Proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder

BACKGROUND: Recurrence of transitional cell carcinoma of the bladder cannot be predicted accurately by traditional criteria alone. This study examined the value of cell proliferative activity, morphometry, and expression of p53, c-erbB-2, and bcl-2 oncogenes in predicting recurrence of superficial papillary urothelial neoplasms of low malignant potential (LMP) and Grade 1 (G1) papillary carcinomas of the bladder. METHODS: Sixty-two patients (mean age, 62 years) with newly diagnosed superficial pTa bladder tumors (19 LMP, and 43 G1) were analyzed retrospectively. All patients underwent transurethral resection (TUR). Median follow-up was 69 months. Serial sections from formalin-fixed, paraffin-embedded material at initial TUR were stained with monoclonal antibodies (MoAbs) DO7, CB11, and bcl-2-124. Cell proliferation was assessed by MIB-1 MoAb, the quantity of argyrophilic nucleolar organizer region-associated proteins (AgNORs), and mitotic count. RESULTS: Of the 62 patients, 42 (67.7%) had one or more recurrences. Recurrence rates were higher in MIB-1 (P < 0.0001) and p53 immunopositive cases (P = 0.02), when the mitotic count was greater than 5 (P = 0.004), and in G1 carcinomas (P = 0.04). In univariate analysis, the disease-free period was shorter for MIB-1 (P < 0.0001) and p53 immunopositive (P = 0.0001) cases, for cases with high AgNOR quantity (P = 0.04), mitotic count greater than 5 (P = 0.01), and in G1 carcinomas (P = 0.002). In multivariate analysis, only MIB-1 immunoreactivity retained independent prognostic significance. CONCLUSIONS: Despite the small cohort, the results confirm the prognostic value of cell proliferation and p53 expression in patients with bladder neoplasms. The results also indicate that MIB-1 immunopositivity is the most significant predictor of recurrence and disease-free survival in superficial LMP and G1 papillary bladder carcinomas.     

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.     

Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression

BACKGROUND: CD9 has been implicated in cell adhesion, motility, and proliferation, and numerous studies have demonstrated its prognostic value in different solid tumors. The objective of this study was to determine the relation of CD9 expression to tumor grade and tumor stage of urothelial carcinoma of the bladder and to define the value of CD9 in predicting the behavior of superficial papillary tumors (SPTs) (pathologic Ta [pTa] and pT1). METHODS: Three hundred twenty patients (118 patients with pTa tumors, 111 patients with pT1 tumors, and 91 patients with pT2 tumors) were examined for CD9 expression using immunohistochemistry applied on formalin fixed, paraffin embedded tissue. Patients were stratified into 3 categories, depending on CD9 expression: positive (> 50% positive cells), reduced (5-50% positive cells), or negative (< 5% positive cells). RESULTS: Loss of CD9 expression was found to be associated significantly with high-grade and high-stage urothelial tumors (P < 0.0001). A reduced/negative (altered) CD9 expression was associated with SPT progression, but not with recurrence (P < 0.001). Patients who had pTa or pT1 tumors with altered CD9 expression had a relative risk of 5.59 (P = 0.005; 95% confidence interval [95% CI], 1.69-18.48) for progression compared with patients who had tumors with positive CD9 expression. Kaplan-Meier curves showed that a lack of CD9 expression was associated significantly with progression free survival (P < 0.001; log-rank test), but not with recurrence. In patients with SPTs, multivariate Cox proportional hazards regression analysis revealed that negative CD9 expression was an independent prognostic marker for the prediction of tumor progression (P = 0.007; 95% CI, 0.11-0.70). CONCLUSIONS: In patients with urothelial bladder carcinoma, CD9 expression was associated significantly with tumor stage and grade, and a loss of CD9 expression was an independent prognostic factor for predicting progression in patients with SPTs. Thus, CD9 immunoexpression is a potential new predictor of tumor behavior in patients with SPTs of the urinary bladder.     

Nucleolar organiser regions (AgNORs) as predictors in transitional cell bladder cancer.

