Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma.

PURPOSE: We examined p53 protein and proliferating cell nuclear antigen immunoexpression as prognostic factors to the outcome of squamous cell carcinoma of the penis in 50 patients. MATERIALS AND METHODS: Penectomy and lymphadenectomy were performed in 14 patients with clinically positive nodes while 36 with cN0 disease were treated with penectomy and kept under surveillance that resulted in subsequent lymphadenectomy due to nodal relapse in 8. Of 21 patients with confirmed nodal metastases 18 died of disease. Immunohistochemical reactions were performed via the avidin-biotin-immunoperoxidase method and the results were compared with tumor pT stage, grade, nodal status and cause specific death. RESULTS: In univariate analysis proliferating cell nuclear antigen staining showed association only with nodal metastasis (p = 0.04) while p53 staining exhibited correlation with tumor pT stage (p = 0.0005), grade (p = 0.02), lymphatic spread (p = 0.02) and cause specific survival (p = 0.003). Multivariate analysis showed that p53 immunoreactivity was the only factor with prognostic significance for disease progression and cause specific survival. Tumor pT stage, grade and proliferating cell nuclear antigen staining had no significance for nodal metastases and cause specific death. CONCLUSIONS: Proliferating cell nuclear antigen staining had no prognostic value for disease progression. Since p53 over expression was associated with tumor progression and cause specific death, perhaps it should be evaluated in staging and therapeutic planning for patients with squamous cell carcinoma of the penis.     

Expression of PCNA, p53, Bax, and Bcl-X in oral poorly differentiated and basaloid squamous cell carcinoma: relationships with prognosis

BACKGROUND: The aim of this study was to compare the clinical features and proliferating cell nuclear antigen (PCNA), p53, Bcl-X, and Bax expression in primary oral basaloid squamous cell carcinoma (BSCC) and poorly differentiated squamous cell carcinoma (PDSCC) matched by stage and site and to assess the possible prognostic significance of these variables. METHODS: Seventeen cases of oral BSCC were compared with 27 PDSCCs matched by stage and tumor site. In addition, PCNA, p53, Bax, and Bcl-X expression in both carcinomas were evaluated in relation to their clinicopathologic features and prognostic values using the Kaplan-Meier method and Cox regression models. RESULTS: No statistically significant differences were found between the groups (BSCC and PDSCC) in regard to clinical features and immunohistochemical reactivity for antibodies PCNA, p53, and Bcl-X. In comparison with PDSCC, the BSCC group exhibited a higher Bax score (p = .031). The 5-year and 10-year overall survival, cancer-specific survival, and disease-free survival rates demonstrated no significant differences between the BSCC and PDSCC groups, and the PCNA, p53, Bax, and Bcl-X also showed no prognostic value. CONCLUSIONS: These results suggest that the clinical and biologic course of BSCC is similar to PDSCC in the oral cavity when clinical stage and site are matched.     

Clinical features and immunoexpression of p53, MIB-1 and proliferating cell nuclear antigen in adrenal neoplasms

PURPOSE: We evaluated the clinical features and immunoreactivity of p53 protein, MIB-1 antigen and proliferating cell nuclear antigen (PCNA) in adrenal neoplasms. MATERIALS AND METHODS: A total of 26 patients with adrenocortical adenoma and 24 patients with carcinoma were treated with adrenalectomy. Clinical features and immunohistochemical reactions were compared in adult vs pediatric tumors. RESULTS: There was a bimodal age distribution of carcinomas and adenomas, with a first peak occurring before age 5 years. The proportion of carcinomas in children (18 of 29) was higher than in adults (6 of 21). Carcinoma and adenoma occurring in children presented more commonly as the virilizing syndrome, while in adults Cushing's syndrome was more common. All adenomas in adults were p53 negative, while in children 4 of 11 adenomas (36%) were p53 positive. Histological Weiss criteria were the most reliable pathological features to distinguish adenoma from carcinoma. Other pathological features, including tumor weight, rate of mitotic figures and immunoexpression of p53 protein, MIB-1 antigen and PCNA, exhibited a striking difference in adenomas and carcinomas but none demonstrated sensitivity or specificity of 100%. Of all the computerized tomographic characteristics analyzed, including tumor size, shape, necrosis/hemorrhage, attenuation and contrast enhancement, only tumor size (greater than 5 cm) showed sensitivity and specificity of 100% in the differential diagnosis. Children and adults with carcinoma had similar curves of survival (p = 0.76). Carcinoma stage and PCNA immunoexpression displayed an association with outcome. CONCLUSIONS: Endocrine syndromes differed in adults and children but other clinical features were similar in both groups. The role of p53 protein, MIB-1 antigen and proliferating cell nuclear antigen in discrimination of adenomas from carcinomas is unclear.     

