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Purpose: Single immediate intravesical instillation of chemotherapy after transurethral resection of bladder tumor (TURBT) has been the gold standard treatment for patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Herein, we conducted a multicenter prospective randomized controlled trial in Japan, comparing recurrence-free survival between single and two-time instillation of pirarubicin (THP) for solitary NMIBC., Methods: Between 2005 and 2009, 257 patients with solitary NMIBC were enrolled and randomized to single instillation of THP (30 mg/50 mL) immediately after TURBT (Group A) or two-time instillation of THP immediately after and 1 day after TURBT (Group B). The primary endpoint was recurrence-free survival. Secondary endpoints included rates of recurrence and adverse effects, including hematuria, micturition pain, difficult urination, pollakiuria, systemic symptoms, and other complications. This study was registered as UMIN C000000266., Results: Of 257 patients, 99 in Group A and 102 in Group B could be evaluated for recurrence. Median follow-up was 71 months. The overall recurrence rate was 39 and 31%, respectively (p = 0.2704). Although the 5-year recurrence-free survival rates were 55.9% and 67.7% in groups A and B, respectively, the difference between groups was not significant (p = 0.2031). No significant differences in adverse effects were observed between groups, except for pollakiuria (7 vs 22%, p = 0.0031). Multivariate analyses did not show that the treatment group was a significant risk factor for bladder cancer recurrence., Conclusions: Postoperative two-time intravesical instillation of THP was not superior to single immediate instillation for preventing recurrence after complete resection of a solitary NMIBC.

Purpose: The optimal dose of intravesical bacillus Calmette-Guérin for the treatment of nonmuscle invasive bladder cancer is controversial. We investigated if induction therapy with low dose bacillus Calmette-Guérin could achieve a complete response rate similar to that of standard dose bacillus Calmette-Guérin, with less toxicity and higher quality of life., Materials and Methods: After transurethral resection, patients with unresectable multiple nonmuscle invasive bladder cancer and/or carcinoma in situ were randomized to receive standard (80 mg) or low dose (40 mg) bacillus Calmette-Guérin instillation induction therapy (weekly, 8 times). The primary end point was noninferiority of low dose bacillus Calmette-Guérin with a null hypothesis of a 15% decrease in complete response rate. Secondary end points were recurrence-free survival, progression-free survival, overall survival, patient compliance, adverse events and quality of life using the EORTC QLQ-C30., Results: In an intent to treat analysis of 166 patients the complete response rates for low dose and standard dose bacillus Calmette-Guérin were 79% (95% CI 0.70-0.88) and 85% (95% CI 0.77-0.92), respectively. Dunnett-Gent analysis revealed that the null hypothesis of inferiority of low dose bacillus Calmette-Guérin in terms of complete response could not be rejected (p = 0.119). However, there were no significant differences between the groups in terms of recurrence, progression and overall survival. Low dose bacillus Calmette-Guérin was associated with significantly less fever (p = 0.001) and micturition pain (p = 0.047), and significantly higher quality of life scores for global quality of life, role functioning and functional impairment., Conclusions: The noninferiority of low dose bacillus Calmette-Guérin was not proven. However, low dose bacillus Calmette-Guérin was associated with lower toxicity and higher quality of life compared to standard dose bacillus Calmette-Guérin in patients with nonmuscle invasive bladder cancer., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: • To confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guérin (BCG) maintenance therapy for non-muscle-invasive bladder cancer., Patients and Methods: • The enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT). • The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS)., Results: • Efficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients. • At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively. • The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P= 0.0190)., Conclusion: • BCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Objectives: We carried out a prospective, randomized, controlled trial to investigate the efficacy and safety of both induction and maintenance therapy with intravesical instillation of bacillus Calmette-Guérin (BCG) for high-risk non-muscle invasive bladder cancer (NMIBC)., Methods: Intravesical instillation of 80 mg Tokyo strain was given to patients with high-risk NMIBC, including carcinoma in situ (CIS), once weekly for eight consecutive weeks as induction therapy. Patients who achieved complete response (CR) were randomly assigned to either the maintenance group or the observation group., Results: A total of 90 patients were enrolled. After induction therapy, 75% of the patients achieved CR and 53 of them were enrolled in the randomized comparative phase. A total of four maintenance instillations were given. Median follow-up was 26.5 and 28.7 months after randomization in the maintenance and the observation group, respectively. Although it was not statistically significant, the 2-year recurrence-free survival rate in the maintenance group (95.8%) was higher than that in the observation group (74.1%, P = 0.078). Univariate analysis identified maintenance therapy as a significant factor influencing recurrence. During induction therapy, 82.2% of patients experienced urination-related adverse drug reactions, but most events were not serious. There were fewer adverse drug reactions with maintenance therapy than with induction therapy. Neither induction therapy nor maintenance therapy reduced patients' quality of life (QOL)., Conclusions: These findings show high levels of efficacy and safety of BCG induction treatment for high-risk NMIBC, and suggest that the number of maintenance instillations could probably be reduced without reducing treatment efficacy or influencing QOL.

