Expression of Ki-67, cyclin D1 and apoptosis markers correlated with survival in prostate cancer patients treated by radical prostatectomy.

OBJECTIVE: The study was designed to analyse the prognostic value of proliferation markers Ki-67 and cyclin D1 and apoptosis in prostate cancer (PC) patients treated by radical prostatectomy. PATIENTS AND METHODS: Two hundred and eleven patients treated by radical prostatectomy for localised prostate cancer were clinically followed up for a mean of 7.3 years. The primary histopathological specimens were re-analysed to ensure uniform histoplthological grading and pT classification. A tissue microarray construction (TMA) was used in immunohistochemisty to assess the expression of Ki-67, cyclin D1 and the apoptosis marker Tag. The results were analysed with light microscopy and the findings were compared to standard histology, pT and clinical follow-up data. RESULTS: The co-expression of Ki-67 and cyclin Dl (p=0.05) was common. High fraction of Ki-67 positive cells and a high fraction of apoptotic cells were often present in same tumours (p=0.05). High apoptotic rate was related to positive surgical margin status (p=0.047). Low expression of Ki-67 was related to a low Gleason score (p<0.001), an absence of either capsule penetration (p = 0.029) or perineural invasion (p=0.004). High expression of cyclin Dl was related to perineural growth (p=0.039). Prostate specific antigen (PSA) recurrence-free survival (RFS) was predicted by Gleason grade (p<0.001) and capsule invasion (p=0.006). High expression of Ki-67 (p=0.03), as well as high apoptotic rate (p=0.04) were related to a high risk of cancer death. In multivariate analysis the seminal vesicle invasion was the only independent predictor of cancer death (p = 0.01). CONCLUSION: The expression of Ki-67, cyclin D1 and a high apoptotic rate are related to a malignant phenotype in prostate cancer, but their prognostic value is inferior to standard histological prognostic factors.

Reduced alpha- and beta-catenin expression predicts shortened survival in local prostate cancer.

UNLABELLED: The aim of this study was to determine the prognostic value of alpha- and beta-catenin expressions in local prostate cancer (PC). MATERIALS AND METHODS: One hundred and eighty-one PC patients treated with radical prostatectomy were followed-up for a mean of 7.3 years. The alpha- and beta-catenin expression were analysed by immunohistochemistry TMT (tissue microarray technique) and light microscopy. RESULTS: Strong a-catenin expression was related to low Gleason grade (p < 0.001), cancer-free seminal vesicles (p = 0.04) and low preoperative PSA (p = 0.02). Strong beta-catenin expression was related to low Gleason grade (p < 0.001) and cancer-free seminal vesicle status (p = 0.03). Absence of nuclear beta-catenin expression was related to local disease (pT1-T2) (p = 0.05). alpha-catenin (p = 0.06), beta-catenin (p = 0.05), Gleason grade (p = 0.03) and capsular invasion (p = 0.01) were related to PSA recurrence in patients who reached PSA zero postoperatively. PSA recurrence-free survival (RFS) was significantly related to Gleason grade (p < 0.001), capsule invasion (p = 0.01), perineural growth (p = 0.05) and preoperative PSA (p = 0.05). In Cox's analysis, independent predictors of PSA RFS were Gleason grade (p < 0.001) and capsular invasion (p = 0.006). Low expressions of alpha- (p = 0.06) and beta-catenin (p = 0.05) were related to shortened PSA RFS. Survival was related to low alpha- (p = 0.011) and beta-catenin (p = 0.016) expressions. Independent predictors of shortened survival were seminal vesicle invasion (p = 0.016) and low alpha-catenin expression (p = 0.049). CONCLUSION: Reduced alpha- or beta-catenin expressions are related to malignant phenotype in local prostate cancer and predict PSA failure as well as shortened survival.

Strong Stromal Hyaluronan Expression Is Associated with PSA Recurrence in Local Prostate Cancer.

