Upender Manne

Prognostic significance of Bcl‐2 expression and p53 nuclear accumulation in colorectal adenocarcinoma

The products of bcl‐2 and p53 genes are involved in the regulation of apoptosis and proliferation and have been associated with prognosis in several malignancies, including colorectal adenocarcinoma. Although 2 European studies have reported a prognostic significance of Bcl‐2 expression in colorectal adenocarcinomas, a study from the United States did not observe such an association. Therefore, we used immunohistochemistry to evaluate the prognostic significance of Bcl‐2 expression, p53 nuclear accumulation and their concomitant expression in 134 US patients with colorectal adenocarcinoma. Antigen retrieval was required for adequate detection of Bcl‐2 expression. Fifty percent of the colorectal tumors were classified as expressing Bcl‐2, and Bcl‐2 expression was associated with longer patient survival. Antigen retrieval was not necessary for detecting nuclear accumulation of p53 by immunohistochemistry. Nuclear accumulation of p53 was detected in 44% of colorectal adenocarcinomas and was associated with decreased patient survival. Tumors that did not express detectable levels of Bcl‐2 but exhibited nuclear accumulation of p53 were associated with the shortest patient survival (log rank, p = 0.001). Multivariate Cox regression analysis demonstrated that Bcl‐2 expression (p = 0.018), p53 nuclear accumulation (p = 0.024) and regional lymph‐node metastasis (p = 0.005) were independent prognostic factors. Although a trend toward an inverse correlation between Bcl‐2 and p53 expression was observed, the prognostic value of Bcl‐2 expression was independent of p53 status. Thus, assessment of both Bcl‐2 and p53 status may be valuable in predicting the prognosis of patients with colorectal adenocarcinomas. Int. J. Cancer 74:346–358, 1997.

Development and Independent Validation of a Prognostic Assay for Stage II Colon Cancer Using Formalin-Fixed Paraffin-Embedded Tissue

PURPOSE Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. PATIENTS AND METHODS A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. RESULTS The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). CONCLUSION This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.

Ep-CAM LEVELS IN PROSTATIC ADENOCARCINOMA AND PROSTATIC INTRAEPITHELIAL NEOPLASIA

PURPOSE The monoclonal antibody (mAb) 323/A3, a second generation high affinity antibody of the 17-1A antibody family, recognizes a 40 kDa transmembrane glycoprotein that has been referred to as Ep-CAM, 17-1A recognized antigen, or EGP40. While Ep-CAM is expressed on the basolateral surface of a variety of epithelia, the strongest expression is frequently detected among several types of carcinoma. In this regard, Ep-CAM may be useful in therapy, in diagnosis, and/or in prognosis. We examined the distribution of Ep-CAM in normal, dysplastic, and malignant prostatic epithelium. MATERIALS AND METHODS Paraffin sections of prostate tissue from 76 patients with clinically localized (pT2) prostatic adenocarcinoma were immunostained with mouse mAb 323/A3 using the avidin-biotin horseradish peroxidase method. RESULTS Within benign prostatic epithelium, immunoreactivity typically was low and frequently was restricted to the luminal cells. In contrast, moderate to strong immunostaining was detected frequently in the luminal cells of high grade prostatic intraepithelial neoplasia (PIN). Furthermore, strong immunostaining usually was detected in the cells of adenocarcinomas. The immunostaining in PIN (p<0.0001) and in adenocarcinoma (p<0.0001) was significantly greater than that observed in the normal epithelium. Expression of Ep-CAM did not vary significantly with the Gleason score of tumors or the clinical outcome of patients. Expression of Ep-CAM was demonstrated also in the malignant prostatic cell lines LNCaP, DU145 and PC3 using immunohistochemistry and an immunoblot technique. CONCLUSIONS These findings suggest that increased levels of Ep-CAM represent an early event in the development of prostatic adenocarcinoma.

African-American and Caucasian disparities in colorectal cancer mortality and survival by data source: an epidemiologic review.

