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Background: Recent clinical trials have reported improved disease-free survival rates of patients with stage pT3-4/ypT2-4 or pN + upper tract urothelial carcinoma (UTUC) on adjuvant nivolumab therapy. However, the appropriateness of the patient selection criteria used in clinical practice remains uncertain., Methods: We retrospectively analyzed 895 patients who underwent nephroureterectomy to treat UTUC. The patients were divided into two groups: grade pT3-4 and/or pN + without neoadjuvant chemotherapy (NAC) or grade ypT2-4 and/or ypN + on NAC (adjuvant immunotherapy candidates) and others (not candidates for adjuvant immunotherapy). Kaplan-Meier curves were drawn to assess the oncological outcomes, including recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Cox proportional hazards models were used to identify significant prognostic factors for oncological outcomes., Results: The Kaplan-Meier curves revealed notably inferior RFS, CSS, and OS of patients who were candidates for adjuvant immunotherapy. Multivariate analysis revealed that pathological T and N grade and lymphovascular invasion (LVI) status were independent risk factors for poor RFS, CSS, and OS., Conclusion: In total, 44.8% of patients were candidates for adjuvant immunotherapy. In addition to pathological T and N status, LVI was a significant predictor of survival, and may thus play a pivotal role in the selection of patients eligible for adjuvant immunotherapy., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Multiple studies have demonstrated the effectiveness of neoadjuvant chemotherapy and adjuvant chemotherapy in patients with upper tract urothelial carcinoma compared with surgery alone. However, no clinical trial has established the superiority of neoadjuvant chemotherapy or adjuvant chemotherapy in terms of perioperative outcomes., Methods: We conducted a retrospective analysis encompassing 164 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy and received perioperative chemotherapy. Of these patients, 65 (39.6%) and 99 (60.4%) received neoadjuvant chemotherapy and adjuvant chemotherapy, respectively. Recurrence-free survival and cancer-specific survival were computed using the Kaplan-Meier method. Additionally, we conducted Cox regression analyses to evaluate the risk factors for recurrence-free survival and cancer-specific survival., Results: Pathological downstaging was seen in 37% of the neoadjuvant chemotherapy group. However, no pathological complete response was observed in this cohort. The Kaplan-Meier curves demonstrated significantly lower recurrence-free survival and cancer-specific survival in patients who received adjuvant chemotherapy. Multivariate Cox regression analysis revealed patients treated with adjuvant chemotherapy exhibited a marked association with inferior recurrence-free survival and cancer-specific survival., Conclusion: Our study has suggested that neoadjuvant chemotherapy would be more effective in high-risk upper tract urothelial carcinoma patients compared with adjuvant chemotherapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 77-year-old man complaining of gross hematuria was referred to our hospital for further examination and treatment. The contrast-enhanced computed tomographic (CT) scan revealed a left ureteral tumor, multiple bladder tumors, para-aortic lymph node metastasis, left supraclavicular lymph node metastasis, multiple liver metastases, and multiple lung metastases. Transurethral resection was performed. One of the multiple bladder tumors, located at the bladder neck, was pathologically diagnosed as urothelial carcinoma, pT1, high grade, G2．We diagnosed the patient with metastatic ureteral cancer (T4N2M1, stage IV). We stated gemcitabine, cisplatin (GC) therapy, but stopped after the first course due to gemcitabine drug eruption. We changed the regimen to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy and the cycle was completed without complications. However, CT scan showed disease progression. After palliative irradiation of the primary lesion, we administered pembrolizumab. Although he was asymptomatic, we diagnosed him with ocular myasthenia gravis because of a high level of serum anti-acetylcholine receptor antibodies and a temporary ptosis in his past history. In spite of the possibility of relapse of myasthenia gravis, treatment with pembrolizumab was continued with his consent since there were no other treatment options. After two courses of pembrolizumab, he was hospitalized due to disease progression and died about three weeks after admission. Myasthenia gravis is a possible immune-related adverse event of pembrolizumab, However, there have been few reports on the successful treatment with this agent in patients with previously diagnosed myasthenia gravis. We report, here, a case of metastatic ureteral carcinoma safely treated with pembrolizumab without relapse of ocular myasthenia gravis.