Background: Although transurethral resection (TUR) is the standard treatment for non-muscle-invasive bladder tumors, 40-80% of tumors recur in spite of complete resection., Objective: To evaluate the efficacy, dose effectiveness and safety of early short-duration intravesical instillation therapy using epirubicin (EPI) administered immediately after TUR and on the next day following TUR., Patients and Methods: Between 1995 and 2001, 303 patients with Ta and T1 non-muscle-invasive bladder carcinoma were enrolled in this study. Patients were randomized into three groups. Group A patients were treated with two intravesical infusions of EPI 20 mg/40 ml saline immediately after TUR and within 24 h. Group B patients were treated with EPI 50 mg/100 ml on the same schedule as group A. Group C patients were treated by TUR alone as a control group. The primary endpoint was a duration to the first recurrence., Results: Of the 303 patients, 79 in Group A, 84 in Group B, and 77 in Group C could be evaluated for recurrence. Median follow-up was 44 months. Median recurrence-free survival durations for Groups A, B, and C were 24, 38, and 13 months, respectively. The difference between Groups B and C was statistically significant (p = 0.04). Adverse reactions related to instillation were observed in about 30% of the patients. These reactions included micturition pain and frequency. These toxicities were mild and transient., Conclusion: Intravesical instillation of EPI 50 mg twice within 24 h after TUR was effective as prophylactic therapy for non-muscle-invasive bladder cancer with tolerable toxicity problems.

We evaluated the need for transurethral biopsy at first follow-up after intravesical bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer. The records of 84 patients with superficial bladder cancer who received a 6- or 8-week course of BCG were reviewed. Pathological results before BCG, cystoscopic findings, urinary cytology, and biopsy results for evaluation of BCG therapy were reviewed. All 19 patients with positive urinary cytology had evidence of positive bladder biopsy results. Fifty-three of 54 patients (98.1%) with no visible recurrent tumor and negative urinary cytology demonstrated negative pathological results on bladder biopsy. When not found in conjunction with positive urinary cytology, erythematous mucosa on cystoscopy was not an indicator of tumor recurrence or residual cancer. In conclusion, routine transurethral biopsy of the bladder for evaluating the response to BCG intravesical therapy is not necessary in patients who have no visible tumor on cystoscopy and negative urinary cytology.

To compare the health-related quality of life of elderly patients after radical cystectomy for bladder cancer in urinary diversion groups: ileal conduit, ureterocutaneostomy, or orthotopic urinary reservoir. The 109 participating elderly patients aged 75 or older completed self-reporting questionnaires: the QLQ-C30, and on satisfaction with urinary diversion methods. Fifty-six patients had undergone constructions for ileal conduit diversion, 31 for ureterocutaneostomy, and 22 for orthotopic urinary reservoir (OUR). The median follow-up period for each group was 4.0 years (range 0.3-11.2), 4.5 years (range 0.3-18.0), and 3.3 years (range 0.3-6.7), respectively. Regardless of the type of urinary diversion, the majority of patients reported having good overall quality of life, although with some problem of pain. No significant differences among urinary diversion subgroups were found in any quality of life area in the QLQ-C30 questionnaire. More patients in the OUR sub-group felt disappointment than those in the ileal conduit or cutaneostomy sub-groups. However, a questionnaire which asked which diversion method would be preferable showed a trend that more patients in the OUR subgroup would have chosen the same one. Health-related quality of life appeared relatively good in these 3 groups. Patient demands and expectations may be so different from the results that the details of each urinary diversion method should be explained thoroughly. OUR construction could be a candidate even for elderly patients.

To compare the quality of life (QOL) in patients with ileal neobladder and sigmoidal neobladder, a retrospective survey was conducted using a formulated questionnaire. Between January and March 1999, a QOL survey was conducted using self-administered questionnaires (EORTC QLQ-C30, IPSS, supplemented with detailed questionnaires about continence, sexual function, and patient's satisfaction with the selected urinary diversion method) for 78 patients with orthotopic urinary reservoir (OUR) who were followed-up for more than 3 months after cystectomy. Among 78 patients, 63 had OUR using an ileal segment (male/female=59/4, median age: 70.8 years old, median follow-up: 1.7 years). Fifteen patients had OUR using a sigmoidal segment (male/female=13/2, median age: 71.9, median follow-up: 3.9). The QLQ-C30 functional evaluation and the items in relation to sexual function showed no differences between the 2 groups. Concerning the voiding condition, bladder emptying, frequency, and urgency, scores in the sigmoidal OUR group were significantly higher. The QOL score concerning voiding conditions, daytime, and nighttime continence and quantity of pad showed a better score in the ileal OUR group. Concerning the satisfaction with methods of urinary diversion, patients in the sigmoidal OUR group expressed less satisfaction than their preoperative expectations. Considering several postoperative voiding conditions, ileal OUR seems superior to sigmoidal OUR.

