Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000548719

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INTRODUCTION: The diagnosis of systemic transthyretin amyloidosis based on prostate biopsy is very rare, and we report this case with a literature review. CASE PRESENTATION: A 73-year-old male patient was referred to our department due to an increased serum prostate-specific antigen level at 10.4 ng/mL while receiving benign prostatic hypertrophy treatment. Prostate needle biopsy was performed, and the pathology revealed transthyretin amyloid deposits in the prostate tissue without adenocarcinoma. Subsequent 99mTc pyrophosphate scintigraphy confirmed the accumulation in the myocardium. The patient was diagnosed with cardiac transthyretin amyloidosis. CONCLUSION: Amyloidosis is a systemic disease where amyloid is deposited in multiple organs, causing various dysfunctions. Considering both our case and previous reports, prostatic amyloidosis may frequently be associated with systemic involvement. The treatments including oligonucleotide therapeutic agents and transthyretin-stabilizing drugs will be more effective with early diagnosis and early treatment, and various symptoms suspicious of systemic amyloidosis should not be missed.

DOI： 10.1002/iju5.70079

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Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pros.70005

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Publishing type：Research paper (scientific journal)  

DOI： 10.1111/iju.70039

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Immune checkpoint inhibitors are the mainstay of treatment for unresectable or metastatic renal cell carcinoma (RCC). However, they can cause immune-related adverse events (irAEs), and the management of these irAEs is critical. The combination of myasthenia gravis, myositis, and myocarditis, which are irAEs, is rare, and it has not been reported to occur with avelumab. This report aimed to present a rare case of RCC metastasis that developed irAEs during avelumab and axitinib combination therapy. CASE PRESENTATION: A 76-year-old woman who underwent radical nephrectomy for clear cell RCC (pT1bN0M0 Grade 3 INFb) at the age of 67 years presented to our hospital after her family doctor noted a pancreatic tumor. She was diagnosed with pancreatic metastasis of RCC based on histopathological examination, and avelumab and axitinib combination therapy was initiated. She developed irAEs, including myasthenia gravis, myositis, and myocarditis, which were treated with steroid pulse therapy. The patient recovered after treatment and was discharged without sequelae. CONCLUSION: Myasthenia gravis, myositis, and myocarditis can occur during avelumab and axitinib combination therapy for RCC. Prompt diagnosis, treatment, and collaboration with other departments are extremely important for managing irAEs.

DOI： 10.1159/000545733

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INTRODUCTION: In the United States, a total of 268,490 men were found to have prostate cancer in 2022, thus making it the most common cancer in men, accounting for 27% of all cancers in the male population. Among all cancers in men, it was the fifth leading cause of death, with 34,500 deaths and a mortality rate of 11%. In 2019, the total number of cases was 94,748, making it the leading cancer in males, accounting for 11% of all male cancers. In terms of mortality, it ranked seventh, with 13,217 deaths and a mortality rate of 1.6%. However, new treatment options for metastatic castration-sensitive prostate cancer (mCSPC) have emerged. Docetaxel has been shown to be effective for both mCSPC and castration-resistant prostate cancer (CRPC). Upfront docetaxel has not been approved in Japan, nor has it been validated in large-scale studies. Furthermore, several agents can be used after docetaxel treatment, but it is unclear which is the most effective. We used a large Japanese health insurance database to determine which agent would be the most effective as a next-line therapy in patients who had received docetaxel. MATERIALS AND METHODS: We used data from medical institutions using the Diagnosis Procedure Combination (DPC), which provides a comprehensive evaluation of medical classifications. The Medical Data Vision database covers approximately 23% of DPC hospitals in Japan. This study analyzed 2938 patients with mCSPC who received docetaxel, followed by CRPC, between April 2008 and December 2021. The study focused on three agents: enzalutamide, abiraterone acetate, and cabazitaxel. Other agents were excluded due to the small number of patients. The following data were analyzed: age, date of CRPC diagnosis, presence of bone metastasis, drug type, and prognosis. RESULTS: This study included 1997 patients with CRPC after upfront docetaxel therapy for mCSPC (enzalutamide [ENZ] group, n = 998; abiraterone acetate [ABI] group, n = 617; and cabazitaxel [CBZ] group, n = 382). The overall survival (OS) time from drug initiation was 456 days in the enzalutamide group, which was significantly longer than that in the cabazitaxel group (p = 0.017, HR 0.94) (ENZ: ABI p = 0.54, HR 0.94; ABI: CBZ p = 0.14, HR 0.75). OS was also compared for the third-line drug in the group that received enzalutamide as the second-line drug, the group that used abiraterone acetate as the third-line drug (ENZ-ABI group), and the group that used abiraterone acetate as the second-line drug. OS from the start of the third-line drug was compared between the ENZ-ABI group and the ABI-ENZ group, which received enzalutamide as the third-line drug, but showed no significant difference (269 vs. 281 days, p = 0.85; HR 1.03). CONCLUSION: ENZ was shown to prolong OS relative to cabazitaxel after the cessation of docetaxel. ENZ was associated with a longer duration of drug use than ABI and CBZ.

