Local and Systemic STAT3 and p65 NF-KappaB Expression as Progression Markers and Functional Targets for Patients With Cervical Cancer.

Cervical cancer, which main etiologic factor is Human Papillomavirus (HPV) infection, continues to be a burden for public health systems in developing countries. Our laboratory has been working with the hypothesis that signals generated in the tumor microenvironment can modulate local and systemic immune responses. In this context, it would be reasonable to think that tumors create pro-tumoral bias in immune cells, even before they are recruited to the tumor microenvironment. To understand if and how signaling started in the tumor microenvironment can influence cells within the tumor and systemically, we investigated the expression of key proteins in signaling pathways important for cell proliferation, viability, immune responses and tolerance. Besides, we used detection of specific phosphorylated residues, which are indicative of activation for Akt, CREB, p65 NFκB, and STAT3. Our findings included the observation of a significant STAT3 expression increase and p65 NFκB decrease in circulating leukocytes in correlation with lesion grade. In light of those observations, we started investigating the result of the inhibition of STAT3 in a tumor experimental model. STAT3 inhibition impaired tumor growth, increased anti-tumor T cell responses and decreased the accumulation of myeloid cells in the spleen. The concomitant inhibition of NFκB partially reversed these effects. This study indicates that STAT3 and NFκB are involved in immunomodulatory tumor effects and STAT3 inhibition could be considered as therapy for patients with cervical cancer.

Age-related acceptability of vaginal self-sampling in cervical cancer screening at two university hospitals: a pilot cross-sectional study.

BACKGROUND: To determine whether age is a barrier against acceptability of cervicovaginal self-sampling in screening for cervical cancer at two gynecology outpatient clinics. METHODS: This is a cross-sectional study involving 116 women over 21 years of age with an abnormal Pap smear. Clinical and laboratorial data were recorded in electronic files. Women received detailed self-collection instructions. After the self-sampling procedure (Evalyn Brush®), women were instructed to answer a questionnaire about vaginal self-sampling acceptability that consisted of seven multiple-choice items. The participants were divided into three age brackets: 21 to 29 years, 30 to 49 years, and 50 years and over. Chi-square, Fischer exact, Kolmogorov-Smirnov and Kruskal-Wallis tests were used. RESULTS: The analysis of the participants' perception of the procedure stratified according to age groups showed a decline in the fear of hurting oneself during the procedure as age increased. Most participants reported that it was very easy to understand how to use the self-sampling brush and that it was easy to use it. Most of them were neither embarrassed nor afraid of getting hurt during the procedure. The majority preferred self-sampling to collection by a healthcare professional. The main reason was practicality: the possibility of choosing the place and time for sampling. CONCLUSIONS: The participating women found self-collection simple to understand and easy to accept regardless of age. The younger women indicated more fear and discomfort in self-sampling, which points to the need for attraction strategies that are more appealing to the younger generations.

Local and systemic immunomodulatory mechanisms triggered by Human Papillomavirus transformed cells: a potential role for G-CSF and neutrophils.

Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by the increase in the frequency of T lymphocytes, neutrophils and M2 macrophages, in cancer patients. We observed a strong negative correlation between the frequency of neutrophils and T cells in precursor and cancer samples, but not cervicitis. In 3D tumor cell cultures, neutrophils inhibited T cell activity, displayed longer viability and longer CD16 expression half-life than neat neutrophil cultures. Systemically, we observed higher plasma G-CSF concentration, higher frequency of immature low density neutrophils, and tolerogenic monocyte derived dendritic cells, MoDCs, also in cancer patients. Interestingly, there was a negative correlation between T cell activation by MoDCs and G-CSF concentration in the plasma. Our results indicate that neutrophils and G-CSF may be part of the immune escape mechanisms triggered by cervical cancer cells, locally and systemically, respectively.

Human papillomavirus and chlamydia trachomatis infections in rheumatoid arthritis under anti-TNF therapy: an observational study.

The objective of this study was to evaluate human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections in RA patients pre- and post-TNF blocker. Fifty female RA patients (ACR criteria), who were eligible to anti-TNF therapy [n = 50 at baseline (BL) and n = 45 after 6 months of treatment (6 M)], and 50 age-matched healthy controls were prospectively enrolled. They were assessed for demographic data, gynecologic, sexual, cervical cytology and histological evaluations, disease parameters and current treatment. HPV DNA and CT DNA testing in cervical specimens were done using Hybrid Capture II assays. At BL, the median current age of RA patients and controls was 49 (18-74) versus 49 (18-74) years, p = 1.0. A trend of lower frequency of HPV infection was observed in AR patients pre-anti-TNF compared with controls (14 vs. 30%, p = 0.054). Further evaluation of AR patients with and without HPV infection before anti-TNF therapy showed that the former group had higher frequency of sexual intercourses (100 vs. 48%, p = 0.014), higher median number of sexual partners [1 (1-1) vs. 0 (0-1), p = 0.032] and higher frequency of abnormal cervical cytology (43 vs. 7%, p = 0.029). Current age, disease duration, disease parameters and treatments were alike in both groups (p > 0.05). At 6 M after TNF blockage, HPV infection remained unchanged in five patients, whereas two became negative and one additional patient turned out to be positive (p = 1.0). CT infection was uniformly negative in RA patients pre- and post-TNF blockage and in controls. Anti-TNF does not seem to increase short-term risk of exacerbation and/or progression of HPV and CT infections in RA patients.

Implementing human papillomavirus testing in a public health hospital: challenges and opportunities.

OBJECTIVES: Robust evidence now supports human papillomavirus (HPV) testing as a more effective option to screening and as more sensitive than cytology in detecting high-grade cervical intraepithelial neoplasia . Our goal was to analyze the performance of the Hybrid Capture II (HC2) assay for high-risk HPV (hrHPV) in women undergoing gynecological examination at a public health hospital as part of the evaluation of HPV screening as an alternative or complement to cytology. STUDY DESIGN: This analysis is a subset of a cross-sectional study carried out at a large public hospital serving a predominantly low-resource population. A total of 705 women were enrolled; the sensitivity and specificity of each test were estimated and compared. RESULTS: The analysis identified 272 hrHPV-positive women (mean age 36.3 years) and 433 hrHPV-negative women (mean age 41.2 years). HPV testing showed a significantly increased sensitivity of the HC2 assay versus cytology (84.5 vs. 69.7%; p < 0.0001) but a lower specificity (49.90 vs. 88.78%; p < 0.0001). CONCLUSION: The combination of both methods seems to be useful in improving detection of cervical lesions.