Objectives: To determine the oncologic safety of laparoscopic nephroureterectomy (LNU), we compared the long-term oncologic outcome of LNU versus open nephroureterectomy (ONU) in patients with upper tract transitional cell carcinoma., Methods: A total of 367 nephroureterectomy procedures were performed at our institutes for upper tract transitional cell carcinoma without distant metastases. Of 224 patients without concomitant or previous bladder cancer, 58 underwent LNU with open intact specimen retrieval plus open distal ureter and bladder cuff removal and 166 underwent ONU. Their data were reviewed and analyzed retrospectively. The mean follow-up was 13.6 months (range 14 to 34) for the LNU group and 28.0 months (range 14 to 36) for the ONU group., Results: Bladder recurrence was recognized in 19 patients (32.8%) after LNU at a median follow-up of 5.6 months compared with 63 patients (38.0%) after ONU. Local recurrence only developed in 2 patients (1.1%) after ONU. One port site metastasis occurred in a patient who had undergone LNU. Distant metastases developed in 10 patients (17.2 %) after LNU and 33 patients (19.9%) after ONU. The frequency of bladder recurrence, local recurrence, and distant metastases did not differ significantly between the two groups. The actual disease-free 2-year survival rates were similar (75.6% versus 81.7%). In all patients, the risk of metastases and death increased with advanced tumor stage and grade, but not by surgical procedure., Conclusions: In the surgical management of upper tract transitional cell carcinoma, LNU does not negatively affect long-term oncologic control and can be considered an alternative modality. Tumor stage and grade are, however, important prognostic factors in the incidence of metastases and cancer-specific mortality.

Background: We report the outcome of radical cystectomy for patients with invasive bladder cancer, who did not have regional lymph node or distant metastases, at 21 hospitals., Methods: Retrospective, non-randomized, multi-institutional pooled data were analyzed to evaluate outcomes of patients who received radical cystectomy. Between 1991 and 1995, 518 patients with invasive bladder cancer were treated with radical cystectomy at 21 hospitals. Of these, 250 patients (48.3%) received some type of neoadjuvant and/or adjuvant therapy depending on the treatment policy of each hospital., Results: The median follow-up period was 4.4 years, ranging from 0.1 to 11.4 years. The 5-year overall survival rate was 58% for all 518 patients. The 5-year overall survival rates for patients with clinical T2N0M0, T3N0M0 and T4N0M0 were 67%, 52% and 38%, respectively. The patients with pT1 or lower stage, pT2, pT3 and pT4 disease without lymph node metastasis had 5-year overall survivals of 81%, 74%, 47% and 38%, respectively. The patients who were node positive had the worst prognosis, with a 30% overall survival rate at 5 years. Neoadjuvant or adjuvant chemotherapy did not provide a significant survival advantage, although adjuvant chemotherapy improved the 5-year overall survival in patients with pathologically proven lymph node metastasis., Conclusions: The current retrospective study showed that radical cystectomy provided an overall survival equivalent to studies reported previously, but surgery alone had no more potential to prolong survival of patients with invasive cancer. Therefore, a large-scale randomized study on adjuvant treatment as well as development of new strategies will be needed to improve the outcome for patients with invasive bladder cancer.

The aim of this study was to reveal the clinical features of anterior urethral recurrence in patients with superficial bladder cancer, and to determine the appropriate treatment. Three hundred and three patients with superficial bladder cancer, who were newly diagnosed and initially treated conservatively in our hospital between 1965 and 1990, were followed for at least 5 years and their clinical outcomes were analyzed. Clinical factors, including anterior urethral recurrence, were evaluated statistically regarding tumor progression. Eight patients (2.6%) had anterior urethral recurrence following superficial bladder cancer. Twenty-four patients (7.9%) had tumor progression and 149 (49.2%) had tumor recurrence. In a multivariate analysis using a logistic model, anterior urethral recurrence was the most important factor, followed by histological grade. Four of 5 patients who were treated for anterior urethral recurrent tumors by transurethral resection showed progression and died of the cancer within one year. Two of the remaining three patients who underwent radical cysto-urethrectomy at the time of anterior urethral recurrence survived. Anterior urethral recurrence following superficial bladder cancer is a predictor for rapid subsequent malignant progression. Once there is anterior urethral recurrence, radical intensive therapy, including radical cysto-urethrectomy, should be carried out immediately.

Objective: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively., Patients and Methods: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies., Results: Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors., Conclusion: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.

Background: We compared the clinical results of orthotopic neobladder reconstruction in elderly patients and those in younger patients retrospectively in order to verify whether age is a critical factor in selecting a method of urinary diversion., Methods: Following radical cystectomy for bladder cancer, 12 patients aged 75 or older and 17 patients under 75 who underwent orthotopic neobladder reconstruction between January 1992 and May 1999 were investigated in this study. The authors TS and BS were among the surgeons who performed operations for all cases. Of the 12 elderly patients, orthotopic neobladders were constructed according to Hautmann's method in nine cases, Studer's method in one case and Reddy's method in two cases. Of the 17 younger patients, these methods were employed in 12, one and four cases, respectively. Operative procedure, early and late complications, prognosis, continence and voiding pattern were investigated in these patients., Results: The follow-up periods for elderly and younger groups ranged from 21.3 to 82.7 months and from 8.8 to 94.2 months, respectively. No difference in operation time, amount of bleeding or postoperative length of hospitalization was observed between elderly and younger patients. The rates of early complications in elderly and younger patients were 41.7% and 35.3%, respectively. Late complication rates were 33.3% and 47.1%, respectively. The difference in these complication rates was not statistically significant. One of the elderly and two of the younger patients had local recurrence and metastasis postoperatively. Those three patients had died of their bladder cancer. No statistically significant difference between groups was recognized in either cause-specific survival or overall survival, nor was there such a difference in relation to micturition/continence., Conclusion: Based on these results, we believe that because age is not a critical factor in the selection of urinary diversion method, neobladder reconstruction following cystectomy for bladder cancer is indicated in elderly patients. As stoma management is difficult for the patients, we consider orthotopic neobladder reconstruction to be the method of choice if the patients' general physical condition allows.

