国内外卡介苗治疗膀胱癌的经验与展望

1976年,美国首次报道,用卡介苗经膀胱灌注,治疗膀胱癌有良好疗效;次年,我国亦作了同样的介绍。实验证明,卡介苗可增强和提高患者的局部和全身免疫,术后治疗的复发率;国外资料为32.91%（化疗组40.61%,未治疗组为87.67%）;我国资料为17.32%（化疗组为34.01%,未治疗组为60.90%）,副反应主要为尿痛、尿频、轻度血尿、低热等一过性反应;很少见全身性副反应。国内所见副反应率低于国外资料。目前,用于治疗膀胱癌的卡介苗,已获本国批准的有5个以上制品;我国同类产品已完成临床Ⅱ期试验,正在申报审核中。本品治疗膀胱癌是一种安全、效好的首选药品。     

膀胱癌术后卡介苗灌注的护理配合

膀胱癌是泌尿系统常见的肿瘤,确诊后应首选手术治疗.据资料记载,手术切除肿瘤或膀胱部分切除术后,约有2/3患者肿瘤复发,故一般术后采用膀胱内药物灌注治疗以防复发[1].我院自1995年以来对32例膀胱癌患者术后采用卡介苗(BCG)灌注治疗,疗效好,副作用少,现就护理体会总结如下.     

中国分支杆菌类免疫调节剂的评述与展望

近年来,中国分支杆菌类制剂有多种,如治疗用卡介苗,卡介苗多糖核酸（已有三个品牌：卡提素、斯奇康和卡舒宁）,冻干卡介苗细胞壁,草分支杆菌注射液（高品名：乌体林斯注射液）及母牛分枝杆菌冻干制剂（即Vaccae苗）,这些制剂均有免疫调节功能,治疗用卡介苗及卡介菌细胞壁主要用于治疗浅表性膀胱癌;卡介苗多糖核酸制剂主要用于预防和治疗慢性气管炎,感冒和哮喘;单分枝杆菌及母牛分枝杆菌制剂以及卡介苗多糖核酸液主要用作结核病的辅助治疗,临床观察,均有明显疗效。     

膀胱癌术后行膀胱灌注化疗的护理进展

膀胱灌注治疗是预防膀胱癌复发的重要手段。本文通过回顾近年来的相关文献,分析总结了膀胱癌术后膀胱灌注化疗的护理和操作方法,为临床护理提供参考。     

经尿道针状电极膀胱肿瘤整块切除术治疗膀胱癌的临床分析

目的:探讨经尿道针状电极膀胱肿瘤整块切除术治疗膀胱癌的临床疗效及安全性。方法:选择2015年1月-2017年1月我院收治的膀胱癌患者100例纳入本次研究,根据简单随机分组法分为观察组(n=51)和对照组(n=49)。对照组使用尿道膀胱肿瘤电切术治疗,观察组采用经尿道针状电极膀胱肿瘤整块切除术进行治疗。比较两组患者临床疗效、手术情况、治疗前后生活质量的变化及并发症的发生情况和复发率。结果:治疗后,两组患者的临床总有效率分别为82.35%、61.22%,观察组显著高于对照组(P0.05);两组患者手术时间比较无显著性差异(P0.05);观察组患者尿管留置时间、术中出血量及住院时间均显著低于对照组(P0.05);两组患者治疗后生活质量评分均较治疗前显著提高,且观察组显著高于对照组(P0.05);两组患者并发症总发生率分别为1.96%、24.49%,复发率分别为9.8%、34.69%,观察组均显著低于对照组(P0.05)。结论:采用经尿道针状电极膀胱肿瘤整块切除术治疗膀胱癌的临床疗效显著优于尿道膀胱肿瘤电切术治疗,其可有效改善患者的生活质量,且安全性更高。     

吡柔比星预防浅表性膀胱癌术后复发的疗效观察

目的：比较吡柔比星与吉西他滨膀胱内灌注预防浅表性膀胱癌术后复发的疗效。方法：40 例浅表性膀胱癌患者根据随机抽 签法分为治疗组与对照组各20 例,所有患者都采用经尿道膀胱肿瘤电切方法,对照组用吉西他滨,治疗组用吡柔比星进行膀胱 灌注,比较两组患者术后复发率的不同。结果：所有患者都完成治疗,随访1 年,治疗组的复发率为5.0 %,对照组为25.0 %,治疗 组的复发率明显低于对照组,对比差异明显,有统计学意义(P<0.05)。经过观察,治疗组的膀胱刺激症状、骨髓抑制、尿道狭窄等不 良反应总体发生率明显少于对照组,两者比较有统计学意义(P<0.05)。结论：相对于吉西他滨,吡柔比星膀胱内灌注预防浅表性膀 胱癌术后复发有很好的效果,不良反应少,在临床上需要根据患者的实际情况来选择不同的灌注药物。     

