Real-world data on the comprehensive genetic profiling test for Japanese patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: comprehensive genomic profiling test has been covered by Japanese health insurance since June 2019. However, no real-world data on the test have been reported with a focus on Japanese patients with prostate cancer. METHODS: we retrospectively reviewed the data of 45 consecutive patients with metastatic castration-resistant prostate cancer, who underwent the comprehensive genomic profiling tests at Kitasato University Hospital between August 2019 and December 2022. Patients' characteristics, prevalence of gene alterations and therapeutic impact of genotype-matched therapy were assessed. RESULTS: genomic data were obtained using a tissue-based test (n = 32) and liquid-based test (n = 13). Actionable genomic alternations were identified in 51.1% of patients, and 22.2% were treated with genotype-matched therapy. The main reason for not receiving genotype-matched therapy was disease progression, accounting for 46.2% (6/13). Kaplan-Meier analysis showed significantly longer overall survival after the comprehensive genomic profiling tests in patients with genotype-matched therapy under public insurance (17.8%, n = 8) than those without it (median: not reached vs. 18.1 months; P = 0.003). Five (62.5%) out of the eight patients with genotype-matched therapy under public insurance had BRCA1 or 2 deleterious alteration. Multivariate analyses showed that BRCA deleterious alteration (17.8%, n = 8) was an independent risk factor for shorter time to castration-resistant prostate cancer (hazard ratio: 2.46, 95% confidence interval: 1.04-5.87; P = 0.041), and no patients with the alteration had ≤5 bone metastases. CONCLUSIONS: the results of this study showed the promising survival outcomes in patients with genotype-matched therapy under public insurance, even in the castration-resistant prostate cancer setting. Further detection of promising therapeutic target gene is expected to increase the number of patients who reach genotype-matched therapies.

Real-world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan.

OBJECTIVES: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre-enfortumab vedotin era, many patients could not receive third-line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real-world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third-line treatment. METHODS: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. RESULTS: At the median follow-up of 28.5 months, the median overall survival from first-line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second- and third-line treatment. Notably, 52% had their treatment terminated before the opportunity for third-line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil-to-lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first-line treatment were independent risk factors for not proceeding to third-line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. CONCLUSIONS: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects.

Patients with Non-Muscle-Invasive Bladder Cancer Previously Treated with Nephroureterectomy Have a High Risk of Recurrence after Bacillus Calmette-Guérin Intravesical Instillation Therapy.

BACKGROUND: There is a high incidence of intravesical recurrence after transurethral resection of bladder tumor for non-muscle-invasive bladder cancer (NMIBC). Intravesical instillation of bacillus Calmette-Guérin (BCG) is widely used to prevent recurrence and progression. There are two types of NMIBC: primary NMIBC and subsequent NMIBC after radical nephroureterectomy (RNU). We compared the clinical outcomes of BCG intravesical instillation therapy between the two types of NMIBC. PATIENTS AND METHODS: This study included a total of 357 patients, who received BCG intravesical instillation therapy to prevent recurrence of NMIBC (pTa/pT1) between 1991 and 2019. Among them, 34 patients had subsequent NMIBC after RNU, and the remaining 323 patients had primary NMIBC. This retrospective study analyzed 68 patients extracted by propensity score matching. Survival curves were estimated using the Kaplan-Meier method, and independent prognostic factors for survival were examined by the Cox proportional hazards model. RESULTS: The 3-year recurrence-free survival (RFS) rates in patients with primary NMIBC and subsequent NMIBC after RNU were 70.7% and 54.8%, respectively (p = 0.036). However, there were no significant differences between the two groups in progression-free survival and cancer-specific survival. Multivariate analysis of RFS showed that only a previous history of upper tract urothelial carcinoma was an independent prognostic and predictive factor. CONCLUSION: Patients with subsequent NMIBC after RNU treated with BCG intravesical instillation therapy have a higher risk of recurrence than those with primary NMIBC. Thus, stringent follow-up is necessary for patients with subsequent NMIBC after RNU.

