全膀胱切除术治疗高危非肌层浸润性膀胱癌的研究进展

目的 非肌层浸润性膀胱癌（NMIBC）主要由三种不同类型的肿瘤组成：乳头状尿路上皮癌局限于黏膜层（Ta），高级别原位癌局限于上皮层（CIS）以及侵犯黏膜下层或固有层的肿瘤（T1）。NMIBC的首选治疗方案是彻底的经尿道膀胱肿瘤电切术（TURBT）和（或）膀胱灌注治疗。但是，仍有部分高危患者具有肿瘤进展的风险，因而需要接受更积极地治疗策略。有研究报道延迟的全膀胱切除术会导致生存获益显著降低，因此对于这些具有疾病进展高危风险的NMIBC患者，选择在何时放弃传统治疗转而接受全膀胱切除术是当前外科医生面临的一个重大挑战。本文综述了当前全膀胱切除术作为初始治疗在NMIBC患者中的应用现状和未来方向。     

吡柔比星膀胱内灌注预防非肌层浸润性膀胱尿路上皮癌复发的机制

目的 观察膀胱内灌注吡柔比星后对正常膀胱组织和膀胱癌组织细胞凋亡的影响,探讨吡柔比星膀胱内灌注预防非肌层浸润性膀胱尿路上皮癌复发的机制.方法 将40例非肌层浸润性膀胱尿路上皮癌患者随机分为3组,15例于经尿道膀胱肿瘤电切术(TUR-BT)前1h、15例于TUR-BT术前24 h行膀胱内灌注(30 mg吡柔比星,在膀胱内保留30 min),对照组10例仅行TUR-BT术.取患者的正常膀胱组织和膀胱癌组织,以荧光显微镜观察吡柔比星的分布,原位末端标记(TUNEL)法检测细胞凋亡,免疫组化染色检测bcl-2和bax的蛋白表达.结果 吡柔比星膀胱内灌注后1h,正常膀胱组织黏膜层偶见吡柔比星荧光,膀胱癌组织可见弥漫分布的吡柔比星荧光,可达肌层.24 h后,在膀胱癌组织内仍可见到吡柔比星的荧光.TUNEL检测结果显示,实验组膀胱癌的凋亡指数显著高于对照组(P<0.01).bcl-2/bax比值与凋亡指数具有相关性.结论 吡柔比星灌注化疗中可选择性作用于非肌层浸润性膀胱尿路上皮癌.通过影响膀胱癌组织bcl-2/bax表达,诱导肿瘤细胞发生凋亡,可能是吡柔比星膀胱内灌注预防非肌层浸润性膀胱尿路上皮癌复发的重要机制.     

HU-150半导体激光联合经尿道膀胱肿瘤电切术治疗非肌层浸润膀胱肿瘤

目的探讨HU-150半导体激光联合经尿道膀胱肿瘤电切术(transurethral resection of bladder tumor,TURBT)治疗非肌层浸润性膀胱肿瘤(non-muscle invasive bladder cancer,NMIBC)的临床疗效和使用安全性。方法回顾分析丰县人民医院2012年7月至2015年7月行HU-150半导体激光联合经尿道膀胱肿瘤电切术29例的临床资料及术后定期行羟基喜树碱或吡柔比星膀胱灌注化疗的门诊随访资料。结果所有患者手术均获成功。病理类型均为膀胱尿路上皮癌,1例浸润至深肌层。无改开放手术病例。术中3例出现闭孔反射,2例闭孔反射强,改行全身麻醉。术后留置尿管7~10 d。术后3例肿瘤复发,再行膀胱癌根治术。1例失访,其他患者均存活。结论 HU-150半导体激光联合经尿道膀胱肿瘤电切术治疗非肌层浸润性膀胱肿瘤具有疗效确切,手术时间短,复发率较低,相互弥补对方不足的优点。     