Prognostic significance of ploidy, MIB-1 proliferation marker, and p53 in renal cell carcinoma

BACKGROUND: Pathologic stage is currently the best prognostic factor for predicting outcomes in renal cell carcinoma. The objective of this study was to evaluate the role of DNA ploidy, p53, and Ki-67 (MIB-1) as individual and combined prognostic factors for survival in patients with renal cell carcinoma (RCC). STUDY DESIGN: From 1995 to 2004, 117 patients (78 men and 39 women; mean age 57.34 years), undergoing partial (n = 22) or radical (n = 95) nephrectomy for renal cell carcinoma were retrospectively analyzed. Analysis of MIB-1, p53, and DNA ploidy was performed. Disease-free and overall survival was calculated using Cox proportional hazard models. A combined score was given to incorporate p53, MIB-1, and ploidy as a single variable. RESULTS: On univariate analysis, tumor size, nuclear grade, MIB-1 <10% (p = 0.0059), ploidy (p = 0.0124), pathologic stage group, metastasis at time of operation, and combined score (p = 0.0024) were markedly associated with disease-free survival. On multivariate analysis, only metastasis and pathologic stage were pronounced. For overall survival, size, nuclear grade, MIB-1 <10% (p = 0.0167), pathologic stage group, metastasis, and combined score (p = 0.0456) were pronounced on univariate analysis. Only metastasis was pronounced on multivariate analysis. CONCLUSIONS: We incorporated a combined score to evaluate MIB-1, ploidy, and p53 as a single variable. A combined score is able to give a stronger predictive value of the cellular characteristics of each tumor. Individually and combined with p53, MIB-1, and ploidy were of prognostic significance on univariate analysis. Pathologic stage and presence of metastasis remain the best predictors of disease-free survival.     

Prognostic indicators in male breast carcinoma

Twenty-nine male breast cancers (MBC) were studied to determine the relationship between expression of several prognostic factors and clinical outcome. Immunohistochemistry employing a labeled streptavidin-biotin method was used to detect the presence of estrogen (ER) and progesterone receptors (PR), cathepsin D (CD), c-erbB-2 oncoprotein, epidermal growth factor receptor (EGFR), and p53; results were visually semiquantitated. DNA ploidy was evaluated by image analysis (CAS 200) of 5 μm fixed embedded Feulgenstained tissue sections. For proliferating cell nuclear antigen (PCNA), nuclear immunostain was quantitated as percentage positive nuclear area (PPNA) by image cytometry (CAS 200). The frequency of expression was ER, 26/29 (89.7%); PR, 19/29 (65.5%); CD, 25/29 (86.2%); c-erbB-2, 5/29 (17.2%); EGFR, 4/29 (13.8%); and p53, 9/29 (31%). Twenty-one (72.4%) were aneuploid; the mean PPNA for PCNA was 37.87% (control 13%). Of 20 patients, 10 (50%) MBC had lymph node metastases; 6 (21%) had distant metastases to lung (1) and bone (5). Five of the patients died of MBC. Excluding the patients with only ductal carcinoma in situ, the 1-and 5-year survival rates were 90.5% and 56.3%, respectively. In this comprehensive study of a large number of available prognostic markers, their frequency (with the exception of higher ER and CD) and prognostic significance were similar to that in female breast carcinoma. Among clinical and standard pathologic unfavorable prognostic indicators, age ≥ 62 years was significant (p = .004). Trends toward reduced survival were associated with axillary lymph node metastases (p = .145), ER negativity (p = .058), PR negativity (p = .116), and aneuploid DNA content (p = .201).     

