Pankaj M. Shah

PROGNOSTIC SIGNIFICANCE OF MOLECULAR MARKERS IN ORAL SQUAMOUS CELL CARCINOMA: A MULTIVARIATE ANALYSIS

Multiple marker accumulation impacts tumor progression and biologic phenotypes affect clinical outcome of patients with head and neck cancer. Hence, this study investigated a battery of molecular markers that may help to reflect biologic aggressiveness and predict prognosis.

CLINICAL SIGNIFICANCE OF MMP-2 AND MMP-9 IN PATIENTS WITH ORAL CANCER

Factors that represent the potential for invasion and metastasis, such as matrix metalloproteinases (MMPs), could predict prognosis of cancer. Therefore, the authors studied plasma and tissue levels of MMP‐2 and MMP‐9 in oral cancer, the leading malignancy in India.

Lipid Peroxidation, Total Antioxidant Status, and Total Thiol Levels Predict Overall Survival in Patients With Oral Squamous Cell Carcinoma

Tobacco is the major etiological factor for oral cancer development through the generation of oxidative stress. Therefore, markers of oxidative stress such as total antioxidant status, lipid peroxidation, and total thiol levels might be useful to monitor oxidative stress and predict overall survival in oral cancer patients. The study included 140 oral cancer patients and 50 healthy controls, who were classified as with the habit of tobacco and no habit of tobacco. Adjacent normal and malignant tissue samples were collected from oral cancer patients. Plasma and tissue levels of lipid peroxidation, thiol, and total antioxidant status were assayed by spectrophotometric methods. Thiol levels were significantly lower in controls with the habit of tobacco (P = .033), oral cancer patients ( P = .0001), and malignant tissues (P = .015) as compared to controls with no habit of tobacco, controls with the habit of tobacco, and adjacent normal tissues, respectively. Tobacco exposure was higher in oral cancer patients than controls with the habit of tobacco. Controls with the habit of tobacco who had lower thiol (odds ratio [OR] = 10.58, P = .008) and high tobacco exposure (OR = 0.251, P = .05) showed an elevated risk of oral cancer development. Patients showing a lipid peroxidation level above the cutoff level as compared to patients below the cutoff level showed poor overall survival, whereas those with thiol and total antioxidant status levels below the cutoff level as compared to their respective counterparts showed poor overall survival. In conclusion, lipid peroxidation and thiol could be useful for predicting the risk of oral carcinogenesis in healthy tobacco consumers and predicting overall survival of oral cancer patients.

Clinical usefulness of telomerase activation and telomere length in head and neck cancer

Telomere shortening at every replication cycle is postulated to limit the life span of human somatic cells. In contrast, activation of telomerase is proposed to be an essential step for cancer cell immortalization. Head and neck cancer is the most common malignancy in the Indian population compared with Western countries. However, there are very few reports on telomerase activity and telomere length in head and neck cancer.

Significance of alterations in plasma lipid profile levels in breast cancer.

Hypotheses. The relationship between lipids and breast cancer is obscure. Until now, conflicting results have been reported on the association between lipids and risk of breast cancer in women. Therefore, the major aim of this study is to examine the role of alterations in lipid profile in breast cancer. Study Design. Plasma lipids (ie, total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very-low-density lipoprotein [VLDL], and triglycerides [TG]) were analyzed from 70 controls, 30 patients with benign breast disease (BBD), 125 untreated breast cancer patients, and 93 posttreatment follow-up samples. Methods. Samples were analyzed using highly sensitive and specific spectrophotometric methods. Results. Plasma TC, LDL, VLDL, and TG were significantly lower (p = .042, p = .003, p = .024, p = .014, respectively) in patients with BBD compared with controls. Plasma TC and HDL were significantly lower (p = .026, p = .0001, respectively), and VLDL and TG were significantly higher (p = .009, p = .05) in breast cancer patients as compared with controls. Plasma VLDL and TG were significantly higher in breast cancer patients as compared with patients with BBD. The receiver-operating characteristic curve showed that plasma TC, LDL, VLDL, and TG levels could significantly discriminate (p = .001, p = .005, p = .005, p = .005, respectively) between controls and patients with BBD. Plasma levels of TC, HDL, VLDL, and TG could significantly distinguish (p = .01, p = .002, p = .001, p = .002, respectively) between controls and breast cancer patients. Plasma levels of VLDL and TG could significantly discriminate (p = .000, p = .000, respectively) between patients with BBD and breast cancer patients. Odds ratio analysis revealed that higher levels of TC and HDL were significantly associated with a reduction in breast cancer risk (p = .01 and p = .0001, respectively), whereas higher levels of VLDL and TG were significantly associated with increased breast cancer risk (p = .001 and p = .002, respectively). Plasma VLDL and TG levels were significantly lower in complete responders as compared with pretreatment levels (p = .000, p = .000, respectively), and plasma TC and LDL levels were significantly lower in nonresponders as compared with pretreatment levels (p = .015, p = .009, respectively). Conclusion. The alterations in lipid profile levels showed a significant correlation with breast cancer risk, disease status, and treatment outcome.

Molecular alterations in oral carcinogenesis: significant risk predictors in malignant transformation and tumor progression.