中国膀胱癌保膀胱治疗多学科诊治协作共识

膀胱癌是泌尿外科常见的恶性肿瘤之一。膀胱尿路上皮癌约占所有膀胱恶性肿瘤的90%, 根据肿瘤是否侵犯膀胱肌层可分为非肌层浸润性膀胱癌和肌层浸润性膀胱癌。根治性膀胱切除术是肌层浸润性膀胱癌和卡介苗治疗失败的高危非肌层浸润性膀胱癌的标准治疗方法。由于患者自身基础疾病以及手术导致的生活质量下降, 许多患者不适合或拒绝根治性膀胱切除术。寻找根治性膀胱切除术以外能够达到治愈的、保留膀胱的治疗方案显得极为重要。保膀胱治疗在一定程度上平衡了肿瘤控制和生活质量, 是根治性膀胱切除术的替代及补充。共识根据国内外循证医学依据, 结合目前中国膀胱癌保膀胱治疗的临床实践与应用经验, 以多学科诊疗模式为基础, 重点探讨了保膀胱多学科诊疗的组织架构和工作流程、保膀胱治疗的患者选择、治疗方案、随访监测以及保膀胱治疗复发后的方案选择, 以期为国内膀胱癌的保膀胱治疗提供一定指导意见。     

EORTC评分系统在非肌层浸润性膀胱癌预后预测中的临床应用

背景与目的:膀胱癌是我国泌尿系统最常见的肿瘤,其中80%为非肌层浸润性,5～15年内的复发率高达60%～85%,其中20%可进展为浸润性肿瘤。本研究探讨欧洲癌症研究与治疗组织(EORTC)建议的非肌层浸润性膀胱癌患者术后复发和进展评分系统用于我国非肌层浸润性膀胱癌患者预后评估的可行性和准确性。方法:选取2003年1月—2005年12月在我科行TUR-BT的213例非肌层浸润性膀胱癌患者。根据EORTC评分系统的影响因素对每位患者的预后风险进行评分,计算各评分等级中每位患者的1年及5年复发率和进展率,并与实际的1年及5年复发率和进展率进行比较。结果:213例患者中,男性153例(71.8%),女性60例(28.2%),年龄41～88岁(平均57岁)。其中96例(45.1%)为复发患者,90例(42.3%)的肿瘤最大直径≥3 cm,97例(45.5%)为多灶性肿瘤,6例(2.8%)伴有原位癌,86例(40.4%)属于T1期,18例(8.4%)为尿路上皮癌3级。1年后,有65例(30.5%)患者发生肿瘤复发,10例(4.7%)患者肿瘤进展为T2期;5年后,有110例(51.6%)患者发生至少1次复发,30例(14.1%)患者进展为T2期及以上。结论:EORTC建议的评分系统可用来预测本院非肌层浸润性膀胱癌患者TUR-BT术后的肿瘤复发和进展风险。但是否适用于国内人群还有待于进一步验证。     

肌层浸润性膀胱尿路上皮癌的治疗进展

膀胱癌是全球常见的癌症,90%以上的膀胱癌为尿路上皮癌（urothelial carcinoma,UC）。UC的治疗与其进展阶段密切相关,肿瘤一旦出现肌层浸润,5年生存率不足40%,且有很高的复发或进展风险,即使接受了根治性手术,仍有50%的患者术后复发,大多数复发时远处转移形成转移性膀胱癌。目前,肌层浸润性膀胱癌（muscle-invasive bladder cancer,MIBC）的治疗标准是在新辅助化疗后行根治性膀胱切除术,但术后患者生活质量欠佳。保留膀胱的综合治疗因其良好的肿瘤反应率和无病生存期而越来越受欢迎。全身化疗仍是局部晚期或转移性膀胱癌的治疗标准,新型药物免疫检查点抑制剂的批准为化疗进展后的晚期患者提供了治疗新方案。此外,FDA 授予了Enfortumab Vedotin和Erdafitinib两种药物突破性疗法认定。本文将就各种疗法在肌层浸润性膀胱尿路上皮癌治疗中的地位及应用进展进行综述。     

