Ekaterini Politi

Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade

Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the steroid receptor superfamily. It is a key regulator of adipogenic differentiation and glucose homeostasis, the ligands of which have also been demonstrated to induce differentiation in human breast, lung and colon cancer cell lines. In the present study, PPAR-gamma expression in cases of non-small cell lung carcinoma (NSCLC) was examined immunohistochemically and was correlated with tumor histological type and grade. Primary tumor samples from 147 patients with NSCLC were immunostained using a monoclonal antibody against PPAR-gamma. Positive PPAR-gamma immunostaining was prominent in 61 out of 147 cases (42%) and negative in the rest. PPAR-gamma positivity was prominent in 37 out of 79 cases (47%) of squamous cell lung carcinoma and in 24 out of 68 ones (35%) of lung adenocarcinoma. PPAR-gamma positivity was most frequently observed in squamous cell tumors (P=0.021) and in tumors of high histological grade of both histological types (P=0.041). Well-differentiated adenocarcinoma cases presented increased frequency for PPAR-gamma positivity compared with moderately and poorly differentiated ones (P=0.001). The intensity and pattern of PPAR-gamma staining in tumor cells were not correlated with histopathological parameters in PPAR-gamma positive cases of NSCLC examined. Our findings support evidence for participation of this protein in the biological mechanisms underlying the carcinogenic evolution in the lung, suggesting also the importance of specific PPAR-gamma ligands as future therapeutic approach in lung cancer.

VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2.

The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis is well characterized; nevertheless, it is also a key element in promoting tumor evasion of the immune system by downregulating dendritic cell maturation and thus T cell activation. We sought to investigate the possible direct effect of VEGF on T cell activation and through which type of VEGF receptor (VEGFR) it exerts this effect. Circulating T cells from healthy donors and ovarian cancer patients were expanded in cultures with anti‐CD3 and IL‐2 with or without VEGF for 14 days, and the number of T cells was assessed. Cultured T cells were also tested for their cytotoxic activity in a standard 4‐hr 51Cr‐release assay, and the expression of VEGFRs 1, 2 and 3 was assayed by flow cytometry, immunocytochemistry and Western blotting. To assess the ability of activated T cells to secrete VEGF, levels in culture supernatants were measured by enzyme linked immunosorbent assay. The addition of VEGF in cultures significantly reduced T cell proliferation in a dose‐dependent manner. Protein expression studies demonstrated that CD3+ T cells express VEGFR‐2 on their surface upon activation. Experiments with anti‐VEGFR‐2 antibodies showed that the direct suppressive effect of VEGF on T cell proliferation is mediated by VEGFR‐2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells and that activated T cells secrete VEGF in the culture environment. Overall, our study shows that T cells secret VEGF and expresses VEGFR‐2 upon activation. VEGF directly suppresses T cell activation via VEGF receptor type 2.

Expression and Clinical Significance of Focal Adhesion Kinase in the Two Distinct Histological Types, Intestinal and Diffuse, of Human Gastric Adenocarcinoma

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase protein, acts as an early modulator of integrin signaling cascade, regulating basic cellular functions. In transformed cells, unopposed FAK signaling has been considered to promote tumor growth, progression and metastasis. The aim of this study was to assess the clinical significance of FAK expression in the two distinct histological types of human gastric neoplasia. FAK expression was assessed immunohistochemically in tumoral samples of 66 gastric adenocarcinoma cases, 30 intestinal and 36 diffuse type, and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity and patients’ survival. In intestinal type carcinomas, enhanced FAK expression was significantly associated with increased tumor proliferative capacity (P = 0.012). In diffuse type carcinomas, FAK staining intensity was significantly correlated with tumor size (P = 0.026) and disease stage (P = 0.024), presenting also a borderline association with nodal status (P = 0.053). In diffuse type carcinomas, enhanced FAK expression was significantly associated with longer overall survival times (log-rank test, P = 0.014), being also identified as an independent prognostic factor in multivariate analysis (Cox regression, P = 0.016). In contrast, patients with intestinal type tumors and enhanced FAK expression were characterized by shorter overall survival times, without though reaching statistical significance (log-rank test, P = 0.092). The current data support evidence that FAK protein may be considered as a diagnostic and prognostic marker in gastric neoplasia. Further studies conducted on larger clinical samples and highlighting on the distinct impact of the two histological types are warranted to delineate the clinical significance of FAK protein in gastric neoplasia.

Prevalence of different HPV types and estimation of prognostic risk factors based on the linear array HPV genotyping test.

The aim of the study was to evaluate the prevalence and risk factors of HPV in a gynecologic population attending outpatient clinics using two new molecular tests. The Amplicor HPV test and the Linear Array (LA) HPV Genotyping test were used for the detection of HPV DNA in 320 women. Multiple logistic regression was used to identify independent prognostic factors of HPV positivity. The agreement between the two methods in terms of their qualitative results was 89.3% (kappa: 0.63). Based on the LA results, the overall prevalence of HPV DNA was 49.1%, 95% confidence interval (95% CI: 43.5%, 54.7%). The prevalence of high‐risk HPV types was 30.3%. The predominant types were HPV‐6 (24.8%) and HPV‐16 (20.4%). Among women with normal cytology, the prevalence of HPV was much higher in those presenting other findings, such as inflammation, than those without other abnormal findings (49.5% vs. 31.5%). On the basis of multivariate analysis, the risk of HPV infection was higher among women with multiple sexual partners [>3 vs. 1: OR = 3.1, 95% CI: (1.5, 7.2)], Pap smear findings [low/high‐grade lesions vs. negative: OR = 2.8, 95% CI: (1.2, 6.5)], the presence of warts [yes vs. no: OR = 3.0, 95% CI: (1.5, 6.3)] and no history of child birth [no vs. yes: OR = 2.6, 95% CI: (1.0, 6.7)]. Younger age was an additional risk factor for HPV infection with carcinogenic genotypes [OR for 1 year increase = 0.93, 95% CI: (0.89, 0.98)]. J. Med. Virol. 81:2059–2065, 2009.

