Prognostic significance of tumor location in high-grade non-muscle-invasive bladder cancer

The management of high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) continues to be a serious clinical problem. The role of many factors related to efficacy of Bacillus Calmette-Guérin (BCG), which is the most useful intravesical agent for these tumors, is still unknown. This study investigated the prognostic value of tumor location in high-grade non-muscle-invasive bladder cancer. Seventy-four patients with HG non-muscle-invasive bladder cancer, without carcinoma in situ (CIS), were treated by transurethral resection of bladder tumor (TURBT). Twenty-eight patients received adjuvant BCG therapy after TURBT. The relation between tumor location and the recurrence capacity was estimated using a Cox regression model. Our results suggest that tumor location is an important prognostic factor for BCG-therapy response in patients with high-grade non-muscle-invasive bladder cancer. Tumors in the bladder neck might have a higher risk of recurrence after intravesical immunotherapy. In addition, tumors in the lateral and posterior bladder walls might be at higher risk of recurrence when treated by TURBT alone.     

Prognostic significance of tumor multifocality on outcomes in patients with upper tract urothelial carcinoma after radical nephroureterectomy: A cohort study

To identify the prognostic impact of tumor multifocality on upper tract urothelial carcinoma (UTUC) outcomes in patients treated with radical nephroureterectomy (RNU). Study included 342 consecutive patients with UTUC. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. Tumor multifocality was significantly associated with a history of previous non-muscle invasive bladder cancer (P < 0.001), tumor size (P < 0.001), gender (P = 0.009), tumor location (P = 0.005), and anemia (P = 0.01). The Kaplan–Meier method showed that tumor multifocality was significantly associated with worse recurrence-free survival (P < 0.001, log rank). Using multivariate analysis, tumor multifocality (HR, 2.86; 95% CI, 2.06 – 3.99; P < 0.001) was independently associated with recurrence free survival. During the follow-up, a total of 128 (37.4%) patients died, including 92 (28.2%) from UTUC. However, tumor multifocality was not associated with CSS (HR, 1.29; 95% CI, 0.89 – 1.96; P = 0.21) in univariate Cox regression analyses. Tumor stage (HR, 11.1; 95% CI, 3.64 – 33.8; P < 0.001), lymph node status (HR, 2.04, 95% CI, 1.05 – 3.94; P = 0.03) and preoperative anemia (HR, 3.50, 95% CI, 2.02 – 6.08; P < 0.001) were the only independent predictors associated with worse cancer-specific survival. Tumor multifocality is an independent prognostic factor of disease recurrence in patients treated with RNU for UTUC. Tumor multifocality is unable to predict cancer specific survival in a single-center series of consecutive patients who were treated with RNU.     

Results of Intravesical Chemo-Hyperthermia in High-risk Non-muscle Invasive Bladder Cancer

Purpose: To examine the effectiveness of mitomycin-C and chemo-hyperthermia in combination for patientswith high-risk non-muscle-invasive bladder cancer. Materials and Methods: Between November 2011-September2013, 43 patients with high-risk non-muscle-invasive bladder cancer undergoing adjuvant chemo-hyperthermiain two centers were evaluated retrospectively. Treatment consisted of 6 weekly sessions, followed by 6 sessions.Recurrence and progression rate, recurrence-free interval and side effects were examined. Analyzed factorsincluded age, gender, smoking status, AB0 blood group, body mass index, T stage and grade, concominant CISassets. The associations between predictors and recurrence were assessed using multivariate Cox proportionalhazard analyses. Results: A total of 40 patients completed induction therapy. Thirteen (32.5%) were diagnosedwith tumor recurrence. Median follow-up was 30 months (range 9-39). Median recurrence-free survival was23 months (range 6-36). The Kaplan-Meier-estimated recurrence-free rates for the entire group at 12 and 24months were 82% and 61%. There was no statistically significant difference between patient subgroups. Coxhazard analyses showed that an A blood type (OR=6.23, p=0.031) was an independent predictor of recurrencefree.Adverse effects were seen in 53% of patients and these were frequently grades 1 and 2. Conclusions:Intravesical therapy with combination of mitomycin-C and chemohyperthermia seems to be appropriate inhigh-risk patients with non-muscle-invasive bladder cancer who cannot tolerate or have contraindications forstandard BCG therapy.     

Polymorphisms in inflammation genes and bladder cancer: from initiation to recurrence, progression, and survival.

