Trend in overall survival from the start of first-line chemotherapy in patients with metastatic urothelial carcinoma.

New approaches involving immune checkpoint inhibitors and antibody-drug conjugates prolong overall survival in patients with metastatic urothelial carcinoma. However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve overall survival in patients with metastatic urothelial carcinoma over time remains unclear. Hence, we investigated the overall survival trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. We retrospectively evaluated 195 patients from a single center. They were treated with chemotherapy, pembrolizumab, or avelumab or enfortumab vedotin. The treatment was categorized into chemotherapy, pembrolizumab or avelumab/enfortumab vedotin period. The new agents prolonged overall survival from the start of first-line therapy. Furthermore, sequential treatment with these agents in real-world clinical practice has been reported to prolong overall survival. These study results will have major implications when a new first-line therapy is approved in the future.

Investigation of eligibility for adjuvant therapy from real-world data of patients with urothelial carcinoma undergoing radical cystectomy and radical nephroureterectomy.

OBJECTIVE: Adjuvant nivolumab prolonged disease-free survival compared with placebo in patients at high risk of recurrence following radical cystectomy or radical nephroureterectomy in the CheckMate 274 trial. However, the ideal eligibility criteria for adjuvant therapy in real-world clinical practice remain controversial. METHODS: We retrospectively analyzed clinical data of 409 patients who underwent radical cystectomy (n = 252) or radical nephroureterectomy (n = 157) and validated the risk of recurrence based on the classification used in the CheckMate 274 trial. We also investigated the impact of perioperative chemotherapy, lymph node dissection and pathological factors on prognosis. RESULTS: The median follow-up time was 37.5 and 32.1 months in bladder cancer and upper tract urothelial carcinoma, respectively. Among the high-risk patients based on CheckMate 274 trial, disease-free survival was considerably shorter for bladder cancer and upper tract urothelial carcinoma patients than for low-risk patients (hazard ratios: 4.132 and 7.101, respectively). The prevalence of adjuvant chemotherapy in high-risk patients was low (24 and 38% for bladder cancer and upper tract urothelial carcinoma, respectively). The extent of lymph node dissection in bladder cancer and presence of lymph node dissection in upper tract urothelial carcinoma did not affect prognosis. Cox proportional multivariate analysis revealed CheckMate 274-high-risk as a poor prognostic factor in bladder cancer and upper tract urothelial carcinoma. CONCLUSIONS: This study validated the risk classification for recurrence following radical cystectomy and radical nephroureterectomy using the CheckMate 274 criteria in real-world practice. Further research would help assess the degree of benefit obtained from adjuvant nivolumab.

Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART).

OBJECTIVES: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC. METHODS: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). RESULTS: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions. CONCLUSIONS: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial.

Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

[A Case of Metastatic Prostate Cancer with Neuroendocrine Differentiation with Long-Term Survival after Multidisciplinary Therapy].

A 74-year-old man visited the urology clinic with the chief complaint of urinary retention in December 2014. Serum level of initial prostate specific antigen (PSA) was 50 ng/ml and he was diagnosed with Gleason Score 4＋4 prostate adenocarcinoma with regional lymphadenopathy (cT3aN1M0). PSA level had declined after the treatment with combined androgen blockade. In November 2018, he was diagnosed with castration resistant prostate cancer (CRPC) as local progression was detected by computed tomography (CT) while PSA level did not increase. Since local symptoms worsened, resulting in repeated hematuria after the treatment with enzalutamide, palliative radiation therapy to the prostate (45 Gy) was performed. Five months later, follow-up CT showed multiple metastasis in bilateral lung and left testicle. Serum level of neuron-specific enolase (NSE) was 24.4 ng/ml without an elevated in serum PSA level. He received rebiopsy of the prostate, but no malignant findings were observed. Consequently, bilateral orchiectomy was performed for diagnosis of left testicular tumor. Pathological examination revealed metastasis of neuroendocrine prostate cancer (NEPC). Chemotherapy using cisplatin and irinotecan was administered after orchiectomy. Complete response of lung lesions was achieved and serum level of NSE decreased within normal range. No recurrence has been confirmed for 4 years after the completion of chemotherapy.

Irradiation plus myeloid-derived suppressor cell-targeted therapy for overcoming treatment resistance in immunologically cold urothelial carcinoma.