DOI： 10.3390/diseases12070162

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OBJECTIVES: To determine the incidence and location of lower extremity deep vein thrombosis in patients undergoing radical cystectomy. METHODS: We performed radical cystectomy in 137 patients with bladder cancer between August 2014 and February 2020. Since 2014, we have had a policy to screen for deep vein thrombosis using lower extremity ultrasonography both before and after radical cystectomy. We determined the incidence and location of deep vein thrombosis and classified it as either proximal or distal type. Furthermore, we explored the incidence of pulmonary embolism within 3 months after radical cystectomy. RESULTS: After excluding six patients with a lack of ultrasonographic data, we evaluated 131 patients. Preoperative deep vein thrombosis (one proximal and 17 distal) was diagnosed in 18 patients (14%) with no symptoms. Postoperative deep vein thrombosis was diagnosed in 41 patients (31%; three proximal and 38 distal), of whom 26 (63%) had new-onset deep vein thrombosis after cystectomy. Three patients, two with proximal and one with distal type deep vein thrombosis, developed nonfatal pulmonary embolism postoperatively. Multivariate analysis showed that preoperative D-dimer levels (odds ratio 5.35, 95% confidence interval 1.74-16.50; P < 0.003), type of urinary diversion (ileal neobladder; odds ratio 11.15, 95% confidence interval 2.16-57.55; P = 0.004), and preoperative deep vein thrombosis (odds ratio 15.93, 95% confidence interval 3.82-66.30; P < 0.001) were significant risk factors for postoperative deep vein thrombosis. CONCLUSIONS: Pre- and post-radical cystectomy whole-leg ultrasonography can lead to an early perioperative diagnosis and immediate treatment of proximal deep vein thrombosis, thereby potentially preventing fatal pulmonary embolism.

DOI： 10.1111/iju.14760

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 75-year-old woman was admitted to our hospital with suspected gastrointestinal perforation and underwent emergency surgery. Bladder perforation was revealed during the surgery, and she was referred to our department. We detected a tumor on the apex of the bladder and performed partial resection of the bladder. Based on histopathological examination, a diagnosis of urachal cancer was established. Gemcitabine and cisplatin (GC) therapy was administered as an adjuvant therapy because of the high risk of peritoneal dissemination. She had the purulent spondylitis and gluteus medius abscess at the first course of GC therapy. We stopped GC therapy within the first course due to the adverse events and decreased performance status. Computed tomography revealed tumor recurrence in the pelvis three months after discontinuation of GC therapy. As the companion diagnostics revealed MSI-High, we administrated pembrolizumab. She was taking prednisolone 5 mg for SLE, but stable disease was observed after 5 courses of pembrolizumab. However, pembrolizumab was discontinued for eight months due to the stent graft insertion for the common iliac artery aneurysm. She had progressive disease after eight months interval of treatment. We restarted pembrolizumab but she was hospitalized for tumor fever after a total of eight courses. The patient died a month later. This seems to be the first case wherein pembrolizumab was administered for urachal cancer with MSI-High.

DOI： 10.5980/jpnjurol.113.68

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(Objectives) We evaluated the association between immune-related adverse events (irAEs) and the efficacy of pembrolizumab therapy in patients with metastatic urothelial carcinoma. (Methods) Data of 42 patients with metastatic urothelial carcinoma treated with pembrolizumab between May 2018 and February 2020 were retrospectively analyzed to determine the association between irAEs and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). (Results) IrAEs were observed in 19 patients (45.2%). Objective response was observed in 15 patients (35.7%). Thirteen (68.4%) of 19 patients who experienced irAEs showed an objective response, whereas two (8.70%) of 23 patients who did not experience irAEs (odds ratio: 15.0, 95% confidence interval [CI]: 1.70-738, P=0.006). PFS and OS in the irAE group were longer than those in the non-irAE group (PFS: hazard ratio: 0.24, 95% CI: 0.11-0.54, P<0.001; OS: hazard ratio: 0.11, 95% CI: 0.03-0.37, P<0.001). (Conclusions) During pembrolizumab treatment, the occurrence of irAEs was significantly associated with higher response and survival prolongation in patients with metastatic urothelial carcinoma.