NY-ESO-1 mRNA expression in transitional cell carcinoma was investigated by reverse transcription-PCR and immunohistochemistry. NY-ESO-1 mRNA was detected in 20 of 62 (32%) tumor specimens. There was a correlation between NY-ESO-1 expression and tumor grade: 0 of 4 (0%) grade 1 (G1), 6 of 26 (23%) grade 2 (G2), and 14 of 32 (44%) grade 3 (G3) tumors were NY-ESO-1 mRNA positive. Immunohistochemical analysis using NY-ESO-1-specific monoclonal antibody ES121 showed that 2 of 14 NY-ESO-1 mRNA-expressing G3 tumors were positive for NY-ESO-1. No NY-ESO-1 staining was observed in the panel of 30 G1 or G2 tumor specimens, including 6 NY-ESO-1 mRNA-positive cases. Sera from an expanded panel of 124 patients with transitional cell carcinoma were tested for the presence of NY-ESO-1 antibody. Seropositivity was observed in 9 of 72 (12.5%) patients with G3 tumors, whereas none of 52 patients with G1 or G2 tumors produced antibody against NY-ESO-1. In the 9 positive patients with NY-ESO-1 antibody, 4 had muscular invasive tumors, and 5 had carcinoma in situ.

An early phase II study (dose-finding study) of amrubicin hydrochloride for superficial bladder cancer was conducted. Amrubicin was dissolved in 30 ml of physiological saline and injected intravesically for 6 consecutive days. The drug solution was retained for 2 hours. Patients were randomly assigned to four groups, which were administered amrubicin at doses of 30, 60, 90, and 120 mg/day, respectively. Of 65 patients registered in this study, 63 were eligible and assessable for toxicities, and 55 assessable for efficacy. The response rate at each dose level was 50.0% (7PRs/14 patients) at 30 mg/day, 53.3% (8 PRs/15) at 60 mg/day, 61.5% (2 CRs + 6 PRs/13) at 90 mg/day, and 69.2% (2 CRs + 7 PRs/13) at 120 mg/day, respectively. These data suggests that the efficacy was related to the doses of amrubicin. The major toxicities were cystic irritabilities, such as micturition pain, pollakisuria and hematuria. These toxicities were related to the doses of amrubicin. Their incidence and the severity were not high compared with those reported about other anthracyclines such as doxorubicin and epirubicin. The optimal dose of amrubicin was estimated to be 90 to 120 mg/day in the intravesical treatment for superficial bladder cancer once a day for 6 consecutive days.

Objectives: To assess the validity of the prophylactic use of pirarubicin ([2'R]-4-O-tetrahydropyranyl-doxorubicin) immediately after transurethral resection of bladder tumour (TURBT), using pharmacodynamic studies., Patients and Methods: The study included 20 consecutive patients with superficial bladder cancer. Pirarubicin (30 mg/50 mL or 30 mg/100 mL, 10 patients each) was instilled immediately after TURBT and retained in the bladder for 1 h. Blood samples were obtained before and at 15, 30, 60 and 120 min after the instillation. After retaining the drug for 1 h all the intravesical fluid was collected and assayed for pirarubicin., Results: The plasma pirarubicin concentration in those receiving either dose was below detectable levels at any time after instillation. The mean recovery rate of pirarubicin in the drained fluid was 73%., Conclusion: The intravesical instillation of pirarubicin immediately after TURBT caused no detectable plasma concentration and few systemic side-effects.

Epidermal growth factor (EGF), a mitogenic polypeptide with a molecular weight of 6000, is excreted in human urine in nanomolar quantities. Recently, some reports showed that urothelial neoplasm was related to the concentration of EGF in urine. In this study, EGF concentration in urine was measured by enzyme-linked immunosorbent assay (ELISA) in 207 samples from 112 male patients (30-90 years old, median 66.2) who had previously been treated for bladder cancer. Then, we tried to clarify the significance of urinary EGF as a marker for recurrence of bladder cancer in comparison with urine cytology. The samples were collected on occasional follow up cystoscopy. Urine from nine age-adjusted males without urological disease was also measured to obtain normal control values. In 123 samples from patients without tumors, EGF concentrations in urine decreased with age. In 84 samples obtained from patients with recurrent tumor, EGF concentrations were significantly lower than those in 123 samples from patients without tumors (P < 0.001) Furthermore, EGF concentrations in longitudinal samples collected the same patients during tumor recurrence and at the times when no tumor was detected were measured in 56 patients. EGF concentrations in the samples collected during tumor recurrence was significantly lower than that in specimens collected when there was no tumor (P < 0.01). There were no significant differences between the same samples collected during tumor recurrence with regard to tumor grade, stage shape and number of tumors. However, EGF concentration in urine from patients with carcinoma in situ (CIS) was lower than that in specimens from patients without CIS. These results indicate the usefulness of determining the EGF concentration as a marker for detecting bladder cancer recurrence. Urine cytology was also examined in the same series and findings were compared with those of urinary EGF. On cytology, class IV and V were considered positive, and on urinary EGF, less than 10 ng/mgCr were considered positive. Sensitivity was 25% for cytology and 57% for urinary EGF, while specificity was 98% and 66%, respectively. The predictive positive value was 0.88 and 0.53, respectively. With the combined use of urinary EGF and cytology, the sensitivity, specificity and predictive positive value were 68%, 64% and 0.92, respectively. In conclusion, urinary EGF seems to be a useful marker for detecting bladder cancer recurrence if performed in addition to cytology. cancer recurrence if performed in addition to cytology.

