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A patient presented with pancytopenia and hypercalcemia after intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) for bladder cancer. Bone marrow biopsy performed six months later revealed noncaseating granulomas with negative stains for AFB. He was diagnosed with sarcoidosis and treated with prednisone. Hypercalcemia resolved, but mild pancytopenia persisted. One year later, he developed sepsis. Blood cultures six weeks later grew Mycobacterium tuberculosis complex, ultimately identified as Mycobacterium bovis. Despite triple antibiotic therapy, the patient progressively declined and expired.

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Aim: Bladder cancer is the second most common urological malignancy after prostate cancer. Increase in the post-void residual (PVR) volume may result in an increase in the risk of cancer recurrence. Methods: Patient demographic data, tumor stage and grade, PVR volume and 2 years follow-up data for recurrence were obtained and evaluated. Results: One-hundred-and-nineteen patients were subdivided into three groups according to PVR urine volume. The increase of PVR volume was related to short recurrence-free survival (RFS) especially for patients with PVR volume of 60 ml or more. Conclusion: Low PVR volume in patients with non-muscle invasive bladder cancer may play a role in reducing cancer recurrence. However further research is needed in this field.

Aim: Bladder cancer is the second most common urological malignancy after prostate cancer. Increase in the post-void residual (PVR) volume may result in an increase in the risk of cancer recurrence. Methods: Patient demographic data, tumor stage and grade, PVR volume and 2 years follow-up data for recurrence were obtained. Results: The increase of PVR volume was related to short recurrence-free survival (RFS) especially for patients with PVR volume of 60 ml or more. Conclusion: Low PVR volume in patients with non-muscle invasive bladder cancer may play a role in reducing cancer recurrence. However further research is needed in this field.

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Bacillus Calmette-Guerin (BCG) immunotherapy can prevent recurrence and progression in selected patients with non-muscle-invasive bladder cancer (NMIBC); however, significant adverse events and treatment failure suggest the need for alternative agents. A commercial anti-infection vaccine comprises a genetically engineered heat-killed Pseudomonas aeruginosa (PA) expressing many mannose-sensitive hemagglutination (MSHA) fimbriae, termed PA-MSHA, which could be a candidate for bladder cancer intravesical therapy. In an immunocompetent orthotopic MB49 bladder cancer model, we characterized the antitumor effects and mechanisms of PA-MSHA compared with those of BCG. Three weekly intravesical PA-MSHA or BCG treatments reduced tumor involvement; however, only PA-MSHA prolonged survival against MB49 implantation significantly. In non-tumor-bearing mice after treatment, flow-cytometry analysis showed PA-MSHA and BCG induced an increased CD4/CD8 ratio, the levels of effector memory T cell phenotypes (CD44, CXCR-3, and IFN-γ), and the proportion of CD11b+Ly6G-Ly6C-IA/IE+ mature macrophages, but a decrease in the proportion of CD11b+Ly6G-Ly6C+IA/IE- monocytic myeloid-derived suppressor cells (Mo-MDSCs) and the expression of suppressive molecules on immune cells (PD-L1, PD-1, TIM-3, and LAG-3). Notably, PA-MSHA, but not BCG, significantly reduced PD-1 and TIM-3 expression on CD4+ T cells, which might account for the better effects of PA-MSHA than BCG. However, in tumor-bearing mice after treatment, the increased proportion of Mo-MDSCs and high expression of PD-L1 might be involved in treatment failure. Thus, modulating the balance among adaptive and innate immune responses was identified as a key process underlying PA-MSHA-mediated treatment efficacy. The results demonstrated mechanisms underlying intravesical PA-MSHA therapy, pointing at its potential as an alternative effective treatment for NMIBC.