OBJECTIVE: HA (hyaluronan) is involved in cell migration, differentiation and cell proliferation, which all are essential to tumour growth. In addition, the cell surface receptor of HA, CD44, is important in cancer cell adhesion, cell migration and tumour neovascularisation. We studied the expression of HA and CD44 and their relationship with other prognostic factors and prostate-specific antigen (PSA) recurrence in local prostate cancer (PC). MATERIALS AND METHODS: 77 PC patients treated with radical prostatectomy were followed-up for a mean of 4 years. HA was detected by using a HA specific probe and CD44 expression was analysed by conventional immunohistochemistry. RESULTS: All specimens expressed HA in tumour stroma and 78% (60/77) of the tumours showed strong stromal expression of HA. The fraction of positively stained specimens for CD44 was 66% (51/77). The strong stromal HA expression was related to perineural infiltration (p = 0.001) and capsule invasion (p = 0.05). No correlation was demonstrated between the stromal HA expression and CD44 expression, preoperative PSA, clinical or pathological T classification, pN status, Gleason grade, seminal vesicle invasion or surgical margin invasion. Reduced CD44 expression was related only to preoperative PSA level (p = 0.008). The PSA recurrence was predicted by strong stromal HA expression, pT classification, seminal vesicle invasion, capsule invasion and surgical margin invasion (p

Inducible nitric oxide synthase (iNOS) expression and its prognostic value in prostate cancer.

OBJECTIVES: The expression of inducible nitric oxide synthase (iNOS) was evaluated in prostate cancer and the results were compared with other prognostic factors and patients outcome. MATERIALS AND METHODS: Clinical and histopathological data and follow-up information of 198 prostate cancer (PC) patients treated between the years 1973 and 1992 at Kuopio University Hospital, Finland were collected from patient files. Archival tumor specimens were used for immunohistochemical analysis of iNOS. The expression of iNOS was analysed by light microscopy and the expression was scored into 3 grades (negative weak or strong). RESULTS: iNOS was expressed in tumor cells and in inflammatory cells inside and around the tumor. Normal and hyperplastic prostate tissues adjacent to tumors were negative or weakly positive for iNOS. The strong iNOS expression in tumor cells was related to high T-classification (p=0.001), metastasis (p=0.06), high Gleason score (p=0.0004), DNA aneuploidy (p=0.0001) and perineural infiltration (p=0.0001). iNOS expression was not linked with the density of tumor infiltrating lymphocytes or the expression of p53. The mean values of Ki-67, mitotic index and S-phase fraction were higher in tumors strongly expressing iNOS. In univariate survival analysis the strong expression of iNOS was a significant predictor of poor survival in the entire cohort (p=0.0002) and in the MO patients (p=0.008), but was not an independent predictor of survival in Cox's multivariate analysis. CONCLUSION: iNOS has been related to stimulative and suppressive effects on cancer cell growth, but the prognostic value of iNOS has not been previously studied in PC. Here we could demonstrate an association between strong iNOS expression and rapid cancer cell proliferation rate, dedifferentiation and advanced stage cancer. The strong iNOS expression was a predictor of poor survival in univariate analysis, but was inferior to established prognostic factors in multivariate analysis.

Neoadjuvant chemotherapy in cervical carcinoma: regulators of cell cycle, apoptosis, and proliferation as determinants of response to therapy and disease outcome.

To evaluate whether cellular markers predict the responsiveness to neoadjuvant chemotherapy (NAC) in cervical cancer, 21 patients with stages I and II cervical carcinomas treated by NAC before surgery were followed up for a mean of 52.3 months. Pre-NAC biopsy and operative specimens were subjected to counting of apoptotic (AI/V) and mitotic (MI/V) indices, detection of human papillomavirus (HPV) DNA, and immunohistochemical analysis of cell cycle and proliferation markers (p21, p53, pRb, proliferating cell nuclear antigen [PCNA], Ki-67) and multidrug resistance gene (MDR1), as related to NAC response (RAC), recurrence-free (RFS), and overall (OS) survival. Adenosquamous histology and lymph node involvement were significant determinants of nonsurvival. All carcinomas contained HPV DNA. In univariate analysis, p21, pRb, and MDRI in the biopsy specimen and PCNA, Ki-67, and pRb in the surgical sample significantly predicted RAC, while age, AI/V number of lymph nodes removed, and MI/V predicted RFS. Highly significant predictors of OS were AI/V number of lymph nodes removed, post-NAC MDR1 expression, MI/V and recurrence. Multivariate analysis confirmed the strong post-NAC effects of histologic type, AI/V, and MDR1 expression for RFS, and recurrence, age, and Ki-67 expression for OS. NAC responders with slightly decreased AI/V and increased MI/V had a poor prognosis.