The predictive value of silver stained nucleolar organiser regions (AgNORs) was assessed in 229 patients with transitional cell bladder cancer followed up for over 10 years. The AgNORs were enumerated in pretreatment biopsy specimens. The AgNORs were related to clinical stage (T) (P = 0.0111), papillarity (P less than 0.0001), WHO grade (P less than 0.0001), DNA ploidy (P = 0.0010) and S-phase fraction (P less than 0.0001). Tumours presenting with pelvic lymph node involvement (P = 0.0085) or metastasis (P = 0.0780) at the time of diagnosis had more AgNORs than tumours confined to the bladder wall. Progression in T-, N- and M-categories (P = 0.0010-0.0030) was related to AgNORs and consequently they predicted bladder cancer related survival (P = 0.0005). The diploid tumours could be regrouped according to survival by AgNORs (P = 0.0001). In papillary tumours AgNORs predicted progression (P = 0.0110) and survival (P = 0.0038). In Ta-T1 tumours AgNORs predicted progression (P = 0.11) and survival (P = 0.0751) and also in T2-T3 tumours AgNORs contributed to survival significantly (P = 0.0039). The AgNORs subdivided WHO grade III tumours according to their ability to progress during the follow-up time (P = 0.0711). In a multivariate analysis AgNORs predicted progression independently in Ta-T1 category (P = 0.0165). AgNORs predicted recurrence free period like SPF (P = 0.0010). In conclusion, AgNORs are inferior to classic prognostic factors or DNA flow cytometric variables in muscle invasive bladder cancers whereas they have independent predictive value in superficial cancers.     

Intravesical therapy for superficial bladder cancer

Approximately 54,400 new cases of transitional cell carcinoma of the bladder were reported in the United States in 1999, with an estimated 12,500 deaths attributable to this cancer. Close to 75% of all bladder tumors are confined to the urothelium (stage Ta, or carcinoma in situ), and nearly 30% of papillary tumors invade the lamina propria (stage T1). The majority of superficial tumors are low grade with low rates of progression. Transurethral resection is the standard initial treatment for transitional cell carcinoma. Intravesical therapy is an important adjunct to transurethral resection in patients with superficial bladder cancer, many of whom are at risk for disease recurrence and progression. Cytotoxic and immunomodulating agents and, more recently, photosensitizers have demonstrated utility against superficial transitional cell carcinoma. Many studies have assessed and continue to examine the efficacy of various agents at different doses and in different combinations and schedules. Recently, valrubicin (Valstar) won Food and Drug Administration (FDA) approval only for the treatment of refractory carcinoma in situ. However, bacillus Calmette-Guérin (BCG) and mitomycin (Mutamycin) remain the most commonly used, most effective agents available for prophylaxis against recurrence and subsequent progression of superficial bladder cancer. This article reviews traditional and alternative intravesical agents useful in the therapy and prophylaxis of superficial transitional cell carcinoma of the bladder.     

Decreasing of p27(Kip1)and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

The p27(Kip1)(p27) protein is a cyclin-dependent kinase inhibitor of the transition from G1 to S phase. It has been reported that decreased p27 protein level is a negative prognostic indicator in human tumours including bladder cancer. We studied the relationship between protein levels of p27, cyclin E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohistochemical staining. Low protein levels of p27 were associated with low staining of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differentiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node metastsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlated with poorly differentiated grade, muscle invasion and lymph node metastsis. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0002). Kaplan-Meier plots of survival rate in patients with low versus high p27 staining showed that low protein levels of p27 were associated with a shortened disease-free and overall survival (P< 0.0001 and P< 0.0001, respectively). Similarly, low staining of cyclin E and high Ki-67 index correlated with a shortened disease-free and overall survival. On multivariate analysis using Cox proportional hazards model, low protein levels of p27 and high Ki-67 index were independent predictors of shortened disease-free (P< 0.0001, P = 0.0031, respectively), and low protein levels of p27, low staining of cyclin E and high Ki-67 index of overall survival (P = 0.0017, P = 0.0009, P = 0.0003, respectively). In superficial bladder tumours (Ta, T1; 86 patients), significant correlations were observed between low p27 staining and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respectively). Among the recurrenced superficial tumours (35 patients), the tumours which remained at a low stage showed high protein levels of p27 and cyclin E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings suggest that decreased protein levels of p27 and cyclin E play a role in the progression of bladder cancer and to evaluate these protein levels may be useful in management of the diseases.     

