TUMOR LOCALIZATION AND SYSTEMIC ABSORPTION OF INTRAVESICAL INSTILLATION OF RADIO-IODINATED IODODEOXYURIDINE IN PATIENTS WITH BLADDER CANCER

PURPOSE: We evaluated tumor uptake and systemic distribution of intravesically instilled iododeoxyuridine (IUdR) in patients with superficial bladder cancer. MATERIALS AND METHODS: We performed 24 intravesical instillation studies in 11 patients with a mean age of 71 years. Radio-iodinated IUdR was administered through a Foley catheter. Gamma camera imaging was done after instillation and after 5 to 7 bladder irrigations. Tumor uptake was estimated by region of interest analysis. Bladder biopsy samples and surgical tumor specimens were tested for acid insoluble (deoxyribonucleic acid incorporated) radioactivity. Blood samples were obtained and analyzed for systemic absorption. RESULTS: Imaging was positive in all patients with bladder cancer. Average tumor uptake plus or minus standard deviation was 0.185+/-0.120% of the instilled dose. Preferential uptake of IUdR in the tumor was observed in all 6 patients undergoing tissue analysis. The tumor-to-normal bladder ratio ranged from 3.2 to 74,000 (median 202). Systemic absorption of IUdR was minimal. Blood sample analysis performed after intravesical instillation in all 11 cases revealed an average uptake of 3.2x10(-5)% instilled dose per ml. (range 0.69x10(-5) to 6.7x10(-5)) in the systemic circulation. Instillation within 24 hours after transurethral bladder tumor resection in 5 cases resulted in a higher but not dangerous average systemic uptake of 7.3x10(-4)% instilled dose per ml. (range 1.3x10(-5) to 2.6x10(-3)). Instillation 1 to 4 weeks after transurethral surgery in 8 cases resulted in no increased systemic absorption with an average blood level of 3.4+/-1.8x10(-5)% instilled dose per ml. There was no detectable distribution of radioactivity into other organs, including the thyroid. We noted no evidence of systemic toxicity in the study. CONCLUSIONS: Intravesical instillation of radio-iodinated IUdR achieves selective localization in the bladder tumor with minimal uptake by the normal bladder and minimal systemic absorption. The use of intravesical IUdR therapy for bladder cancer appears to be promising and requires further study.     

ＭＭＣ和ＢＣＧ交替灌注防治膀胱癌术后复发

目的：观察丝裂霉素Ｃ（ＭＭＣ）和卡介苗（ＢＣＧ）化学免疫预防膀胱癌术后复发的疗效。方法：对８６例浅表性膀胱癌患者术后应用ＭＭＣ２０mg和ＢＣＧ６０mg,每周１次进行交替膀胱藻注,共灌注１２次,以后每间隔３个月灌注１次,持续２年,结果：随记２．４－８年,平均４．８４年,肿瘤复发率为８．１％,结论：ＭＭＣ和ＢＣＧ交替膀胱灌注可减少膀胱癌术后复发率。     

Urothelial susceptibility to tumor cell implantation: comparison of cauterization with N-methyl-N-nitrosourea

To determine whether or not transitional cell carcinoma cells will preferentially implant and grow on an altered urothelial surface, cauterization and instillation of N-methyl-N-nitrosourea (MNU) were used to alter the murine bladder urothelium. Transplantable tumor cells (2.09 X 10(6) ) were placed into the bladders of 53 mice. Tumor cell implantation occurred in only 6 per cent of the mice with a normal bladder, whereas tumors were present in 28 per cent of mice pretreated with intravesical MNU and in 67 per cent of mice which had a portion of the bladder cauterized prior to insertion of tumor cells (p less than 0.005). This study not only establishes the optimal technique for implantation in this experimental model, but also suggests that seeding may be a contributory factor in the high recurrence rate following endoscopic treatment of bladder tumors in man.     