High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer.

Several epithelial tumours accumulate hyaluronan (HA) which promotes cancer cell invasion and metastasis. We analysed the expression of HA and its receptor CD44 and their prognostic value in 166 prostate cancer patients followed up for a mean of 13 years; standard deviation (S.D.) 2.7; range 8.7-21.4 years. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognising all forms of CD44. The peri- and intratumoral stroma from half of the patients strongly expressed immunohistochemically detectable HA in < or = 15% of the stromal area; the tumours in the remaining half expressed HA in > 15% of the area. The staining of cancer cells for HA was scored positive or negative, and for CD44 the median value of 80% of positive tumour cells was used as a cut-off point. The expression of HA in cancer cells was weakly associated with perineural infiltration of the tumour (P = 0.03) and high Gleason score (P = 0.002). There was also a significant inverse relationship between the expression of HA and CD44 in cancer cells (P < 0.001). The high level of HA in the peri-and intratumoral stroma was related to metastasis, high T-category, high Gleason score, perineural infiltration and high mitotic activity of the tumour (for all P < 0.001). There was a significant inverse relationship between the expression of CD44 in cancer cells and high level of strong expression of HA in the tumour stroma (P < 0.001). A low fraction of CD44-positive cells was related to a high TM-category, high Gleason score and rapid cell proliferation (for all P < 0.0001; M/V P value = 0.0013). In the univariate survival analysis, the high level of strong expression of HA in tumour stroma predicted an unfavourable outcome in the entire series (P = 0.003) and also in the M0 tumours (P = 0.07), while in T1-2 M0 tumours the prognostic value did not reach the level of statistical significance (P = 0.1). A low fraction of CD44-positive cells predicted a poor outcome in the entire series (P < 0.001) and also in M0 tumours (P = 0.003). Cancer cell-associated HA expression had no prognostic value in any tumour categories. In the multivariate analysis of prognostic factors, HA expression in the cancer cells or in the tumour stroma had no additional value to the standard prognostic factors TM-classification, Gleason score and CD44 expression. Our results show that stromal HA accumulation is related to several malignant features and adverse clinical outcome in prostate cancer. However, further studies based on uniformly treated patient cohorts are needed to establish the clinical significance of these findings in current clinical practice.

Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer.

BACKGROUND: The adhesion molecule CD44 standard (CD44s), and its variant isoforms v3 and v6 are associated with cell-to-cell adhesion. The down-regulation of CD44 standard and its variant isoform CD44v6 is linked with early cancer cell dissemination, but the relationship between CD44v3 and malignant features of prostate cancer (PC) has not been established previously. METHODS: The expression of CD44s and its CD44v3 and CD44v6 isoforms was analysed by immunohistochemistry in 209 archival PC biopsy specimens to establish their prognostic value. RESULTS: Down-regulation of CD44s and CD44v6 was related to high T classification, metastasis, high Gleason score, DNA aneuploidy, high S-phase fraction, high mitotic index, perineural growth and dense amount of tumour infiltrating lymphocytes (p < 0.03 for all). Down-regulation of CD44s and CD44v6 was related to poor survival in the entire cohort (p < 0.0001), in M0 tumours (p < 0.001) and in T1-2M0 tumours (p < 0.05). In needle biopsies and TURP specimens, the prognostic impact of the investigated parameters was similar. In the multivariate analysis, T classification (p = 0.0009), presence of metastases (p < 0.0001), Gleason score (p = 0.0060) and CD44v6 (p = 0.0220) expression were independent prognostic factors. In M0 tumours, T classification (p < 0.0001) and CD44v6 (p = 0.003) independently predicted survival. CONCLUSION: Down-regulation of CD44s and its CD44v6 isoform is related to tumour malignancy and unfavourable prognosis in PC.

Expression of CD44 and its variant isoform v3 has no prognostic value in gastric cancer.