Molecular markers in breast cancer: can we use c-erbB-2, p53, bcl-2 and bax gene expression as prognostic factors?

We examined the prognostic value of c-erbB-2, p53, bcl-2 and bax overexpression in breast cancer. Immunostaining for c-erbB-2, p53, bcl-2 and bax gene expression was performed on 121 paraffin-embedded specimens of Stage I, II and III breast cancer patients diagnosed and treated in Hippokration Hospital, Athens Medical School, between 1986 and 1992. The primary tumor from 27 (24.1%), 69 (59%), 18 (15%) and 63 (53.4%) patients stained positively for c-erbB-2, p53, bcl-2 and bax gene expression, respectively. Significant correlations were found between bax overexpression and age (P=0.04), tumor size (P=0.02) and disease stage (P=0.001), while no other significant associations were found between other molecular markers and clinical or histological parameters. None of the individual molecular markers examined proved to be independent prognostic factor for patients with breast carcinoma. C-erbB-2, p53, bcl-2 and bax genes have limited prognostic value. An approach that combines several molecular markers with established clinicopathological criteria may help physicians make more accurate predictions of prognosis in patients with breast cancer.     

Expression of the cyclin-dependent kinase inhibitor p27 in transitional cell bladder cancers: Is it a good predictor for tumor behavior?

OBJECTIVES: Progression of the cell cycle is regulated by the interactions of cyclins, cyclin dependent kinases (CDKs) and CDK inhibitors (CDKIs). p27 is a member of the universal cyclin-dependent kinase inhibitor family. The level of p27 protein expression decreases during tumor development and progression in some epithelial, lymphoid and endocrine tissues. It has been suggested that p27 is an independent prognostic factor in various human cancers. The prognostic value of p27 protein expression is not completely understood in bladder cancer yet. AIMS: To investigate the immunohistochemical expression of p27 in transitional cell bladder cancers and its relationship with clinicopathological data, proliferating cell nuclear antigen (PCNA) and p53 oncoprotein immunoreactivity. METHODS: The expression of p27 protein was immunohistochemically analyzed in paraffin-embedded specimens of 75 patients with transitional cell carcinoma of the bladder. p27 expression was compared with tumor grade, stage, growth pattern, disease-free survival, progression, PCNA and p53 immunoreactivity. RESULTS: Expression of p27 was not significantly related to clinicopathologic parameters, disease-free survival, progression, PCNA and p53 immunoreactivity. CONCLUSION: The results indicate that p27 is not a good predictor for outcome of transitional cell carcinoma of the bladder.     

Prognostic value of p53, proliferating cell nuclear antigen, and Ki-67 expression in undifferentiated nasopharyngeal carcinomas

In this study the prognostic importance of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 expression was analyzed along with the clinical parameters in 35 consecutive patients with undifferentiated nasopharyngeal carcinomas. Immunohistochemistry was used to detect p53, PCNA, and Ki-67 staining. Among the clinical findings, stage IV disease (P = 0.01), cranial nerve paralysis (P = 0.02), and lymph node metastasis (P = 0.06) were associated with shorter survival. The p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor to predict the outcome. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining was suggestive of prognosis. A proliferation index of Ki-67 less than 10% indicated longer survival (P = 0.03). There was no correlation between Ki-67 staining and PCNA index. As a result, the prognostic value of Ki-67 may alert the physician to more aggressive and adjuvant treatment modalities.     

