ATP—TCA技术指导浅表性膀胱癌术后灌注化疗的临床应用

目的：探讨生物荧光体外肿瘤药敏检测技术（ATP—TCA）在浅表性膀胱癌肿瘤细胞药敏试验中的应用,探讨该技术在指导膀胱癌个体化治疗上的应用价值。方法：对40例浅表性膀胱癌标本进行肿瘤细胞分离,原代培养,应用ATP—TCA技术检测肿瘤标本对五种常用化疗药物的敏感率和耐药率。试验组术后选用最敏感的化疗药物对患者常规行膀胱灌注化疗,对照组选择丝裂霉素进行术后常规化疗。术后随访2年,评价两组膀胱癌复发情况。结果：40例标本中,吡柔比星（THP）、羟基喜树碱（HCPT）、丝裂霉素（MMC）、表柔比星（EPI）、吉西他滨（GEM）的敏感率分别为75．0％、10．0％、5．0％、37．5％、10．0％,肿瘤细胞对五种化疗药物的敏感率和耐药率差异有统计学意义（P〈0．01）。膀胱肿瘤对化疗药物的敏感性存在个体差异。术后随访2年,药敏组膀胱癌复发率为17．5％（7／40）,对照组膀胱癌复发率为37．5％（15／40）。两组肿瘤复发率差异有统计学意义（P〈0．05）。结论：应用ATP—TCA技术检测出的药敏结果能够反映个体对化疗药物的敏感性,可以作为选择灌注化疗用药的理论基础,指导临床用药进行个体化治疗。同时,应用ATP—TCA技术指导临床膀胱癌术后灌注化疗,可显著降低浅表性膀胱癌患者术后复发率,提高临床疗效。     

组织培养药敏测试法在表浅膀胱肿瘤化疗药敏测试中的应用价值

目的：探讨Hoffman式组织培养药敏测试法在表浅膀胱癌腔内化疗药敏测试中的应用价值。方法：对31例表浅膀胱癌分别进行Hoffman式组织培养，对丝裂霉素C(MMC)进行改良MTT法药敏测试，检测MMC在浓度为1g/L、作用时间为2h情况下对表浅膀胱癌的生长抑制率。采用MMC 40mg加生理盐水40m1对表浅膀胱癌进行术后标准腔内化疗，并随访20个月。结果：18例培养成功，15例进入药敏测试，其中9例对MMC敏感，6例不敏感。术后腔内化疗随访结果显示敏感者有2例复发，不敏感者有5例复发；单因素Kaplan—Meier生存分析显示敏感者无复发生存率明显高于不敏感者。与临床实际疗效比较，该药敏测试法的特异性为75．0％，敏感性为85．7％，准确率达80．0％。结论：组织培养药敏测试法不仅可以检测表浅膀胱癌对化疗药物的敏感性，还能预测利用敏感药物进行腔内化疗的预后。     

保留膀胱手术后不同辅助治疗方法治疗肌层浸润性膀胱癌的疗效评价

目的：探索保留膀胱手术＋动脉灌注化疗＋膀胱内灌注化疗治疗肌层浸润性膀胱癌的临床疗效。方法：对经尿道膀胱肿瘤电切或膀胱部分切除术后确诊为肌层浸润性膀胱癌（T2N0M0）的168例患者均采用保留膀胱治疗方法,分为三个治疗组：综合治疗组68例,术后采用动脉灌注化疗＋膀胱灌注化疗;动脉灌注化疗组48例,术后仅采用动脉灌注化疗;膀胱灌注化疗组52例,术后仅采用膀胱灌注化疗。结果：观察期内,综合治疗组患者中92．6％（63／68）无复发及转移,2．9％（2／68）在术后6、13个月出现全身多处转移死亡。动脉灌注化疗组患者中79．2％（38／48）无复发及转移,4．2％（2／48）在术后9、18个月出现全身多处转移死亡。膀胱灌注化疗组患者中44．2％（23／52）无复发及转移,15．4％（8／52）在术后10～96个月转移而死亡。三组疗效按复发率任何两组间比较,差异均有统计学意义（P〈0．05）。按癌性死亡率比较,综合治疗组、动脉灌注化疗组分别与膀胱灌注化疗组的差异均有统计学意义（P〉〈0．05）。结论：肌层浸润性膀胱癌（T2N0M0）患者,采用保留膀胱手术＋髂内动脉灌注化疗＋膀胱内灌注化疗的综合治疗方法,能有效减少肿瘤复发、预防转移、提高患者的生活质量,患者易于接受,值得进一步探讨。     