AIMS: To study the controversial role of transmembrane glycoprotein CD44 as a moderator of tumour spread and as a prognostic factor in gastric cancer. METHODS AND RESULTS: The expression of all CD44 forms and that with exon v3 was assessed in 198 stage I-IV gastric adenocarcinomas using immunohistochemistry. CD44 expression was found in 72% and CD44v3 in 55% of the cases. The intensity of CD44 expression was associated with the level of invasion and with hyaluronan expression, while the frequency of CD44 positive cells was not significantly related to any of the clinical or histological features of the tumours. CD44v3 expression failed to show any association with the clinical or histological variables examined. Neither total CD44 nor CD44v3 expression affected survival. The most important prognostic factors in this cohort were the level of invasion, lymph node status, tumour size and vascular or perineural invasion. CONCLUSIONS: Changes in CD44 or CD44v3 expression level do not predict tumour spread or patient survival in gastric cancer.

CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma.

OBJECTIVE: Theclinical efficacy of neoadjuvant chemotherapy (NAC) in distinct groups of cervical cancer patients has been well documented, but parameters at the cellular level regulating the different responsiveness to this treatment have not been adequately explored. METHOD: A series of 21 patients with stage Ib and IIa bulky cervical carcinomas were treated by preoperative NAC with three courses of cisplatin, epirubicin, etoposide, and bleomycin prior to radical hysterectomy, and subsequently followed up for a mean of 52.3 months. Biopsies taken prior to NAC and operative specimens were subjected to immunohistochemical (IHC) staining for alpha-catenin, beta-catenin, E-cadherin, and CD44 isoform 6 (CD44v6), to uncover the role of adhesion molecules as determinants of the response to NAC and disease outcome. RESULTS: Seven of the twenty-one (33.3%) women died of the disease; adenosquamous (n = 4 cases) histology (RR 4.50, 95% CI 1.85-10.68) and lymph node involvement (RR 6.00, 95% CI 0.42-85.26) were significant determinants of nonsurvival. All 21 carcinomas were human papillomavirus DNA positive. The factors predicting the response to NAC in univariate analysis were: CD44v6 expression in the pre-NAC and post-NAC samples (P = 0.00056 and P = 0.00336, respectively). In multiple logistic regression analysis, the factors with independent predictive value for response to NAC were CD44v6 expression prior to (P = 0.0099) and after (P = 0.0470) NAC. In univariate survival analysis, the most significant (P < 0. 001) predictors of recurrence-free survival (RFS) were age and number of lymph nodes removed. In multivariate survival analysis, the independent predictor for RFS was only histological type (P = 0. 0064). Overall survival (OS) was predicted in a Cox model by recurrence (P = 0.0033), CD44v6 expression after NAC (P = 0.013), and patient's age (P = 0.039). CONCLUSIONS: These data indicate that CD44v6 is involved in the response to NAC, and eventually in disease outcome. This implicates that the assessment of CD44v6 expression might help in selecting patients who are likely to respond to NAC, i. e., women with significantly reduced CD44v6 expression in their tumors before treatment. Noteworthy, the response to NAC did not predict a favorable disease outcome.

Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer. Finbladder Group.

Immunoreactivity of p21WAF1/CIP1 and cyclin D1 proteins was assessed in a cohort of 207 patients with superficial (pTa-pT1) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21WAF1/CIP1 positive (> or = 5% of cells positive) and cyclin D1 positive (> or = 10% of cells positive), respectively. The p21WAF1/CIP1 expression was related to cyclin D1 immunolabelling (P < 0.001) but not to the other variables studied. The expression of cyclin D1 was inversely associated with T category (P = 0.001), WHO grade (P = 0.006), MIB-1 score (P = 0.014), p53 expression (P = 0.001), and bcl-2 (P = 0.011) immunoreactivity. In univariate analysis, T category (P = 0.0001), WHO grade (P < 0.0001), MIB-1 score (P < 0.0001), bcl-2 (P = 0.0092), p53 (P = 0.0016) and p21WAF1/CIP1 (P = 0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D1 was without any prognostic significance (P = 0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P = 0.03), whereas tumor grade (P = 0.002) and cyclin D1 expression (P = 0.04) were independent predictors of tumor recurrence. Only the WHO grade (P = 0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21WAF1/CIP1 and cyclin D1 immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease.