Expression of cyclooxygenase-2 in normal urothelium, and superficial and advanced transitional cell carcinoma of bladder

PURPOSE: We compared the differential expression of cyclooxygenase-2 in normal bladder tissue, primary bladder transitional cell carcinoma and transitional cell carcinoma metastases to lymph nodes, and determined whether cyclooxygenase-2 expression is associated with molecular alterations commonly found in bladder transitional cell carcinoma and clinical outcomes after radical cystectomy. MATERIALS AND METHODS: Immunohistochemical staining for cyclooxygenase-2, survivin (Novus Biologicals, Littleton, Colorado), p21, p27, pRB, p53, MIB-1, Bax, Bcl-2, cyclin D(1) (Dakotrade mark), cyclin E (Oncogene, Cambridge, Massachusetts) and caspase-3 (Cell Signaling, Beverley, Massachusetts) was performed on archival bladder specimens from 9 subjects who underwent cystectomy for benign causes, 21 patients who underwent transurethral resection and 157 consecutive patients after radical cystectomy, and on 41 positive lymph nodes. RESULTS: Cyclooxygenase-2 was expressed in none of the 9 normal bladder specimens (0%), 52% of transurethral resection specimens, 62% of cystectomy specimens and 80% of lymph nodes involved with transitional cell carcinoma. Cyclooxygenase-2 expression was associated with higher pathological stage, lymphovascular invasion and metastases to lymph nodes (p=0.001, 0.045 and 0.002, respectively). Cyclooxygenase-2 expression was associated with altered expression of p53 (p=0.039), pRB (p=0.025), cyclin D1 (p=0.034) and caspase-3 (p=0.014). On univariate analysis cyclooxygenase-2 expression was associated with an increased risk of disease recurrence and bladder cancer specific mortality (p=0.0189 and 0.0472, respectively). However, on multivariate analysis only pathological stage and metastases to lymph nodes were associated with disease recurrence (p<0.001 and <0.001) and survival (p<0.001 and 0.015, respectively). CONCLUSIONS: Cyclooxygenase-2 is not expressed in normal bladder urothelium. Cyclooxygenase-2 over expression is associated with pathological and molecular features of biologically aggressive disease, suggesting a role for cyclooxygenase-2 in bladder cancer development and invasion.     

Impact of the expression of Aurora-A,p53, and MIB-1 on the prognosis of urothelial carcinomas of the upper urinary tract

ObjectivesTo investigate whether overexpression of p53, MIB-1, and Aurora-A on protein level played a role in the relapse of urothelial carcinomas of the upper urinary tract (UC-UUT).Materials and methodsThe following data from the files of 42 patients treated for UC-UUT were collated: age, prior history of cancer, tumor stage and grade, and disease progression. Immunohistochemistry (IHC) for p53, MIB-1, and Aurora-A was performed on tissue microarray sections from tumor tissue.ResultsPatients aged 46 to 100 years (mean 70.6 years). Overall, 23 (54%) patients died from progression of UT-UCC. The surgical stage was significantly associated with MIB-1 and Aurora-A overexpression (P = 0.004 for each). Univariate analysis showed that relapse was significantly associated with ureteral localization (P = 0.02), the presence of vascular invasion (VI) (P = 0.003), high grade (P = 0.04), high stage UT-UCCs (P = 0.02), and p53 (P = 0.01), Aurora-A (P = 0.01), and MIB-1 overexpression (P = 0.02). In multivariate analysis, relapse was associated with high grade (P = 0.04), high stage (P = 0.04), VI (P < 0.0001, respectively), and p53 (P = 0.04) and Aurora-A (P = 0.02) overexpression but not with MIB-1 overexpression (P = 0.06). In addition, expressions of p53, MIB-1, and Aurora-A were significantly associated with presence of VI (P = 0.008, P = 0.001, and P = 0.003, respectively).ConclusionAurora-A and p53 are important factors in UC-UUT development and might be useful as independent factors for predicting clinical outcome and presence of VI. Aurora-A seems to influence the development of VI and tumor aggressiveness via a mechanism not clearly elucidated yet.     

Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas

BACKGROUND: Prognostic markers for pancreas cancer, such as CEA, CA19-9, ploidy analysis, and S-phase determination using flow cytometry, have not been consistently predictive. We chose to evaluate nuclear proliferation, as measured by the MIB-1 monoclonal antibody and digital image analysis, as a prognostic marker in pancreatic carcinoma, and compare the findings with DNA ploidy and S-phase analysis. MIB-1 identifies the Ki67 antigen present in nuclei of cells in all phases of the cell cycle except G0. METHODS: We retrospectively reviewed 33 patients with pancreatic adenocarcinoma resected for cure between 1989 and 1994 with available fixed tissue. Sectioned tissue was stained with MIB-1, and the number of positively stained nuclei determined and expressed as a MIB-1 labeling index (LI) by quantitative image analysis. Disaggregated nuclei were analyzed by flow cytometry using standard techniques. RESULTS: MIB-1 LI for pancreas cancers was heterogeneous within and between cancers. The MIB-1 LI for the cancers was 28 +/- 15 (median 29). There was no correlation between survival and MIB-1 expression (R(2) = 0.03). Likewise, there was no correlation between MIB-1 LI and percentage of cells in S-phase, G(2)/M, or total proliferating cells (S+G(2)/M; R(2) = 0.01), nor was there a difference between MIB-1 LI and ploidy (P = 0.88). CONCLUSIONS: We conclude that in our patient population, nuclear proliferation in pancreatic cancer, as determined by expression of Ki67 nuclear antigen, does not appear to correlate with survival and is not a useful prognostic marker. Despite intuitive thoughts to the contrary, there is no correlation between cell cycle analysis as determined by flow cytometry and Ki67 expression in pancreas cancer. Current methods of assessing prognosis after curative resection of cancer of the pancreas, including lymph node and margin status, tumor size, and possibly DNA ploidy as determined by flow cytometry, are not augmented by the assessment of nuclear proliferation by image analysis using the MIB-1 monoclonal antibody.     

Biological markers in non-small cell lung cancer. Retrospective study of 10 year follow-up after surgery

BACKGROUND: The biological markers in non-small cell lung cancer (NSCLC) have been widely studied and encouraging results have shown that products of some oncogenes and other molecular markers can predict the aggressiveness of the disease and the outcome of the patients. METHODS: To verify the reliability of these prognostic markers we have studied retrospectively the expression of c-erbB-2 and 67Ki (growth regulation), p53 (cell cycle regulation and apoptosis), bcl-2 (apoptosis) and CD31 and CD34 (angiogenesis) in 78 patients operated on for NSCLC with curative intent between January 1987 and December 1988 and followed up for 10 years. For the determination of the biological markers we have used the ABC (Avidin-Biotin-Peroxidase complex) immunohistochemical method. The Cox regression model was used for the univariate and multivariate analysis. RESULTS: Nineteen patients (24%) were alive after 10 years and 59 (76%) died. The univariate analysis of the relationship between the 10-year survival and the expression of the markers was significant only for p53 (p=0.0097). Stratifying the patients according to the 3 histological subtypes (squamous cell carcinoma, adenocarcinoma and large cell undifferentiated carcinoma) the correlation between markers and survival pointed out that the only significant one was p53 (p=0.0459) in adenocarcinoma. In the same way considering the stages p53 was significant in stage IIIa (p=0.0357). The multivariate analysis emphasized that p53 was the only significant marker with respect to the 10-year survival (p=0.0091). Examining the histological groups significant was only p53 in adenocarcinoma (p=0.0192) and in large cell undifferentiated carcinomas (p=0.0290). This marker is also significant in pathological stage II (p=0.0271) and IIIa (p=0.0402). Apart from histology and staging the 10-year survival was 33% for p53 negative versus 10% for p53 positive. In patients with adenocarcinoma the 10-year survival was 40% for p53 negative and 6% for p53 positive. CONCLUSIONS: In conclusion our results emphasize the importance of p53 as a prognostic factor in 10-year survival in patients with adenocarcinoma and in stage II and IIIa.     