经尿道膀胱肿瘤电切术中活检的应用研究

目的：探讨膀胱肿瘤电切术（transurethral resection of bladder tumor,TURBT）中肿瘤基底部及边缘部位活检的应用价值及意义。方法收集2010年3月至2013年4月行 TURBT 术的膀胱癌患者58例,病理类型均为膀胱尿路上皮癌。术中活检28例（活检组）,活检部位包括肿瘤基底部和创面边缘可疑黏膜;未活检30例（未活检组）。观察两组术后1年肿瘤复发、进展情况。结果（1）活检组：1例活检发现肿瘤肌层浸润,行根治性全膀胱切除术;27例为非肌层浸润性尿路上皮癌,其中5例行二次TURBT ,包括3例活检未见肌层组织及2例活检见上皮异形增生,另22例活检未见异常。随访1年,肿瘤复发5例,进展2例。（2）未活检组：2例为肌层浸润性膀胱癌,28例为非肌层浸润性膀胱癌。随访1年,肿瘤复发10例,进展6例。结论TURBT 术中行肿瘤基底部及边缘可疑部位活检,有助于明确肿瘤分期分级,提高残余肿瘤的检出率,明确电切范围及深度,并为二次 TURBT 提供参考依据。     

中性粒／淋巴细胞比值在正常人群及不同分期膀胱尿路上皮癌患者中的意义

目的:评估中性粒细胞与淋巴细胞比率（neutrophil-lymphocyte ratio,NLR）在膀胱尿路上皮癌（urothelial carcinoma,UC）患者及正常人群中的意义。方法:随访非肌层浸润性膀胱癌患者（non muscle-invasive bladder cancer,NMIBC）、肌层浸润性膀胱癌患者（muscle-invasive bladder cancer,MIBC）和健康体检患者。根据受试者工作曲线（receiver operator characteristic curve,ROC）确定不同类型膀胱癌患者术后是否出现复发及转移的最佳NLR值以及膀胱癌患者中NMIBC患者区别MIBC患者的最佳NLR值。收集患者T分期、G分级、肿瘤数量、复发时间、3年无复发生存率、无瘤生存率。结果:NLR值在正常健康人群及癌症患者中存在差异,在NMIBC患者及MIBC患者中存在差异（P＜0.05）。NLR值在NMIBC患者的肿瘤T分期、G分级、肿瘤大小、肿瘤数量、复发时间及无瘤生存时间中存在差异（P＜0.05）,在MIBC患者的肿瘤T分期中存在差异（P＜0.05）。结论:NLR值很可能为患者的疾病辅助诊断及预后提供一项经济可行的炎症标志物。     

转移性膀胱癌靶向免疫检查点的治疗进展

膀胱癌是泌尿系统中最常见的恶性肿瘤,据美国国家癌症研究所(National Cancer Institute, NCI)的监测、流行病学和结果(Surveillance、Epidemiology and End Results,SEER)数据库统计,每年约有76 960例新发膀胱癌病例,其中男性58 950例,位于男性最常见肿瘤第4位.[1].膀胱癌最常见的病理类型是尿路上皮癌,初诊时的膀胱癌患者,约75%为非肌层浸润性,25%为肌层浸润性.在非肌层浸润性膀胱癌中,组织学分级是最影响患者预后的因素;在浸润性膀胱癌中,分期仍是影响预后的关键因素.[2].非肌层浸润性膀胱癌与肌层浸润性膀胱癌有着明显不同的预后,因此在治疗上也有明显差异.非肌层浸润性膀胱癌的治疗主要是以局部切除后辅助膀胱内灌注卡介苗或化疗治疗,而肌层浸润性膀胱癌的治疗主要是手术、化疗、放疗的综合治疗.对于转移性膀胱癌而言,化疗一直是其标准治疗,但随着NCI发起的癌症和肿瘤基因图谱计划(Cancer Genome Atlas,TCGA)的进展,靶向EGFR、FGFR-3、VEGF、 mTOR、STAT3、雄激素受体以及CD24等分子靶点的治疗在临床前的研究中均显示了潜在的效果.[3].近两年来,靶向免疫检查点(checkpoint)的药物更是在转移性膀胱癌中显示了令人欣喜的疗效,本文现就靶向checkpoint的免疫治疗在转移性膀胱癌中的应用及新进展进行总结和阐述.     