Prognostic value of CD44 standard, variant isoforms 3 and 6 and -catenin expression in local prostate cancer treated by radical prostatectomy.

OBJECTIVE: The clinical and histological data of prostate cancer patients were compared with the expression of CD44 standard (CD44s), variant isoforms CD44v3, CD44v6 and alpha-catenin. The prognostic value of these adhesion molecules was also analysed. PATIENTS AND METHODS: We analysed the clinical and histological data of 87 prostate cancer patients treated by radical prostatectomy in two Finnish hospitals. The mean (SD) age of the patients at diagnosis was 64 years (6) and the mean follow-up was 3 years (8). Immunohistochemistry was used to detect the expression of CD44s and its v3 (CD44v3) and v6 (CD44v6) isoforms and alpha-catenin. RESULTS: The mean (SD) fractions of positively stained cancer cells were 38 (38), 10 (22), 56 (41) and 93% (17) for CD44s, CD44v3, CD44v6 and alpha-catenin, respectively. Low fractions of CD44s- and CD44v6-positive cancer cells were related to high preoperative prostate-specific antigen (PSA) levels (p<0.05 for both). Low fraction of CD44s positive cancer cells was linked with presence of seminal vesicle invasion (p = 0.07), surgical margin positivity (p = 0.09), high Gleason score (p = 0.04) and high mitotic index (p = 0. 02). Low fraction of CD44v3-positive cancer cells was related to positive surgical margins (p = 0.05), high Gleason score (p = 0.04), presence of perineural infiltration (p = 0.02) and absence of tumour-infiltrating lymphocytes (p = 0.02). Low fraction of CD44v6-positive cancer cells was related to high pT classification (p = 0.07), capsule invasion (p = 0.03), positive surgical margins (p = 0.05), high Gleason score (p = 0.008), perineural infiltration (p = 0.0001) and high mitotic index (p = 0.001). alpha-Catenin expression was not related to any of the clinicopathological variables included in this study. Gleason score (p = 0.001), pT classification (p = 0.007), perineural infiltration (p = 0.01) and the fraction of CD44v3-positive cancer cells (p = 0.04) were predictors of PSA failure in univariate analysis. pT category (p = 0. 012), Gleason score (p = 0.02) and expression of CD44v3 (p = 0.0003) were independent predictors of PSA failure. CONCLUSIONS: The expression of CD44s, CD44v3 and CD44v6 is related to tumour differentiation. The expression of CD44v3 independently predicts PSA failure in addition to Gleason score and pT category during a short-term follow-up.

The prognostic value of inducible nitric oxide synthase in local prostate cancer.

OBJECTIVE: To compare the clinical and histological data from patients with prostate cancer with the results of the immunohistochemical analysis of inducible nitric oxide synthase (iNOS), and thus determine the prognostic value of iNOS. PATIENTS AND METHODS: The study included 82 patients (mean age 64.6 years, SD 6.1) with local prostate cancer treated by radical prostatectomy in two Finnish hospitals. Their mean (SD) follow-up was 3.3 (2.2) years. An immunohistochemical method was used to detect the expression of iNOS in these specimens, and the expression graded according to staining intensity as none, weak or strong. RESULTS: There was weak or strong expression of iNOS in 25 (31%) and 56 (68%) of the patients, respectively, and one specimen was negative for iNOS. Strong expression of iNOS was related to high a preoperative prostate specific antigen (PSA) level (P = 0.006) and high pT classification (P < 0.001), but not to nodal status, grade, seminal vesicle or capsular invasion, surgical margin status, perineural infiltration, tumour infiltrating lymphocytes or proliferation rate of cancer cells. A PSA failure was detected in 29 patients but was not predicted by iNOS expression. A Cox multivariate analysis showed that surgical margin positivity, seminal vesicle involvement and number of tumour infiltrating lymphocytes predicted the PSA failure. CONCLUSION: A high expression of iNOS was related to a high pT classification and the preoperative PSA level but not to other established prognostic factors; iNOS expression was not a predictor of PSA failure in patients with local prostate cancer.

Expression of activator protein 2 in prostate cancer is related to tumor differentiation and cell proliferation.