BACKGROUND: Radiotherapy (RT) has recently been highlighted as a partner of immune checkpoint inhibitors. The advantages of RT include activation of lymphocytes while it potentially recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). This study aimed to investigate the mechanism of overcoming treatment resistance in immunologically cold tumours by combining RT and MDSC-targeted therapy. METHODS: The abscopal effects of irradiation were evaluated using MB49 and cisplatin-resistant MB49R mouse bladder cancer cells, with a focus on the frequency of immune cells and programmed cell death-ligand 1 (PD-L1) expression in a xenograft model. RESULTS: MB49R was immunologically cold compared to parental MB49 as indicated by the fewer CD8+ T cells and lower PD-L1 expression. Polymorphonuclear MDSCs increased in both MB49 and MB49R abscopal tumours, whereas the infiltration of CD8+ T cells increased only in MB49 but not in MB49R tumours. Interestingly, PD-L1 expression was not elevated in abscopal tumours. Finally, blocking MDSC in combination with RT remarkably reduced the growth of both MB49 and MB49R abscopal tumours regardless of the changes in the frequency of infiltrating CD8+ T cells. CONCLUSIONS: The combination of RT and MDSC-targeted therapy could overcome treatment resistance in immunologically cold tumours.

[A Case of Metastatic Urothelial Carcinoma with Pseudoprogression of Liver Metastasis during the Treatment with Pembrolizumab].

A 75-year-old woman with a complaint of gross hematuria was referred to our hospital. The patient was diagnosed as having bladder cancer (cT3bN1M0) and received two cycles of chemotherapy with gemcitabine and cisplatin. Radical cystectomy with pelvic lymph node dissection and bilateral ureterostomy was performed after achieving partial response in a lymph node metastasis following chemotherapy. Based on the pathological diagnosis of high-grade (G3) urothelial carcinoma (ypT3aN2), two more cycles of adjuvant chemotherapy with gemcitabine and cisplatin were administered. Four months after completing adjuvant chemotherapy, pulmonary and hepatic metastases appeared, and treatment with pembrolizumab was initiated. The size of the lung metastasis decreased, while that of the liver metastasis increased 2 months after administering pembrolizumab. However, considering treatment beyond progression using checkpoint inhibitors, pembrolizumab was continued, resulting in marked tumor shrinkage of the liver metastasis. After that, pembrolizumab treatment was temporarily discontinued, and radiation therapy was administered for a new lymph node metastasis at the tracheal bifurcation. Eventually, the lymph node metastasis shrank, and the treatment with pembrolizumab was recommenced for 1 year and the metastases remained shrumken.

Hyperbaric oxygen significantly improves frequent urination, hyperalgesia, and tissue damage in a mouse long-lasting cystitis model induced by an intravesical instillation of hydrogen peroxide.

AIM: To investigate whether hyperbaric oxygen (HBO) is effective for the pathophysiological findings in an IC/PBS-like mouse model induced by intravesical hydrogen peroxide (H2 O2 ). METHODS: Six-week-old ICR female mice (N = 16) were divided into four experimental groups: (1) sham control with intravesical vehicle instillation twice, and without subsequent treatment (N = 4); (2) H2 O2 instillation twice, followed by HBO (100% O2 , 2 ATA, 30 min per session) (N = 4); (3) H2 O2 instillation twice, followed by dummy hyperbaric treatment (air, 2ATA, 30 min per session) (N = 4); and (4) H2 O2 instillation twice, followed by no treatment (N = 4). Body weight, voiding frequency, tidal voiding volume, and individual bladder pain threshold using the von-Frey test were measured. Whole body uptake of an inflammation-specific fluorescent pan-cathepsin was assessed by an in vivo imaging. Immunohistochemical staining and the mRNA expression of several biomarkers associated with chronic inflammation in resected bladders were evaluated. RESULTS: The HBO-treated group showed significant improvement in voiding frequency, tidal voiding volume, and the individual bladder pain threshold. Moreover, HBO markedly suppressed H2 O2 -induced inflammation, edema, and fibrosis in bladder wall, concomitant with a significant decrease in mRNA expressions of inflammation biomarkers and a significant increase in endothelial nitric oxide synthase expression. HBO also inhibited the expression of transient receptor potential channels induced by H2 O2 instillation. CONCLUSION: These results suggest that HBO contributes to elimination of H2 O2 -induced long-lasting cystitis through the repair of chronically inflamed bladder tissue and inhibition of the bladder sensory system.