In this study an attempt was made to establish the significance of a battery of molecular alterations and thereby identify risk predictors in oral carcinogenesis. For this purpose, EGFR, Stat3, H-ras, c-myc, p53, cyclin D1, p16, Rb, Ki-67 and Bcl-2 were localized immunohistochemically in normal mucosa (n=12), hyperplasia (n=35), dysplasia (n=25), early stage carcinoma (n=65) and advanced stage carcinoma (n=70). Deregulation occurred at an early stage and the number of alterations increased with disease progression. Using multivariate logistic regression analysis, the significant risk predictor for hyperplasia from normal mucosa was Ki-67 (OR=5.75, p=0.021); the significant risk predictors for dysplasia from hyperplasia were EGFR (OR=12.96, p=0.002), Stat3 (OR=17.16, p=0.0001), p16 (OR=5.50, p=0.039) and c-myc (OR=5.99, p=0.052); the significant risk predictors for early stage carcinoma from dysplasia were p53 (OR=6.63, p=0.0001) and Rb (OR=3.81, p=0.056); and the significant risk predictors for further progression were EGFR (OR=5.50, p=0.0001), Stat3 (OR=4.49, p=0.0001), H-ras (OR=4.05, p=0.001) and c-myc (OR=2.99, p=0.015). Cyclin D1 holds a key position linking upstream signaling pathways to cell cycle regulation. Gene products of the mitogenic signaling pathway play an equally significant role as cell cycle regulatory proteins in the hyperplasia-dysplasia-early-advanced-carcinoma sequence and together may provide a reference panel of markers for use in defining premalignant lesions and predicting the risk of malignant transformation and tumor progression.

Cytokeratin and vimentin expression in breast cancer

BACKGROUND The transition from epithelial keratin to mesenchymal vimentin expression marks an important step in the malignant progression of breast cancer. This study analyzed the clinical significance of cytokeratin and vimentin in patients with breast cancer. MATERIALS AND METHODS Expression of cytokeratin and vimentin was evaluated by immunohistochemistry on paraffin-embedded tissue sections of patients with breast cancer. RESULTS Loss of cytokeratin was seen in 11% of the patients. A clearer trend towards loss of cytokeratin was observed in patients with stage IV disease and PR negativity. Weak cytokeratin expression was present in patients who developed recurrence or metastatic disease. Loss of cytokeratin was associated with reduced overall survival in univariate and multivariate analysis, gain of vimentin expression was seen in 57% of breast carcinoma patients. It was higher in patients with lymph node positivity, advanced stage, HER2 positivity, and disease recurrence or metastasis. Multivariate survival analysis indicated that gain of vimentin expression was associated with reduced relapse-free survival. CONCLUSION Loss of cytokeratin and gain of vimentin expression are indicators of biologically aggressive breast carcinoma.

Serum Fucosylation Changes in Oral Cancer and Oral Precancerous Conditions : α-L-Fucosidase as a Marker

The objective of the current study was to investigate the clinical usefulness of serum fucose, fucosylated glycoproteins (fucoproteins), fucosyltransferase (FucT), and α‐L‐fucosidase in oral carcinoma.

Spontaneous Chromosomal Instability in Breast Cancer Families

Spontaneous chromosomal instability has been correlated with cancer predisposition. In the present study, the phenomenon has been evaluated using two cytogenetic markers, namely, frequency of spontaneous sister chromatid exchanges (SCE) and spontaneous chromosomal aberrations (CA) in peripheral blood lymphocytes of hereditary breast cancer (HBC) patients (n = 11) and healthy blood relatives (HBR, n = 36). A statistically significant difference was observed for both the endpoints between HBC patients and controls (P < 0.001), HBC patients and HBR (P < 0.001), as well as HBR and controls (P < 0.001). Thus, 63.64% of the HBC patients and 25% of HBR showed a mean CA/cell value higher than the highest mean CA/cell value of the controls (0.11 CA/cell). Similarly, 81.81% of the HBC patients and 61.11% of HBR showed a mean SCE/cell value higher than the highest mean SCE/cell value of the controls (9.60 SCE/cell). Chromosomal aberrations were more frequently observed in the B and E group of chromosomes in HBC patients and HBR. These findings primarily indicate the high level of chromosomal instability in breast cancer families, and might be one of the predisposing factors for high risk of cancer in HBR.

Matrix Metalloproteinases and Their Inhibitors: Correlation with Invasion and Metastasis in Oral Cancer

Matrix metalloproteinases (MMPs) have been implicated in invasion and metastasis of various malignancies. The study evaluated a comprehensive profile of MMP-2 and MMP-9 and their inhibitors, tissue inhibitor of metalloproteinases-2 (TIMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1), respectively in 50 controls and 75 patients with oral squamous cell carcinoma (OSCC). Blood samples from controls and patients as well as malignant and adjacent normal tissues from the patients were collected. The study examined pro, active and total forms of MMP-2 and MMP-9 using zymography. Enzyme-linked immunoassay (ELISA) and reverse transcription polymerase chain reaction were carried out to evaluate protein levels and mRNA expression; respectively, for the MMPs and TIMPs. Plasma pro, active and total MMP-2, MMP-9 as well as TIMP-1 and TIMP-2 levels were significantly higher in oral cancer patients as compared to the controls. mRNA expression of the MMPs and TIMPs was significantly higher in malignant tissues as compared to adjacent normal tissues. A significant positive correlation was observed between levels of proMMP-9 and active MMP-9 with differentiation, stage and infiltration. ProMMP-2 and active MMP-2 exhibited significant positive correlation with differentiation and lymph node involvement. The multivariate analysis of ELISA results revealed a significant positive correlation between MMP-2, TIMP-1 and TIMP-2 levels with lymph node involvement, stage and differentiation. The receiver operating characteristic curve (ROC) analysis showed that the levels of MMPs and TIMPs have significant discriminatory efficacy to differentiate between controls and patients. The results indicate that MMP-2, MMP-9, TIMP-1 and TIMP-2 have significant clinical usefulness for oral cancer patients. Zymographic analysis is a simple, cost effective, rapid and sensitive alternative assay.