Loss of ABO blood group antigen expression has been reported in transitional cell carcinoma (TCC) of the bladder. Synthesis of the ABO blood group antigen was genetically determined by allelic variants of the ABO gene assigned on 9q34.1. We analyzed loss of heterozygosity (LOH) and promoter hypermethylation of the ABO gene in TCC and compared them with alterations of A antigen expression in TCC, dysplasia and normal urothelium. A total of 81 samples of TCC of the bladder obtained from transurethral resection (TUR) (n=44) and radical cystectomy (n=37) were examined. Expression of the A antigen was evaluated by immunohistochemical staining (IHC) using anti-A antigen monoclonal antibody. LOH of the ABO gene locus was examined by blunt-end single-strand DNA conformational polymorphism (SSCP) analysis using flouresence-based auto sequencer. Promoter hypermethylation of the ABO gene were examined by bisulfite PCR-SSCP (BiPS) analysis and/or methylation-specific PCR (MSP). Loss of A allele and/or hypermethylation were significantly associated with abnormal expression of the A antigen in cases undergoing TUR (P=0.02) and radical cystectomy (P=0.0005). For the analysis of the concomitant dysplasia in 23 cases with TCC of the bladder, the expression of the A antigen was maintained, regardless of the A allelic loss or methylation status in the tumor. In conclusion, A allelic loss and hypermethylation in the promoter region of the ABO gene showed significant correlation with reduction of A antigen expression in TCC, while the expression of the A antigen is maintained in concomitant dysplasia or normal urothelium, suggesting that loss of the ABO gene and/or its promoter hypermethylation is a specific marker for TCC.

Purpose: We elucidated the role of methylation in the promoter region of the 1 gene in bladder carcinogenesis, particularly in those comprising carcinoma in situ., Materials and Methods: A total of 49 cases of transitional cell carcinoma of the bladder obtained from transurethral resection were examined. Methylation status of the 1 promoter region was analyzed by methylation specific polymerase chain reaction from chemically modified DNA after Na-bisulfite treatment. Loss of heterozygosity on 16q was examined by blunt end single strand DNA conformation polymorphism using 4 tetranucleotide repeat microsatellite markers assigned on 16q13 to 22.1. E-cadherin expression was evaluated by immunostaining on formalin fixed, paraffin embedded tissue sections using anti E-cadherin murine monoclonal antibody, HECD1 and standard avidin-biotin immunoperoxidase complex technique., Results: Analysis of the 49 bladder transitional cell carcinoma samples showed 1 promoter methylation in 23 (47%). Methylation of the 1 gene did not correlate with tumor stage (p = 0.2097) but with high grade transitional cell carcinoma (p = 0.0416). 1 promoter methylation was observed at a significantly higher frequency in the carcinoma in situ positive group than in the carcinoma in situ negative group (16 of 18 cases or 89% versus 7 of 31 or 23%, p <0.0001) and it strongly correlated with abnormal E-cadherin expression (p <0.0001). We found 16q loss of heterozygosity in 16 of 47 cases (34%), which correlated with higher histological grade (p = 0.0069) but not with the presence of the carcinoma in situ component (p = 0.1235)., Conclusions: This study showed that 1 gene promoter methylation is strongly associated with bladder transitional cell carcinoma comprising carcinoma in situ.

We report the results of prospective randomized study which was designed to evaluate prophylactic effects of intravesical bacillus Calmette-Guerin (BCG) in the treatment of superficial transitional cell carcinoma of the bladder. A total of 44 cases who had no previous treatment of bladder cancer were randomly assigned to BCG or control groups after TUR. BCG group (23 cases) received intravesical instillation of 80 mg BCG (Tokyo strain) at one week intervals for 6 weeks, at two week intervals for 12 weeks, and at one month intervals for 20 months. In BCG groups, 3 cases had recurrence at 6 months and 1 case at 9 months, while the other 19 cases had no recurrent disease for 3 to 34 months (average 20.3 months) of follow-up. Control group (21 cases) had no further treatment after TUR. In control group, recurrence was seen at 3 months in 3 cases, at 6 months in 5 cases, at 9 months in 2 cases, at 12 months in 3 cases and at 21 months in 1 case. Only 7 cases in the control group were free of recurrence for 8 to 45 months (average 32.3 months) of follow-up. One and two year-recurrence rates in BCG group (18.4%, 18.4%) was significantly (p less than 0.01) lower than those in control group (63.2%, 68.9%). Among the complications of intravesical BCG were cystitis (76.2%), low grade fever (13.0%), and several days' persistent gross hematuria (13.0%). Most of these signs were self-limited and only in 2 cases instillation of BCG was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Our objective was to develop new methods of chemotherapeutic treatment for bladder tumors. Once or twice a week under cystoscopy 10 to 20 mg, doxorubicin hydrochloride were administered directly into the tumors. This procedure was repeated until the size of the tumors was reduced or had disappeared completely under cystoscopic study. A new type of flexible needle was fabricated for this purpose. In 9 patients studied the total success rate was 78%. No significant side effects were seen in any of the patients.