Viral-mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene has been demonstrated by several investigators to confer sensitivity to nucleoside analogs such as ganciclovir (GCV) in a variety of tumor cells including brain, prostate, bladder, kidney, ovary, head and neck, lung, pancreas, and liver cancers. Fourteen suicide gene clinical protocols using adenovirus vectors have been conducted, including four in prostate cancer. Two additional protocols for prostate cancer are in preparation in Japan and the Netherlands. A study conducted at Baylor College of Medicine was the first to demonstrate the safety of HSV-tk plus GCV therapy for human prostate cancer and the anticancer activity of gene therapy in this disease. However, it is still in the early stage of its development, with a number of problems to be overcome. Systemic delivery, specific introduction, and specific expression of the target gene are the major issues to be managed in order to establish a clinically relevant treatment strategy.

Numerical aberrations of chromosomes 7 and 9 of exfoliated cells from the urinary tract were examined using fluorescence in situ hybridization (FISH). To minimize contamination with inflammatory, squamous and normal transitional cells all samples were stained using Giemsa's solution and clusters of transitional cells were selected for FISH analysis. Samples collected from 21 patients who had cystoscopic monitoring for bladder cancer were used in this study. Cystoscopy was positive in seven patients and five biopsy-proven transitional cell carcinomas were identified. Among the patients with cancer recurrence, numerical chromosomal aberrations were detected in four cases (sensitivity: 80%) and positive cytology in two cases. This preliminary pilot study shows FISH can be a useful tool for the detection of recurrence during a follow up of bladder cancer.

As postoperative adjuvant therapy for superficial bladder cancer, intravesical instillation therapy is commonly conducted. In this case, from the view point of prevention of intraoperative dissemination, commencement of instillation therapy at an early postoperative period is preferred. However, increased drug permeability is suspected because of damage to the bladder mucosa during operation. Therefore, this study was conducted to investigate the plasma level of epirubicin (EPI) instilled immediately after transurethral operation. EPI (20 mg/40 ml or 50 mg/100 ml) was instilled immediately after a transurethral operation, and retained in the bladder for 1 h. Blood samples were obtained before instillation, as well as 30, 60, 120 and 240 min after instillation, and EPI levels were assayed. The mean EPI concentrations (ng/ml) among the 20-mg/40 ml group (n = 5) were < 2.5 and < 2.0 at 30 and 60 min, respectively, after which they were undetectable. The 50-mg/100 ml group (n = 5) recorded 5.0, 4.4 and < 3.0 after 30, 60 and 120 min, respectively, and after 240 min it was undetectable. Intravesical instillation of EPI immediately after a transurethral operation causes a small increase in the plasma level and it is thought to cause small systemic side effects.

To establish a method for reasonable clinical use of adriamycin (ADM) and pirarubicin (THP) in the intravesical chemotherapy for superficial bladder cancer, intracellular concentrations of these drugs were examined in culture cell lines (T-24, T-24/ADM and FHS736b1) with variable durations of contamination. The intracellular concentration of THP showed a plateau at 15-30 min. contamination in T-24, and in T-24/ADM, and showed the time dependence of contamination in FHS736b1, human normal bladder mucosa cell line. The intracellular concentration of ADM showed the time dependence of contamination in T-24, T-24/ADM and FHS736b1. And these concentrations of THP were 20 times higher than those of ADM. In conclusion, it seems better that THP was retained for 5-15 min. in the bladder in the intravesical chemotherapy, from the point of view of drug efficacy and preventing side effects. And it seems good that ADM was retained for more than 30 min. in the case with drug sensitive tumors.

SM-5887 is a novel anthracycline derivative. Experimental studies of its intravesical chemotherapy were carried out to elucidate its histopathological effect on the normal bladder mucosa and the pharmacokinetics in Beagle dogs. Forty mg (4,000 micrograms/ml), 60 mg (6,000 micrograms/ml) and 80 mg (8,000 micrograms/ml) of SM-5887 dissolved in 10 ml of physiological saline were instilled into the empty bladders of dogs with bilateral cutaneous ureterostomy, respectively. SM-5887 instilled intravesically scarcely passed into the blood. In only one dog of five instilled with 80 mg of SM-5887 intravesically, the serum level of 0.0248 micrograms/ml was detected 2 hours after instillation, but all the others were below the detection limit (0.020 micrograms/ml). Excretion of SM-5887 into the urine was also low. The highest urinary excretion was observed 6 hours after instillation of 80 mg of SM-5887, yet the concentrations of SM-5887 and its metabolites in the urine were extremely low. The urinary concentrations of SM-5887 and its active metabolite, 13-OH derivative, were 0.029 micrograms/ml and 0.131 micrograms/ml, respectively. Other metabolites were not detected. The distribution of SM-5887 in the bladder mucosa and muscular layer was almost equal, but the concentration of its active metabolite, 13-OH derivative, was 5 to 10 times higher in the bladder mucosa than in the bladder muscular layer. The distributions of SM-5887 in the organs other than the bladder, that is, the cortex and medulla of kidney, heart, lung, liver, and spleen, were very low, and those of a 13-OH active metabolite were even lower. In addition, SM-5887 barely affected the normal bladder mucosa. In dogs instilled with 80 mg of SM-5887, no histological change was observed in the bladder mucosa and submucosal layer even after 6-hour retention at the highest concentration of 8,000 micrograms/ml.

Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti-cancer drugs, including cis-diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti-cancer drugs was studied in CDDP- and ADM-resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug-resistant cell lines (T-24/ADM, CI-7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin-biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti-MT antibody. In addition, other potential mechanisms of drug resistance, such as P-glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione-S-transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1- and 2.5-fold when compared with parent cell lines (CI-7, T-24). GSH, GSSG and GST levels were unchanged and P-glycoprotein was not over-expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p < 0.05) in cases with lower pathological tumor grades.(ABSTRACT TRUNCATED AT 250 WORDS)

A collaborative randomized clinical trial on the intravesical administration of Adriamycin (ADM) with or without verapamil (VR), a calcium-channel blocker, as chemotherapy of superficial bladder cancer (Ta, T1) was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Arm A consisted of ADM given at 50 mg/50 ml saline, and arm B consisted of ADM given at 50 mg/40 ml saline plus five ampules (25 mg/10 ml saline) of injectable VR. The drugs were instilled into the bladder for 3 consecutive days, and three such courses were given with a 4-day interval between each course for a total of nine instillations. A total of 96 patients (48 in arm A and 48 in arm B) were entered into this study. The two treatment groups showed no significant difference in background factors. Of the 40 evaluated arm-A patients, 24 (60.0%) showed a response (CR + PR), whereas 19 (48.7%) of the 39 patients in arm B responded. The difference between these response rates was not statistically significant. As for adverse reactions to the intravesical chemotherapy, local inflammatory symptoms were observed in half of the patients, although no systemic reaction was observed. No significant difference was found between arm A and arm B, except for urinary turbidity. In conclusion, at the dose employed in the present clinical trial, there was no clear enhancement of the effect of ADM combined with VR in patients with superficial bladder cancer. Further clinical studies are required to determine the optimal doses of ADM and VR for their combination in intravesical chemotherapy.

Background: Carbohydrate signals are important in tumor metastasis., Methods: Expression of binding sites for fucose-binding proteins (FBP) of Lotus tetragonolobus were immunohistochemically analyzed in patients with transitional cell carcinoma., Results: The survival of patients with invasive bladder cancer was associated with the degree of expression of FBP binding sites. Overall actuarial 5-year survival and cancer-corrected 5-year survival rates were much worse in patients with strong expression of FBP binding sites than in those with no or weak expression (P < 0.001 and P < 0.05, respectively). Strong expression of FBP binding sites in patients with Stage T3-4 disease or disease beyond Stage T2 with lymphatic permeation also was correlated with increased disease progression. Autopsies revealed that FBP binding sites were strongly expressed in all primary tumors with metastasis and in most of the metastatic tissues., Conclusion: The degree of expression of FBP binding sites correlates with the increased metastatic potential of bladder cancer and with poor patient survival times.

Twenty-one patients with superficial bladder cancer entered an analysis of single dose (2'R)-4'-O-tetrahydropyranyladriamycin (THP) or adriamycin (ADM) administration. The patients in each group that have been or not have been treated previously with anti-cancer drugs were randomized into two groups, one was given THP and the other ADM. Thirty-mg of THP or ADM dissolved in 30 ml of physiologic saline was instilled into the bladder, and retained for 1 hour. After 1 hour retention of the drugs, tumor tissues and normal mucosas were removed by punch biopsy forceps transurethrally. The tissue concentrations of THP and ADM were estimated by high performance liquid chromatography. The tissue concentrations of THP and ADM in the tumors were significantly greater (p < 0.05) than those in the normal bladder mucosas. The tissue concentration of THP in the tumors were greater than that of ADM. The tissue concentrations of THP and ADM in the tumor of patients who have been treated with anti-cancer drugs previously were less than those of patients who have not. This results demonstrated that prior therapy with anti-cancer drug may cause a resistance for intravesical instillation chemotherapy. However in patients with prior therapy, the tissue concentration of THP in the tumors were greater than that of ADM. Based on these findings, THP has been shown to be were effective as an intravesical instillating agent especially, in cases with prior chemotherapy.