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BACKGROUND: Intravesical bacillus Calmette-Guerin (BCG) therapy is the treatment of choice for patients with T1 or high-grade superficial bladder cancer or those with carcinoma in situ after transurethral resection. A personal history of tuberculosis infection has been viewed as a relative contraindication for BCG therapy, because it may increase the risk of complications or decrease the treatment effectiveness. We determined the safety and efficacy of intravesical BCG treatment for patients with prior tuberculosis infection by analyzing the data obtained from the National Health Insurance Research Database in Taiwan. METHODS: We included patients who were newly diagnosed with bladder cancer from 2000 to 2009 and who received adjuvant intravesical BCG therapy within 3 months after the surgery. We excluded those who developed upper urinary tract cancer during the study period. Disease recurrence, disease progression, and major adverse effects were compared between patients with and without a prior diagnosis of tuberculosis infection until December 31, 2011. RESULTS: Among the 3915 patients included, 187 (4.8%) had been previously diagnosed with tuberculosis infection. The proportion of men (84.0% versus 76.9%) and older patients was higher in the group with a prior tuberculosis infection than in those without a prior tuberculosis infection. Significant differences in disease recurrence (20.3% versus 22.8%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.63-1.21, p = 0.404) or disease progression (10.2% versus 12.8%, HR, 0.74; 95% CI, 0.46-1.17, p = 0.191) were not observed between the two groups. None of the patients with a prior tuberculosis infection had severe urinary tract infections, whereas four (0.1%) patients without such an infection developed severe urinary tract infections. CONCLUSION: A prior tuberculosis infection did not affect the treatment efficacy or safety of intravesical BCG treatment. The efficacy and safety of intravesical BCG therapy are comparable between bladder cancer patients with and without prior tuberculosis infections.

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BACKGROUND: To evaluate the effect of intravesical bacillus Calmette-Guerin (BCG) instillation therapy after second transurethral resection (TUR) on primary T1 bladder cancer. METHODS: The subjects were 180 patients diagnosed with T1 bladder cancer at our university and at affiliated hospitals between January 1990 and December 2015. Tumor residual rate, intravesical recurrence rate, and risk factors for intravesical recurrence were investigated. RESULTS: The median follow-up period was 26 (1-175) months. Of the 180 patients, 78 (43%) underwent a second TUR. Residual tumors were detected in 42 patients (53.8%), and no up-staging cases were observed. Within the whole group, 42 patients were treated with intravesical BCG therapy following a second TUR (group 1), 36 were treated with second TUR alone (group 2), 28 were treated with intravesical BCG therapy alone (group 3), and 74 were treated without second TUR or intravesical BCG therapy (group 4). The 1- and 5-year recurrence-free survival rates of the four groups were 80.7 and 59.7% (group 1), 69.0 and 26.3% (group 2), 76.3 and 56.6% (group 3), 64.6 and 48.6% (group 4), respectively. There was no significant difference between group 1 and group 3 (p = 0.401). Intravesical BCG therapy was the only factor preventing intravesical recurrence (p = 0.013). CONCLUSIONS: Intravesical BCG therapy alone showed a significant preventive effect with regard to intravesical recurrence. In our cohort, however, second TUR did not improve recurrence-free survival in those individuals who underwent BCG instillation.

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The present study aimed to investigate the effect of the negative costimulatory molecule programmed death-ligand 1 (PD-L1) on immunotherapy with OK-432, following transurethral resection of bladder tumors in non-muscle invasive bladder cancer (NMIBC), and to elucidate the underlying mechanism. PD-L1 was detected by immunohistochemical staining in tumor specimens from 55 cases of NMIBC following postoperative immunotherapy with OK-432. The PD-L1 mRNA and protein expression levels were measured in the bladder cancer T24 cell line and the human uroepithelial SV-HUC-1 cell line, following treatment with interleukin (IL)-2, interferon (IFN)-α and IFN-γ, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. PD-L1 was widely expressed in the NMIBC tumors, with 56.4% (31/55) of specimens exhibiting positive staining. When compared with PD-L1-negative patients, PD-L1-positive patients exhibited significantly increased recurrence [48.4% (15/31) vs. 16.7% (4/24)] and progression [16.1% (5/31) vs. 4.2% (1/24)] rates (P<0.05). RT-qPCR and western blotting demonstrated that cytokines IL-2, IFN-α and IFN-γ markedly upregulated PD-L1 mRNA expression rates and protein levels in bladder cancer T24 cells (P<0.05), but had no significant effect in non-tumor SV-HUC-1 cells. In conclusion, PD-L1 expression was negatively-associated with the efficacy of OK-432 intravesical immunotherapy in patients with NMIBC. The results indicated that the involved mechanism occurred via upregulation of PD-L1 by immune cytokines, which in turn suppressed the antitumor effectiveness of the immune system, thereby promoting tumor recurrence and progression.