A 41-year-old male was admitted to the hospital for frequent urination and severe retardation before voiding. Roentgenography revealed exophytic lesions which were located mainly in the trigone of the bladder, and he underwent transurethral resection. The pathological diagnosis was cystitis glandularis. There was no literature which reported cystitis glandularis causing urinary disturbance. This case, moreover, had been diagnosed as cystitis glandularis 13 years before by endoscopical biopsy. The origin of cystitis glandularis and its potentiality as a pre-malignant lesion were discussed from the clinical course for over 10 years.

During the period from 1976 to 1981, 364 patients with bladder carcinoma were seen at the Keio University Hospital. Extensive preoperative investigation of pulmonary, cardiovascular, and renal function was obtained in all patients. Of the 12 patients studied, 9 underwent a one-stage total cystectomy and ileal loop diversion and the remaining 3 a two-stage procedure. Of the 9 patients, decreased FEV 1.0 per cent by spirometry was noted in 5, ECG abnormality such as bundle branch blocks in 8, and diminished creatinine clearance ranging from 28 to 68 ml/min were observed in all 9. Major postoperative complications included pyelonephritis in 2 patients, pneumonia in 1, pelvic abscess in 2, renal insufficiency in 3, and paralytic ileus in 2. There was no immediate postoperative death. In these elderly patients, functional reserve of the lung, heart, and kidney is less than optimal and is further decreased by major surgical procedures. Therefore, total cystectomy in the elderly patients is justifiable only in a selected group of patients, when functional status of the vital organ is thoroughly worked up and prophylactic and therapeutic measures are instituted promptly if indicated.

Thirteen patients with carcinoma of the bladder have been treated by arterial infusion of doxorubicin hydrochloride pre-operatively. Teflon catheters 0.25 mm in diameter were inserted by the Seldinger technique and the tips were placed in the aorta between the origin of the inferior mesenteric artery and the aortic bifurcation. The doses administered ranged from 80 mgs to 250 mgs with an average of 125 mgs. A response rate of 69% was seen. In 3 cases tumours disappeared; in a further 6 patients some tumour regression was apparent. One patient died from cardiac insufficiency. Although this method of treatment remains to be fully evaluated, preliminary results suggest that it may be an effective pre-operative treatment.

Flow cytometric (FCM) examination of DNA distribution based on heterogeneity index score (HIS) and ploidy pattern and of bladder irrigation specimens were compared with conventional urine cytologic examinations to evaluate the diagnostic efficacy of each method. Of 56 patients with histologically proved bladder tumors, 24 (43%) had positive urine cytology, 41 (73%) had positive FCM, and 45 (80%) had positive urine cytology and/or positive FCM. When bladder tumors were graded histologically, 8 of 11 patients (73%) with grade I bladder carcinoma, 22 of 28 patients (79%) with grade II, and 15 of 17 patients (88%) with grade III had positive urine cytology and/or positive FCM. Of the 28 patients with grade II, 12 with positive urine cytologic results had higher mean HIS (117.5) when compared with 16 (61.1) in whom urine cytology was negative. Of those who continued to have positive FCM in the face of negative findings on cystoscopic and urine cytologic examinations during follow-up, 3 patients eventually were found to have tumors (2 distal ureter, 1 bladder). These results indicate that FCM examinations for DNA distribution of bladder irrigation specimens are as useful as conventional urine cytology in the management of bladder tumors, can be more sensitive for detection and monitoring of the disease, and can contribute further to accurate diagnosis of the disease when combined with conventional urine cytology.