Efficacy of Intravesical Instillation Therapy with Low-Dose Tokyo-172 Bacillus Calmette-Guérin to Prevent Recurrence of Non-Muscle-Invasive Bladder Cancer and Treat Carcinoma in situ: A Multi-Institutional Retrospective Study.

INTRODUCTION: There are various doses, durations, and strains of bacillus Calmette-Guérin (BCG) intravesical instillation therapy, but optimal treatment has not yet been established. We retrospectively investigated the efficacy and safety of low-dose BCG therapy for non-muscle-invasive bladder cancer (NMIBC) and carcinoma in situ (CIS) in a multicenter study. METHODS: From 1991 to 2019, 323 patients who received BCG therapy to prevent recurrence of NMIBC were analyzed as group A. Similarly, 147 patients who received BCG therapy for the treatment of CIS were analyzed as group B. Patients received low- or full-dose Tokyo-172 strain or full-dose Connaught strain, and the three strains were compared. Survival curves were estimated by the Kaplan-Meier method, and independent risk factors for intravesical recurrence were examined by multivariate logistic regression. RESULTS: Recurrence-free survival (RFS) in group A was significantly better for the Connaught strain than the low-dose Tokyo-172 strain (p = 0.026), but not between the low- and full-dose Tokyo-172 strains (p = 0.443). RFS of group B, cancer-specific survival, and progression-free survival in both groups did not show statistically significant differences. Logistic analysis of group A showed that for intravesical recurrence, only pT1 was a significant risk factor, and there were no differences between the BCG strain and dose and no significant factors in group B. There were also no differences in the completion rate in both groups, but adverse events such as urinary frequency and feeling of residual urine were significantly lower with the low-dose Tokyo-172 strain. CONCLUSION: There was no difference in efficacy between the low- and full-dose Tokyo-172 strains, but to minimize adverse events, the low-dose Tokyo-172 strain may be worth considering.

Real-world treatment patterns and oncological outcomes in early relapse and refractory disease after bacillus Calmette-Guérin failure in non-muscle-invasive bladder cancer.

OBJECTIVE: To assess real-world oncological outcomes between the radical cystectomy (RC) group and non-RC group for early relapse and refractory disease. METHODS: We retrospectively analyzed 953 patients with recurrent non-muscle-invasive bladder cancer (NMIBC) who received bacillus Calmette-Guérin (BCG) at 31 affiliated hospitals from 2000 to 2019. Patients with missing data on the timing of failure were excluded and 871 patients remained eligible, of whom 447, 357, and 67 were classified as early relapse/refractory disease, intermediate/late relapse disease, and intolerant disease, respectively. For early relapse/refractory disease, patients were divided into two salvage treatment groups: RC and non-RC. The clinicopathological variables of each group were examined using Kaplan-Meier plots and proportional Cox hazard ratios with matched score analyses to compare oncological outcomes between the two groups. RESULTS: Significantly worse progression-free survival and cancer-specific survival (CSS) were confirmed in the early relapse/refractory disease group compared to the intermediate/late relapse group. Of the 88 salvage patients in the RC group with early relapse/refractory disease, ≤pT1 was observed in 47, pT2 in 11, and ≥pT3 in 28 (two patients with unknown pT category). In early relapse/refractory disease, the RC group showed significantly high-risk tumor compared to the non-RC group. However, no significant difference was observed in CSS after matched score analyses (p = 0.45) between the RC and non-RC groups. CONCLUSIONS: This study found that the RC group showed no significant superiority compared to the non-RC group in CSS for early relapse/refractory disease in terms of first salvage therapy.

[Clinical Outcome of Microsatellite Instability-High Patients Treated with Pembrolizumab and Genetic Counseling].