Study of T lymphocytes infiltrating peritoneal metastases in advanced ovarian cancer: associations with vascular endothelial growth factor levels and prognosis in patients receiving platinum-based chemotherapy.

Introduction: The presence of CD3+ tumor-infiltrating lymphocytes (TILs) has been found to correlate with improved survival in epithelial ovarian cancer, but the association of TIL subpopulations with clinical outcome remains controversial. We performed a prospective analysis of TIL subpopulations from patients with epithelial ovarian cancer and their activation status and studied their association with prognosis. Methods: Flow cytometric analysis was performed on TIL subpopulations isolated from 45 fresh ovarian tumor specimens, obtained during surgery, after mechanical dissociation and enzymatic degradation. Vascular endothelial growth factor and tumor necrosis factor &agr; levels in ascites and serum were measured by enzyme-linked immunosorbent assay. Results: Significantly increased numbers of CD56+ cells (natural killer and natural killer-like T cells; P = 0.045), activated CD4+HLA-DR+ cells (P = 0.046), and activated CD8+CD25+ cells (P = 0.028) were found in serous and endometrioid carcinomas compared with mucinous and clear cell carcinomas. A high percentage of CD4+CD25hi cells (regulatory T cells) and activated CD4+HLA-DR+ cells significantly associated with improved median overall survival (not reached vs 35 months [P = 0.0241] and not reached vs 35 months [P = 0.0144], respectively) and median progression-free survival (30 months vs 14 months [P = 0.0819] and 30 months vs 13 months [P = 0.0479], respectively). Vascular endothelial growth factor ascites levels were inversely correlated with CD14+ (&rgr; = −0.529, P = 0.001), whereas HLA-DR8+CD8 lymphocytes were inversely correlated with both ascites and serum vascular endothelial growth factor levels (&rgr; = −0.494, P = 0.006, and &rgr; = −0.586, P = 0.037, respectively). Conclusions: The presence of regulatory T cells and activated CD4+ cells within the tumor microenvironment is associated with improved overall and progression-free survival in patients with ovarian cancer.

Ovarian carcinoma presenting with axillary lymph node metastasis: A case diagnosed by fine‐needle aspiration and brief review of the literature

Ovarian carcinoma is a lethal disease and a main cause of morbidity and mortality among gyneocological malignancies. Metastatic ovarian carcinoma to the axillary node is an expectionally infrequent pathological entity. We report a case of ovarian carcinoma, which presented with axillary lymph node metastasis and review the previously documented cases. A 63‐year‐old woman with a medical history of stage IIIb ovarian carcinoma was admitted to our hospital complaining of a mass in her right axilla. Fine‐needle aspiration (FNA) biopsy was performed. Cytological examination revealed a poorly differentiated carcinoma with immunocytochemical features consistent with metastatic ovarian carcinoma. This case illustrates a rare presentation of ovarian carcinoma and underlines the need to consider it in the differential diagnosis of axillary lesions. Diagn. Cytopathol. 2008.

Primary Hepatic Neuroendocrine Tumor with Exophytic Growth

BACKGROUND: Primary hepatic neuroendocrine tumor with exophytic growth is a unique entity. CASE: A 74-year-old man presented to our hospital with abdominal discomfort. Diagnostic imaging procedures revealed a 15 x 10-cm mass in the liver with exophytic growth. The tumor was adjacent to the stomach, and clinical suspicion of gastrointestinal stromal tumor of the stomach was very strong initially. The cytologic and immunocytochemical examination of aspirated material showed features similar to those of neuroendocrine tumor. Systemic staging procedures showed no evidence of metastasis or other primary site. The histopathologic results of the excised tumor confirmed the cytologic diagnosis. CONCLUSION: Primary neuroendocrine tumor with exophytic growth is a rare entity and can be diagnosed with cytology and immunocytochemistry.

Epidermal growth factor receptor and proliferating cell nuclear antigen expression in urine ThinPrep specimens

Objective:  To evaluate proliferating cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR) expression in urine ThinPrep (TP) specimens, to compare these findings with clinical and histological features and to determine whether these immunomarkers are predictive of clinical stage.

Standardized categorical reporting of cytopathology results: the strengths and weaknesses of a constantly evolving and expanding system.

Since the success of the Bethesda nomenclature system in standardizing Pap smear results, there has been growing interest in adopting Bethesda‐like standardized categorical formats in areas of nongynecologic cytopathology. Standardized categorical reporting may have several advantages over descriptive reporting, in enhancing cytopathologist‐clinician communication and inter‐institutional exchange of information, providing better guidance for treatment planning, and facilitating statistical analysis for research purposes or quality control studies. On the other hand, descriptive reporting may be more effective as a tool of communication between cytopathologists, may better express the uncertainty of the observer in diagnostically difficult and equivocal cases and may better serve the purposes of training and continuing education of cytopathologists. Future studies on the pros and cons of the different reporting systems used in cytopathology may provide further insight on these issues. The most problematic areas need to be identified and optimal solutions decided. Despite the ongoing debate on the optimal reporting format in cytopathology, there is general agreement on the need for high quality cytology reports (whether descriptive or standardized) in terms of their diagnostic accuracy, clarity and clinical value. Diagn. Cytopathol. 2013;41:917–921.

Altered expression of adhesion molecules in inflammatory cervical smears

Objective:  The aim of the present study was to evaluate the expression of pan‐cadherin and β‐catenin in cervical smears with various types of infectious agents.