经尿道2微米激光切除术与电切术治疗浅表性膀胱癌的疗效观察

目的:比较经尿道2微米激光切除术与电切术治疗浅表性膀胱癌的临床疗效。方法:按照随机数字表法将2014年1月-2015年1月我院收治的浅表性膀胱癌患者分为两组,观察组(61例)行经尿道2微米激光切除手术,对照组(46例)行电切术,比较两组的手术效果、治疗前后的炎症因子水平及并发症。结果:观察组手术时间、导尿管留置时间、住院时间及术中出血量少于对照组,差异有统计学意义(P0.05)。治疗后两组患者IL-6、IL-10以及TNF-α水平均较治疗前升高,但是观察组治疗后的IL-6及TNF-α水平低于对照组,IL-10水平高于对照组,差异有统计学意义(P0.05)。两组患者术后均发生不同程度的并发症,其中观察组膀胱穿孔、闭孔神经反射的发生率为3.28%、1.64%,分别低于对照组的17.39%、13.04%,差异有统计学意义(P0.05)。结论:浅表性膀胱癌采用经尿道2微米激光切除术治疗具有明显的临床手术效果,减少术后并发症,同时对患者炎症因子的影响较小,临床有重要的参考价值。     

THP在早期非肌层侵润性膀胱癌定位诊断与治疗中的临床应用

目的：探讨THP在早期非肌层侵润性膀胱癌定位诊断与治疗中的临床应用价值。方法：已诊断非肌层侵润性膀胱癌患者45例,术中均实行THP膀胱灌注,灌注后15min置入膀胱镜,观察膀胱内粘膜,将THP橙色染色区域作为实验组进行活检,其他未染色区域作为对照组随机活检,活检组织行病理检查。TUR—BT术后将45例患者随机分为3组。在不同的时间点开始灌注（术后即刻、术后6小时、术后7天）,比较复发率和平均复发时间。结粜：两组间比较具有统计学意义（P〈0.05）恶性粘膜吸收THP敏感度和特异度分别为100％、63．5％;TUR-BT术后即刻灌注及6小时后灌注的总复发率明显低于术后7天灌注,差异有统计学意义（P〈0．05）。结论：THP对非肌层侵润性膀胱癌早期定位诊断准确、安全性好,同时术后早期灌注THp可以降低肿瘤的复发率,值得临床推广。     

THP在早期非肌层侵润性膀胱癌定位诊断与治疗中的临床应用

目的:探讨THP在早期非肌层侵润性膀胱癌定位诊断与治疗中的临床应用价值。方法:已诊断非肌层侵润性膀胱癌患者45例,术中均实行THP膀胱灌注,灌注后15min置入膀胱镜,观察膀胱内粘膜,将THP橙色染色区域作为实验组进行活检,其他未染色区域作为对照组随机活检,活检组织行病理检查。TUR-BT术后将45例患者随机分为3组,在不同的时间点开始灌注(术后即刻、术后6小时、术后7天),比较复发率和平均复发时间。结果:两组间比较具有统计学意义(P<0.05)恶性粘膜吸收THP敏感度和特异度分别为100%、63.5%;TUR-BT术后即刻灌注及6小时后灌注的总复发率明显低于术后7天灌注,差异有统计学意义(P<0.05)。结论:THP对非肌层侵润性膀胱癌早期定位诊断准确、安全性好,同时术后早期灌注THP可以降低肿瘤的复发率,值得临床推广。     

腹腔镜膀胱癌根治术的治疗效果及对血清前梯度蛋白-2的影响及其意义

目的:探讨腹腔镜膀胱癌根治术的治疗效果及对血清前梯度蛋白-2(AGR2)的影响及其意义。方法:选取2013年3月～2016年5月我院收治的80例膀胱癌患者为研究对象,同时选取同期体检健康的志愿者30例作对照组。膀胱癌患者择期行腹腔镜根治术,观察手术时间、术中出血量、术后肠道排气时间、住院时间和术后并发症。采用ELISA法检测膀胱癌患者术前和术后4周血清AGR2水平的变化。术后随访至2017年12月25日,分析血清AGR2水平与患者总生存期(OS)和无进展生存期(PFS)的关系。结果:80例患者顺利完成腹腔镜根治术,无中转开放手术,无死亡,手术时间(359.8±45.7)min,术中出血量(423.8±109.4)mL,术后肠道排气时间(3.2±1.4)d,术后住院时间(12.9±2.4)d。膀胱癌患者术前血清AGR2水平显著高于对照组[(33.5±9.4) vs.(8.5±2.1)ng/m L,P0.05],术后4周血清AGR2较术前显著降低[(17.8±4.1) vs.(33.5±9.4) ng/mL,P0.05]。术后4周血清AGR2低水平患者PFS(23vs14月,P0.05)和OS (36vs23月,P0.05)均显著大于高水平患者(P0.05)。结论:腹腔镜膀胱癌根治术治疗效果满意,可显著降低患者血清AGR2水平。血清AGR2水平的变化有助于腹腔镜根治术的治疗效果和预后预测。     

Caseating granulomas on the glans penis as a complication of bacille calmette-guérin intravesical therapy

Intravesical instillation of bacille Calmette-Guérin (BCG) in patients with superficial bladder cancer or with carcinoma in situ of the bladder is a frequently used therapeutic option. As with other cancer therapies, BCG instillation has its share of side effects and complications. This case report highlights an uncommon complication.     