A randomized prospective study was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. Eligible patients were randomized into three groups: 1) adriamycin (ADM) group; intravesical instillation with 50 mg of ADM dissolved in 100 ml physiological saline, 2) mitomycin C (MMC) group; intravesical instillation with 30 mg of MMC dissolved in 100 ml of physiological saline, 3) control group; transurethral resection or transurethral coagulation only. The characteristic features of our protocol consisted of frequent (six times) instillations of the drugs within two weeks after transurethral resection, followed by instillations on two consecutive days at four-week intervals for two years. Furthermore, large quantities (100 ml) of instillation fluid containing relatively low concentrations of the drugs (500 micrograms/ml for ADM or 300 micrograms/ml for MMC) were employed. One hundred and forty-four patients have been submitted to the study; 110 patients were fully evaluable for recurrence and 34 patients were eliminated as non-evaluable patients. The cumulative five-year non-recurrence rates of the patients with multiple tumors were 32% in the MMC group, 25% in the ADM group and 7% in the control group. The cumulative non-recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. It is considered that this instillation therapy with ADM and MMC is useful for preventing the recurrence of superficial bladder cancers.

Metallothionein (MT) is a low molecular-metal binding protein with multiple biological functions. Recently, MT has been implicated as a factor involved in resistance to anticancer drugs, which presumably inactivates anticancer drugs, including cisplatin, and doxorubicin. In this report, we investigated the relationship of MT expression with the clinical features in bladder cancer and renal cell carcinoma. In 35 cases of bladder cancer, 10 cases of renal cell carcinoma and 3 cases of normal mucosa of bladder, the expression of MT was immunohistologically examined by avidinebiotin-peroxidase (ABC) staining of paraffin-embedded tissue specimens with anti-MT antibody. Intense MT expression was noted in all cases of normal mucosa of bladder. MT was detected in 10 of 35 cases of bladder cancer, with the incidence of MT expression being significantly higher increases with lower pathological tumor grade. MT was detected in 8 of 10 cases of renal cell carcinoma, and all of the their normal renal tubules showed more intense staining. A number of hypotheses can be proposed from these observations. First, our observation of decreased MT expression in poorly differentiated carcinomas, which are the more proliferating tumors, this suggests correlation of MT expression with proliferative status of cancer. Second, the higher incidence of MT expression in renal cell carcinoma than in bladder cancer may suggest that it is a factor responsible for the lower efficacy of chemo-therapy in renal cell carcinoma than in bladder cancer.

A case-controlled collaborative study on the intravesical administration of Adriamycin in the presence or absence of verapamil, a calcium-channel blocker, as chemotherapy of superficial bladder cancer was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Although little is known about the expression of P-glycoprotein in superficial bladder cancer, it may be a cause of multidrug resistance (MDR). Verapamil was used as an inhibitor of P-glycoprotein. Arm A consisted of Adriamycin given at 50 mg/50 ml saline, and arm B constituted Adriamycin given at 50 mg/40 ml saline plus 5 ampules (10 ml) of injectable verapamil. The drugs were instilled into the bladder for 3 consecutive days in each of 3 consecutive weeks for a total of 9 instillations. No significant difference in antitumor effects was observed between arm A and arm B. Recurrent tumors responded better than did primary tumors to both arm-A and arm-B treatments (P = 0.012). In both treatment arms, significant differences (P = 0.031) in the response rate were found between tumors with diameters of less than 1 cm and those measuring 1-3 cm in diameter. Although the number of evaluable patients was limited, recurrent subjects who had previously received Adriamycin instillations responded in both treatment arms.

Thirty-seven cases of superficial bladder cancer were treated with 4'-epi-adriamycin (EPI) by intravesical instillation to investigate the optimal dosage and treatment schedule. Patients were randomized into either group A: 50 mg/day for 6 days (regimen A) or group B: 60 mg/day for 3 days X 2 courses with 4 days interval (regimen B). Seventeen cases were evaluated in both groups, three cases were ineligible in group B. Patient characteristics such as age, sex, size of tumor, stage and grade were not significantly different between the two groups. Response rates were 41.2% (group A) and 70.6% (group B), while incidence of toxicity was 47.1% and 50.0% respectively. There is a trend in favor of regimen B which deserves to be more extensively verified.

Intravesical instillation of anticancer agents is one of the most effective methods for treating superficial bladder cancer. We evaluated the effects of including 4'-Epi-Adriamycin, a derivative of Adriamycin, in intravesical instillation chemotherapy. Thirty-five patients with superficial bladder tumors were treated with 4'-Epi-Adriamycin. The patients received 2 courses of 3 consecutive daily instillations of 50-80 mg 4'-Epi-Adriamycin dissolved in 30 ml of physiological saline, with an interval of 4 days. Of the 33 cases which could be fully evaluated, complete regression was observed in 4 cases and partial regression (greater than 50%) in 14 cases, showing an effectiveness rate of 55%. Side effects such as pollakisuria and miction pain occurred in 9 cases. The rate of effectiveness of this treatment was approximately equivalent to the results that we reported using Adriamycin and the occurrence and degree of side effects were lower.

We evaluated the effects of 4'-epi-Adriamycin (EPI), a derivative of Adriamycin (ADR), in intravesical instillation chemotherapy. The patients received two courses of three daily instillations of 50-80 mg EPI dissolved in 30 ml physiological saline on 3 consecutive days, with an interval of 4 days between courses. Full evaluation was possible in 33 of 35 patients with superficial bladder tumors treated with EPI. Complete response was observed in 4 cases and partial response in 14 cases, giving a response rate of 55%. Side effects such as pollakiuria and pain on micturition occurred in 9 cases. EPI appears to be an effective agent for intravesical instillation chemotherapy in patients with superficial bladder tumors.