PURPOSE: Since chronic inflammation contributes to tumorigenesis, we hypothesized that the risk and clinical outcome of bladder cancer (BC) might be modulated by genetic variations in inflammation genes. METHODS: Using the TaqMan method, we genotyped single nucleotide polymorphisms in interleukin (IL) -6 (-174 G-->C), IL-8 (-251 T-->A), tumor necrosis factor-alpha (TNF-alpha; -308 G-->A), and peroxisome proliferator-activated receptor gamma (PPARG; Pro12Ala), and determined their associations with BC initiation and clinical outcome. RESULTS: We found that the IL-6 variant genotype (C/C) was associated with an increased BC risk (OR, 1.77; 95% CI, 1.25 to 2.51). There were joint effects between the variant IL-6 genotypes and smoking status, and between the variant genotypes of IL-6 and other genes. To assess effect on recurrence, we grouped non-muscle-invasive BC patients according to intravesical Bacillus Calmette-Guerin (BCG) treatment status: no BCG, induction BCG (iBCG), and maintenance BCG (mBCG). In the Cox proportional hazards model, the variant IL-6 genotype was associated with an increased recurrence risk (hazard ratio [HR], 4.60; 95% CI, 1.24 to 17.09) in patients receiving mBCG. The variant PPARG genotype was associated with a reduced recurrence risk (HR, 0.41; 95% CI, 0.20 to 0.86) among untreated patients. In patients with non-muscle-invasive BC, the variant IL-6 genotype was associated with an increased progression risk (HR, 1.88; 95% CI, 0.80 to 4.11). In patients with invasive BC, variant IL-6 was associated with improved 5-year overall and disease-specific survival (HR, 0.43; 95% CI, 0.19 to 0.94 and HR, 0.39; 95% CI, 0.15 to 1.00, respectively). CONCLUSION: Inflammation gene polymorphisms are associated with modified BC risk, treatment response, and survival.     

Adjuvant intravesicular pharmacotherapy for superficial bladder cancer.

In 1990, bladder cancer, excluding carcinoma in situ, was estimated to contribute 49,000 cases of cancer. In men 75 years old or older, it became the fifth leading cause of cancer deaths. Of patients with bladder cancer, 75%-80% initially present with superficial bladder tumors. Treatment of these tumors has three objectives: 1) to eradicate existing disease, 2) to provide prophylaxis against tumor recurrence, and 3) to avoid deep invasion into the muscle layers of the bladder. Transurethral resection is the primary treatment to eradicate superficial bladder tumors, but 40%-80% of these tumors recur. Because of these high recurrence rates, adjuvant intravesicular pharmacotherapy with cytotoxic and immunomodulatory drugs has gained widespread use. The past two decades of clinical investigations in superficial bladder cancer have provided valuable information on the biology and treatment of the disease. Multivariate analyses have indicated that tumor grade and stage are the most important prognostic variables commonly available to the clinician to identify the patient at greatest risk of developing muscle-invasive or metastatic bladder cancer. These studies have also identified groups at low risk for tumor recurrence and invasive bladder cancer. Randomized trials have shown that recurrence rates are decreased by adjuvant intravesicular pharmacotherapy with a number of drugs: bacillus Calmette-Guérin vaccine (BCG), doxorubicin, ethoglucid (Epodyl), mitomycin-C, teniposide, and thiotepa. However, few studies indicate that adjuvant intravesicular pharmacotherapy can prevent progression to invasive bladder cancer in the high-risk patient with superficial bladder cancer. Additional clinical trials are needed to determine whether such therapy can prevent invasive and metastatic bladder cancer and improve disease-free survival in this group. In addition, the identification of tests (e.g., monoclonal antibody tests, chromosomal analyses, and tumor marker assays) that can help to identify high-risk patients is needed to better develop therapeutic strategies for superficial bladder cancer.     

Diagnosis and management of superficial bladder cancer

Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as "superficial" disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as "flat" mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guérin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-alpha with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened.     

Single monthly bacillus Calmette-Guérin intravesical instillation is effective maintenance therapy to prevent recurrence in Japanese patients with non-muscle-invasive bladder cancer

Background

A series of bacillus Calmette-Guérin (BCG) bladder instillations is the gold standard therapy to prevent recurrence after transurethral resection of bladder tumor (TUR-Bt) of non-muscle-invasive bladder cancer (NMIBC). However, in some cases the outcome is not optimal with the standard 6- to 8-week protocol and therefore interest has focused on additional maintenance therapy. The present study was conducted to assess the utility of single monthly intravesical instillation treatments for up to 1?year in Japanese patients.