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: a retrospective study.

BACKGROUND: Alternative anti-androgen therapy (AAT) with flutamide after combined androgen blockade (CAB) therapy with bicalutamide for metastatic prostate cancer is common. However, no studies have compared enzalutamide without AAT with enzalutamide after AAT with flutamide as treatment for castration-resistant prostate cancer (CRPC). We aimed to compare the efficacies of flutamide and enzalutamide for CRPC. METHODS: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered flutamide or enzalutamide between May 2014 and December 2017. Patients with flutamide failure were administered enzalutamide. We evaluated the (1) prostate-specific antigen (PSA) best response with initial therapy, (2) PSA progression-free survival with initial therapy (PSA-PFS), (3) PSA best response with enzalutamide therapy, (4) PSA-PFS of enzalutamide therapy, and (5) overall survival (OS). RESULTS: As first-line therapy, patients were administered enzalutamide (n = 29) or flutamide (n = 26). In the flutamide group, 18 patients showed disease progression and were administered enzalutamide. PSA best response was statistically higher in the enzalutamide group. PSA-PFS was significantly longer in the enzalutamide group [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.19-0.92, p = 0.024]. However, there was no significant difference in PSA best response with enzalutamide therapy and PSA-PFS between the first- and second-line enzalutamide therapies (HR 0.80, 95% CI 0.33-1.94, p = 0.62). There was no significant difference in OS between enzalutamide and flutamide groups (HR 1.85, 95% CI 0.53-6.42, p = 0.33). CONCLUSIONS: AAT with subsequent flutamide after CAB therapy with bicalutamide may be suitable for some CRPC patients.

Near infrared fluorescence imaging system for laparoscopic partial nephrectomy.

INTRODUCTION: Recently, the use of indocyanine green (ICG) with near infrared fluorescence (NIRF) imaging has emerged as an alternative technique for the real-time delineation of resection margins during partial nephrectomy (PN). We aimed to assess the feasibility of using NIRF imaging with ICG during laparoscopic partial nephrectomy (LPN) to delineate the margin between normal renal parenchyma and renal cortical tumors. MATERIALS AND METHODS: A retrospective comparison of real-time tumor margin identification and operative outcomes was conducted for 83 patients who underwent LPN with NIRF imaging (IMAGE1 system) and 74 patients who did not. RESULTS: Tumor margins were identified in 82% of cases in the NIRF group, with a rate of 79% for the clear cell renal carcinoma cases only. Volume of blood loss was higher for the NIRF than normal imaging group (p = 0.015), while the warm ischemia time was significantly shorter (p < 0.01) for the NIRF group. There was no significant difference in the pre to postoperative change in estimated glomerular filtration rate (p = 0.38) or rate of severe complications (Clavien grade ≥ 3; p = 0.88). The rate of positive surgical margins was comparable between the groups (3%; p = 0.91). CONCLUSIONS: NIRF imaging with ICG during LPN was safe and feasible, although the surgical outcomes with NIRF alone was not significantly superior to the ones with conventional methods.

Case in which percutaneous fibrin glue injection was useful for refractory urinary fistula following robot-assisted partial nephrectomy.

Introduction: Urinary fistula is a rare complication following robot-assisted partial nephrectomy. For cases refractory to conservative treatment, only ureteral stent placement and percutaneous drainage are the established treatment alternatives. Case presentation: A 44-year-old man presented with urinary fistula 3 weeks after robot-assisted partial nephrectomy for right renal cell carcinoma. Follow-up observations were conducted for 2 weeks; however, no improvements were observed. Additionally, the patient did not improve following percutaneous drainage and ureteral stent insertion. Subsequently, the patient received percutaneous injections of fibrin glue, with the urinary fistula showing significant improvements on the following day. Conclusion: Our findings indicated that percutaneous fibrin glue injection can effectively treat refractory urinary fistula following partial nephrectomy.

[Vesicouterine fistula - Youssef syndrome : a case report].

A 38-year-old woman was referred to our hospital with a chief complaint of cyclic hematuria and amenorrhea after Caesarean section. Magnetic resonance imaging showed vesicouterine fistula. The patient was treated with luteinzing hormone-releasing hormone analog to stop menstruation for six months. We performed transperitoneal closure of the vesicouterine fistula. Normal menstruation resumed after 4 months, and the symptoms disappeared. This case was considered Youssef syndrome (cyclic hematuria without vasinal amenorrhea or urinary incontinence). We discuss the cause of this syndrome.