DOI： 10.5980/jpnjurol.112.179

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Recently, the effectiveness of anti-programmed death 1 (PD-1) antibody therapy in the treatment of renal cell carcinoma (RCC) has been established. Nevertheless, efficacy has been reported to be limited to only 10-30% of patients. To develop more effective immunotherapy for RCC, we analyzed the immunological characteristics in RCC tissues by immunohistochemistry (IHC). We prepared a tissue microarray that consisted of tumor tissue sections (1 mm in diameter) from 83 RCC patients in Kanagawa Cancer Center between 2006 and 2015. IHC analysis was performed with antibodies specific to immune-related (CD8 and Foxp3) and immune checkpoint (programmed death ligand 1 (PD-L1) and 2 (PD-L2), B7-H4 and galectin-9) molecules. The numbers and proportions of positively stained tumor cells or immune cells were determined in each section. From multivariate analysis of all 83 patients, higher galectin-9 expression was detected as a factor associated with worse overall survival (OS) (P = 0.029) and that higher stage and higher B7-H4 expression were associated with worse progression-free survival (PFS) (P < 0.001 and P = 0.021, respectively). Similarly, in multivariate analysis of 69 patients with clear cell RCC, though not statistically significant, there was a trend for association between higher galectin-9 expression and worse OS (P = 0.067), while higher stage was associated with worse PFS (P < 0.001). This study suggests that higher galectin-9 expression is an independent adverse prognostic factor of OS in RCC patients. Therefore, to develop more effective personalized immunotherapy to treat RCC, it may be important to target not only PD-1/PD-L1, but also other immune checkpoint molecules such as galectin-9.

DOI： 10.1007/s00262-020-02608-6

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PURPOSE: Reports frequently describe the worsening of oncologic outcome in patients who developed high-grade complications after curative surgery for esophageal, gastric, and breast cancers. We investigated the extent of this correlation in patients with bladder cancer after radical cystectomy (RC). METHODS: During 2002-2017, we performed 326 RC and urinary diversion procedures and collected data regarding complications in these patients within 90 days postoperatively. We evaluated the severity of complications based on the modified Clavien-Dindo classification (grades 0-5). Grade ≥ 3 complications were considered high grade. After adjusting for confounding factors using a Cox regression model, we calculated the hazard ratios (HRs) for high-grade complications associated with recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: During a median follow-up period of 61 months, 38 patients (12%) developed high-grade complications (grade ≥ 3). The main causes (76%) of high-grade complications were gastrointestinal and infection problems. The RFS and CSS differed significantly between patients with high-grade complications and those without complications. After adjusting for confounding factors in the multivariate analysis, high-grade complications remained a significant risk factor for both RFS [HR 2.11; 95% confidence interval (CI) 1.07-4.15, p = 0.030] and CSS (HR 2.74; 95% CI 1.05-7.14, p = 0.039). CONCLUSIONS: High-grade complications after RC led to worse RFS and CSS outcomes, similar to those observed in patients with other cancers. A large-scale study is needed to further verify these findings, and discussions of knowledge and experiences are required to reduce the incidence of postoperative high-grade complications.

DOI： 10.1007/s11255-019-02341-9

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Immune checkpoint molecules, such as PD-1/PD-L1, are reported to be closely associated with suppression of antitumor immunity, and their inhibitors have been used to treat various cancers including bladder cancer. However, there have been only a few studies investigating the effects of Bacillus Calmette-Guerin (BCG) administration on expression of the immune checkpoint molecules in bladder cancer. The current study examined the expression of PD-L1 and PD-L2 before and after BCG in non-muscle-invasive bladder cancer (NMIBC) patients. Tissue microarrays of 22 BCG-resistant NMIBC patients were stained by immunohistochemistry with antibodies against PD-L1, PD-L2, and CD8, and were compared between before and after BCG. The expression levels of PD-L1, but not of PD-L2, were significantly increased after BCG treatment on tumor cells (p < 0.001) and tumor-infiltrating inflammatory cells (p = 0.030) within tumor tissues, as well as on inflammatory cells within non-tumor normal tissues (p = 0.003). Although CD8+ T cells were significantly increased within tumor tissues (p = 0.005) and non-tumor normal tissues (p = 0.007) after BCG treatment, they might be not effective for anti-tumor immunity. This study demonstrated for the first time that expression of PD-L1, which might contribute to the immune escape mechanism, was enhanced on tumor tissue after BCG treatment in BCG-resistant NMIBC patients. Our finding thus propose that immunotherapy with anti-PD-1/PD-L1 antibodies could be feasible as combination treatment with BCG or as secondary treatment at relapse after BCG in NMIBC patients.