肌层浸润性膀胱癌保留膀胱手术后不同辅助治疗方法的疗效评价

目的探索保留膀胱手术＋动脉灌注化疗＋膀胱内灌注化疗治疗肌层浸润性膀胱癌的临床疗效。方法对经尿道膀胱肿瘤电切或膀胱部分切除术后确诊为肌层浸润性膀胱癌（T2N0M0）的168例患者,充分向患者及其家属介绍病情和治疗建议,对拒绝或不适合膀胱全切的患者经患者及其家属同意,均采用保留膀胱治疗方法,分为3个治疗组：（1）综合治疗组：68例,术后采用动脉灌注化疗＋膀胱灌注化疗;（2）动脉灌注化疗组：48例,术后仅采用动脉灌注化疗;（3）膀胱灌注化疗组：52例,术后仅采用膀胱灌注化疗。结果168例膀胱癌（T2N0M0）患者,观察期内,综合治疗组患者中92．65％（63／68）无复发及转移,7．45％（5／68）分别在术后6、8、12、18、20个月复发,2．94％（2／68）在术后6、13个月出现全身多处转移死亡,11．76％（8／88）非膀胱癌导致死亡。动脉灌注化疗组患者中79．17％（38／48）无复发及转移,20．83％（10／48）在术后1～28个月复发,4．17％（2／48）在术后9、18个月出现全身多处转移死亡,12．50％（6／48）非膀胱癌导致死亡。膀胱灌注化疗组患者中44．23％（23／52）无复发及转移,55．77％（29／52）在术后1～24个月复发,15．38％（8／52）在术后10～96个月转移而死亡,13．46％（7／52）非膀胱癌导致死亡。3组疗效按复发率任何两组间比较,均有统计学差别（P均〈0．05）。3组疗效按癌性死亡率任何两组间比较,综合治疗组与动脉灌注化疗组相比,差异无统计学意义（P均〉O．05）;综合治疗组、动脉灌注化疗组均低于膀胱灌注化疗组,差异均有统计学意义（P均〈O．05）。3组患者分组治疗后非膀胱癌导致死亡率任何两组间比较,无统计学差异（P均〉o．05）。结论肌层浸润性膀胱癌（T2N0M0）患者,采用保留膀胱手术＋髂内动脉灌注化疗＋膀胱内灌注化疗的综合治疗方法,能有效减少肿瘤复发、预防转移、提高患者的生活质量,患者易于接受,值得进一步探讨。     

经尿道膀胱电切术后吡柔比星灌注治疗表浅性膀胱癌临床分析

目的总结膀胱肿瘤电切术（transurethral resection of bladder tumor,TURBt）加吡柔比星（tetrahydnopyrany adriamyrin,THP）灌注治疗表浅性膀胱癌的疗效。方法48例表浅性膀胱癌患者,均行TURBt,术毕用THP40mg＋注射用水40ml行灌注化疗30min,术后每周化疗1次,共8次,然后改为每个月1次,持续1年。结果均顺利完成手术,术中未出现膀胱穿孔、膀胱出血等并发症。48例患者平均随访2.1（0.5~3）年,术后1年内6例在非原来位置复发（12.5%）,再次行TURBt加THP灌注,随访1年无复发。结论TURBt加THP膀胱灌注疗效确切,可降低复发率,是治疗表浅膀胱癌的有效方法。     