5 years intravesical instillation with mitomycin-C and pirarubicin as a prophylactic treatment for superficial bladder cancer

PURPOSE: We studied prophylactic intravesical instillation of mitomycin C (MMC) and pirarubicin (THP) following transurethral resection of bladder tumor (TUR-Bt) for superficial bladder cancer. MATERIALS AND METHODS: Forty-six evaluable patients were administered intravesically 20 mg of MMC dissolved in 20 ml saline on day 1 and 20 mg of THP dissolved 20 ml 5% dextrose on day 2. The patients were followed up by cystscopy and urinary cytology. Intravesical instillations were performed once a month and continued for 5 years. RESULTS: The non-recurrence rates at 1, 3 and 5 years were 88.8%, 79.5% and 67.0%, respectively. No significant differences were observed between grade 1-2 and 3, male and female, and solitary and multiple tumors. Although the side effects were relatively mild, 6 patients were stopped intravesical instillation. CONCLUSIONS: Because non-recurrence rates of our report is not better than previous reports with shorter treatment periods, intravesical MMC and THP instillation for 5 years is not beneficial to the patients with superficial bladder cancer.     

经尿道气化切割术加灌注治疗表浅型膀胱肿瘤65例报告

目的：探讨表浅型膀胱肿瘤经尿道气化切割术加灌注防治术后复发减少小良反应的方法。方法：对65例膀胱肿瘤患者采用经尿道气化切割电极气化切割肿瘤及肿瘤基底部周围0.5～1.0cm正常膀胱黏膜，深达浅肌层。手术切割完毕，用无菌蒸溜水多次灌注冲洗膀胱，术后第1周开始用丝裂霉素C（MCC）20mg灌注膀胱，每周1次，共6次，然后每4周1次，持续1年以七。结果：本组65例均顺利完成手术，术中无膀胱穿孔，出血量较少，均未输血。术后无尿路感染、继发性出血及膀胱破裂等并发症。联合灌注后均未出现膀胱剌激症状，无血尿、发热、全身不适及白细胞下降。所有患者随访5个月～8年，复发11例，复发率16.9％。结论：经尿道气化切割加灌注治疗表浅型膀胱肿瘤是一种简单有效对方法，易于掌握及推广。     

米托蒽醌灌注预防膀胱癌术后复发的疗效观察(附98例报告)

目的　评价米托蒽醌 (MTZ)膀胱灌注预防浅表性膀胱癌术后复发的疗效和安全性。方法　对 98例浅表性膀胱癌患者行TURBT或膀胱部分切除术 ,术后 1周予MTZ 12mg 生理盐水 5 0ml膀胱内灌注 ,药物于膀胱内保留 2h ,每周 1次 ,连续 8周 ,以后每月 1次 ,连续 12个月。定期做血尿常规、肝肾功能及膀胱镜检查 ,并记录每次膀胱灌注后的全身及局部反应。　结果　 98例均未见全身性药物不良反应 ,随访 6～ 2 4个月 ,平均 13个月 ,复发 6例 ,复发率 6 .2 %。　结论　MTZ膀胱灌注防止膀胱癌术后复发疗效满意 ,安全性好     

