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Bacillus Calmette-Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of the patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole-blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in another cohort. The genome-wide association study indicated 19 candidate SNPs (rs1607282, rs7825442, rs1319325, rs3738088, rs4250, rs11894207, rs161448, rs2764326, rs2814707, rs3787194, rs58081719, rs3095966, rs73520681, rs16877113, rs16887173, rs10269584, rs11772249, rs118137814, and rs61094339) associated with BCG failure. Following the cumulative analysis of candidate SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. This study showed that several SNPs were possibly associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The cumulative models of these SNPs may have value in clinical applications, although this should be confirmed in future studies.

Background/aim: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC)., Patients and Methods: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer., Results: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4%), Ta: n=15 (10.5%) and T1: n=29 (20.3%). No patients showed up-staging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis)., Conclusion: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer., Materials and Methods: We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia., Results: We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer., Conclusions: Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Although it is well known that radiotherapy for prostate cancer increases comorbid rate of secondary bladder cancer, the effect of aging and smoking with radiotherapy on incidence rate of secondary bladder cancer remains unknown. Then, this study investigated the combinational effect of external beam radiotherapy for prostate cancer and aging or smoking on comorbid rate of secondary bladder cancer., Methods: This study included 754 Japanese patients with prostate cancer treated with radiotherapy (n = 319) and radical prostatectomy (n = 435) from 2000 through 2013. The relationship between therapeutic modality for prostate cancer as well as age or smoking status and comorbid rate of secondary bladder cancer was examined., Results: During the median follow-up period of 4.3 and 3.1 years, secondary bladder cancer occurred in 11 (3.4%) and 5 (1.1%) of patients with prostate cancer treated with external beam radiotherapy and radical prostatectomy, respectively. The 5-year bladder cancer-free survival rate was 97.3% in the external beam radiotherapy group and 99.4% in the radical prostatectomy group. Age (hazard ratio = 1.15, P = 0.027) and ever smoking (hazard ratio = 5.65, P = 0.011) were significant predictive factors of secondary bladder cancer incidence in the external beam radiotherapy cohort, but not in the radical prostatectomy cohort. Inversely, among men with ever smoking, but not among older men, external beam radiotherapy (hazard ratio = 9.64, P = 0.0052) was a significant risk factor of secondary bladder cancer., Conclusions: Taken together, these findings suggest that smoking history might be one of criteria to choose radical prostatectomy than external beam radiotherapy for prostate cancer, and that age would not be a criterion for therapeutic selection in terms of secondary bladder cancer., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: To examine the clinical significance of preoperative urine cytology in patients with low-grade bladder cancer., Patients and Methods: We retrospectively investigated the records of 155 patients diagnosed with primary low-grade (Ta) urothelial carcinoma of the bladder between January 2000 and September 2014., Results: Patients with class III or greater cytology had significantly higher-grade (G2) (p=0.01), larger tumors (≥15 mm, p=0.0009) and significantly shorter recurrence-free survival compared to patients with class II or lower cytology (p<0.0001). However, Cox proportional hazards analysis for recurrence-free survival only identified tumor size (≥15 mm) (hazard ratio=5.97, 95% confidence interval=2.39-17.29; p<0.0001) as a predictor of poor prognosis, although patients with class III or higher preoperative cytology showed a tendency towards frequent intravesical recurrence (hazard ratio=1.98, 95% confidence interval=0.96-4.2; p=0.063)., Conclusion: Preoperative urine cytology, in addition to tumor size, might be a useful predictor of intravesical recurrence of bladder cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Radiotherapy for prostate cancer is associated with an increased incidence of secondary bladder cancer (BC). We investigated the incidence, clinicopathological characteristics, and prognosis of BC after radiotherapy, surgical therapy, and primary androgen-deprivation therapy (ADT) for prostate cancer. This study included 1,334 Japanese patients with prostate cancer treated with radiotherapy (n=631), surgical therapy (n=437), and primary ADT (n=266). During the median follow-up period of 51.2, 44.8, and 45.5 months, secondary BC occurred in 14 (2.2%), 5 (1.1%), and 0 (0%) of patients with prostate cancer treated with radiotherapy, surgical therapy, and primary ADT, respectively. The 10-year BC-free survival rate was 91.3% in the radiotherapy group, 97.4% in the surgical therapy group, and 100% in the primary ADT group. The rates of intravesical recurrence, progression to muscle-invasive BC, and BC-specific death might be higher in secondary BC after radiotherapy compared with after surgical therapy. There was a significant difference in the incidence of secondary BC among different therapeutic modalities for prostate cancer in Japanese men, indicating significantly lower comorbidity rates of secondary BC after primary ADT for prostate cancer compared with radiotherapy.