Biologic differences between noninvasive papillary urothelial neoplasms of low malignant potential and low-grade (grade 1) papillary carcinomas of the bladder.

We investigated the expression of oncogenes p53, c-erbB-2, and bcl-2 and cell proliferative activity in 62 newly diagnosed superficial pTa papillary bladder tumors. Based on the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications, 19 were urothelial neoplasias of low malignant potential (LMP) and 43 low-grade (grade 1) papillary carcinomas. All the patients underwent transurethral resection and were followed up to 97 months; 42 had recurrences. Initial biopsies were tested for p53, c-erbB-2, and bcl-2 proteins using DO7, CB11, and bcl-2 124 monoclonal antibodies. Cell proliferation was assessed by MIB-1 mAb and mitotic count. LMP had significantly lower MIB-1 (p = 0.002) and p53 immunopositivity (p = 0.03), mitotic count (p = 0.006), and recurrence rates (p = 0.04) than did grade 1 cases, whereas no difference was observed for c-erbB-2 and bcl-2 expression. The median disease-free survival for LMP was 76 months but only 15 months for grade 1 cases (p = 0.002). Although the cohort is small, the results indicate that the distinction between LMP and low-grade (grade 1) papillary urothelial neoplasias, as proposed by the 1998 WHO/ISUP and 1999 WHO classifications, reflects different biologic activity and clinical behavior; however, a long-term follow-up is advisable also for patients with LMP.     

Case control study of prognostic markers and disease outcome in inflammatory carcinoma breast: a unique clinical experience

Inflammatory breast carcinoma (IBC) is a rare but aggressive form of breast cancer. In this first-ever study, we investigated the role of nine prognostic markers' expression (estrogen receptor [ER], progesterone receptor [PR], p53, C-erbB-2, epidermal growth factor receptor [EGFR], cathepsin D [CD], proliferating cell nuclear antigen [PCNA], DNA ploidy, and S-phase fraction [SPF]) and disease outcome in IBC cases compared with the control group. A case control study of IBC was conducted on 40 test cases with two controls per case matching age, grade, and number of axillary lymph nodes sampled. During 7 years of this study, 10% of all patients with breast cancer had IBC. In this study, 84% of IBC cases showed positive axillary lymph nodes compared with 63% in control group. The expression of nine prognostic markers, that is, ER, PR, p53, C-erbB-2, EGFR, CD, PCNA, SPF, and DNA ploidy, was studied by immunohistochemistry and flow cytometry. Hormone receptor status showed an inverse correlation (p < 0.05). Among p53, C-erbB-2, EGFR, and CD in the IBC group, only p53 showed a significant correlation, with 70% positivity in IBC versus 48% positivity in the control group (p < 0.05). Much higher SPF and PCNA positivity was seen in the IBC group compared with the control group (p < 0.05). DNA ploidy also showed a significant correlation compared with the control group (p < 0.05). After a median follow up of 18 months, median overall survival in the IBC group was 1.8 years (range 0.6–5.8 years) compared with 3.0 years (range 2.5–7.0 years), with a p value of 0.0001.     