[Endocervicosis/endosalpingiosis of the bladder: a case report].

Endocervicosis/ endosalpingiosis of the bladder is a very rare benign condition, with a total of 34 documented cases found in the literature. Herein, we report a 35-year-old woman with suspected bladder cancer following a cystoscopic examination, which revealed a mass on the right posterior bladder wall. Transurethral resection of the lesion was performed, and both pathological and immunohistochemical findings confirmed a diagnosis of endocervicosis/ endosalpingiosis. Recurrence was seen 6 months later in a follow-up cystoscopic examination and a partial cystectomy was performed. Since endocervicosis/ endosalpingiosis tends to recur, a partial cystectomy is the best therapeutic option for patients with persistent symptoms or recurrence.

Successful case of olaparib treatment for castration-resistant prostate cancer with multiple DNA repair gene mutations: Use of comprehensive genome profiling for treatment-refractory cases.

Herein, we report a case of a 59-year-old man with advanced castration-resistant prostate cancer with rectal invasion. Multimodal treatment, including drug therapy, surgery, and radiation therapy was sequentially performed; however, lymph node metastases repeatedly occurred. Tumor genomic profiling using FoundationOne CDx identified pathogenic alterations in three DNA repair genes, including BRCA2 frameshift mutation. Olaparib, a poly-ADP ribose polymerase inhibitor, showed marked response. Castration-resistant prostate cancer with multiple DNA repair genes was successfully treated with olaparib; comprehensive genome profiling can lead to its optimal clinical management.

A retrospective study on optimal number of cycles of the first-line platinum-based chemotherapy for metastatic urothelial carcinoma.

BACKGROUND: Recently, switch maintenance with avelumab has been approved for the treatment of advanced or metastatic urothelial carcinoma (UC), with no progression after four to six cycles of first-line platinum-based chemotherapy. However, the optimal number of cycles of platinum-based chemotherapy has not been determined. OBJECTIVE: To analyze the clinical characteristics of patients with advanced UC who were treated with platinum-based chemotherapy and investigate the association between the number of cycles of the treatment and the patients' overall survival. METHODS: A total of 124 patients with advanced UC who were treated with first-line platinum-based chemotherapy at Osaka City University Hospital between April 2009 and January 2020 were retrospectively reviewed. RESULTS: Of the 124 patients, clinical information regarding overall survival was available for 115 patients. The median age was 72 years (range, 43-95 years). Only 59 patients (51.3 %) were treated with gemcitabine and cisplatin, and 52 patients (45.2 %) were treated with gemcitabine and carboplatin. The median number of cycles was three (1-8), and the percentage of patients who discontinued chemotherapy due to progressive disease was 80.3%, 64.0%, and 86.4% in those receiving one to three, four, and five or more cycles, respectively. Moreover, no difference in overall survival was observed between patients who received four cycles and those who received five or more cycles at both univariate and multivariate levels. CONCLUSIONS: The present study shows that five or more cycles of first-line platinum-based chemotherapy did not prolong overall survival compared with four cycles, suggesting that four cycles of chemotherapy might be sufficient, considering the new treatment strategy involving switch maintenance with avelumab.

[Epithelioid angiomyolipoma : a case report].

A 63-year-old woman with a right renal tumor diagnosed by ultrasound, consulted our hospital in October 2008. The findings of her physical examination were unremarkable. The results of urinalysis and other routine blood tests were normal. The urinary cytology was negative for malignant cells. Dynamic computed tomography showed a right renal mass (diameter, 7.5 cm), which was enhanced in the early phase and washed out in the late phase. We initially thought that the patient had renal cell carcinoma. Therefore, laparoscopic right nephrectomy was performed in October 2008. The tumor section was found to be encapsulated, and focal hemorrhage and necrosis were observed. Histological examination of the tumor by hematoxylin-eosin staining revealed that it contained polygonal cells, eosinophilic cytoplasm and large nuclei. Immunohistochemical staining of anticytokeratin antibodies AE1/AE3 and CAM5.2 (markers for renal cell carcinoma) was negative. However, immunohistochemical staining of HMB-45, a marker for melanoma, was positive. The patient was finally diagnosed with epithelioid angiomyolipoma. She did not show any evidence of tumor recurrence for 25 months after the surgery.

