Inflammation on the cervical papanicolaou smear: evidence for infection in asymptomatic women?

BACKGROUND: The significance of the possible presence of infection on the Pap smear of asymptomatic women based on cytological criteria is practically unknown. MATERIALS AND METHODS: A total of 1117 asymptomatic nonpregnant women had Pap smear tests and vaginal as well as cervical cultures completed (622 with and 495 without inflammation on the Pap smear). RESULTS: Out of the 622 women with inflammation on Pap test, 251 (40.4%) had negative cultures (normal flora present), while 371 (59.6%) women had positive cultures with different pathogens. In contrast, the group of women without inflammation on Pap test displayed significantly increased percentage of negative cultures (67.1%, P < 0.001) and decreased percentage of positive cultures (32.9%, P < 0.001). Bacterial vaginosis was diagnosed more frequently in both groups and significantly more in the group with inflammation on Pap smear compared to the group without inflammation (P < 0.02). CONCLUSIONS: A report of inflammatory changes on the cervical Pap smear cannot be used to reliably predict the presence of a genital tract infection, especially in asymptomatic women. Nevertheless, the isolation of different pathogens in about 60% of the women with inflammation on the Pap smear cannot be overlooked and must be regarded with concern.

Extra copies of chromosomes 16 and X in invasive breast carcinomas are related to aggressive phenotype and poor prognosis.

BACKGROUND: Breast cancer is a genetically complex disease, which involves the accumulation of various structural and numerical chromosomal aberrations. AIM: To assess the numerical status of chromosomes 16 and X by interphase cytogenetics, in 114 women with primary invasive breast carcinomas, in relation to clinicopathological parameters, patients' overall survival and indices of cell growth (c-erbB-2, topoisomerase IIalpha (topoIIalpha)) and cell survival (caspase-3, bcl-2). EXPERIMENTAL DESIGN: Chromogenic in situ hybridisation with pericentromeric probes was performed for molecular analysis, while oestrogen and progesterone receptors, cerbB-2, topoIIalpha, caspase-3 and bcl-2 expression was immunohistochemically detected (ABC/HRP). The results were statistically assessed by univariate and multivariate analyses. RESULTS: Polysomy of chromosomes 16 and X was detected as the predominant aberration (73.7% and 57.9%, respectively). Gain of chromosome 16 copies was associated with high nuclear grade (p = 0.009), increased tumour size (p = 0.041), advanced stage (p = 0.002), the expression of topoIIalpha (p = 0.005) and worse overall survival by multivariate analysis (p = 0.032). Chromosome X polysomy was increased in ductal carcinomas of high histological grade (p = 0.008), in high nuclear grade tumours (p = 0.001), and was associated with the expression of topoIIalpha (p = 0.005), loss of caspase-3 (p = 0.036) and impaired prognosis of ductal carcinomas (p = 0.041). CONCLUSIONS: Polysomy of chromosomes 16 and X was reported as the predominant alteration in phenotypically aggressive breast tumours, characterised by poor differentiation, increased growth potential and impaired prognosis, whereas gain of chromosome X in particular is probably implicated in cell survival.

Tissue inhibitor of metalloproteinase-2 as a multifunctional molecule of which the expression is associated with adverse prognosis of patients with urothelial bladder carcinomas.

PURPOSE: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase (MMP) activity controlling the breakdown of extracellular matrix components and, thus, play an important role in the process of invasion and metastasis. Moreover, there are several new functions, growth control, apoptosis, and angiogenesis-, in which TIMPs seem to be involved. The aim of this study was to elucidate the role of TIMP-2 in human urothelial cancer assessing TIMP-2 protein expression in 106 urothelial bladder carcinomas and evaluating its importance relative to clinicopathologic parameters (age, gender, histological grade, and stage) and patient survival, as well as to markers associated with cell growth and apoptosis (Ki-67, p53, and bcl-2). EXPERIMENTAL DESIGN: Immunohistochemistry (avidin-biotin complex method-horseradish peroxidase) was performed to detect TIMP-2, Ki-67, p53, and bcl-2 proteins using monoclonal and polyclonal antibodies. Statistical analysis was univariate and multivariate. RESULTS: TIMP-2 immunohistochemical expression was observed in stromal fibroblasts and in cancerous cells in 26.4% and 69.8% of cases, respectively. TIMP-2 stromal but not cancerous cell expression associated significantly with the high histological grade of carcinomas (P < 0.0001) and the advanced stage of the disease (P = 0.001). TIMP-2 either stromal or cancerous cell expression correlated significantly with the expression of Ki-67 proliferation indice (P = 0.02 and P = 0.044, respectively) and the mutant p53 protein (P = 0.043 and P = 0.045, respectively). In univariate survival analysis patients with positive TIMP-2 stromal cell immunohistochemical expression had a significantly worse overall survival in comparison with TIMP-2 stromal cell-negative patients (log rank test: P = 0.0002). However, in multivariate survival analysis the only independent survival factors were the stage of the disease and patient age. CONCLUSIONS: TIMP-2 protein expression in either the stromal or cancerous cells is associated with the proliferation index Ki-67 and the apoptosis-related protein p53. These findings are in keeping with in vitro studies reporting a growth-promoting ability of TIMP-2 and its involvement in apoptosis regulation. On the other hand, TIMP-2 stromal cell expression only was associated with adverse prognosis of urothelial bladder cancer patients.

MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival.

Crucial event in the metastasis of cancer cells is the secretion of matrix metalloproteinases (MMPs), which are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-2 (MMP-2) is a gelatinase, which degrades basement membrane type-IV collagen. Immunohistochemistry was performed to detect MMP-2 protein in 135 infiltrative breast carcinomas. MMP-2 was studied along with clinicopathological parameters (tumor size, histological type, nuclear and histological grade, stage, lymph node status, ER, and PR), patients' survival and tissue inhibitor metalloproteinase-2 (TIMP-2), Ki-67, and p53 proteins. MMP-2 immunoreactivity was detected in the cytoplasm in cancer cells in 102 (75.6%) and in both tumor and tumor stromal cells in 37 (27.4%) of 135 cases respectively. MMP-2 reactivity in cancer cells displayed a statistically significant association with tumor size > 2 cm (p = 0.022). In tumor stromal cells a strong parallel association was observed between the expression of MMP-2 and TIMP-2 (p = 0.015), while an inverse correlation was found between MMP-2 and both Ki-67 and p53 (p = 0.033 and p = 0.034 respectively). In the subgroup with negative lymph nodes MMP-2 was also inversely associated with p53 in cancer cells (p = 0.045). Finally a statistically significant association was revealed using Kaplan-Meier and Cox's proportional hazard regression model between the MMP-2/TIMP-2 phenotype and patients' better survival (p = 0.021). Our results point out the strong relation between MMP-2 and TIMP-2 and the effect of the MMP-2/TIMP-2 phenotype in the patients' overall survival. The inverse correlation between MMP-2 and both Ki-67 and p53 can be explained by the potential inhibition of MMP-2 by TIMP-2. These results suggest the necessity of further investigation.

Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP-1 in breast cancer, the expression of TIMP-1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki-67, c-erb-B-2, bcl-2) and clinical outcome. TIMP-1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP-1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c-erbB-2 expression (p<0.05). On the other hand, increased TIMP-1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP-1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co-expressing high levels of TIMP-1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP-1, particularly its growth-promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP-1 with tumour cell differentiation is suggested by its topographical correlation with ER detection.

Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome.

Breast carcinoma is a genetically and phenotypically heterogeneous disease and is frequently associated with nonrandom chromosomal alterations. The aim of this study was to investigate the numerical aberrations of chromosome 20 in breast cancer. The observed chromosome-specific numerical abnormalities were evaluated along with the established clinicopathological parameters, the immunohistochemical expression of ER, PR, p53, c-erbB-2, Ki-67 and patients' survival. Nonisotopic in situ hybridization was applied to interphase cell nuclei on paraffin embedded tissue sections. Polysomy of chromosome 20 was the prevalent alteration in 45 of 50 (90%), monosomy in 2 of 50 (4%) and disomy in 3 of 50 (6%) cases. Invasive ductal carcinomas displayed a higher percentage of polysomy than lobular ones. A statistical significant association was demonstrated between Ki-67 immunohistochemical expression and polysomy of chromosome 20. Disomy was inversely correlated with Ki-67, while monosomy was suggestively associated with PR positive expression. Among the patients, those with the highest levels of polysomy showed the worst survival. In conclusion, the gain of chromosome 20 is the prevalent aberration in patients with breast carcinomas and may be useful prognostic marker in breast cancer.

Correlation of tissue inhibitor of metalloproteinase-2 with proliferative activity and patients' survival in breast cancer.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous regulators of matrix metalloproteinases (MMPs). They are believed to possess several distinct cellular functions, particularly the contradictory activities of inhibiting MMPs and promoting tumor cell growth. Immunohistochemistry was performed to detect TIMP-2 protein in 136 infiltrative breast carcinomas. TIMP-2 protein was analyzed in parallel with clinicopathologic features (tumor size, histologic type, nuclear and histologic grade, stage), patients' overall survival and ER, PR, Ki-67, topo IIalpha, c-erbB-2, p53 and bcl-2 proteins. Statistical analysis was performed using univariate and multivariate models analysis. Immunoreactivity for TIMP-2 was observed in cancer cells and stromal fibroblasts in 106 (77.94%) and 104 (76.47%) of 136 cases, respectively. TIMP-2 protein expression in stromal fibroblasts showed a statistically significant inverse correlation with tumor size (P =.014). An inverse correlation was also observed between TIMP-2 epithelial immunoreactivity and nuclear and histologic grade (P =.036 and P =.007, respectively). TIMP-2 protein reactivity showed statistically significant positive associations with topo IIalpha and bcl-2 in stromal and cancer cells, respectively (P =.032 and P =.001, respectively). TIMP-2 protein expression in cancer and stromal cells was associated with better patients' overall survival (P =.002 and P =.038, respectively). When evaluated by the Cox's proportional hazard regression model, this association was further established, but only as far as TIMP-2 expression in tumor epithelium was concerned (P =.019). Our results support the multifunctional potential of TIMP-2 through its correlation on the one hand to a favorable outcome, due to its MMP inhibitory activity and on the other to topo IIalpha contributing to its growth factor activity.