Determination of Proliferation Index By MIB-1 Immunostaining in Early Stage Breast Cancer Using Quantitative Image Analysis

Abstract: Several clinicopathologic variables influence prognosis in breast cancer, including stage, histologic grade, nodal status, and tumor size. Multiple studies have shown an independent value of proliferation index as a prognostic variable for the stratification into favorable and unfavorable groups. The monoclonal antibody MIB-1 reacts with the same antigen site, not epitope, as recognized by the Ki-67 antibody. Like Ki-67, MIB-1 reacts with cells in the late G₁, S, M and G₂ phases of the cell cycle, but MIB-1 has the advantage of reacting with formalin-fixed, paraffin-embedded material. The authors investigated the feasibility of using image analysis to quantitate the MIB-1 antibody staining (proliferation index [PI]) and predict survival in a series of 230 patients with stage I and stage II breast cancer. In a univariate Cox regression model, larger values of MIB-1 were related to shorter survival times (p < 0.001). Exploratory statistical procedures were used to categorize the patients into good, intermediate, and poor survival groups using the following proliferation indices as cut-points: <5%, 5–11%, and >11 %, respectively. Higher clinical stage was associated with higher MIB-1 values and shorter survival (p = 0.01, and p = 0.003, respectively). Tumor size (p = 0.02) and nodal status (p = 0.05) were also associated with higher values of MIB-1. After adjusting for age, clinical stage, nodal status, and tumor size in a multivariate analysis, MIB-1 retained its prognostic significance (p < 0.0001) when considered as either a continuous or categorical variable. There were no significant associations between MIB-1 determined proliferation index and age (p = 0.54), histologic grade (p = 0.69), nuclear grade (p = 0.06) or the presence of vascular invasion (p =.66). There is a strong statistical relationship between cell proliferative activity, as determined by MIB-1 expression, and survival in early stage breast cancer.     

Biomarkers for breast cancer

Molecular biomarkers for breast cancer are of several types. Risk biomarkers are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering and inherited germ-line abnormalities. Surrogate endpoint biomarkers are tissue, cellular or molecular alterations that occur between cancer initiation and progression. These biomarkers are utilized as endpoints in short-term chemoprevention trials. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen (PCNA); ER and PR overexpression; markers of oncogene overexpression such as c-erbB-2, TGF-a and EGFr; indicators of apoptotic imbalance including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals such as overexpression of c-myc and related proteins; loss of differentiation markers such as TGF-b II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as VEGF overexpression. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors.     

p53 and ki67 expression as prognostic factors for cancer-related survival in stage T1 transitional cell bladder carcinoma

OBJECTIVE: To determine prognostic factors for survival in bladder transitional cell carcinoma (TCC), and the prognostic value of p53 and ki67. MATERIAL AND METHODS: A study was made of patients with stage T1 primary bladder TCC (n = 175). The immunohistochemical study was carried out using DO7 and MIB-1 monoclonal antibodies, for p53 and ki67, respectively. Kaplan-Meier methodology was used for the survival analysis, and the log-rank test was applied in order to determine accumulated probability rates of survival. Moreover, Cox's multivariate regression analysis was also used to establish the variables associated with survival. Receiver operating characteristic (ROC) curves were also drawn, with the aim of determining the prognostic capacity of p53 and ki67. RESULTS: The average follow-up period was 7.3 years. Cancer-related survival rates at 5 and 10 years were 89.51 and 80.68%, respectively. The increase in p53 and ki67 expressions paralleled the histological grade, both markers showing significant inter-group differences (P = 0.0000). The variables which modified cancer-related survival significantly in the univariate analysis were the following: tumour multifocality, solid microscopic morphology, large cell nucleus and a high expression of p53 and ki67. Independent cancer-related survival variables were: age, tumour size of >3 cm, a solid microscopic growth pattern and expression of p53. CONCLUSIONS: The expression of p53, increase in age, tumour size of >3 cm and microscopic growth pattern are independent predictors for cancer-related survival. A positive correlation was observed, indicating that, the higher the expression of p53, the greater the probability of death.     