Prospective studies have demonstrated the efficacy of pembrolizumab in patients with previously treated unresectable or metastatic microsatellite instability-high(MSI-H)cancers. Pembrolizumab has been covered by the Japanese health insurance system since December 2018. The frequency of MSI-H in patients is as low as approximately 2%. In addition, some patients with MSI-H cancers are diagnosed with Lynch syndrome. In the present study, we retrospectively investigated patients who received MSI testing at Kitasato University Hospital from April 2019 to June 2020. We also investigated the therapeutic effect of pembrolizumab for MSI-H cancers and patients who received genetic counseling for Lynch syndrome. Results identified that 5 out of 263 patients who underwent MSI testing(1.9%)had MSI-H. The therapeutic outcomes of pembrolizumab in those patients were as follows: 1(20%)complete response, 3(60%)partial response, and 1(20%) progressive disease. The positive-outcome rate of MSI-H treatment in our institution was comparable to that in the previous reports. The high response rate of pembrolizumab was confirmed in the present study. Four out of 5 patients received genetic counseling at the genetic clinic, and 1 patient underwent genetic testing for Lynch syndrome. No deleterious variant of Lynch syndrome was detected in the genetic testing.

[Recurrent Urothelial Carcinoma in the Uretero-Vesical Junction Treated with Partial Ureterectomy and Ureteroneocystostomy during Long-Term Follow-Up : A Case Report].

A 54-year-old woman who had been treated with transurethral resection of bladder tumor for nonmuscle invasive urothelial carcinoma approximately nine years before presented with gross hematuria. Cystoscopy demonstrated a papillary tumor at the left side of the ureteral orifice. Magnetic resonance imaging showed a 1.3 cm non-muscle invasive lesion in the lower ureter from the ureteral orifice. She suffered from connective tissue disease treated with steroids. To avoid renal failure, we performed partial ureterectomy and ureteroneocystostomy. Pathological findings revealed pT1 urothelial carcinoma with negative surgical margin. There have been no signs of recurrence during eight years of follow-up after the last treatment.

[A Case of Hydrocephalus Due to Brain Metastasis from Renal Cell Carcinoma Successfully Treated with Axitinib].

We report a case of hydrocephalus due to brain metastasis from renal cell carcinoma treated with axitinib. A 65-year-old man had undergone right radical nephrectomy for renal cell carcinoma in 2010. The pathological diagnosis indicated clear cell carcinoma G3, pT1a. After adjuvant treatment with interferon-α, computed tomography, in 2011, revealed multiple lung metastases. He was administered sorafenib. Because of progressive lung metastases, sunitinib was administered. The lung metastases were progressive and bone scan revealed multiple bone metastases. The patient was administered axitinib 10 mg/day in February 2014. Brain metastases were found in both the lateral ventricles in the same month and were controlled using axitinib. The patient, however, experienced adverse events such as diarrhea and hand foot syndrome, and the axitinib dosage was titrated. Cognitive function declined rapidly in August 2015. Brain magnetic resonance imaging revealed hydrocephalus due to brain metastasis from renal cell carcinoma. Axitinib was administered again. Cognitive function improved within approximately 10 days. Furthermore, hydrocephalus improved, and the patient was discharged on the 21st day.

[A Case of Emphysematous Pyelonephritis with Pneumoderma Treated by Open Surgical Drainage].

Emphysematous pyelonephritis (EPN) is an acute, severe necrotizing infection of the renal parenchyma and perirenal tissue. A 72-year-old female patient with uncontrolled diabetes mellitus was admitted to a hospital with loss of consciousness and, fever. Laboratory data suggested acute inflammation and hyperosmolar hyperglycemic syndrome. The left EPN was accurately diagnosed after abdominal computed tomographic (CT) scan revealed renal parenchymal gas and fluid within the subcutaneous tissue and mediastinum. The patient was transferred to our institution and underwent emergent open surgical drainage. However, a CT scan performed 3 days after the drainage revealed the presence of fluid in the left perinephric space. CT-guided drainage of the left perinephric fluid was performed. The patient was finally discharged after complete recovery from severe inflammation.

A multi-institutional retrospective study of open versus laparoscopic nephroureterectomy focused on the intravesical recurrence.