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Approximately 75% of bladder cancers are non-muscle-invasive bladder cancer (NMIBC), and 50% of NMIBC patients who are treated with transurethral resection (TUR) have a recurrence of the disease and 5-25% of these patients progressed to muscle-invasive disease after repeated recurrences. NMIBC patients receive various treatments aimed at reducing disease recurrence and progression. Although the recurrence rate of disease remains above target, thus increasing treatment cost, the true rate of recurrence after the primary surgery is controversial. Recurrences can be categorized as either true recurrence due to aggressive tumor biology and implantation of floating cancer cells or false recurrence such as small, flat, or carcinoma in situ lesions overlooked in the primary procedure. Here we discuss new diagnostic methods and treatment options to improve outcomes and reduce recurrence rates in NMIBC.

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CONTEXT: Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non-muscle-invasive bladder cancer (NMIBC) but warrants special consideration. OBJECTIVE: To review the contemporary literature on the diagnosis and management of CIS. EVIDENCE ACQUISITION: A systematic search using broad terms to capture the diagnosis and treatment of CIS was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Full-text original articles, reviews, and editorials from 1966 to 2014 in English were included. References from selected articles, relevant guidelines, and conference abstracts were searched. Abstracts were excluded. EVIDENCE SYNTHESIS: A total of 1887 articles were identified, of which 120 were used in this review. Most reports were retrospective and heterogeneous in caseload. There is a lack of standardised classification of CIS. Many studies consider CIS in the context of NMIBC without a clear separation of the subset with CIS. Recent prospective phase 2 and 3 studies have improved the evidence base. CONCLUSIONS: We are beginning to understand that CIS has a spectrum of biologic potential. Bacillus Calmette-Guérin immunotherapy appears superior to other intravesical agents and may alter the natural history of CIS. New imaging modalities, agents, and treatment strategies have emerged in recent years with the aim of better identification of CIS, more bladder-preserving treatments, and prevention of surgical overtreatment. PATIENT SUMMARY: Improvements in imaging techniques combined with new bladder-preserving treatments will continue to have an impact on the outcomes of bladder carcinoma in situ.

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INTRODUCTION: To investigate the effects of intravesical immunotherapy on semen parameters in young patients with non-muscle invasive bladder tumour. METHODS: A total of 17 sexually active male patients < 45 years of age underwent transurethral resection of bladder tumour (TURBT) from Jan 2010 to Dec 2012. On HPE analysis, T1 high grade was found in 16 patients and Ta grade high grade in 1 patient. Associated CIS was found in 4 patients. Induction course of 6 weeks of adjuvant BCG therapy was given. Semen analysis was done 1 week prior to BCG therapy and 3 months after BCG therapy. Serum levels of hormones like total testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were also measured. RESULTS: Mean age of patients at diagnosis was 34.6 (29-43) years. Total semen volume was found to be decreased in 2 patients. Main parameter which was deteriorated was total sperm concentration which was significantly decreased in 12 patients and 5 patients even had their counts below oligospermia levels. Seven patients had associated decrease in sperm motility. However, no patient showed significant difference in other semen parameters. Also no patient had any change in androgen hormonal status except 2 patients in which serum testosterone was found to be non-significantly decreased. CONCLUSION: Intravesical therapy with BCG was found to adversely affect spermatogenesis and cause oligospermia. It is important that relatively young patients must be informed of these effects and advised to have sperm preservation before instillation of BCG therapy to avoid fertility issues in future.

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