Vasectomy impairs spermatogenesis through germ cell apoptosis mediated by the p53-Bax pathway in rats

PURPOSE: The pathophysiology of impaired spermatogenesis after vasectomy has not been completely investigated. We examined the role of p53 protein in cell cycle arrest and apoptosis of germ cells after vasectomy in the rat. MATERIALS AND METHODS: Eight-week old rats underwent bilateral vasectomy and the testes were harvested 1, 4, 8, 12 and 24 weeks after surgery. Germ cell apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) and electrophoresis assay of DNA fragmentation. Western blot analysis and immunohistochemistry were performed to examine the expression of p53, proliferating cell nuclear antigen, Bax, Bcl-2, p21WAF1/Cip1 and Gadd45. To evaluate spermatogenesis, testicular weight and percent of haploid cells flow cytometry was done. RESULTS: Spermatogenesis impairment was associated with increased p53 and decreased proliferating cell nuclear antigen expression at the delayed phase more than 8 weeks after vasectomy. The number of TUNEL positive germ cells was increased at the early 1-week and delayed phases after vasectomy. Bax but not p21WAF1/Cip1 or Gadd45 expression was increased. p53, Bax and TUNEL positive cells were co-localized in the seminiferous tubules. CONCLUSIONS: Spermatogenesis was impaired after vasectomy by apoptosis but not by cell cycle arrest. The p53-Bax pathway effects apoptosis in the delayed phase after vasectomy in some seminiferous tubules.     

Ectopic pituitary adenoma with malignant transformation

We report here a case of ectopic pituitary adenoma with malignant transformation after repeated relapses. First, an ectopic pituitary adenoma producing follicle-stimulating hormone was found in the nasal cavity extending to the frontal cranial fossa. Despite repeated surgical resections of the tumor, it recurred three times in 2 years. The tumor gradually showed cellular atypia, mitosis, and necrosis. Immunohistochemical analyses revealed that the expressions of proliferating cell nuclear antigen and MIB-1 increased progressively. Moreover, the expression of p53 was detected at the second recurrence. Finally, at the third recurrence the tumor showed dissemination to the subarachnoid space and multiple metastases in the brain. The patient died of the tumor 10 months after the last resection. These findings indicate that the ectopic pituitary adenoma became malignant. To our knowledge, this is the first report on malignant transformation of ectopic pituitary adenoma. It is important to know that ectopic pituitary adenomas show malignant transformation and that the above parameters (proliferating cell nuclear antigen, MIB-1, and p53) may be useful indicators of the malignant potential of both ectopic and sellar pituitary tumors.     

Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer

BACKGROUND: The use of adjuvant chemotherapy in early breast carcinoma is controversial, with most advocating its use in high-risk patients as defined by specific clinicopathologic parameters. Both bcl-2 and p53, which play a role in determining tumor growth by their effects on apoptosis and cell proliferation respectively, may serve to delineate this subset more accurately. The purpose of this study was to determine the prognostic value of bcl-2, Bax, and mutant p53 in stage I breast cancer. STUDY DESIGN: A total of 75 patients with stage Ic breast carcinoma diagnosed from 1989 to 1992 were identified retrospectively and clinicopathologic parameters such as age, tumor size, estrogen receptor (ER) and progesterone receptor (PR) status, disease-free survival and overall survival obtained. Paraffin-embedded formalin-fixed tissues were immunostained with bcl-2, Bax and p53 monoclonal antibodies using a standard avidin biotin peroxidase reaction. Stained slides were evaluated by two independent pathologists for staining intensity and percentage of cells staining positively. Cox regression was used for multivariate survival analysis using the clinicopathologic parameters and molecular markers. Chi-square tests were used for frequency tables. RESULTS: Mean patient age was 58 years (range 29 to 79 years) with a median followup of 80 months from time of diagnosis. The most common histopathology was infiltrating ductal carcinoma. Neither bcl-2 nor Bax expression was associated statistically with disease-free or overall survival. Expression of mutant p53 was associated with a significant decrease in both 5-year disease-free survival (70% versus 98%, p 相似文献