Methods

A total of 75?stage Ta and T1 patients who had undergone TUR-Bt were retrospectively evaluated, all first receiving 80?mg BCG (Tokyo 172 strain) given once a week, 6–8 times, for primary prophylaxis. Comparison was then made of groups with (group A, 48 patients) and without (group B, 27 patients) additional maintenance BCG therapy given once a month 6–8 times.

Results

Recurrence-free survival rates at 5?years in groups A and B were 83.0 and 51.9% (P?=?0.006), despite the greater proportion of T1 patients and the longer follow-up period in the group A patients. Significant protection against recurrence persisted on multivariate analysis with adjustment for age, stage, grade, and tumor number.

Conclusions

These findings indicate maintenance BCG therapy of single intravesical instillations given once a month with our protocol to be definitely effective for prophylactic use, especially in stage Ta patients. Further evaluation of parameters such as the continuance period and dose protocol is warranted.     

瘦素在非肌层浸润性膀胱癌中的表达及其意义

[目的]探讨瘦素在非肌层浸润性膀胱癌中的表达情况,组织并分析其与膀胱癌患者临床病理特征及预后的关系。[方法]收集112例膀胱移行细胞癌组织和20例正常膀胱组织的病理切片,采用免疫组化方法检测膀胱癌和正常膀胱组织中瘦素的表达。[结果]正常膀胱组织中瘦素的表达水平明显低于肿瘤组织（P=0．032）。在低级别、高级别膀胱癌中,瘦素的阳性表达率分别为43．8％、75．8％,差别有统计学意义（辟0．001）。本组随访6-102个月,其中67例出现复发。复发组与未复发组中瘦素的阳性表达率分别为70．1％和46．7％,差别有统计学意义（P=0．013）。但瘦素表达与患者年龄、性别、肿瘤数目、大小及分期无明显相关性（P〉0．05）。[结论]瘦素表达在膀胱癌组织中明显高于正常膀胱组织,瘦素的检测有助于膀胱癌诊断及预后评估。     

EORTC 危险评分系统对T1 期非肌层浸润性膀胱癌患者的预后评价

目的：评价欧洲癌症研究与治疗组织（EORTC）膀胱癌预后风险评分表对T 1 期非肌层浸润性膀胱癌（non-muscle-invasive bladder cancer ,NMIBC ）患者预后判断的准确性。分析T 1 期NMIBC 复发进展相关因素,探讨更适用于T 1 期NMIBC 的危险分层方法。方法：回顾性分析2011年1 月至2013年6 月天津医科大学肿瘤医院108 例行经尿道膀胱肿物电切术的T 1 期NMIBC 患者的临床病理资料。根据患者不良预后指标进行评分,应用ROC 曲线获取临界值重新进行危险分层,建立新的危险评分模型。结果：108 例患者中男性90例（83%）、女性18例（17%）,中位年龄65（24~ 88）岁,21例（19.4%）复发,11例（10.2%）进展。结论：EORTC评分系统对T 1 期NMIBC 患者复发进展预测效能不准确。肿瘤大小及既往复发概率为肿瘤复发的独立性预后因素,肿瘤分级及既往复发概率为肿瘤进展的独立性预后因素。应用新的危险评分模型能够更准确的预测T 1 期NMIBC 患者的复发进展风险。     

Prognostic value of tumor size in gastric cancer: an analysis of 2,379 patients

Tumor size has been included into the staging systems of many solid tumors, such as lung and breast. However, tumor size is not integrated in the staging of gastric cancer, and its prognostic value for gastric cancer needs to be reappraised. A total of 2,379 patients who received radical resection for histopathologically confirmed gastric adenocarcinoma were enrolled in the present study. Tumor size, originally presented as continuous variable, was categorized into small gastric cancer (SGC) group and large gastric cancer (LGC) group using an optimal cutoff point determined by Cox proportional hazards model. The associations between tumor size and other clinicopathological factors were checked using Chi-square test. Survival of gastric cancer patients was estimated by using univariate Kaplan–Meier method, and the survival difference was checked by using the log-rank test. The significant clinicopathological factors were included into the Cox proportional hazards model to determine the independent prognostic factors, and their hazard ratios were calculated. With the optimal cutoff point of 4 cm, tumor size was categorized into SGC group (≤4 cm) and LGC group (>4 cm). Tumor size closely correlated with age, tumor location, macroscopic type, Lauren classification, and lymphatic vessel invasion. Moreover, tumor size was also significantly associated with depth of tumor invasion and status of regional lymph nodes. The 5-year survival rate was 68.7 % for SGC group which was much higher than 40.2 % for LGC group. Univariate analysis showed that SGC had a better survival than LGC, mainly for patients with IIA, IIB, and IIIA stage. Multivariate analysis revealed that tumor size as well as age, tumor location, macroscopic type, Lauren classification, lymphatic vessel invasion, depth of tumor invasion, and status of regional lymph nodes were independent prognostic factors for gastric cancer. Tumor size is a reliable prognostic factor for patients with gastric cancer, and the measurement of tumor size would be helpful to the staging and management of gastric cancer.     