Auxotrophic recombinant Mycobacterium bovis BCG overexpressing Ag85B enhances cytotoxicity on superficial bladder cancer cells in vitro

BCG therapy remains at the forefront of immunotherapy for treating patients with superficial bladder cancer. The high incidence of local side effects and the presence of non-responder diseases have led to efforts to improve the therapy. Hence, we proposed that an auxotrophic recombinant BCG strain overexpressing Ag85B (BCG ?leuD/Ag85B), could enhance the cytotoxicity to the human bladder carcinoma cell line 5637. The rBCG was generated using an expression plasmid encoding the mycobacterial antigen Ag85B to transform a BCG ?leuD strain. The inhibitory effect of BCG ?leuD/Ag85B on 5637 cells was determined by the MTT method, morphology observation and a LIVE/DEAD assay. Gene expression profiles for apoptotic, cell cycle-related and oxidative stress-related genes were investigated by qRT-PCR. Bax, bcl-2 and p53 induction by BCG ?leuD/Ag85B treatment was evaluated by Western blotting. BCG ?leuD/Ag85B revealed a superior cytotoxicity effect compared to the control strains used in this study. The results showed that the expression level of pro-apoptotic and cell cycle-related genes increased after BCG ?leuD/Ag85B treatment, whereas the mRNA levels of anti-apoptotic genes decreased. Interestingly, BCG ?leuD/Ag85B also increased the mRNA level of antioxidant enzymes in the bladder cancer cell line. Bax and p53 proteins levels increased following treatment. In conclusion, these results suggest that treatment with BCG ?leuD/Ag85B enhances cytotoxicity for superficial bladder cancer cells in vitro. Therefore, rBCG therapy may have potential benefits in the treatment of bladder cancer.     

Production of MCP-1 and RANTES in bladder cancer patients after bacillus Calmette-Guerin immunotherapy

Bacillus Calmette-Guerin (BCG) therapy induces a local immunological response mediated by cellular immune and inflammatory reactions that enhance its anti-tumor efficacy in bladder cancer. Monocyte chemotactic protein-1 (MCP-1) and the "regulated on activation normal T expressed and secreted" chemokine (RANTES) are potent chemotactic molecules that attract monocytes and memory T cells. MCP-1 and RANTES levels in patients with superficial bladder cancer treated with intravesical instillations of BCG are significantly higher than in untreated cancer patients and controls. In the present study, the subjects were divided into three groups: (1) control subjects; (2) bladder cancer patients who did not receive BCG treatment; (3) bladder cancer patients who received intravesical administration of BCG. No differences in the basal production and expression of MCP-1 and RANTES mRNA were observed between BCG-treated and untreated patients. BCG treatment influenced the monocyte response to phytohemagglutinin (PHA) and BCG stimulation. After 24-h incubation, monocytes from BCG-treated bladder cancer patients released more MCP-1 and RANTES than those from untreated bladder cancer patients and controls. The anti-tumor effects of BCG observed in superficial bladder cancer therapy may depend on stimulation of the investigated chemokines, which attract monocytes/macrophages and memory T cells.     

Virus therapy for bladder cancer

Approximately 50,000 cases of superficial bladder cancer are diagnosed annually in the United States. Immunotherapy utilizing intravesical BCG is the most effective standard therapy for superficial transitional cell carcinoma of the bladder. Based on ease of administration, limited systemic dissemination, and the demonstrated activity of immunotherapy, superficial bladder cancer is an excellent target for virus based gene and immunotherapy. Thus far, clinical trials of virus therapy for bladder cancer have yielded mixed results. In this paper the results of several virus based clinical trials for bladder cancer are reviewed.     