表浅性膀胱癌灌注化疗的个体化研究

目的 :探讨对表浅性膀胱癌制定个体化膀胱灌注化疗方案的临床意义。方法 :对 48例表浅性膀胱癌标本行原代细胞培养及药物敏感试验 (药敏 ) ,患者随机分为两组 ,一组用丝裂霉素C(MMC)灌注 ,另一组根据药敏结果 ,选择敏感的化疗药物 ,平均随访时间 1 2个月。结果 :各化疗药物的平均抑瘤率 ,原发组分别为吡柔比星 (THP) 50 .0 %、阿霉素 (ADM ) 53 .1 % ,MMC 56 .2 %、米托蒽醌 (MH) 4 7.0 % ,复发组为THP 38.0 %、ADM43 .8% ,MMC 43 .8%、MH 31 .0 % ,组内各化疗药物抑瘤率差异无显著性意义 ,而原发组抑瘤率显著高于复发组 (P <0 .0 5) ;MMC灌注组无瘤率为 58.3 % ,药敏组无瘤率为 79.1 % ,差异有显著性意义 (P <0 .0 5)。结论 :应根据药敏结果 ,选择相对敏感的化疗药物 ,制订个体化膀胱灌注化疗方案 ,以提高疗效 ,减少肿瘤复发率     

卡介苗膀胱灌注后尿后尿白细胞介素2及肿瘤坏死因子含量测？…

目的：寻找能早期评估表浅膀胱癌术后行卡介苗（ＢＣＧ）免疫治疗效果的精确指标。方法：分析采用ＣＴＬＬ－＾３Ｈ－ＴｄＲ掺入法及夹心法酶联免疫吸附试验，测定３２例表浅膀胱癌术后行ＢＣＧ膀胱灌注者尿液中白细胞介素２（ＩＬ－２）及肿瘤坏死因子（ＴＮＦ）含量。结果：全部病例均获随访２６￣６７个月，平均４３．５个月。３２例中有６例复发（１８．７％），复发患者灌注后尿液中ＩＬ－２及ＴＮＦ含量分别为（１４．３４±６     

组织培养加药物敏感性测定在表浅膀胱癌术后丝裂霉素灌注化疗中的指导作用

目的 探讨组织培养加药物敏感性测定在指导表浅膀胱癌术后丝裂霉素(MMC)膀胱灌注化疗中的应用价值.方法 原发表浅膀胱移行细胞癌患者41例.男30例,女11例.平均年龄55岁.TNM分期:Ta 10例、T1 31例.病理分级:G1 9例、G2 22例、G3 10例.采用经尿道电切或膀胱部分切除术保留膀胱.肿瘤标本依次行三维组织培养和改良噻唑盐(MTT)法药物敏感性测定.生长抑制率>70%为高度敏感,50%～70%为中度敏感,<50%为不敏感.41例患者术后均行MMC标准膀胱灌注化疗.无复发随访时间5年,中途复发者则随访结束.结果 41例患者癌组织经1 g/L浓度MMC作用2 h后不敏感13例,其中Ta 1例、T1 12例(P=0.009),G1 1例、G2 7例、G35例(P=0.101).灌注化疗后随访3～5年,复发16例(39%),其中Ta 1例、T1 15例(P=0.059),G210例、G3 6例(P=0.016).对MMC不敏感组的复发率为77%(10/13),敏感组仅为21%(6/28,P=0.004).单因素Kaplan-Meier生存分析和Log-rank检验结果显示,平均无肿瘤复发时间不敏感组为16.5个月,敏感组为49.2个月(P<0.001).多因素Cox回归分析显示对MMC敏感性是独立预后因子(P=0.008).此法预测MMC膀胱灌注化疗效果的准确率为78%.结论 利用组织培养药物敏感性测定方法指导表浅膀胱癌术后MMC灌注化疗,可提高疗效,降低肿瘤复发率.     