胃癌根治术后早期复发的临床病理特点及预后分析

目的:探讨胃癌根治术后早期复发的相关因素及预后分析。方法:回顾性分析235例胃癌根治术后复发患者的临床病理资料,对相关参数进行单因素和多因素分析。Kaplan-Meier法进行预后的生存分析。结果:235例患者平均复发时间为术后24.3个月,其中早期复发145例（≤2年）,晚期复发90例（＞2年）。单因素分析显示手术方式、肿瘤大小、脉管侵犯、浸润深度、淋巴结转移、TNM分期、术后化疗与早期复发相关（P<0.05）。多因素分析显示肿瘤大小（P=0.001）、淋巴结转移（P=0.007）、术后化疗（P=0.011）是早期复发的独立影响因素。生存分析显示肿瘤大小（P=0.013）、TNM分期（P<0.01）是预后的独立影响因素。结论:肿瘤大小、淋巴结转移、术后化疗是胃癌早期复发的独立影响因素,且预后与肿瘤大小、TNM分期密切相关。     

Phase III prevention trial of fenretinide in patients with resected non-muscle-invasive bladder cancer.

PURPOSE: The study aims to evaluate the efficacy and toxicity of fenretinide in preventing tumor recurrence in patients with transitional cell carcinoma (TCC) of the bladder. EXPERIMENTAL DESIGN: We conducted a multicenter phase III, randomized, placebo-controlled trial of fenretinide (200 mg/day orally for 12 months) in patients with non-muscle-invasive bladder TCC (stages Ta, Tis, or T1) after transurethral resection with or without adjuvant intravesical Bacillus Calmette-Guerin (BCG). Patients received cystoscopic evaluation and bladder cytology every 3 months during the 1-year on study drug and a final evaluation at 15 months. The primary endpoint was time to recurrence. RESULTS: A total of 149 patients were enrolled; 137 were evaluable for recurrence. The risk of recurrence was considered to be "low" in 72% (no prior BCG) and intermediate or high in 32% (prior BCG) of the evaluable patients. Of the lower-risk group, 68% had solitary tumors and 32% had multifocal, low-grade papillary (Ta, grade 1 or grade 2) tumors. The 1-year recurrence rates by Kaplan-Meier estimate were 32.3% (placebo) versus 31.5% (fenretinide; P = 0.88 log-rank test). Fenretinide was well tolerated and had no unexpected toxic effects; only elevated serum triglyceride levels were significantly more frequent on fenretinide (versus placebo). The Data Safety and Monitoring Board recommended study closure at 149 patients (before reaching the accrual goal of 160 patients) because an interim review of the data showed a low likelihood of detecting a difference between the two arms, even if the original accrual goal was met. CONCLUSIONS: Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder.     

Superficial bladder cancer

Opinion statement Superficial bladder cancer can be resected with minimal morbidity, but the patients are at high risk for tumor recurrence. Tumors can be divided into low-, intermediate-, and high-risk categories based on tumor grade, stage, and pattern of recurrence. Low-risk tumors are best treated with a single instillation of chemotherapy such as thiotepa, doxorubicin, or mitomycin. Intermediate-risk tumors can be treated with chemotherapy, but, similar to high-risk tumors, will often require immunotherapy. High-risk tumors are best treated with intravesical bacille Calmette-Guerin (BCG) using a 3-week maintenance schedule. Side effects of BCG immunotherapy can be reduced by logarithmic reductions in the dosage of BCG. Patients who fail BCG may be rescued with BCG plus interferon-alfa or radical cystectomy.     

PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression

BACKGROUND: PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder. METHODS: Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment. RESULTS: PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment. CONCLUSIONS: Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.     

Intravesical mitomycin C combined with local microwave hyperthermia in non-muscle-invasive bladder cancer with increased European Organization for Research and Treatment of Cancer (EORTC) score risk of recurrence and progression

Purpose

To assess the activity of intravesical chemotherapy and local microwave hyperthermia (ICLMH) in increasing the disease-free interval (DFI) in patients with non-muscle-invasive bladder cancer (NMIBC) and treatment toxicity.

Methods

Forty-two patients with a diagnosis of high-risk NMIBC, according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, were treated with an intensive schedule of ICLMH using 40 mg mitomycin C. The treatment consisted of 4 weekly sessions, followed by 6 sessions delivered every 2 weeks, and by 4 monthly sessions, for a total of 14 sessions over 8 months. The DFIs before and after treatment were compared in each patient.

Results

The schedule was completed as planned by 32 patients (76.2 %). The percentage of disease-free patients the year before study was 14.9 % (95 % CI 5.5–28.8) versus 88.8 % (95 % CI 73.7–94.8) after ICLMH (p < 0.0001). Patient EORTC scores, multifocality, and tumour stage were all associated significantly and independently with a higher risk of recurrence after ICLMH treatment with HR of 41.1 (p = 0.01), 17.7 (p = 0.02), and 8.5 (p = 0.02), respectively. After a median follow-up of 38 months, 24 patients (57.1 %) did not show evidence of disease, whereas 13 patients (30.9 %) underwent disease recurrence and 5 patients (11.9 %) showed also stage progression. Toxicity consisted in grades 1 and 2 frequency, non-infectious cystitis, and haematuria.

Conclusions

ICLMH significantly increases the DFI of NMIBC patients with high EORTC score for recurrence and progression. Toxicity of the intensive treatment schedule was generally mild.     

Fibulin-3在T1期非肌层浸润性膀胱癌组织中的表达及其与肿瘤复发和进展的相关性

目的:检测Fibulin-3在T1期非肌层浸润性膀胱癌组织中的表达,探讨其与膀胱癌复发和进展的相关性。方法:收集我院泌尿外科2013年1月至2014年12月期间确诊为T1期非肌层浸润性膀胱癌的患者34例,免疫组织化学法检测膀胱癌组织中Fibulin-3的表达水平,分析Fibulin-3表达与患者临床病理特征的关系,进行Fibulin-3表达水平与膀胱癌复发和进展的相关性分析。结果:34例患者中有22例Fibulin-3高表达,12例Fibulin-3低表达;Fibulin-3表达水平与肿瘤分级相关,高级别癌组织中Fibulin-3表达水平显著增高,差异有统计学意义（P<0.05）;随访结果显示,8例患者出现了复发,5例患者出现了进展;肿瘤分级和Fibulin-3高表达与复发和进展相关,为肿瘤复发和进展的影响因素（P<0.05）;8例复发患者的中位复发时间为15（4~48）个月,5例进展患者的中位进展时间为21（8~32）个月。Fibulin-3表达的Kaplan-Meier曲线显示,Fibulin-3低表达患者具有较高无进展生存率（P<0.05）。将单因素有意义的指标纳入Cox回归分析,回归方程差异具有统计学意义（P<0.05）;Fibulin-3高表达和肿瘤分级是膀胱癌患者复发和进展的独立危险因素（P<0.05）。结论:Fibulin-3高表达是T1期非肌层浸润性膀胱癌复发和进展的独立预后因素,对Fibulin-3水平进行检测可以预测膀胱癌复发和进展,为膀胱癌术后及时治疗提供指导。     

The epidermal growth factor receptor and the prognosis of bladder cancer

Epidermal growth factor is found in high concentrations in urine, and its receptor (EGFr) has been identified in certain bladder tumors. This study was performed to determine whether receptor positivity in the tumor was associated with a poor clinical outcome. One hundred one patients with newly diagnosed bladder cancer were studied prospectively by immunohistochemical staining for the EGFr. There were 76 men and 25 women, with a mean follow-up of 30 months; 49 had tumors invading muscle: 18 were pTl (tumor invading lamina propia) and 34 were pTa (tumor confined to urothelium). Strong staining for the EGFr was found in 48% of tumors and was associated with high stage (P less than 0.001). Death of bladder cancer (40 of 101) was associated independently with high stage (P less than 0.0001) and EGFr positivity (P less than 0.001). In patients with pTa and pTl tumors, EGFr positivity was associated with multiplicity (P less than 0.01), time to recurrence (P less than 0.03), and recurrence rate (P less than 0.004). Tumor progression was associated with EGFr positivity (P less than 0.0001) and multiplicity (P less than 0.05). EGFr were found on a significant proportion of bladder tumors: such tumors were more likely to result in death, recurrence, and progression.     