AIM: Intravesical recurrence (IVR) after nephroureterectomy for upper tract urothelial carcinoma (UTUC) is relatively frequent, occurring in about 30-50% of patients. The aim of this study was to investigate the differences of the prognosis and IVR between open and laparoscopic surgery and to elucidate the risk factor of IVR. PATIENTS AND METHODS: We retrospectively analyzed data from 403 patients with UTUC treated with laparoscopic or open nephroureterectomy at six affiliated hospitals between 1990 and 2015. The clinicopathological factors of each group were examined using Kaplan-Meier plots, and univariate and multivariate analyses. RESULTS: There was no difference in recurrence and cancer-specific mortality between open and laparoscopic surgery in univariate and multivariate analyses. There was no significant difference in IVR rate between the laparoscopic and open groups (p = .22). Among the patients with IVR, 84% of patients relapsed within 2 years. Univariate analysis of IVR showed a significant increase in patients with low-grade (p = .03, HR = 1.64) or low-stage urothelial carcinoma (pT1 or lower, p = .006, HR = 1.77) with no lymph node involvement (p = .002, HR = 10.3) or lymphovascular invasion (p = .009, HR = 1.79). Surgical modality was not an independent factor. In multivariate analysis, there was no independent predictive factor for IVR. CONCLUSIONS: There was no difference in recurrence, cancer-specific mortality, and IVR between open and laparoscopic surgery. On the other hand, our results suggested that the low malignant potential tumor may be a risk factor for IVR. This finding provides insight into IVR, which may help with the development of personalized prevention and treatment strategies.

Expression of Membranous CD155 Is Associated with Aggressive Phenotypes and a Poor Prognosis in Patients with Bladder Cancer.

Objective: To investigate the relationship between clinicopathological findings and membranous CD155 (mCD155) or cytoplasmic CD155 (cCD155) expression in bladder cancer (BC). Methods: We retrospectively analyzed 103 patients with BC who underwent radical cystectomy between 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining was performed to evaluate CD155 expression in tumor cells. Cases with > 10% expression on the membrane or cytoplasm of tumor cells were positive. The Fisher's exact test was used for categorical variables and the Kaplan−Meier method was used for survival outcomes. Univariate and multivariate Cox regression hazard models were used to evaluate the survival risk factors. Results: Cases that were mCD155-positive were associated with high-grade tumors (p = 0.02), nodal status (p < 0.01), and pT stage (p = 0.04). No association with any clinicopathological factor was observed in the cCD155 cases. Kaplan−Meier analysis showed that mCD155-positive cases had shorter periods of recurrence-free survival (p = 0.015) and cancer-specific survival (p = 0.005). Only nodal status was an independent predictor for both cancer-specific survival and recurrence-free survival in multivariate analysis (p = 0.02 and p < 0.01, respectively). Conclusion: mCD155 expression may be a marker of an aggressive phenotype and a poor prognosis in patients with BC.

Serum Epiplakin Might Be a Potential Serodiagnostic Biomarker for Bladder Cancer.

Tumor markers that can be detected at an early stage are needed. Here, we evaluated the epiplakin expression levels in sera from patients with bladder cancer (BC). Using a micro-dot blot array, we evaluated epiplakin expression levels in 60 patients with BC, 20 patients with stone disease, and 28 healthy volunteers. The area under the curve (AUC) and best cut-off point were calculated using receiver-operating characteristic (ROC) analysis. Serum epiplakin levels were significantly higher in patients with BC than in those with stone disease (p = 0.0013) and in healthy volunteers (p < 0.0001). The AUC-ROC level for BC was 0.78 (95% confidence interval (CI) = 0.69-0.87). Using a cut-off point of 873, epiplakin expression levels exhibited 68.3% sensitivity and 79.2% specificity for BC. However, the serum epiplakin levels did not significantly differ by sex, age, pathological stage and grade, or urine cytology. We performed immunohistochemical staining using the same antibody on another cohort of 127 patients who underwent radical cystectomy. Univariate and multivariate analysis results showed no significant differences between epiplakin expression, clinicopathological findings, and patient prognoses. Our results showed that serum epiplakin might be a potential serodiagnostic biomarker in patients with BC.

PD-L1 expression in tumor-infiltrating lymphocytes (TILs) as an independent predictor of prognosis in patients with pN0 bladder cancer undergoing radical cystectomy.