二次TUR联合即刻灌注治疗非肌层浸润性膀胱癌的临床研究

目的:观察二次TUR联合即刻膀胱灌注化疗药物治疗非肌层浸润性膀胱癌的安全性及疗效。方法:T1期非肌层浸润性膀胱癌患者120例分为2组:实验组58人,患者在第一次TUR术后24h内膀胱灌注化疗药物,4-6周行二次TURBt,以后按常规膀胱灌注化疗;对照组62人,TUR术后1周常规膀胱灌注化疗。观察两组肿瘤复发情况以及不良反应。结果:本组总复发率21.7%(26/120)。实验组1年内复发1例(1.7%),1-2年内复发4例(6.9%);对照组1年内复发8例(12.9%),1-2年内复发13例(21.0%),两组复发率比较差异有统计学意义(P<0.05)。实验组不良反应8例,对照组不良反应7例,比较差异无统计学意义(P>0.05)。结论:即刻膀胱灌注化疗及二次TUR可降低非肌层浸润性膀胱癌的复发率,不良反应并无增加。     

Diagnosis and management of superficial bladder cancer

Superficial transitional cell carcinoma is defined as a transitional cell urothelial tumor that is confined to the mucosa, stages Ta or CIS, or with invasion of the lamina propria, T1. The initial treatment is transurethral resection with an attempt to remove all tumor. This should provide an accurate histologic grade and stage, and from this information a prognosis can be determined. The important predictive factors that correlate with a new occurrence or true recurrence and the development of a subsequent tumor with muscle invasion are a high tumor grade, lamina propria invasion, a positive cytology following resection, multifocal tumors, dysplasia or carcinoma in situ from mucosal biopsies of normal appearing urothelium, and a prior history of bladder cancer. Based on these factors, the recurrence rate varies from 30 to 80% and progression with a muscle invasive tumor up to 30%. Intravesical chemotherapy or "immunotherapy" following tumor resection has been shown to diminish the likelihood of a recurrence. Thiotepa has been used for the longest period of time. It is relatively inexpensive, safe if myelosuppression is closely monitored, and effective. Mitomycin C was more effective than Thiotepa in randomized trials, but is significantly more expensive. This has retarded its use as a first-line agent. It has been shown to eradicate persistent tumor in 30 to 40% of patients who have failed Thiotepa. Mitomycin C is also highly effective when used for prophylaxis. Intravesical bacillus Calmette-Guerin (BCG) has recently been demonstrated to be an effective intravesical therapeutic agent. It is effective both for treatment and prophylaxis. BCG is relatively safe and inexpensive.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tumor grade and stage as prognostic variables in upper tract urothelial tumors

Clinical and pathologic data of 54 patients with clinically localized transitional cell tumors of the upper urinary tract were reviewed to determine the significance of tumor grade and stage on patient survival. There were 43 tumors of the renal pelvis (one bilateral) and 11 tumors of the ureter. The primary tumor was staged by the new TNM classification into low stage (Ta: limited to mucosa; T1: lamina propria invasion) and high stage (T2: muscularis invasion; T3; invasion beyond the muscularis). Tumors were low stage (Ta/T1) in 28 cases (51.8%) and advanced (T2/T3) in 26 cases (48.2%). Twenty-five of 54 (46.3%) of the patients had low grade (Grades 1 and 2) and 29 of 54 (53.7%) had high grade (Grades 3 and 4) tumors. Median survival for all patients from date of diagnosis was 31 months, with a 5-year survival rate of 45.8%. Grade (low/high) matched stage (low/high) in 45 of 54 patients (83%). Median survival for patients with low grade tumors was 66.8 months compared to 14.1 months in patients with high grade tumors. Median survival for low stage tumors was 91.1 months and for high stage tumors was 12.9 months. These differences in survival related to both tumor stage (P = 0.001) and grade (P = 0.004) were statistically significant by log-rank test. Fourteen of the 54 patients (25.9%) developed local recurrence and 29 (53.7%) developed distant metastases. The lung was the most common site of metastasis. Eighteen patients (33.3%) had or developed transitional cell carcinoma of the bladder, which preceded the diagnosis of transitional cell carcinoma of the upper tract in seven cases and developed subsequently in 11 cases. Primary tumor stage by the new TNM classification is a better predictor of prognosis than tumor grade, although both variables are strongly predictive of patient course and survival. The advantages of the new TNM classification are discussed.     