DOI： 10.18632/oncotarget.26122

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 34-year-old man presented with scrotal pain and slight fever. The scrotal pain was improved by the treatment of antibiotics, but the slight fever remained and an abdominal protuberance appeared. Computed tomography showed a 22 cm abdominal tumor with lipid density. He was then referred to our hospital. He was diagnosed as retroperitoneal liposarcoma and a surgical resection was performed for retroperitoneal tumor and surrounding organs. Histopathological diagnosis was dedifferentiated liposarcoma. 3 months after surgery, a PET/CT scan showed multiple lung metastases. We treated the patient with AI therapy by doxorubicin and ifosfamide. After 6 courses were performed, a complete response was achieved. 30months after the initial surgery, a PET/CT scan showed there was just one metastasis which was in the left lung. Thoracoscopic lung tumor resection was performed. Histopathological diagnosis was metastatic dedifferentiated liposarcoma. As adjuvant therapy, we treated with IE therapy by ifosfamide and VP-16. 3 courses were performed. 3 years and 6 months after the first surgery, he has had no recurrence up to the present day.

DOI： 10.5980/jpnjurol.109.25

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A 74-year-old man underwent transurethral resection for a bladder tumor (TURBT). The pathological diagnosis was urothelial carcinoma, grade 3 pT2 at least. He desired preservation of the bladder. Thus, MEC (methotrexate 100-150 mg/body (day 1), etoposide 100 mg/m2 (day 2-4), cisplatin 20 mg/m2 (day 2-6)) chemotherapy was administered for 2 courses. The next year, he had a relapse in the bladder, and the pathological diagnosiswasurothelial carcinoma, grade 2 pTa and pTis. He underwent Calmette-Guerin Bacillus (BCG) immunotherapy for 6 courses that resulted in a complete response without recurrence for 6 years. Six months after the latest examination, he complained of difficulty in voiding. An 8 cm tumor in the bladder and enlargement of obturator lymph node were detected. The pathological diagnosis by TURBT was small cell carcinoma. He rejected cystectomy, so we applied MEC therapy again. After 2 courses of MEC therapy, the bladder tumor and lymphadenopathy markedly shrunk in image and almost disappeared subsequently. The patient refused further therapy, but he had been followed without recurrence for 48 monthsafter the chemotherapy.

DOI： 10.14989/ActaUrolJap_63_6_245

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We describe a case of testicular tumor with multiple metastasis to the lung,retoroperitoneal lymph node, and brain. After chemotherapy the retroperitoneal lymph node and brain metastasis disappeared,but the multiple pulmonary metastases but not disappear,although they were reduced in size. Since the human chorionic gonadotoropin (HCG) was persistently dected at a low level,we performed a testosterone tolerance test. The HCG level became undetectable for a while,but was detected at a low level again. Then the patient underwent residual tumor removal of some of the residual pulmonary disease,which was diagnosed as tumor necrosis. The patient has been followed on an ambulatory basis after surgery for 12 months without recurrence. In this case a definitive diagnosis was difficult,because of the low positive level of HCG.

DOI： 10.14989/ActaUrolJap_63_3_119

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18F-fluorodeoxy glucose positron emission tomography (FDG-PET) for evaluation of the post chemotherapy residual tumor of the seminomatous testicular germ cell tumor is recommended by several guidelines. We report a case whose residual tumor was evaluated by FDG PET but the results were difficult to interpret. A 41-year-old male with left seminomatous germ cell tumor of the testis and 60 mm retroperitoneal lymph node (RPLN) metastasis was referred to our hospital. The International Germ Cell Consensus Classification (IGCCC) was good prognosis. After high orchiectomy, three cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy normalized the tumor marker and the RPLN decreased to 15 mm. The standardized uptake value (SUV) max at the RPLN by FDG-PET was 2.93. Although residual viable cells were suspected, the SUV max was relatively low. Thus surveillance without additional therapy was selected. After observation for 25 weeks, the tumor grew to 25 mm. Then four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy were indicated for the recurrence. The RPLN was decreased to 15 mm, but the SUV max was still as high as 2.67 at 6 weeks after the last chemotherapy. We dissected the residual tumor suspecting viable cancer, but the pathological examination revealed necrotic tissue without any viable cells. He has had no signs of recurrence for 1 year and 9 months after the operation.

DOI： 10.14989/ActaUrolJap_62_7_383

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Language：Japanese   Publisher：泌尿器科紀要刊行会  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(公社)日本人間ドック・予防医療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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