Arthritis following intravesical instillation of BCG for urothelial cancers

BACKGROUND: Intravesical instillation of bacillus Calmette-Guerin (BCG) is efficient for prophylaxis of superficial bladder cancer and treatment for carcinoma in situ (CIS) of the upper urethelial cancer. However, the incidence of adverse effects is relatively high, and those include reactive arthritis. We retrospectively evaluated the incidence and the outcome of reactive arthritis following intravesical BCG therapy for urothelial cancers. PATIENTS AND METHODS: Intravesical instillations of BCC were performed in 192 cases (218 courses) between January 1998 and January 2002. BCG was instilled for prophylaxis of superficial bladder cancer recurrence in 170 (195 courses), treatment for CIS in 7 (8 course), and treatment for CIS in 7 (8 courses), and treatment for CIS in upper urinary tract in 15 (15 courses). RESULTS: Arthritis was recognized in 8 cases (3.7%, 8/218 courses), and 7 of them were identical to reactive arthritis following BCG therapy. Remaining 1 patient was diagnosed as rheumatoid arthritis (RA), and the relation between arthritis and intravesical BCG instillation was unclear. Mean number of BCG instillation was 5.6 (3-8 times). All reactive arthritis were occurred within 4 weeks after the last BCG instillation, i.e., BCG induced urinary tract infection, and 6 of them were polyarthritis. Concurrence of conjunctivitis was seen in one patient. HLA-B27 was negative in 4 examined patients. A nonsteroidal anti-inflammatory drug (NSAID) was used in all 8 patients, anti-tuberculous agents were used in 3, and prednisolone was added in 3, Arthritis was improved within 2 months in patients received prednisolone, however, it persisted longer than 3 months in patients without prednisolone. CONCLUSION: Arthritis was recognized in higher incidence than previous reports following intravesical instillation of BCG. All cases except one, diagnosed as RA, were diagnosed as reactive arthritis (Reiter's syndrome). However, correlation between HLA-B27 and arthritis was not clear in this study. Administration of steroidal drug was thought to improve arthritis in shorter duration.     

膀胱癌经尿道电切除术后吡柔比星膀胱灌注预防复发临床观察

目的:探讨吡柔比星膀胱内灌注预防膀胱癌术后复发的疗效、安全性。方法:45例膀胱癌经尿道电气化术后患者分2组,分别用吡柔比星和卡介苗定期行膀胱内灌注,随访10～33个月,了解灌注后肿瘤复发情况及并发症。结果:卡介苗组复发率为13.6%(3/22),副反应率为81.8%(18/22);吡柔比星复发率为13.0%(3/23),副反应率为91.3%(21/23),两组肿瘤复发率、并发症无显著差异,但卡介苗严重副反应高于吡柔比星(P<0.05)。结论:吡柔比星膀胱灌注预防膀胱癌复发的有效率与卡介苗相同,但严重副反应明显减少,是一种有效的药物。     

盐酸米托蒽醌膀胱灌注预防尿路上皮移行细胞癌复发

目的：评价盐酸米托蒽醌膀胱灌注预防尿路移行上皮细胞癌膀胱内复发的有效性、患者耐受性及其毒副作用。方法：对21例手术后经病理检查证实为尿路上皮移行细胞癌而且保留膀胱的患者，以盐酸米托蒽醌作膀胱灌注，记录膀胱灌注过程中的相关情况。结果：随访1～12个月，4例复发，1例恶化，复发率为19．0％(4／21)，1年未复发率76．2％(16／21)，平均无瘤间期10．3个月。9例发生局部并发症，复查血常规及肝、肾功能灌注前后差异无统计学意义。结论：初步随访证实，盐酸米托蒽醌降低尿路上皮移行细胞癌术后复发，大部分患者耐受良好，无明显全身毒副作用。     

Enhancement of bacillus Calmette-Guerin attachment to the urothelium by removal of the rabbit bladder mucin layer.

It has been established that the urothelial mucin layer functions as a bacterial anti-adherence factor. Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer. The proposed mechanism of action of Bacillus Calmette-Guerin is adherence to the urothelium with induction of an immunologic and/or inflammatory response. The current study was designed to determine if rabbit bladder mucin removal results in increased Bacillus Calmette-Guerin urothelial adherence. PAS and colloidal iron stains were used to demonstrate that intravesical instillation of 50% acetone renders rabbit bladder urothelium mucin deficient. The urothelium remains mucin deficient at two hours, but by 24 hours the mucin layer has been regenerated. Two hours following intravesical 3H-labeled Escherichia coli administration, bacterial adherence was 29-fold greater in mucin deficient than mucin intact rabbits (p = 0.05). By 12 hours, the difference in adherence was not significant. Two hours following intravesical administration of 3H-labeled Bacillus Calmette Guerin, mucosal adherence was 21-fold greater in mucin deficient compared to mucin intact rabbits (p = 0.002). After mucin removal, Bacillus Calmette Guerin urothelial adherence was significantly increased. The significant increase in Bacillus Calmette Guerin adherence after mucin removal may be clinically exploitable.     

Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer

PURPOSE: We determined if a single intravesical instillation of gemcitabine (2',2'-difluorodeoxycytidine) could prevent the implantation of urothelial cancer cells in the bladder wall of mice, and if 4 weekly treatments could eliminate early implanted bladder cancer in this model. MATERIALS AND METHODS: Tumor implantation and orthotopic bladder tumors were induced in mice by electrocautery of the bladder wall and subsequent instillation of MB49 bladder cancer cells. In the first experiment the tumor cell suspension was left in place for 30 minutes, immediately followed by bladder irrigation and a single intravesical instillation of 250 or 500 microg gemcitabine for 10, 30, 60 or 120 minutes. In the second experiment dwell time was 2 hours, bladders were not irrigated after tumor cell instillation and mice were treated with 4 weekly instillations starting 24 hours after tumor cell implantation. The animals were monitored for side effects and bladder cancer signs, and autopsied at the end of followup. RESULTS: A single intravesical instillation of 500 microg gemcitabine (10 mg/ml) for 30 minutes decreased tumor outgrowth significantly from 90% (control) to 30% (chi-square test p = 0.022). Gemcitabine at 250 microg and prolonged instillations of 500 microg during 60 or 120 minutes were less effective. In the second experiment a short dwell time (30 minutes) was effective at 500 microg doses, resulting in an outgrowth decrease in 89% (control) to 30% of mice, whereas longer instillations (greater than 120 minutes) resulted in significantly reduced tumor outgrowth (11% at 250 microg). The apparent loss of efficacy as a factor of time could not be fully explained. Prolonged bladder distention caused by increased bladder volume due to diuresis may have resulted in trauma and caused enhanced susceptibility to tumor implantation. In the second experiment prolonged instillations (greater than 120 minutes) at 250 microg or higher doses (500 microg) were effective with 11% and 30% outgrowth, respectively. CONCLUSIONS: If given early (within 30 minutes.) after tumor cell seeding, gemcitabine is effective for preventing tumor cell implantation and the resulting tumor outgrowth.     

吡喃阿霉素膀胱内灌注预防浅表性膀胱癌术后复发

目的　评价吡喃阿霉素 (THP)膀胱内灌注预防浅表性膀胱癌术后复发的疗效和安全性。　方法　对 45例浅表性膀胱癌患者行经尿道膀胱肿瘤电切术 (TURBt)或膀胱部分切除术 ,术后定期应用THP(4 0mg/ 40ml)膀胱内灌注 ,每次药物在膀胱内保留 30min。　结果　 45例患者随访 9～ 12个月 ,无肿瘤复发 44例 (97.8% ) ,复发 1例。未见有全身性药物不良反应 ,仅 2例膀胱灌药后出现短时间轻度膀胱刺激症状。　结论　THP膀胱内灌注预防浅表性膀胱癌术后复发疗效满意 ,病人耐受性好 ,副作用小     

Prophylactic intravesical BCG for bladder tumor after surgery of upper tract urothelial carcinoma

We report the result of prophylactic intravesical instillation of BCG after surgery of upper tract urothelial carcinoma. The BCG Tokyo 172 strain was given preoperatively and/or postoperatively, as a rule, in a dose of 80 mg in 30 ml saline instilled into the bladder. Only one (14.3%) of the 7 patients with intravesical BCG developed bladder tumor at 14 month after surgery, while (45.4%) of 11 patients who did not receive intravesical BCG suffered from bladder tumor within 2 years after surgery. Prophylactic intravesical instillation of BCG reduced significantly (p less than 0.005) the recurrence of bladder tumor after the surgery of renal pelvis and ureteral tumor.     