Apoptotic and proliferation indexes in primary superficial bladder tumors

Whether apoptotic index [AI] and/or Ki-67 labeling index [Ki-67LI] add prognostic information in bladder cancer remains unclear. Mean AI and Ki-67 LI increased with grade and stage in 147 superficial bladder tumors. AI (>1.7%) correlated with tumor size, grade and proliferation. Ki-67 LI (>10%) correlated with higher grade and stage. Tumor size and Ki-67 LI were independent predictors of disease-free and progression-free survival, respectively. Tumor size, patient's age and tumor's recurrence predicted overall survival. We conclude that conventional clinical parameters and Ki-67 LI define risk groups of bladder tumors, while AI has limited value.     

Prognostic value of p53, p21/WAF1, Bcl-2, Bax, Bak and Ki-67 immunoreactivity in pT1 G3 urothelial bladder carcinomas.

pT1 G3 bladder carcinomas are heterogeneous with respect to tumor recurrence and progression. Whereas some urologists treat these carcinomas by repeated transurethral resections often followed by intravesical chemotherapy or BCG instillation, others recommend cystectomy after tumor recurrence or early cystectomy after the initial diagnosis. Our goal was to determine the prognostic value of p53, p21/WAF1, Bcl-2, Bax, Bak, and Ki-67 immunoreactivity in these tumors. There were 30 patients with a new histopathological diagnosis of pT1 G3 urothelial carcinoma based on a transurethral resection specimen. Representative sections of these specimens were examined for the above markers. All patients were followed up regularly and were classified as being tumor free or having tumor recurrence or progression. The mean follow-up period was 43 months (range: 8-102 months). Twenty-five patients underwent radical cystectomy and 7 of these (28%) suffered from tumor progression and died of bladder cancer. In 5 patients, surgery was limited to a transurethral resection and 4 of these patients developed superficial tumor recurrence. There was a significant difference in tumor-free survival between patients with p53-immunoreactive (mean: 30 months) and p53-negative tumors (mean: 82 months; p = 0.0341). Bcl-2 positivity was also associated with decreased tumor-free survival (p = 0.043). The other markers had no significant prognostic impact. We conclude that p53 and Bcl-2 immunoreactivity labels the most aggressive pT1 G3 bladder carcinomas.     

A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer

Between August 1981 and July 1984, 93 patients with polychronotopic superficial papillary carcinoma (Ta and/or T1), flat carcinoma in situ (Tis), or concomitant superficial papillary and in situ bladder carcinoma were entered into a prospective randomized trial of maintenance v nonmaintenance intravesical bacillus Calmette-Guérin (BCG) therapy. Forty-six patients who received BCG weekly for 6 weeks were compared with 47 patients receiving the six-weekly doses of BCG plus monthly BCG for 2 years. Both groups were evaluated every 3 months by cytology, cystoscopy, and biopsy. A significant reduction in the number of recurrent tumors per patient-month was demonstrated for both groups (P less than .0001); however, the difference in reduction of tumors between the two groups was not significant. Additionally, patients receiving maintenance and nonmaintenance therapy had similar tumor recurrence and progression rates. These results indicate that monthly maintenance BCG does not prevent, delay, or reduce tumor recurrence or progression observed with the 6-week regimen. Maintenance BCG was associated with increased local toxicity, primarily dysuria, frequency, and urgency. Dosage reduction was required in 22 of 47 patients (46.8%). When the data were subjected to multivariate analysis, the presence or absence of tumor following induction BCG and PPD skin test results were found to be significant variables. Controlling for either the presence or absence of tumor following induction BCG, tumor recurrence and progression rates were not significantly different for the two treatment groups. However, the absence of tumor after induction BCG was associated with a longer disease-free duration (P = .00001) and time to progression (P = .095). Patients with a reactive tuberculin skin test before and after induction BCG had significantly less tumor recurrences than patients with different PPD skin tests results (P = .02). Tumor progression was not related to tuberculin skin testing.