Over the past four decades in the United States, there has been a divergent trend in mortality rates between African-Americans and Caucasians with colorectal cancer (CRC). Rates among Caucasians have been steadily declining, whereas rates among African-Americans have only started a gradual decline in recent years. We reviewed epidemiologic studies of CRC racial disparities between African-Americans and Caucasians, including studies from SEER and population-based cancer registries, Veterans Affairs (VA) databases, healthcare coverage databases, and university and other medical center data sources. Elevated overall and stage-specific risks of CRC mortality and shorter survival for African-Americans compared with Caucasians were reported across all data sources. The magnitude of racial disparities varied across study groups, with the strongest associations observed in university and non-VA hospital-based medical center studies, while an attenuated discrepancy was found in VA database studies. An advanced stage of disease at the time of diagnosis among African-Americans is a major contributing factor to the racial disparity in survival. Several studies, however, have shown that an increased risk of CRC death among African-Americans remains even after controlling for tumor stage at diagnosis, socioeconomic factors, and co-morbidity. Despite advances in treatment, improvements in the standard of care, and increased screening options, racial differences persist in CRC mortality and survival. Therefore, continued research efforts are necessary to disentangle the clinical, social, biological, and environmental factors that constitute the racial disparity. In addition, results across data sources should be considered when evaluating racial differences in cancer outcomes.

Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates.

This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n = 40) and FNA samples (n = 65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma (P < .001). In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs 0%; P < .001) and mesothelin (62% vs 0%; P = .01) and absence of staining for clusterin-beta (90% vs 7%; P < .001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.

MUC1 and MUC2 expression in pancreatic ductal carcinoma obtained by fine‐needle aspiration

Mucins are high molecular weight glycoproteins that are produced by various epithelial cells including those found in the pancreas. MUC1 and MUC2 are two well characterized mucin antigens. The objective of the current study was to examine the pattern of phenotypic expression of MUC1 and MUC2 in pancreatic lesions obtained by fine‐needle aspiration biopsy (FNA) and to determine the utility of MUC1 and MUC2 as markers for pancreatic ductal carcinoma.

Predictive Capacity of Three Comorbidity Indices in Estimating Mortality After Surgery for Colon Cancer

PURPOSE Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI). PATIENTS AND METHODS The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer-specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared. RESULTS For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer-specific survival. For the other risk factors, there was little variation in the point estimates across the three models. CONCLUSION The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.

Prognostic Significance of p53 Codon 72 Polymorphism Differs with Race in Colorectal Adenocarcinoma

Purpose: Several studies have examined the prognostic value of the codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma, but none have addressed patient race/ethnicity. Therefore, this study assessed the prognostic value of this polymorphism in African American and Caucasian colorectal adenocarcinoma patients separately. Experimental Design: Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic Caucasians were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the χ2 test and Kaplan-Meier and Cox regression models. Results: The incidence of p53 mutations was similar in African American and Caucasian patients (50% versus 54%, respectively); however, the homozygous Pro72 allele frequency was higher in African Americans (17%) as compared with Caucasians (7%). In contrast, the homozygous Arg72 allele frequency was higher in Caucasians (36%) than in African Americans (19%). In African Americans but not Caucasians, the Pro/Pro phenotype significantly correlated with a higher incidence of missense p53 mutations and with nodal metastasis. African Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality (log-rank P = 0.005 versus. P = 0.886) and risk of death due to colorectal adenocarcinoma (hazard ratio, 2.15; 95% confidence interval, 1.02-4.53 versus hazard ratio, 1.60; 95% confidence interval, 0.69-3.18) than those with the phenotype Arg/Arg or Arg/Pro. Conclusions: The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival.

The Chemokine CXCL8 in Carcinogenesis and Drug Response

Although the functions of chemokines in the regulation of immune processes have been studied in some detail, the role of these biomolecules in cancer is not fully understood. Chemokines mediate migration of immune cells and other functions related to immunity. They are also involved in oncogenesis and in tumor progression, invasion, and metastasis through mechanisms similar to their roles in immune functions. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. Consequently, chemokines and their receptors present potential therapeutic targets for anticancer drugs. The chemokine CXCL8, also known as interleukin-8 (IL8), is a proinflammatory molecule that has functions within the tumor microenvironment. Due to its potent angiogenic effects and the activity of the chemokine and its receptors in the promotion of invasion and metastasis, CXCL8 and its receptors are now considered as attractive targets for cancer therapy. This review relates the current understanding of the regulation, signaling, and functions of CXCL8 that contribute to tumor growth and metastasis, and of its role in drug response.

Molecular differences in mucoepidermoid carcinoma and adenoid cystic carcinoma of the major salivary glands.

Objective/Hypothesis Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), the most common malignancies of the major salivary glands, are clinically and pathologically different. To determine whether MEC and ACC have different molecular characteristics, we examined the expression of erbB‐2, erbB‐3, epidermal growth factor receptor (EGFR), and transforming growth factor‐α (TGF‐α), important molecular features in other malignancies.