3). Of the 516 patients with localized or locally advanced RCC, 124 (24.0 %) had recurrence after surgery. Lung metastasis was observed most frequently. The 10-year cancer-specific survival rates were 92.4, 91.0, 64.1 and 11.8 % for stages I, II, III and IV, respectively. The late recurrence rates in patients with localized and locally advanced RCC 5 and 10 years after initial surgery were 8.5 and 3.7 %, respectively. Cancer death more than 10 years after initial treatment of the disease occurred in 16 patients. Of the 16 patients, 9 had localized disease at the time of the initial surgery. Specific findings that characterized them were not identified in these patients., Conclusions: Late recurrence of RCC is not rare. Cancer-specific death more than 10 years after the initial treatment was observed in 16 patients with localized or advanced disease. No specific findings were identified to characterize these patients with late cancer death.

Background: We retrospectively investigated short-term functional and oncological outcomes of partial nephrectomy (PN) for the anatomically or functionally solitary kidney in patients with renal cell carcinoma., Methods: Between 1993 and 2011, 193 partial nephrectomies were performed and 16 (8.3 %) had an imperative indication in our institution. The patients' characteristics, peri- and postoperative complications, surgical margin status and postoperative changes in estimated glomerular filtration rates (eGFR) were assessed., Results: The median follow-up period was 31.2 months and median age was 69.5 years. Open and laparoscopic PN were performed for 13 and 2 patients, respectively. One patient received ex-vivo PN followed by autotransplantation. There was no case with a positive surgical margin. All patients survived at the final day of observation. Median preoperative eGFR was 48.67 mL/min/1.73 m(2) and the reduction rate of eGFR at 3 months after operation was 20.9 % (0-50.2). Three patients (18.8 %) required temporary hemodialysis after operation and all these patients had stage 4 chronic kidney disease (CKD) before operation. Only one patient needed chronic hemodialysis at 8 months after operation., Conclusions: PN can be performed safely and provides feasible functional and oncological outcomes. Preoperative CKD stage 4 patients may have a risk of temporary hemodialysis in the perioperative period.

Background: Resection of the inferior vena cava (IVC) is occasionally performed for patients with advanced malignancy in the retroperitoneum. In the current study, we assessed the oncological effectiveness of IVC resection combined with tumor resection. We also addressed peri- and postoperative complications associated with resection and reconstruction of the IVC., Methods: Between 1984 and 2011, a total of 23 patients underwent caval resection concurrently with retroperitoneal tumor excision. Primary tumor histology was renal cell carcinoma in 19 patients, metastatic germ cell tumor in 2, and leiomyosarcoma, and adrenal cancer in 1 patient each. Clinicopathological data from these patients were retrospectively reviewed., Results: IVC reconstruction was performed by direct suture in 11 patients, patch repair in 8 and graft replacement in 3 patients. Interruption of the IVC was performed in one patient. There was no lethal complication or pulmonary embolism. Intracaval thrombosis, although patent, was observed in four patients after surgery. All patients underwent infrarenal IVC reconstruction. The median follow-up was 12 months (range 1-121 months). Of the 20 patients without distant metastasis at the time of surgery, complete resection was achieved in 14, whereas 6 patients had positive margins. Although nine patients developed distant metastases postoperatively, there was no local recurrence. The overall survival, progression-free survival and cause-specific survival in those RCC patients without distant metastasis at the time of surgery were 56.1, 47.0 and 60.4%, respectively, at 5 years., Conclusions: For advanced malignancies involving the IVC, resection is a safe and feasible procedure for selected patients.

Background: This study retrospectively evaluated the clinical relevance of transurethral prostate biopsy (TUPB) before radical cystectomy by comparing the pathology of prostatic urethra biopsy specimens with that of cystectomy specimens., Methods: Of 294 patients who underwent cystectomy and urinary diversion, 101 men with preoperative TUPB were included in this study. For these patients, if the result of TUPB was positive for urothelial carcinoma, we performed urethrectomy as a rule. If it was negative, we presented the option of urethral preservation and decided the final type of urinary reconstruction. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of TUPB were assessed, and we investigated the number of final urethral recurrences. We also tried to identify which clinical and pathological findings by TUPB most accurately predicted the disease remaining in the prostate of cystectomy specimens., Results: Of the 25 patients with positive TUPB, 18 had disease in the prostatic urethra or stroma of cystectomy specimens. There were 3 patients with negative TUPB but with involvement of the prostate in cystectomy specimens. Thus, TUPB achieved 86% sensitivity, 91% specificity, 72% PPV, and 96% NPV. Two patients (1.9%) had urethral recurrence in this period. Among the findings for TUPB, non-papillary tumors most accurately predicted the disease in the prostate of cystectomy specimens., Conclusions: TUPB achieved a high NPV and the urethral recurrence rate was acceptable. If TUPB was negative, patients could have chance urethral preservation. Thus, our clinical decision for urethrectomy based on the result of TUPB is still useful.

Background: The aim of this study was to evaluate the distribution of lymph node metastasis in extended lymphadenectomy for patients with bladder cancer., Methods: We analyzed 31 patients who underwent extended lymphadenectomy at radical cystectomy for bladder cancer between April 2008 and February 2010. Specimens were evaluated as 14 separate packages from predesignated anatomical locations. The lymph node mapping was prospectively registered., Results: The median lymph node count was 37 (range 19-68). Ten (32%) patients had lymph node metastasis. The positive rates at each lymph node site were 0% at the left internal iliac, 13% at the left obturator, 3.2% at the left external iliac, 6.5% at the right internal iliac, 10% at the right obturator, 16% at the right external iliac, 3.2% at the left common iliac, 3.2% at the right common iliac and 6.5% at the presacral node. No lymph node metastasis was detected in the Cloquet, paracaval, aortocaval or paraaortic nodes. One (3.2%) patient had a skip metastasis from the left obturator to the presacral node., Conclusions: Extended lymphadenectomy provides more accurate lymph node staging. We suggest that it is better to perform lymphadenectomy at least below the aortic bifurcation including the presacral node.

Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the gold standard for treatment of muscle-invasive bladder cancer. Recent retrospective series suggest that extended PLND provides a survival benefit, probably by removing undetected micrometastases. There have been several studies suggesting the survival benefit of extended PLND, not only for patients with node-negative disease but also for those who are node positive. The optimal boundaries of PLND seem to be at least up to the level of aortic bifurcation, including Marcille's fossa, under the present circumstances. Because retrieval of more lymph nodes may help to improve the prognosis of patients, careful approaches should be considered both surgically and pathologically. PLND should be performed for all patients who undergo RC. Prospective randomized studies will give us the answer to the question of whether extended PLND should be performed routinely.