卡介苗膀胱灌注后尿白细胞介素2及肿瘤坏死因子含量测定及意义

目的：寻找能早期评估表浅膀胱癌术后行卡介苗（BCG）免疫治疗效果的精确指标。方法：分别采用CTLL－3H－TdR掺入法及夹心法酶联免疫吸附试验，测定32例表浅膀胱癌术后行BCG膀胱灌注者尿液中白细胞介素2（IL-2）及肿瘤坏死因子（TNF）含量。结果：全部病例均获随访26～67个月，平均43．5个月。32例中有6例复发（18．7％），复发患者灌注后尿液中IL－2及TNF含量分别为（14．34±6．83）u／ml及（78．63±37．45）ng／L，未复发患者IL-21、TNF含量分别为（21．41±9．23）u／ml及（106．76±49．13）ng／L，复发与未复发患者间IL－2、TNF水平比较均有显著性差异（分别P＜0．01和＜0．05）。结论：测定尿液中IL-2及TNF含量对判断表浅膀胱癌术后BCG灌注治疗的预后有重要的参考价值。     

吡柔比星膀胱灌注预防浅表性膀胱癌术后复发

目的：评价吡柔比星（THP）膀胱内灌注预防浅表性膀胱癌术后复发的近期疗效。方法：对34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，术后定期用THP（30mg/40ml）作膀胱内灌注，每周1次共8次，以后每月1次共1年。每次药物在膀胱内保留40min。结果：经10－12个月随访，无肿瘤复发32例，复发2例，复发率为5．9％；未见全身性药物不良反应，仅5例患者出现轻度膀胱刺激症状。结论：THP膀胱内灌注预防浅表性膀胱癌术后得发近期疗效满意，副作用轻，耐受性良好。     

上尿路肿瘤术后膀胱内灌注化疗价值的探讨

目的：探讨上尿路肿瘤术后预防性膀胱内灌注化疗的价值。方法：选取诊断为单侧上尿路肿瘤、无淋巴结及远处转移、不伴发膀胱肿瘤及无膀胱癌病史并行根治性肾输尿管全切除术的患者82例,对其中41例术后接受膀胱内灌注化疗者（研究组）与41例未接受膀胱内灌注化疗者（对照组）进行1：1配对研究,配对条件为肿瘤的病理分期、单发／多发和所处器官一致,患者的性别相同。研究组术后行羟基喜树碱膀胱内灌注化疗,每次40mg,每周1次,共6～8次;对照组随诊观察。结果：平均随访46（26～66）个月,研究组及对照组术后膀胱癌的发生率分别为22．0％（9例）及43．9％（18例）（P〈0．05）,再发膀胱癌的中位时间分别为13（3～59）个月及28（3～57）个月（P〈0．05）。结论：对不伴发膀胱癌及无膀胱癌病史的上尿路肿瘤患者,根治术后短疗程的羟基喜树碱膀胱内灌注化疗可有效降低膀胱癌的再发比例,延长肿瘤的再发时间。     

草分枝杆菌膀胱灌注预防膀胱癌复发的临床研究

目的：探讨草分枝杆菌膀胱灌注预防浅表性膀胱肿瘤复发的临床疗效。方法：将浅表性膀胱癌术后患者60例随机分为草分枝杆菌灌注疗法组和卡介苗灌注疗法组,各30例。灌注前和灌注后1个月分别采血测定患者自然杀伤细胞（NK细胞）,CD4^＋／CD8^＋比值,观察其值并比较分析。结果：患者进行草分枝杆菌灌注疗法组NK细胞,CD4^＋／CD8^＋比值明显高于卡介苗灌注疗法组。结论：草分枝杆菌膀胱内灌注防治膀胱癌无全身毒副作用,提高患者的免疫功能,可以减少膀胱癌的复发率。     