OBJECTIVES: Activator protein 2 (AP-2) is a DNA-binding transcription factor that can activate the expression of p21 (waf1/cip1), which in turn causes growth arrest of cells through inhibition of cyclin-dependent kinases required in G1-S progression. The aims of the present study were to analyze the expression of AP-2 in prostate cancer and to relate the results of AP-2 immunohistochemistry to other known prognostic factors and patient survival. METHODS: AP-2alpha was demonstrated by an immunohistochemical method in 215 prostate cancer cases, and the results of immunohistochemistry were related to other known prognostic factors and patient survival. RESULTS: The expression of AP-2alpha in carcinomas was usually weak and cytoplasmic, similar to normal prostatic epithelium adjacent to tumors. In 6% of the tumors, the expression was strong, and in 15% no staining signal was detected. Nuclear expression was detected in 22% of cases. Low fraction of AP-2-expressing cells was related to high mitotic index, Ki67 labeling and high expression of p21 (waf1/cip1). Nuclear expression of AP-2 was related to high Gleason score, advanced T category, DNA aneuploidy and high S-phase fraction. Nuclear expression was an indicator of unfavorable disease outcome, but in multivariate analysis, expression of AP-2 had no prognostic value. CONCLUSIONS: Cytoplasmic expression of AP-2alpha is reduced in poorly differentiated prostate carcinomas. The rare nuclear expression occurs in a small proportion of tumors which are aneuploid, have a high T category and high Gleason score. The expression of AP-2 seems to have no prognostic value in prostate cancer.

Expression of inducible nitric oxide synthase in colorectal cancer and its association with prognosis.

BACKGROUND: The expression of inducible nitric oxide synthase (iNOS) has been reported to be altered in a number of tumours, but its role in tumour biology is still unclear. METHODS: iNOS was studied in a series of 157 colorectal carcinoma patients and its relation to tumour grade, stage, cell cycle regulators, cell proliferation as well as survival was assessed. RESULTS: iNOS intensity was moderate or intense in 37% of the tumours. iNOS intensity and percentage of positive cells were higher in Dukes A and B tumours than in Dukes C and D tumours, and low iNOS expression intensity was related to high histological grade. iNOS expression correlated positively with cell cycle regulators p21 and AP-2. There was also a high iNOS expression intensity and high fraction of iNOS positive cells in tumours with a high amount of tumour infiltrating lymphocytes (TILs). The cancer related survival was significantly lower among patients with a low signal for iNOS and low iNOS percentage in tumour epithelium. In multivariate analysis iNOS was not an independent prognostic factor. CONCLUSIONS: These results suggest that iNOS has a protective role in colorectal carcinogenesis, but further studies are required to establish the clinical significance of iNOS in colorectal cancer.

Prognostic value of MIB-1 score, p53, EGFr, mitotic index and papillary status in primary superficial (Stage pTa/T1) bladder cancer: a prospective comparative study. The Finnbladder Group.

OBJECTIVE: A prospective randomized study was undertaken to determine whether cell proliferation indices (M/V index, MIB1), papillary status, the expression of p53 and epidermal growth factor receptor (EGFr) have prognostic value in superficial (pTa-pT1) bladder cancer (SBC). METHODS: 207 patients with primary SBC were followed up over a period of 4.9 (range 3.7-6.0) years. M/V index and papillary status were assessed by light microscopy, and expression of MIB1, p53 and EGFr was assessed by immunohistochemistry. The results of histopathological analyses were related to the survival data of the patients. RESULTS: Using univariate analysis, stage (p < 0.001), grade (p < 0.001), papillary status (p < 0.001), MIB1 (p < 0.001), M/V index (p < 0.001), EGFr (p < 0.001) and p53 (p = 0.002) were significant predictors of progression. Using multivariate analysis, MIB-1 score and papillary status were independent predictors of progressive disease and cancer-specific survival. Tumor grade was the only independent predictor of recurrence. CONCLUSION: Evaluation of tumor cell proliferation rate by M/V index or by MIB1 immunohistochemistry and assessment of papillary status by light microscopy are useful prognostic tools in tailoring treatment and follow-up schedule of patients with SBC.