E-cadherin immunoreactivity correlates with recurrence and progression of minimally invasive transitional cell carcinomas of the urinary bladder

E-cadherin is a transmembrane glycoprotein involved in intercellular adhesion. Abnormal (i.e., lost or decreased) expression of E-cadherin has been linked to invasiveness of many malignant tumors, including bladder carcinomas. To our knowledge, studies analyzing the prognostic impact of E-cadherin immunoreactivity especially in minimally invasive transitional cell bladder carcinomas (stage pT1) have not been published in the Anglo-American literature. In the present study, we immunostained 69 cases of pT1 transitional cell bladder carcinomas for E-cadherin using multitissue arrays. The results were compared with p53 and Ki-67 antigen immunoreactivity, clinicopathological parameters and the patients' outcome. E-cadherin immunoreactivity, which was found abnormal in 42% of cases, correlated significantly with substage (pT1a/pT1b; p=0.029) and p53 index (p=0.041) and tendentiously with Ki-67 antigen index (p=0.089) and age (p=0.07). By univariate Cox regression analysis, abnormal E-cadherin immunostaining correlated significantly (p=0.005) with early tumor recurrence, but not with early tumor progression (p=0.168). In a multivariate analysis, this parameter was identified, besides tumor grade (p=0.002), as an independent predictor of recurrence-free survival (p=0.016). Concerning tumor progression, age was identified as the single independent prognostic parameter (p=0.041), but E-cadherin immunoreactivity displayed a tendentious independent predictive value in this respect (p=0.071). We conclude from our data that immunohistochemical E-cadherin staining may provide additional prognostic information in patients with pT1 bladder carcinomas.     

The prognostic value of KI-67 proliferation index in transitional cell carcinoma of renal pelvis and ureter

The investigation deals with Ki-67 immunoreactivity assay in upper urinary tract transitional cell carcinoma (TCC) with respect to grade, stage and survival after radical surgery. In a retrospective study (5yrs) of 37 patients with TCC of the renal pelvis and ureter, who had undergone radical nephroureterectomy and bladder resection, pT1-pT4 lesions and G1-G3 tumors were identified. Ki-67 expression was evaluated by immunohistological staining (1:100; MIB-1; Immunotech. Inc., Westbrook, USA). By using fifteen x600 visual fields, Ki-67 labeling index (number of positive cells per 100 tumor cells) was found (mean +SD--29.7 +/- 9.22). There was a correlation between the index and tumor stage (p < 0.001) and grade (p = 0.002). The Ki-67 values in excess of 27 corresponded to high risk of bladder recurrence (p < 0.001) and short duration of recurrence development (p = 0.067) whereas, for the index of under 22, five-year progression-free survival was more frequent (p < 0.001). Having been tested in that study, discriminative modeling yielded the following parameters: sensitivity and specificity for bladder recurrence was 93% and 79% while for 5-year progression-free survival- 89% and 100%.     

Cell proliferation of transitional cell bladder tumours determined by PCNA/cyclin immunostaining and its prognostic value.

Cell proliferation of transitional cell bladder cancer (TCC) was determined by PCNA (proliferating cell nuclear antigen)/cyclin immunostaining in 178 TCCs and the results were related to established prognostic factors, progression and survival during a mean follow-up period of 10 years. The fraction of PCNA/cyclin positive nuclei was related to T-category (P = 0.008), papillary status, WHO grade, DNA ploidy, S phase fraction, M/V index (volume corrected mitotic index) and AgNORs (silver stained nucleolar organiser regions) (for all P less than 0.001). TCCs presenting with pelvic lymph node metastasis at diagnosis had a significantly higher growth fraction than the tumours confined to the bladder wall (P less than 0.001). The fraction of PCNA/cyclin positive nuclei predicted progression in T-, N- and M-categories (P less than 0.001). In Ta-T1 tumours high fraction of PCNA/cyclin positive nuclei predicted metastasis (P = 0.019). In survival analysis the fraction of PCNA/cyclin positive nuclei predicted survival in the entire cohort (P less than 0.001) and in Ta-T1 tumours (P = 0.0005). In a multivariate survival analysis the fraction of PCNA/cyclin positive nuclei showed independent predictive value in the entire cohort (P = 0.046), in papillary tumours (P = 0.006) and in Ta-T1 tumours (P = 0.015). The results show that the growth fraction as determined by PCNA/cyclin immunostaining is a significant prognostic variable in TCC.     