Endoscopic management of upper tract urothelial carcinoma: Improved prediction of invasive cancer using a ureteroscopic scoring model

Background

The aim of this study was to investigate clinical and ureteroscopic factors considered as important for the prediction of invasive upper tract urothelial carcinoma (UTUC) and establish a model using a new ureteroscopic scoring.

Bladder cancer: imperatives for personalized medicine

Although the age-adjusted incidence of urothelial carcinoma has stabilized or declined in developed nations as a result of tobacco and environmental regulations, the rising numbers of the elderly and the shift in the tobacco epidemic to underdeveloped and rapidly industrializing nations with less stringent environmental controls augur a major growth in the worldwide burden of this disease. Current understanding of the molecular pedigree of urothelial carcinoma indicates that the disease follows a two-pathway model. The first of these, the common non-muscle-invasive papillary disease (Ta) defined by fibroblast growth factor receptor 3 (FGFR3) mutations and Ras pathway signaling, is characterized by a very low (< 5%) incidence of progression to invasive disease and very low disease-specific mortality.The second, or more lethal form is characterized by carcinoma in situ and invasive (lamina propria or deeper) tumors featuring p53 and Rb defects with a high risk of disease-specific mortality. For high-risk non-muscle-invasive disease, optimized intravesical therapeutics, including adequate transurethral resection, peri-operative intravesical chemotherapy, adjuvant intravesical bacille Calmette-Guérin and/or timely cystectomy, are needed to minimize disease-specific mortality and maximize quality of life. In muscle-invasive organ-confined disease, surgery remains the standard of care, with neoadjuvant chemotherapy providing a survival benefit in a subset of patients. Research strategies that identify disease subsets of muscle-invasive bladder cancer that benefit or do not benefit from adjunctive chemotherapy are required to reduce the relatively high number-needed-to-treat associated with this approach. To facilitate major therapeutic progress in the disease, accelerated study of experimental therapeutics connected to a fuller portrait of the heterogeneous molecular pathophysiology of bladder cancer is needed. Effective multidisciplinary collaboration is imperative in order to implement existing knowledge, enable priority research, reduce costs, and improve on the clinically relevant endpoints of survival and quality of life.     

The usefulness of the level of the muscularis mucosae in the staging of invasive transitional cell carcinoma of the urinary bladder

The initial biopsy specimens from 50 patients with high-grade invasive transitional cell carcinoma of the urinary bladder were evaluated for depth of invasion. Stages were assigned according to the following system: T1A, invasion of connective tissue superficial to the level of the muscularis mucosae; T1B, invasion to the level of the muscularis mucosae; T1C, invasion through the level of the muscularis mucosae but superficial to the muscularis propria; and B, invasion into the muscularis propria. Follow-up from the Yale Tumor Registry at a median time of 4.6 years showed that tumors invasive to levels T1A and T1B had a 75% 5-year survival, but tumors invasive through the level of the muscularis mucosae but apparently superficial to the muscularis propria (level T1C) had an 11% 5-year survival, which was comparable with the survival of patients with tumors invasive of the muscularis propria. This study suggests the prognostic importance of assessing the depth of invasion in initial biopsy specimens, even when the specimens lack a muscularis propria.     