Interferon (IFN) was used in the treatment of superficial bladder tumors. Interferon (IFN-beta, IFN-gamma) was instilled into the bladder at dosages ranging from 16 billion to 36 billion U IFN per 30 ml physiological saline. The IFN was instilled into the bladder once a day or twice a day for 10 to 20 days. In this trial, ten patients with superficial bladder tumors were treated at Okayama City Hospital, and of these, 1 CR, 3 PR, 2 MR and 4 NC were obtained. There were no signs of either irritable bladder or general side effects. IFN (especially IFN-beta) is considered a useful drug for superficial bladder tumors in intravesical chemotherapy.

UFT (a mixture of futraful and uracil) was administered orally to 15 cases of recurrent and superficial bladder cancer principally for more than 4 weeks at the doses of 300 or 600 mg per day. The result was evaluated by Koyama-Saito's response criteria. Of 14 evaluable cases, complete remission was noted in 5. Two cases of advanced bladder cancer were treated with UFT combined with irradiation therapy, and one case was found that cancer cells degenerated severely in the primary lesion pathologically. Another case was recognized that lung metastasis disappeared completely. As the side effects, anorexia occurred in 2 cases with 600 mg per day and 1 case with 300 mg, but it was not so severe to terminate UFT therapy. From above-mentioned results, UFT seems to be a useful drug for the treatment of bladder cancers.

4'-Epi-adriamycin (EPI) is a new derivative of adriamycin (ADM). The cytotoxic effect of EPI on the T24 cell line, an established cell line from human urinary bladder carcinoma, the distribution of the drug in blood, urine and tissues of various organs and histopathological change in the bladder mucosa in dogs following intravesical instillation of the drug, were studied. The cytotoxicity of EPI on the cultured T24 cells was examined by a colony formation method. After 2 hours exposure, EPI was slightly less cytotoxic than ADM, but showed higher cytotoxicity than mitomycin C or aclacinomycin A. The drug levels in blood, urine and tissues were measured by HPLC following bladder instillation in Beagle dogs with bilateral cutaneous ureterostomy. They were elevated in proportion to the drug concentration instilled intravesically. After 50 mg of EPI dissolved in 10 ml of physiological saline was instilled intravesically, the blood levels of EPI were not elevated significantly and reached the maximum levels of only 0.222 microgram/ml. The total amount of EPI excreted into the urine during the 10 hours after instillation was 389 micrograms which was equivalent to 0.78% of instilled EPI. The tissue levels of 50 mg of EPI after 6 hours retention were 1216 +/- 1094 micrograms/g in the bladder mucosa, 259 +/- 250 micrograms/g in the bladder muscular layer, 7.65 +/- 1.19 micrograms/g in the iliac node, 22.1 +/- 4.8 micrograms/g in the cortex of kidney, 15.1 +/- 3.8 micrograms/g in the medulla of kidney, 11.3 +/- 1.0 micrograms/g in liver and 5.80 +/- 1.20 micrograms/g in the heart. To examine the effect of the drug on the bladder mucosa, 50 mg of EPI was instilled intravesically. After 6 hours retention, bladder mucosa was observed through a microscope and a scanning electron microscope. Only exfoliation in the mucosa was observed sporadically and no histological change was observed in the submucosal layer. The above results suggest that EPI is a suitable drug for intravesical chemotherapy to bladder cancers.

Intravesical instillation of adriamycin (ADM) or mitomycin C (MMC) was carried out for the purpose of preventing the recurrence of superficial bladder cancers (Ta and T1) after transurethral resection or transurethral coagulation. First, eligible patients were divided into two groups (solitary and multiple) and then they were randomized into the following three groups: (1) ADM group, intravesical instillation with 50 mg ADM dissolved in 100 ml physiological saline; (2) MMC group, intravesical instillation with 30 mg MMC dissolved in 100 ml physiological saline; (3) control, transurethral resection or transurethral coagulation alone. The drugs were given six times by instillation within 2 weeks after TUR or TUC; after 2 weeks the drugs were administered for 2 consecutive days every 4 weeks for 2 years. Of the 134 patients admitted to the study, 103 were evaluable and 31 were eliminated as non-evaluable patients. The cumulative nonrecurrence rates were 73.6% for ADM, 63.4% for MMC, and 22.5% for controls after a follow-up of 24 months. The cumulative non recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. The incidence of side effects was low and the grade of these side effects mild. This instillation therapy with ADM and MMC was considered useful for preventing the recurrence of superficial bladder cancers.

Intra-arterial infusion chemotherapy in combination with angiotensin II was performed in 5 patients with advanced bladder cancer (all T3M0). The infusion catheter was inserted from a femoral artery into the internal iliac artery. The basic dosage was 70 mg/m2 of Cis-diammine-dichloroplatinum (CDDP) and 40 mg/m2 of Adriamycin (ADM) or 4'-0-tetrahydropyranyl-ADM (THP) in combination with 20-40 micrograms angiotensin II over a total duration of 20 minutes for both sides. Of the 5 patients, 3 CR and 2 PR were obtained by only one or two courses of intra-arterial infusion chemotherapy. Histological examination showed no viable cells in the three CR cases. Intra-arterial infusion chemotherapy in combination with angiotensin II may thus be clinically useful for advanced bladder cancer.