Multivariate analysis of survival, recurrence, progression and development of mestastasis in T1 and T2a transitional cell bladder carcinoma

BACKGROUND: Determination of prognosis factors associated with survival, recurrence, progression, and development of metastasis in T1 and T2a transitional cell carcinoma (TCC) of the bladder is discussed. METHODS: A study was conducted of a group of 210 patients with primary bladder TCC at classification T1 (n = 175) and T2aN0M0 (n = 35). A total of 177 variables were studied in each patient. The monoclonal antibodies used were the following: DO7 (p53) and MIB-1 (Ki-67). Prognosis was obtained using Kaplan-Meier methodology and Cox proportional hazards model. RESULTS: The average follow-up period was 6.7 years. Cancer-related survival rates at 5 and 10 years were 82.96% and 74.78%, respectively. The independent survival variables were the following: age and expression of p53. Recurrence free survival at 5 and 10 years stood at 51.80% and 42.71%, respectively. The independent recurrence variables were T2a classification, tumor multifocality, tumor size of greater than 3 cm, carcinoma in situ in random biopsy, and expression of Ki-67. Progression free survival rates at 5 and 10 years were 75.31% and 69.16%, respectively. The independent progression variables were age, T2a classification, and expression of p53. Metastasis free survival rates at 5 and 10 years stood at 87.23% and 84.55%, respectively. The expression of p53 was the sole variable to provide an independent prediction of metastasis. CONCLUSIONS: The expression of p53 clearly has an independent effect on the prediction of survival, progression and development of metastasis, showing a dose-response effect. Tumor multifocality and T2a classification are the variables that best predict recurrence.     

Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma

BACKGROUND: Proliferative activity in tumors depends on regulation of the cell cycle. p27(Kip1) (p27) plays a pivotal role as a negative regulator of the cell cycle. A decrease in p27 expression has been reported in many kinds of tumors, but little is known regarding p27 in patients with renal cell carcinoma (RCC). METHODS: Expression of p27 and the related cyclins (cyclin A, cyclin E, and cyclin D1) was examined immunohistochemically in 67 patients with of clear cell RCC. The Ki-67 labeling index (MIB-1 LI) and clinicopathologic parameters related to a poor prognosis also were analyzed. To determine their prognostic significance, univariate and multivariate survival analyses were performed. RESULTS: In tumors, there was considerable immunoreactivity for cyclin A, cyclin D1, and MIB-1, and the mean values for each were 1.08%, 16.1%, and 1.5%, respectively. Cyclin E expression was rare. The expression of p27 was correlated strongly with the expression of cyclin A (correlation coefficient, 0.432; P < 0.0004) and cyclin D1 (correlation coefficient, 0.476; P < 0.0004). Also, an inverse correlation was present between p27 expression and tumor size (P = 0.0377). In univariate analysis, the unfavorable prognostic factors were high TNM stage (P < 0.0001), large tumor size (P = 0.0016), high histologic grade (P = 0.0104), and low p27 expression (P < 0.0001). In multivariate analysis, high TNM stage (P = 0.0035) and low p27 expression (P = 0.0235) were independent prognostic factors for disease specific survival in patients with RCC. CONCLUSIONS: The results of this study suggest that low p27 expression may be a significant and independent, unfavorable prognostic factor in patients with renal cell carcinoma.     

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.     

Cyclin D1 expression in transitional cell carcinoma of the bladder: correlation with p53, waf1, pRb and Ki67

Normal cell proliferation is closely regulated by proteins called cyclins. One of these, cyclin D1, in combination with its corresponding cyclin-dependent kinase (cdk), is essential for G(1)/S phase transition. Cyclin/cdk complexes are generally inhibited by cyclin-dependent kinase inhibitors(ckis), some of which are induced by wild-type p53. The aims of this study were: to investigate levels of cyclin D1 expression in transitional cell carcinoma (TCC) of the bladder; to correlate these results with data concerning the expression of p53, waf1, pRb and Ki67; and to determine whether cyclin D1 expression could predict clinical outcome. Paraffin-sections from 150 newly diagnosed bladder tumours (Ta/T1 = 97; T2-T4 = 53) were stained for cyclin D1 using immunohistochemistry and a cyclin D1 index assigned. These results were correlated with data relating to the expression of p53 and waf1 by the same tumours. A representative subset of 54 tumours (Ta/T1 = 28; T2-T4 = 26) was also stained for Ki67 and 55 were stained for pRb. The clinical course of each patient was recorded and multivariate analyses of risk factors for tumour recurrence, stage progression and overall survival were performed. Positive staining for cyclin D1 was found in 83% of tumours. The staining pattern varied between tumours with nuclear, cytoplasmic or a combination of the two evident in different tumours. 89% of Ta/T1 and 74% of T2-T4 tumours showed nuclear staining with or without cytoplasmic staining. The median value for cyclin D1 staining was significantly higher in Ta/T1 tumours (41%) compared with T2-T4 tumours (8%, P< 0.005) with 26% of muscle-invasive tumours demonstrating absent staining. In addition, the median value for cyclin D1 staining was significantly higher in G1/G2 tumours (43%) compared with G3 tumours (14%, P< 0.005). There was a significant positive correlation between expression of cyclin D1 and waf1 expression (P< 0.0001) as well as pRb expression but not between cyclin D1 expression and expression of p53. Ki67 expression was significantly associated with increasing tumour stage (P< 0.005) and histological grade (P< 0.05) but did not correlate with cyclin D1 expression. A cyclin D1 index > or = 8% was associated with significantly better survival in those patients with muscle-invasive disease (T2-T4). In addition, there was a significantly higher progression rate for those patients with Ta/T1 disease whose tumours demonstrated cytoplasmic cyclin D1 staining. These results indicate that cyclin D1 expression is significantly higher in low-stage, well differentiated bladder tumours and strongly correlates with waf1 expression. In a multivariate analysis, cyclin D1 expression is an independent prognostic indicator of survival in those patients with muscle-invasive disease.     

Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy

OBJECTIVE: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively. PATIENTS AND METHODS: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies. RESULTS: Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors. CONCLUSION: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.     

The prognostic significance of tumour cell proliferation in squamous cell carcinomas of the oesophagus.

Tumour samples from 150 patients with squamous cell carcinoma of the oesophagus were investigated immunohistochemically with the monoclonal antibody MIB-1, which recognises proliferating cells. Using light microscopy, the number of MIB-1-positive tumour cells was counted in the areas with the highest proliferative activity. The MIB-1 index was determined as the proportion of MIB-1-positive and MIB-1-negative tumour cells. A considerable variation of the MIB-1 indices was found between the different tumours with a minimum of 6% and a maximum of 95% (median, 33%). The MIB-1 index correlated significantly with the mitotic activity in the tumour tissue (r = 0.33; P = 0.0001) and with the proportion of apoptotic tumour cells (r = 0.25; P = 0.0017). No significant correlation was found between the MIB-1 index and various other prognostic parameters including pT classification, pN classification, tumour grade, blood vessel invasion and lymphatic vessel invasion. In the univariate survival analysis no significant difference was found between tumours with low (< or = 33%) and high MIB-1 index (> 33%) 5-year survival rate: low MIB-1 index, 19.2%; high MIB-1 index, 22.2%). In a Cox proportional hazard regression analysis only the parameters lymphatic vessel invasion (P = 0.0001), pT classification (P = 0.0034) and pN classification (P = 0.0256), but not the MIB-1 index, could be verified as independent prognostic variables. In conclusion, evaluation of the MIB-1 index does not provide prognostic information for oesophageal cancer patients.     

Tumor size and T stage correlate independently with recurrence and progression in high-risk non-muscle-invasive bladder cancer patients treated with adjuvant BCG

We conducted a retrospective study to determine the prognostic significance of age, gender, associated carcinoma in situ, stage, number of tumors, and tumor size for patients with high-risk non-muscle-invasive bladder tumors treated with bacillus Calmette-Guérin (BCG). Data were evaluated on 144 high-risk patients with non-muscle-invasive bladder cancer treated with BCG immunotherapy after the initial treatment with transurethral resection. According to their response to BCG, patients were divided into groups, and the differences in factors, associated with recurrence and progression, were evaluated. Patients were categorized into two groups: group A, complete responders without recurrence and without progression, and group B, patients with recurrence and with progression. Furthermore, group B was divided into two subgroups: group B1, patients with recurrence, and group B2, patients with progression. Univariate analysis of group B showed that only tumor size of >3 cm diameter (hazard ratio (HR) 11.99; 95 % confidence interval (CI) range 5.69–25.3; p?<?0.001) is associated with recurrence. After multivariate analysis, the same factor appeared to be prognostic for recurrence as well. In addition, group B2 was statistically correlated with group B1. Univariate analysis proved that tumor stage (Ta or T1) is the unique factor associated with progression (HR 6.4; 95 % CI 1.29–31.9; p?=?0.02). Tumor stage seems to be associated with disease's progression after the multivariate analysis too. Tumor size and stage may serve as prognostic factors, because of its independent correlation with recurrence and progression for patients with high-risk non-muscle-invasive bladder tumors treated with BCG.     