The effect of tumor invasion patterns on pathologic stage of bladder urothelial carcinomas

The aim of this study was to investigate tumor invasion pattern, its heterogeneity and association with histopathological features and stage in invasive urothelial carcinoma of the bladder. We studied 62 cases of invasive urothelial carcinoma of the bladder. World Health Organization (WHO) 1973, WHO/ISUP1998 and WHO 1999 systems were used for tumor grading. Pathologic staging of each case was done according to 1997 TNM system. During evaluation of the slides three main tumor invasion patterns were detected: “nodular”, “trabecular” and “infiltrative”. In addition, homogeneity or heterogeneity of invasion patterns was also recorded for each case. Of sixty-two invasive cases, 17 (27%) had nodular, 36 (58%) trabecular, and 9 (15%) infiltrative invasion pattern. There was a statistically significant difference between invasion patterns in relation to pathologic stage (pT) (p=0.001), but not to grade. Of the 17 cases with nodular invasion pattern and 36 tumors with trabecular invasion pattern, 13 (77%) and 26 (72%) were pT1, respectively, whereas 8 of 9 infiltrative cases (89%) were advanced stage (pT2-3). According to heterogeneity, forty-two cases (68%) had homogeneous, while the remaining 20 (32%) had heterogeneous invasion pattern. Of the 42 homogeneous cases 34 (81%) were pT1, whereas 14 of 20 heterogeneous cases (70%) were advanced stage (p=0.000). The different invasion patterns seem to have a large impact on pathologic stage, especially the infiltrative pattern. In addition, invasion heterogeneity appears to be of value in determination of biologic aggressiveness in urothelial carcinoma.     

Expression of cell cycle proteins in T1a and T1b urothelial bladder carcinoma and their value in predicting tumor progression

BACKGROUND: Cell cycle proteins are important markers in predicting tumor behavior in urothelial carcinoma of the bladder. The objectives of this study were 1) to determine the expression levels of some of those markers in a series of patients with bladder carcinoma, 2) to define their value in distinguishing T1a (minimally invasive) from T1b (invasive) tumors, and 3) to evaluate their use as predictive factors in the progression of T1a and T1b tumors. METHODS: Tumor specimens from 101 patients were included (22 Ta specimens, 34 T1a specimens, 15 T1b specimens, and 30 T2 specimens). A tissue microarray from the 101 paraffin embedded tissue blocks was constructed. Immunohistochemistry for p16, p27, p21, p53, cyclin D1, and Ki-67 were performed. To evaluate T1a and T1b tumor progression, clinical and follow-up data were available for all 49 patients. RESULTS: Cyclin D1 and p27 were the only markers that showed a significant association with tumor stage and tumor grade (cyclin D1: P = 0.002 and P > 0.00, respectively; p27: P = 0.024 and P = 0.031, respectively). The results indicated that a combination of p21 (odds ratio, 5.7; 95% confidence interval [95% CI], 1.3-24.8 [P = 0.022]) and p16 (odds ratio, 3.7; 95% CI, 0.8-16.5 [P = 0.081]) may have potential use in distinguishing T1b tumors from T1a tumors. Finally, none of the markers examined were found to have predictive value for T1a and T1b tumor progression. CONCLUSIONS: The expression of cyclin D1 and p27 was associated with the most important prognostic factors (tumor stage and grade). The combination of p21 and p16 may have value in distinguishing T1b tumors from T1a tumors, although this finding must be evaluated in much larger series. Finally, none of the markers studied appeared to have predictive value for disease progression in patients with T1a and T1b urothelial bladder tumors.     

Current status of the treatment of urothelial tumors

Cancer of the urinary bladder, renal pelvis and ureter is usually transitional cell carcinoma. One third of cases of urethral cancer are also transitional cell carcinoma. In planning the treatment for these urothelial cancers, the anatomic stage (Ta-T4), the histologic grade (1-3), tumor multiplicity and tumor size are generally taken into account. Superficial and low-grade tumors can usually be treated by transurethral resection. However, such patients run the risk of subsequent tumor recurrence in the bladder. This risk may be reduced by intravesical administration of anti-neoplastic agents and BCG. Diffuse carcinoma in situ (CIS) should be treated intravesically before deciding on surgical extirpation of the bladder. Patients with tumors showing deep muscle invasion are usually managed by surgery. The role of adjuvant chemotherapy and/or radiation therapy is currently under investigation. Patients with unresectable cancer and/or metastases are candidates for systemic chemotherapy. This form of therapy is now resulting in an increased number of complete and partial remissions. However, there is still no evidence that systemic chemotherapy prolongs the duration of survival, especially in patients showing partial remission.