Expression of cyclins A and D and p21(waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival.

We have studied 118 renal cell carcinomas to analyse the expressions of cyclins A and D1 and p21(waf1/cip1), and their relationship to clinical and histopathological parameters as well as to clinical outcome. Cyclins A and D1 and cyclin-dependent kinase inhibitor p21 (waf1/cip1) were not expressed in normal renal tissue. Staining signals of cyclin D1 and p21(waf1/cip1) were always nuclear but cyclin A was also expressed in the cytoplasm of the tumour cells. The mean (range) fractions of cyclin A, cyclin D1 and p21(waf1/cip1)-positive tumour cells were 2.2% (range 0-20%), 23.3% (range 0-90%) and 6.8% (range 0-70%) respectively. The expression of cyclin A was related to venous invasion, high nuclear grade, high mitotic rate, high Ki-67 and high PCNA expressions (P < or = 0.006 for all). The expression of cyclin D1 was linked with age over 65 years, low nuclear grade and high p53 expression (P < or = 0.05 for all). An inverse correlation was present between p21(waf1/cip1) and cyclin D1 (P = 0.011). Cyclin A predicted survival in the entire study group (P = 0.0014), in T1-4/N0-2/M0 (P = 0.0007) and in T1-2/N0/M0 tumours (P = 0.0007). Cyclin A was also a powerful predictor of disease-free survival in T1-4/N0/M0 (P = 0.0027) tumours (P = 0.0007). Cyclin D1 and p21(waf1/cip1) were not significantly related to survival or disease-free survival in any of the groups. In the entire material the independent prognostic factors were the presence of distant metastases (relative risk (RR) 5.16, P < 0.001), T category (RR 2.68, P < 0.001), Ki-67 expression (RR 1.02, P = 0.026) and cyclin A expression (RR 1.12, P = 0.001). The independent predictors in T1-4/N0/M0 tumours were T-category (RR 2.67, P = 0.001) and cyclin A (RR 1.21, P < 0.001), and in T1-2/N0/M0 tumours the only significant predictor was cyclin A (RR 1.19, P = 0.0002). In renal cell carcinoma, cyclin A is a powerful and independent prognostic factor in all clinical stages of the disease, whereas cyclin D1 and p21(waf1/cip1) have no prognostic value.

p22/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis.

p21/WAF1 expression was studied in a series of 162 colorectal carcinoma patients and its relation to p53- and activator protein (AP)-2 expressions and to stage as well as survival was assessed. p21 expression was moderate or intense in 33% of the tumours, and 53% of the tumours had moderate or strong p53 staining intensity. Eighty-nine percent of the tumours showed a weak cytoplasmic AP-2 signal. As expected, p21 and p53 stainings were inversely related to each other (P < 0.001). There was a significant positive association between p21 and AP-2 expression levels (P= 0.01). p21 intensity and percentage were higher in Dukes' A and B stages (P< 0.001). The cancer-related survival and recurrence-free survival (RFS) rates were significantly lower among patients with a low signal for p21 (P< 0.001) and low p21 percentage in tumour epithelium (P < 0.001). High p53 staining intensity in tumour epithelium predicted poor survival (P = 0.01) and RFS (P = 0.003). In the multivariate analysis, p21 percentage distribution independently predicted cancer-related survival in all cases, and p21 expression intensity in T1-4/N0-3/M0 and T1-3/N0/M0 cases. p21 percentage distribution was an independent predictor of RFS in all and T1-3/N0/M0 cases. AP-2 staining did not reach any prognostic significance. These results suggest that the immunohistochemical detection of cyclin-dependent kinase inhibitor p21 could be used to predict more precisely the outcome of colorectal cancer patients.

Alpha-catenin expression has prognostic value in local and locally advanced prostate cancer.