MRP-1/CD9和HSP60在膀胱癌中的表达

目的:探讨MRP-1/CD9和HSP60的表达与膀胱癌发生发展的关系.方法:应用免疫组织化学技术(SP法)检测CD9和HSP60在75例膀胱移行细胞癌标本,15例正常膀胱组织中的表达.结果:CD9和HSP60在正常膀胱组织均高表达,41.2%和42.7%的膀胱癌对CD9和HSP60显示了表达减低.不同临床分期和病理分级的膀胱癌中CD9的表达有差异(P＜0.05),根据预后表浅性膀胱癌的复发浸润组和非浸润组中CD9和HSP60表达有差异(P＜0.05).结论:CD9和HSP60可能与膀胱癌的发生发展有关,它们可能作为判断膀胱癌预后的新指标.     

Prognostic significance of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in voided urine samples from patients with transitional cell carcinoma of the bladder.

PURPOSE: To study the role of urinary matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in bladder cancer and their relationship to tumor progression. EXPERIMENTAL DESIGN: MMP-1 and TIMP-1 were measured by ELISA in urine samples from 131 patients with bladder tumors (7 cis, 74 Ta, 29 T1, and 21 T2-T4; 46 G(1), 41 G(2), and 37 G(3)), 5 patients with prostate cancer, 33 patients with benign lower urinary tract disorders, and 36 healthy volunteers. Complete clinical data were available for 100 patients with bladder cancer with a median follow-up time of 24 months (range: 4-39 months). RESULTS: MMP-1 was detected in urine samples from 21 of 131 (16%) patients with bladder cancer but was undetectable in samples from all other groups (P < 0.0001). Urinary MMP-1 was detected in a higher percentage of patients with T2-T4 tumors and G(3) tumors than patients with cis/Ta/T1 or G(1)-G(2) tumors (P = 0.04 and P = 0.0074, respectively). Patients with detectable concentrations of urinary MMP-1 had higher rates of disease progression (P = 0.04) and death from bladder cancer (P = 0.02) than patients with undetectable urinary MMP-1. All patient groups had higher urinary TIMP-1 concentrations than healthy volunteers (P = 0.02). Patients with muscle-invasive tumors had higher concentrations of urinary TIMP-1 than patients with cis/Ta/T1 tumors (P = 0.037), but there was no association between TIMP-1 and tumor grade. Urinary TIMP-1 levels strongly correlated with tumor size (P = 0.0002). Progression-free survival rates were lower for patients with urinary TIMP-1 concentrations above the median (1.8 ng/ml, P = 0.04), but urinary TIMP-1 levels were not related to disease-specific survival. Patients with T2-T4 tumors and G(3) tumors had significantly lower urinary MMP-1:TIMP-1 ratios than patients with Ta/T1 bladder tumors (P = 0.039) or G(1)-G(2) tumors (P = 0.0415). CONCLUSIONS: Where urinary MMP-1 is detectable, the patient is more likely to have a bladder tumor of advanced stage or grade and may be at increased risk of disease progression and death of bladder cancer. The relationship between urinary TIMP-1, muscle-invasion, and disease progression in bladder cancer is at variance with its role as an inhibitor of MMPs and warrants additional evaluation.     

Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study.

PURPOSE: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non-muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression. EXPERIMENTAL DESIGN: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome. RESULTS: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of T(a) or T(1) tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis. CONCLUSION: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non-muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.     

膀胱癌PCNA蛋白表达及其与复发的关系

[目的]探讨增殖细胞核抗原（proliferating cell nuclear antigen,PCNA）蛋白在膀胱癌中的表达情况,并分析其与临床病理特征及复发的关系。[方法]148例膀胱移行细胞癌患者标本,25例癌旁正常组织标本作为对照,采用免疫组化SP法检测PCNA蛋白的表达。[结果]癌旁正常组织中PCNA蛋白的阳性表达水平明显低于肿瘤组织（16.0%vs50.7%,P〈0.001）。PCNA蛋白的表达与膀胱癌的分级、分期、复发有关（P〈0.05）,与患者的年龄、性别、肿瘤数目及肿瘤大小无关（P〉0.05）。本组104例浅表性膀胱癌（Ta～T1）随访2～95个月,其中复发64例,复发组与未复发组PCNA蛋白的阳性表达率分别为56.3%和15.0%（P=0.001）。[结论]PCNA蛋白在膀胱癌中高表达,其高表达提示预后不良。