Whole bladder photodynamic therapy for orthotopic superficial bladder cancer in rats: a study of intravenous and intravesical administration of photosensitizers

PURPOSE: Photodynamic therapy after intravenous injection of Photofrin (QLT Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted bladder and skin photosensitivity, which limits its clinical application. In an attempt to overcome these limitations photodynamic therapy after intravesical instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat bladder tumor model was explored and compared with intravenous Photofrin for photodynamic therapy efficacy and phototoxicity. MATERIALS AND METHODS: At 2 weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2 mg./ml. intravesically). The ALA concentration for intravesical instillation was 300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda = 630 nm.) was performed 4 hours after drug administration. Tumor control and complications were evaluated. RESULTS: Photodynamic therapy with intravenous Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats 6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no photodynamic therapy related deaths in groups receiving intravesical instillation of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously plus 50 J./cm.(2) (60) were significantly different from that in controls (44). CONCLUSIONS: Intravesical instillation of Photofrin or ALA can achieve the same photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat bladder tumor model with less phototoxicity to normal tissues.     

Fundamental studies on intravesical instillation of carboquone for treatment of urinary bladder tumors--on the effects of intravesical instillation of carboquone in normal beagle dogs

The effects of intravesical instillation of Carboquone at the clinically used doses of 5 and 10 mg on the normal mucosa of female beagle dogs was compared with that of 10 mg Mitomycin C used as the control drug. Intravesical instillation for 48 hours of 10 mg carboquone/20 ml phosphate buffer solution (PBS) after bilateral cutaneous uretrostomies produced severe inflammatory changes in all layers of the bladder wall. However, no secondary effects were observed in blood laboratory examinations or histological examinations of the whole organ after autopsy. Phosphate buffer solution produced no remarkable secondary effects in animals. Five milligrams carboquone per 20 ml PBS was instilled intravesically once a week for 3 weeks in normal animals. Cystoscopically , the bladder mucosa recovered normally. Blood laboratory examinations showed no abnormal results, but the bladder epithelium had regenerative epithelial hyperplasia and slightly inflammatory changes in the submucosal layers. Two of the three control animals given instillation of 10 mg of Mitomycin C/20 ml PBS had slight leucopenia at 7 days after the last intravesical instillation, but leucocyte count was normal at the end of the experiment. Cystoscopic and histological examination of the epithelium of the urinary bladder revealed severe inflammatory changes in 2 of the 3 animals.     

膀胱内翻性乳头状瘤的诊断和治疗(附24例报告)

目的探讨膀胱内翻性乳头瘤(IPB)的发病特点及其诊治方法。方法回顾性分析24例IPB的临床资料。20例采用经尿道膀胱肿瘤电切术(TURBT),4例行膀胱部分切除术,术后膀胱灌注化疗预防复发。结果患者术后生存良好,20例获得随访3个月~12年,未见肿瘤复发或恶变。结论IPB是一种少见的尿路上皮肿瘤,预后良好。诊断依赖于膀胱镜检及术后病理检查,TURBT是其标准的治疗方法,术后予膀胱灌注化疗有利于预防复发。     

Comparison of intravenous and intravesical administration of chloro-aluminum sulfonated phthalocyanine for photodynamic treatment in a rat bladder cancer model.