Purpose: There are several reports of androgen receptor in bladder cancer cases but androgen receptor expression and the function of androgen/androgen receptor signaling in bladder cancer remain unclear. We investigated androgen receptor expression and the role of androgen/androgen receptor signaling in bladder cancer., Materials and Methods: We evaluated AR mRNA expression in bladder cancer tissue by quantitative real-time polymerase chain reaction. The role of androgen receptor in cell growth and drug sensitivity was also evaluated in vitro and in vivo in several bladder cancer cell lines., Results: AR mRNA expression inversely correlated with bladder cancer grade, stage and spread. Of several bladder cancer cell lines UMUC3 and MBT-2 markedly expressed androgen receptor transcript and protein. In each cell line androgen/androgen receptor signaling blockade using androgen deprivation, blockade knockdown and antiandrogen agents decreased cell growth, colony formation and cell viability. Androgen receptor expression was implicated in doxorubicin resistance. Inversely androgen receptor deprivation and knockdown made UMUC3 cells sensitive to doxorubicin. Finally, castration slightly suppressed UMUC3 tumor growth in vivo, although this did not attain statistical significance., Conclusions: AR transcript expression inversely correlates with bladder cancer clinicopathological characteristics. Androgen/androgen receptor signaling has an important role in the growth and vulnerability to doxorubicin of bladder cancer cells that express androgen receptor. Androgen/androgen receptor signaling might be a possible prophylactic and therapeutic target for bladder cancer that shows androgen receptor expression., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Bladder cancer patients who are refractory to chemotherapy have a poor prognosis. Furthermore, additional chemotherapies provide little benefit to patients who have relapsed after an initial response. Recently, it was reported that several molecular pathways are implicated in bladder carcinogenesis, including the epidermal growth factor receptor (EGFR) pathway, the vascular endothelial growth factor (VEGF) pathway and the Ras-MAPK pathway. We hypothesized that sunitinib would be effective in bladder cancer as it is an oral inhibitor of multiple receptor tyrosine kinases, including VEGF receptors, platelet derived growth factor (PDGF) receptors and stem cell factor receptor (c-KIT), and is a standard first-line treatment of advanced clear cell renal carcinoma. In the present study, the antiproliferative effects of sunitinib were clearly demonstrated in KK47, KK47/DDP20 and KK47/ADR cell lines in vitro due to the suppression of ERK1/2 phosphorylation. In a mouse model, the antitumor effects of sunitinib were again clearly seen. Also, treatment with sunitinib decreased the abundance of regulatory T cells (Tregs). However, cytotoxic T lymphocyte (CTL) activity was not induced sufficiently as compared with an IFN-α-treated group. Our results suggested that sunitinib was effective in chemotherapy-resistant bladder cancer patients. On the other hand, these findings provided the rationale for combination therapy with sunitinib and immune-based cancer therapy for advanced malignancies to prevent the occurrence of rebound phenomena.

We have recently established a unique model system of nonmyeloablative allogeneic stem cell transplantation (SCT) for treatment of murine solid tumors, based on cyclophosphamide-induced tolerance. An injection of allogeneic donor spleen cells and bone marrow cells (BMC) followed by cyclophosphamide treatment induced a stable mixed chimerism with long lasting tolerance to the allografts. A donor lymphocyte infusion (DLI) in the cyclophosphamide-induced tolerant mice exerted strong anti-tumor effects on an MBT-2 murine bladder tumor, MBT-2 via their graft versus tumor (GVT) activity. In the present study, we determined whether a cyclophosphamide-induced reduction of naturally occurring regulatory T cells (Tregs) was associated with the anti-tumor activity in our nonmyeloablative SCT system. The number of recipient CD4+ CD25+ Foxp3+ Tregs significantly decreased 3 days after an intraperitoneal injection of cyclophosphamide in C3H/HeN mice that had been injected with spleen cells and BMC of donor AKR/J mice, compared with the number of CD4+ CD25+ Foxp3- T cells. An adoptive transfer of CD4+ CD25+ T cells from naïve C3H/He x AKR/J F1 mice into recipient mice 1 day after DLI significantly suppressed the expansion and IFN-γ production of host-reactive donor CD4+T cells and hampered the MBT-2 anti-tumor activity when compared with the transfer of CD4+ CD25- T cells. These results indicated that cyclophosphamide-induced reduction of recipient Tregs is associated with retardation of tumor progression via the expansion of host-reactive donor T cells and IFN-γ production after DLI in our nonmyeloablative SCT system., (Copyright © 2011 UICC.)

Purpose: Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion., Experimental Design: Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells., Results: Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box-binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCCsup cells that expressed Twist1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility., Conclusion: The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics., (©2010 AACR.)

Purpose: We evaluated the use of narrow-band imaging (NBI) cystoscopy for the detection of bladder cancer and analyzed its diagnostic efficacy in cases of carcinoma in situ (CIS) and in cases with known urine cytology results., Patients and Methods: A prospective controlled study of NBI was conducted in 104 consecutive patients with definite or suspected bladder cancer. Transurethral targeted biopsies were performed after white light imaging (WLI) and NBI cystoscopy, and the histologic outcomes were compared., Results: A total of 313 biopsies were taken, including 161 from sites identified as potentially abnormal by NBI and/or WLI cystoscopy, and 152 from apparently normal sites. The percentage of malignancies in the sites identified only by NBI was 55.7% (39/70 places). In 26.9% of patients (28/104), bladder tumors were detected only by NBI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio of a negative test (NLR) for the detection of bladder tumors using NBI in all patients were 92.7%, 70.9%, 63.4%, 94.7%, and 0.10, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of CIS using NBI were 89.7%, 74.5%, 78.8%, 87.2%, and 0.14, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of bladder tumors using NBI in patients with positive vs negative urine cytology were 85.4% vs 98.4%, 75.7% vs 66.3%, 61.2% vs 64.5%, 92.0% vs 98.5%, and 0.19 vs 0.02, respectively., Conclusions: NBI is a simple and effective method for identifying bladder tumors including CIS without the need for dyes because of its high sensitivity, high NPV, and low NLR.

To investigate the molecules that regulate the acquisition of cis-diamminedichloroplatinum (II) (cisplatin) resistance, we performed cDNA microarrays using two pairs of parental and cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1), endoplasmic reticulum membrane protein, in cisplatin-resistant cells. The suppression of IP3R1 expression using small interfering RNA in parental cells prevented apoptosis and resulted in decreased sensitivity to cisplatin. Contrarily, overexpression of IP3R1 in resistant cells induced apoptosis and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP3R1 expression was closely associated with the acquisition of cisplatin resistance in bladder cancer cells.