OBJECTIVES: Checkpoint inhibitors have led to a paradigm shift in urothelial carcinoma (UC) treatment. However, the relationship between PD-L1 expression status and oncological outcomes in UC patients remains uncertain. Here, we investigated the prognostic value of PD-L1 expression status in patients with UC of the bladder (UCB) who underwent radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively analyzed pathological specimens from 97 UCB patients treated with RC from 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining using SP263 was performed to evaluate PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). Kaplan-Meier plots and proportional Cox hazard ratios were examined to assess the relationship between PD-L1 expression and clinicopathological parameters and survival outcomes. RESULTS: Of the 97 specimens, 19.5% contained PD-L1-positive TCs, and 35.0% contained PD-L1-positive TILs. Regarding clinicopathological factors, PD-L1-positive TCs and TILs were significantly associated with high-grade tumors (TCs, P = 0.01; TILs, P = 0.003). Kaplan-Meier analyses showed that PD-L1-positive TCs were not correlated with survival rates. However, PD-L1-positive TILs were significantly associated with better recurrence-free survival (RFS; P = 0.03) and better cancer-specific survival (CSS; P = 0.02). Univariate analysis, but not multivariate analysis, CSS indicated that PD-L1-positive TILs were significant predictors of patient prognoses. Multivariate analysis showed that PD-L1-positive TILs independently predicted CSS in patients without lymph node metastasis (pN0). CONCLUSION: Positive PD-L1 expression is associated with high-grade tumors. PD-L1-positive TILs are independent predictors of favorable survival outcomes in surgically resected UCB patients at stage pN0.

Complete biochemical response following metastasis-directed radiotherapy for oligometastatic prostate cancer: A case report.

Localized treatment has recently become an option for treating oligometastatic prostate cancer. Metastasis-directed therapy (MDT) is a new approach for localized treatment, and many clinical trials are ongoing. In the present case, biochemical recurrence occurred 8 months after a radical prostatectomy for localized prostate cancer, and oligometastases were diagnosed via whole-body magnetic resonance imaging. Metastasis-directed radiotherapy (MDRT) was performed on all oligometastatic sites. After MDRT without androgen deprivation therapy, the prostate-specific antigen (PSA) decreased to an undetectable level and did not increase for 24 months.

Robot-assisted laparoscopic radical cystectomy is a safe and effective procedure for patients with bladder cancer compared to laparoscopic and open surgery: Perioperative outcomes of a single-center experience.

OBJECTIVE: We compared the perioperative outcomes of patients with bladder cancer according to three different procedures: robot-assisted laparoscopic radical cystectomy (RALC), laparoscopic radical cystectomy (LRC), and open radical cystectomy (ORC). METHODS: From April 2008 to March 2017, 36 consecutive patients underwent radical cystectomy and ileal conduit with RALC (n = 10), LRC (n = 10), or ORC (n = 16). All patients underwent RALC and LRC with extracorporeal urinary diversion. Perioperative data were patient demographics, perioperative laboratory data including hematocrit and creatinine, intraoperative crystalloids and colloids, estimated blood loss (EBL), allogeneic transfusion, respiratory parameters including maximum end-tidal carbon dioxide (EtCO2) and respiratory rate, arterial blood gas data including highest pH, partial pressure of CO2 (PaCO2), partial pressure of oxygen (PaO2), operative time, opiate consumption including intraoperative and postoperative anesthesia, time of hospital stay, time to oral intake and normal diet, and adverse events. RESULTS: EBL was less for RALC than for other procedures (p = 0.0004). No blood transfusions were performed for RALC, but ORC required significant blood transfusions (p = 0.003). Respiratory rate was highest and PaCO2 was lowest for RALC. Preoperative creatinine levels were significantly worse for the RALC group, but no significant differences were noted after surgery. There were no significant differences among the groups in regard to hematocrit levels. Operative time, laparoscopic time, intraoperative anesthesia, and postoperative anesthesia did not differ among the groups. High-grade adverse events were only seen for ORC. CONCLUSION: Although RALC required a steep Trendelenburg position, which might add elements of risk, RALC was safe even for this small cohort.