Photodynamic therapy is an experimental treatment of superficial bladder tumors. Photofrin, a mixture of porphyrins, is the only photosensitizer in clinical use in the U.S.A. and its major side effect is prolonged cutaneous phototoxicity. In order to circumvent this problem of phototoxicity, new photosensitizers are being examined. Cutaneous phototoxicity may also be minimized by local administration of photosensitizer. Therefore, in this study, we investigated the photosensitizer chloro-aluminum sulfonated phthalocyanine (CASPc) in vivo in a rat bladder carcinoma model, and compared two different routes of CASPc administration. AY-27 rat bladder carcinoma cells were transplanted into rat bladders. Eight days after tumor transplantation the biodistribution of CASPc in bladder, skin, muscle and bladder tumor was determined by fluorescence measurements after dye extraction. Photosensitizer administered by intravenous injection and intravesical instillation, were compared. The concentration of CASPc in bladder and bladder tumor after intravenous injection and intravesical instillation was similar. The ratio of dye uptake between tumor and normal bladder after either administration was approximately two. Although no systemic absorption of the photosensitizer was observed after intravesical instillation, there was no reduction in tumor uptake or in the ratio between tumor to normal surrounding tissue. Therefore, no systemic side effects of skin phototoxicity are expected upon intravesical instillation. The microscopic biodistribution of CASPc after intravenous injection and intravesical instillation was also compared. After intravenous injection, the photosensitizer was distributed within the whole tumor with increased fluorescence around the microvasculature. In the normal bladder wall, weak fluorescence was seen in the area of the vasculature in the submucosa and the muscularis. After intravesical instillation, strong fluorescence was detected only at the tumor surface and in normal urothelium; no fluorescence was found in other areas of the tumor or in submucosa or muscularis. A comparison of the photodynamic treatment of model bladder tumors showed that tumor destruction after either method was similar but that there were less side effects to normal bladder wall after intravesical instillation of the CASPc. Intravesical administration of photosensitizers may, therefore, be a viable alternative to intravenous injection with potential for reduced systemic and normal tissue toxicity.     

Requirement of a thymus dependent immune response for BCG-mediated antitumor activity

Surgical adjuvant intravesical bacille Calmette-Guerin (BCG) therapy is an effective method of treating superficial transitional cell carcinoma of the bladder. The role of the immune response in the antitumor activity of intravesical BCG is not known. We investigated the requirement of a thymus-dependent immune response for the inhibition of the growth of the intravesically implanted mouse bladder tumor, MBT-2. Intravesical BCG had no antitumor activity when administered to athymic nude mice bearing MBT-2 tumors. In two experiments tumor outgrowth in control and BCG-treated mice was identical. Adoptive transfer of BCG sensitized splenocytes (one spleen equivalent per mouse injected intravenously immediately prior to the first BCG treatment) syngeneic to the MBT-2 tumor transferred delayed hypersensitivity reactivity to BCG antigens and restored the antitumor activity of intravesical BCG. In two separate experiments mice receiving splenocytes plus BCG had 0 and 20% tumor outgrowth compared with 100% in control mice (p less than .02 and p less than .05, respectively). These results demonstrate that the antitumor activity of intravesical BCG therapy requires a thymus-dependent immune response.     

膀胱内灌注盐酸表柔比星预防膀胱癌术后复发92例临床对照研究

目的研究盐酸表柔比星膀胱灌注预防经尿道膀胱癌电切术(TURBt)术后复发的疗效。方法对184例膀胱癌患者在TVRBt术后行膀胱灌注化疗,平均分成两组:Ⅰ组(92例)定期膀胱内灌注盐酸表柔比星,术后第1天使用50 mg,膀胱内灌注保留2 h,1周后开始常规灌注化疗,每周1次连续3次,然后每月1次连续11次,共1年;Ⅱ组(92例)为对照组灌注丝裂霉素40mg,灌注方法同Ⅰ组。结果随访10～46个月,平均(30±4)个月。复发率Ⅰ组为6.5%,Ⅱ组为17.4%,差异有统计学意义(P0.05);不良反应包括尿路刺激症状、肉眼血尿等,两组比较差异无统计学意义。结论 TURBt后早期膀胱内灌注盐酸表柔比星化疗,可以显著降低膀胱肿瘤复发率。