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。     

Molecular followup of newly diagnosed bladder cancer using urine samples

PURPOSE: Patients with superficial bladder cancer can be treated with transurethral resection. However, 50% to 70% of them have intravesical recurrence after transurethral resection and muscle invasive disease develops in 10% to 20%, which is eventually indicated for radical cystectomy. Therefore, reliable predictors of intravesical recurrence are required for management of superficial bladder cancer. We investigated whether detection of the loss of heterozygosity in urine samples would be available as a sensitive diagnostic modality for recurrence of bladder cancer. MATERIALS AND METHODS: Urine samples, cancer tissue and peripheral blood lymphocytes were obtained from 37 patients with newly diagnosed bladder cancer, and analyzed for the loss of heterozygosity on chromosomes 9 and 17p by single strand DNA conformation polymorphism analysis. RESULTS: Chromosomal loss was detected on 24 (65%) cancer tissues and 26 (70%) urine samples. The loss of heterozygosity on chromosome 17p was detected in 19 (51%) urine samples, mostly in cancers with higher grades and/or stages. During postoperative followup of 24 patients with superficial bladder cancer who had undergone transurethral resection, intravesical recurrence did not develop in 9 of 10 without chromosomal aberrations in urine samples. In contrast, intravesical recurrence developed in 11 of 14 patients who had a loss of heterozygosity in urine samples. This loss showed a significant correlation with the intravesical disease-free period (p = 0.004). Multivariate analysis revealed that the loss of heterozygosity in urine samples was a significant predictor of intravesical recurrence. CONCLUSIONS: Detection of the loss of heterozygosity in urine samples is available as a sensitive marker for predicting intravesical recurrence of superficial bladder cancer.     

Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder cancer eradication. a pilot study on marker lesion

OBJECTIVE: To assess the feasibility and safety of two novel methods for intravesical chemotherapy administration in patients suffering from superficial bladder carcinomas. To draw preliminary considerations concerning the ablative effect on marker lesion using novel approaches compared to standard intravesical chemotherapy. METHODS: Eighty patients suffering from single, recurrent, low-stage, low-grade superficial bladder tumor entered a prospective nonrandomized study. Thirty-six of them were treated by means of mitomycin C instillation as a standard procedure. In 29 patients mitomycin C solution was administered in combination with local microwave-induced hyperthermia and in 15 patients the mitomycin C solution was administered according to the electromotive drug procedure. The treatment was scheduled as a short term neo-adjuvant regimen prior to transurethral resection. Feasibility and safety of the different procedures were evaluated on an outpatients basis. The local toxicity induced by different approaches was defined and compared using a subjective questionnaire. RESULTS: Both intravesical chemotherapy administered in combination with hyperthermia and according to the electromotive drug technique appeared to be feasible and safe. Local toxicity induced by thermo-chemotherapy was more severe than that registered for electromotive drug technique and standard intravesical chemotherapy. Local toxicity was always short and self healing without early or delayed major complications. A higher complete response rate on marker lesion was observed after thermo-chemotherapy compared to other administration methods. CONCLUSION: The intravesical administration of mitomycin C can be safely performed in the form of both thermo-chemotherapy and electromotive drug approach with an increased ablative success rate on small superficial tumor involving only minimal local side effects.     

Usefulness of ATP-sensitivity-assay of intravesical instillation therapy of anti-cancer agents for superficial bladder cancer

Intravesical instillation of anti-cancer drugs for superficial urinary bladder cancer is generally carried out with the aim of prophylaxis against recurrence and chemotherapy against tumor. But since sensitivity of tumor cells to each anti-cancer drug differs individually, the anti-cancer drug to be used should also be decided individually. We selected a new sensitivity test, ATP-sensitivity-assay, which measures intracellular adenosine triphosphate (ATP) volume by Luciferin-Luciferase reaction, for the decision of the anti-cancer drug. In this paper, we evaluated the direct anti-tumor activity of the drugs that were decided by ATP-sensitivity-assay of intravesical chemotherapy. Six drugs, that are Doxorubicin (ADM), Mitomycin C (MMC), Pirarubicin (THP-ADM), Cytarabine (Ara-C), Bleomycin (BLM) and Cisplatin (CDDP) were tested in this research and size of tumors of six patients reduced to 34-93% after 6 times' installation. A woman got cystitis induced by ADM after 3 times' instillation but instillation was completed. ATP-sensitivity-assay is useful for deciding the anti-cancer drugs for intravesical chemotherapy and prophylaxis for superficial bladder cancer.