A mathematical model of combined bacillus Calmette-Guerin (BCG) and interleukin (IL)-2 immunotherapy of superficial bladder cancer

We report a mathematical model that describes the growth of superficial bladder cancer and the effect thereupon of immunotherapy based on the administration of Bacillus Calmette-Guerin (BCG) combined or not with interleukin-2 (IL-2). Intravesical instillations of BCG performed after surgical removal of tumors represents an established treatment with approximately 50% success rate. So far, attempts to improve this efficiency have not led to essential changes. However, convincing clinical results have been reported on the combination of IL-2 to BCG, even though this is still not applied in current practice. The present model provides insights into the dynamical outcomes arising in the bladder from the interactions of immune cells with tumor cells in the course of BCG therapy associated or not with IL-2. Specifically, from the simulations performed using seven ordinary and non-linear differential equations we obtained indications on the conditions that would result in successful bladder cancer treatment. We show that immune cells -effector lymphocytes and antigen-presenting cells-expand and reach a sustainable plateau under BCG treatment, which may account for its beneficial effect, resulting from inflammatory “side-effects” which eliminate residual or eventual newly arising tumor cells, providing thus protection from further cancer development. We find, however, that IL-2 does not actually potentiate the effect of BCG as regards tumor cell eradication. Hence, associating both under the conditions simulated should not result in more efficient treatment of bladder cancer patients.     

Localization and expression of inducible nitric oxide synthase in patients after BCG treatment for bladder cancer

Treatment with Bacillus Calmette Guerin (BCG) bladder instillations is an established treatment modality for superficial urinary bladder cancer and carcinoma in situ (CIS), but the anti-tumor mechanisms following BCG instillations remain largely unknown. Previous data show increased nitric oxide (NO) concentrations in the urinary bladder from patients treated with BCG suggesting that NO-formation may be involved in the BCG mediated effect. In the present study we evaluated 11 patients with urinary bladder cancer who had received BCG treatment and 11 tumor free control subjects. We performed immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) on bladder biopsies to establish inducible nitric oxide synthase (iNOS) protein levels and localization as well as iNOS mRNA expression. Endogenous NO formation in the bladder was also measured. In patients with bladder cancer who had received BCG treatment iNOS-like immunoreactivity was found in the urothelial cells but also in macrophages in the submucosa. Furthermore, endogenously formed NO was significantly increased (p<0.001) in the BCG treated patients and they had a ten-fold increase in mRNA expression for iNOS compared to healthy controls (p=0.003). In conclusion iNOS was found to be localized to the urothelium and macrophages underlying it. Our study also confirms elevated levels of endogenously formed NO and increased mRNA expression and protein levels for iNOS in patients with BCG treated bladder cancer. These data further support the notion that NO may be involved in the anti-tumor mechanism that BCG exerts on bladder cancer cells.     

Mathematical Model of Pulsed Immunotherapy for Superficial Bladder Cancer

We present a theoretical study of superficial bladder cancer growth and its treatment via pulsed immunotherapy with Bacillus Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis. BCG pulsed immunotherapy is a clinically established procedure for the treatment of superficial bladder cancer. In this paper, periodic BCG instillations are modeled using impulsive differential equations, which are studied using a combination of analytical and numerical techniques. In this way, we determine critical threshold values of the BCG instillation dose and rate of pulsing for successful treatment. We also identify treatment regimes in which tumor destruction occurs, but undesirable side effects are maintained at low levels by the immune system.     

Presence of interleukin-2 in urine of superficial bladder cancer patients after intravesical treatment with bacillus Calmette-Guérin

Summary Urine samples were obtained from patients with superficial bladder cancer after immunotherapy with bacillus Calmette-Guérin (BCG). The patients were repeatedly (once a week for 6 consecutive weeks) treated with intravesical administration of approximately 5 × 10⁸ culturable particles of BCG. Some patients received more than six BCG instillations. The urine samples were investigated for the presence of interleukin-2 (IL-2) in an in vitro bioassay using a murine cytotoxic T cell line (CTTL-16) that shows IL-2-dependent growth. Preliminary experiments indicated the presence of inhibitory factors in the urine. This inhibitory activity was abolished after 24 h dialysis. In a neutralization assay with both polyvalent and monoclonal anti-(human IL-2) antibody it was demonstrated that there was indeed IL-2 in the urine samples. In 8 of 11 patients the presence of IL-2 in the urine was demonstrated. The IL-2 production was directly related to the BCG administration as samples obtained just before the BCG instillation were always negative. In IL-2-positive samples a maximum level of IL-2 was observed between 2 h and 6 h after the BCG instillation. In urine samples obtained 24 h after the BCG IL-2 was not detected. In most patients the urine became positive after the third or fourth BCG instillation     

卡介苗（BCG）膀胱冲洗预防膀胱癌复发的研究

探讨不同方法预防膀胱肿瘤术后复发的效果.将1994～2001年85例膀胱肿瘤术后患者分为2组,BCG(卡介苗)80 mg加生理盐水50 mL、噻替哌50 mg加生理盐水50 mL,行膀胱内冲洗预防膀胱肿瘤复发,评价其疗效.随访2～5 a,BCG组复发率37.1%,噻替哌组复发率50.8%.2组比较有统计学差异.结果显示,BCG和噻替哌均能预防膀胱肿瘤术后复发,但BCG优于噻替哌.