[Excellent growth following testosterone replacement therapy in identical twin with bilateral anorchia].

Bilateral anorchia is defined as the complete absence of testicular tissue with a normal male karyotype and phenotype. Although the precise etiology is not well understood, mechanical causes during or after testicular descent have been suggested, while genetic factors have also been reported. We treated a patient with bilateral anorchia who obtained excellent growth bytestosterone replacement therapyas compared with his normal identical twin. The patient was diagnosed with negative elevation of testosterone after hCG administration and surgical exploration confirmed the absence of a testicular structure. We began testosterone replacement therapyfrom 13 years old with the goal of matching the development of his brother. Four months after initiating therapy, the patient showed voice breaking and pubic hair growth. Thereafter, there were scant differences in height and secondarysexual characteristics as compared with his brother.

Pilot experience of simultaneous robotic-assisted partial nephrectomy for bilateral renal tumors-single center analysis.

INTRODUCTION: Bilateral renal tumors accounts for approximately 3% of renal tumors. However, surgical treatment methods for bilateral renal tumors have not yet been established. It is imperative to balance the need for curative surgery with the goal of maximal functional preservation in patients with bilateral synchronous renal tumors. Therefore, partial nephrectomy may be the optimal surgical treatment for bilateral synchronous renal tumors. METHODS: We conducted a retrospective, observational study to analyze the clinical outcome of simultaneous robotic-assisted partial nephrectomy (RAPN) for bilateral renal tumors at our institution between 2016 and 2019. A total of eight patients were enrolled and the number of renal masses in the 16 kidneys was 18. RESULTS: There was no positive surgical margin after RAPN in our case series and no local recurrence or metastasis during the follow-up period. The only complication of simultaneous RAPN in the present case series was that one patient experienced acute kidney injury after operation without need for dialysis therapy. CONCLUSION: Our study suggests that simultaneous RAPN for bilateral renal tumors might be feasible both for the preservation of renal function and for oncological outcome such as negative surgical margin.

[Early initiation of antiplatelet therapy after urological surgery : a prospective study].

In recent times, the number of patients receiving antiplatelet drugs for the prevention of cardiovascular and cerebrovascular diseases has been increasing. We examined the possibility of early initiation of antiplatelet therapy after urological operations. Between April 2008 and February 2009, 62 patients who received antiplatelet drugs and underwent urological surgeries (open surgery, transurethral surgery and laparoscopic surgery) and prostate biopsies were examined. Of the 62 patients, 59 were randomized into 2 groups ; 32 patients receiving antiplatelet treatment initiation within 24 hours (early group) and 29 patients receiving this treatment more than 24 hours (late group) after the urological operation. The end point of this study was the re-cessation of antiplatelet therapy because of the development of postoperative complications (hematuria, blood loss, etc.) and cardiovascular and cerebrovascular events within 1 month. There was no significant difference in the urological events observed between these groups, including 2 of the 32 (6.3%) patients in the early group and 3 of the 27 (11.1%) in the late group. Cardiovascular and cerebrovascular diseases were not noted in any of the patients within 1 month. In conclusion, we think that it is possible to initiate antiplatelet therapy within 24 hours after urological operations and prostate biopsies in the absence of active blood loss. Early initiation may prevent the risk of cardiovascular and cerebrovascular disease in the future.

[A case of urethrovaginal fistula caused by a foreign body in the vagina].

A 25-year-old woman had a urethrovaginal fistula caused by a foreign body in her vagina. The patient had sought an appointment with a gynecologist for removal of the foreign body in her vagina. However, one day before the scheduled appointment, she developed acute urinary retention and visited the emergency room of our hospital. A urinary catheter inserted into the urethra was found to come out through the vagina. The foreign body, a bottle cap made of polypropylene and measuring 48 x 28 mm in size, was removed. A cystourethroscopic examination confirmed the presence of the urethrovaginal fistula. Repeat cystourethroscopy performed after one month of conservative management showed a persistent urethrovaginal fistula, which had, in fact, increased in size as compared with that at the initial examination. Surgery was undertaken for repair of the fistula ; fistula closure was successfully accomplished by suture in three layers : urethral wall, subcutaneous tissue, and the vaginal wall. This is the second report of a urethrovaginal fistula caused by a foreign body in the vagina.