Normally functioning cell-cell adhesion plays an important role in the maintenance of tissue architecture and cell cohesion. E-cadherin is an important adhesion molecule of epithelial cells. In many types of cancer the expression of E-cadherin is reduced leading to increased risk of disease progression. alpha-Catenin is one of the intracellular elements of the E-cadherin-catenin complex. The abnormalities in the expression of alpha-catenin seem to associate with malignant cellular features and disease progression in prostate cancer. To further analyse the significance of alpha-catenin expression, we studied 215 cases of prostate cancer by immunohistochemistry and the results were related to other known prognostic factors and patient survival during a mean follow-up period of 13 years. alpha-Catenin expression was down-regulated in 19% of the cases and 3% of the tumours were totally alpha-catenin-negative. The abnormal alpha-catenin expression and cytoplasmic signal were significantly linked with high T-category, metastatic disease, high Gleason score, perineural growth, high mitotic rate, high S phase fraction and DNA aneuploidy (P < 0.05 for all). In the survival analysis, reduced alpha-catenin expression (P = 0.06) and cytoplasmic signal (P = 0.04) were related to unfavourable patient outcome. In the multivariate analysis, including TM-classification and Gleason score, alpha-catenin expression had independent prognostic value in T1-2 M0 tumors. In the M0 tumours, abnormal alpha-catenin signal was independently associated with recurrence-free survival as well. The results indicate that down-regulation of alpha-catenin is related to several malignant cellular features, and it seems to have prognostic significance in the early phases of cancer progression. We suggest that alpha-catenin expression can provide prognostic information in early prostate cancer.

Reduced expression of alpha catenin is associated with poor prognosis in colorectal carcinoma.

AIMS: To investigate alpha catenin expression in surgically resected human colorectal cancers to evaluate its prognostic value during long term follow up. METHODS: Immunohistochemistry was used to compare the expression of alpha catenin with conventional prognostic factors in 187 colorectal cancer patients treated in Kuopio University Hospital and followed up for a mean of 14 years. The hypothesis that the intensity of expression of alpha catenin and its distribution in cancer cells is correlated with survival was tested with the long-rank test, hazard ratios, and their confidence intervals. RESULTS: Uniform membranous alpha catenin staining localised to the intercellular borders was observed in 46% of the tumours; 55% of all tumours had either heterogeneous or negative alpha catenin expression, and staining intensity was either negative or weak in 42% of the tumours. The cancer related and recurrence-free survival rates were lower among patients with a weak alpha catenin intensity in tumour epithelium (p < 0.001), a low fraction of positive tumour cells (p < 0.001), and an additional cytoplasmic accumulation of alpha catenin (p < 0.001). In multivariate analysis, the intensity of alpha catenin expression in tumour epithelium predicted cancer related survival independently; alpha catenin localisation in tumour epithelium was an independent prognostic factor of recurrence-free survival in the group as a whole and in the T1-3N0M0 tumour subgroup. CONCLUSIONS: A low proportion of positive carcinoma cells, additional cytoplasmic accumulation of alpha catenin, and reduced expression intensity in tumour epithelium predict a poor survival rate. The results suggest that alpha catenin has prognostic significance in colorectal cancer.

Prognostic value and expression of p21(waf1/cip1) protein in prostate cancer.

BACKGROUND: p21(waf1/cip1) protein is a cyclin-dependent kinase inhibitor able to arrest the cell cycle at the G1 phase by inhibiting DNA replication. The expression of p21(waf1/cip1) and its prognostic value in prostate cancer are largely unexplored. METHODS: We used immunohistochemistry to analyze the expression of p21(waf1/cip1) in 213 prostate cancer cases, and the results were related to other known prognostic factors and patient survival during a long-term follow-up. RESULTS: The expression of p21 (waf1/cip1) protein was significantly associated with high Gleason score (P = 0.001), DNA aneuploidy (P = 0.013), high S-phase fraction (P = 0.019), and expression of Ki-67 (P = 0.021) and bcl-2 (P = 0.001) as well as cyclin A (P = 0.035) and D proteins (P<0.001). In univariate survival analysis the signal of p21(waf1/cip1) was significantly related to unfavorable prognosis (P = 0.010) both in the entire cohort and in local tumors (P = 0.034). In multivariate analysis, M-category, clinical T-category, Gleason score, and patient age were independent prognostic factors. In local tumors the expression of p21(waf1/cip1) together with clinical T-category and S-phase fraction were significant independent predictors of cancer related survival. CONCLUSIONS: The results suggest that the expression of p21(waf1/cip1) protein is associated both with cell proliferation and patient survival in prostate cancer.