A role for the fibrinolytic system in postsurgical adhesion formation

To look for evidence of a fibrinolytic insufficiency as a cause of adhesion formation. Retrospective and prospective study. University medical center. Retrospective study: 50 patients undergoing laparoscopy, divided into patients with and without endometriosis. Prospective study: 18 patients undergoing infertility surgery involving a second-look laparoscopy. During all surgical procedures, adhesions were scored, and peritoneal fluid and plasma were collected. Parameters of the fibrinolytic system were measured to establish a possible relation with the presence and formation of adhesions. In patients with endometriosis and adhesions, significantly higher peritoneal fluid concentrations were found for plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and plasminogen, compared with patients with endometriosis but without adhesions. In the prospective study, initial peritoneal PAI-1 concentrations correlated significantly with the extent of adhesion formation (r(s) = 0.49) and adhesion-improvement scores (r(s) = -0.52). Also, the change in concentration of tPA and fibrinogen from the initial surgical procedure to the second-look laparoscopy correlated significantly with adhesion-improvement scores (DeltatPA: r(s)= 0.50; Deltafibrinogen: r(s) = -0.64). This first prospective study in humans adds further weight to the hypothesis that adhesions are caused by an insufficiency in peritoneal fibrinolytic activity. Plasminogen activator inhibitor-1 is a potential marker for the identification of patients at risk for developing adhesion

Association of allele-specific HLA expression and histopathologic progression of cervical carcinoma

Immunohistochemical studies have shown that loss of HLA expression is observed in cervical carcinomas but not in premalignant CIN lesions, indicating that downregulation of HLA is linked to tumor progression. The present study was performed to investigate whether the degree of HLA expression in cervical cancer correlates with more advanced disease as defined by histopathological features. Frozen tissue sections from 49 patients with squamous carcinoma of the cervix FIGO stage IB to IIB were stained with HLA class I monomorphic, locus- and allele-specific monoclonal antibodies. Histological data indicative of local disease, i.e., depth of invasion, tumor size, stage, and systemic spread of the disease, such as tumor-positive lymph nodes, were collected by reviewing the histological slides. Univariate analysis revealed that loss of HLA-A locus and A2-allele expression showed a positive, significant correlation with both presence of tumor-positive lymph nodes (P = 0.04 and 0.02, respectively) and the number of lymph nodes involved (both P = 0.04). These results strongly support the idea that, specifically in an immunogenic cancer type such as cervical cancer, tumor cells escape immunosurveillance and gain growth advantage by allele-specific downregulation of the HLA-A2 molecule. In view of the development of immunotherapeutical interventions in cancer, upregulation of HLA class I molecules may prove to be a useful additional tool in the combat against immunogenic tumors

Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer

Cervical carcinoma is the second most frequent cancer type in women worldwide. Both inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the extracellular matrix, has been shown to have a role in tumor progression. The aim of this study was to investigate versican expression, and its association with tumor-infiltrating inflammatory cell subsets and with clinicopathological parameters in human cervical cancers. We have studied the expression of versican in 149 cervical cancers using immunohistochemistry and mRNA in situ hybridization. Versican was predominantly expressed in the stroma (myofibroblasts). Using quantitative real-time-PCR, V0 was found to be the most prominent isoform. High stromal versican expression was significantly associated with a low number of tumor-infiltrating T cells (P=0.018) and particularly a low number of CD8-positive T cells (cytotoxic T cells; P=0.002). Stromal versican expression was significantly higher in patients with an infiltration depth > 14mm (P=0.004) and in patients with parametrial invasion (P=0.044). Stromal versican expression was not associated with survival. Our results suggest that versican expression in the stromal compartment of cervical cancers results in reduced numbers of intraepithelial CD8-positive T cells and enhanced local invasion. Modern Pathology (2010) 23, 1605-1615; doi:10.1038/modpathol.2010.154; published online 20 August 201

Angels and demons: Th17 cells represent a beneficial response, while neutrophil IL-17 is associated with poor prognosis in squamous cervical cancer

The role of interleukin (IL)-17 in cancer remains controversial. In view of the growing interest in the targeting of IL-17, knowing its cellular sources and clinical implications is crucial. In the present study, we unraveled the phenotype of IL-17 expressing cells in cervical cancer using immunohistochemical double and immunofluorescent triple stainings. In the tumor stroma, IL-17 was found to be predominantly expressed by neutrophils (66%), mast cells (23%), and innate lymphoid cells (8%). Remarkably, T-helper 17 (Th17) cells were a minor IL-17 expressing population (4%). A similar distribution was observed in the tumor epithelium. The Th17 and granulocyte fractions were confirmed in head and neck, ovarian, endometrial, prostate, breast, lung, and colon carcinoma. An above median number of total IL-17 expressing cells was an independent prognostic factor for poor disease-specific survival in early stage disease (p = 0.016). While a high number of neutrophils showed at trend toward poor survival, the lowest quartile of mast cells correlated with poor survival (p = 0.011). IL-17 expressing cells and neutrophils were also correlated with the absence of vaso-invasion (p < 0.01). IL-17 was found to increase cell growth or tightness of cervical cancer cell lines, which may be a mechanism for tumorigenesis in early stage disease. These data suggest that IL-17, primarily expressed by neutrophils, predominantly promotes tumor growth, correlated with poor prognosis in early stage disease. Strikingly, a high number of Th17 cells was an independent prognostic factor for improved survival (p = 0.026), suggesting Th17 cells are part of a tumor suppressing immune response

High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients

Purpose: Cervical cancer is now known to be caused by infection with an oncogenic type of the human papillomavirus (HPV). However, little is known about the continued role of HPV once cancer has been established. Here, we describe the quantitative relation between HPV DNA copy number and mRNA expression of the viral oncogenes (E6 and E7) and the prognostic value of both measures in cervical cancer patients. Experimental Design: We studied the number of viral DNA copies and the level of HPV E6/E7 mRNA expression in 75 HPV 16-positive or HPV 18-positive International Federation of Gynecology and Obstetrics stage Ib and IIa cervical cancer patients. Measurements were done with quantitative PCR. DNA copy number analysis was done on pure tumor cell samples enriched with flow sorting. mRNA expression data were compensated for the percentage of tumor cells included. Results: The number of viral DNA copies was not predictive of survival in cervical cancer patients. In contrast, high HPV E6/E7 mRNA expression was strongly related to an unfavorable prognosis (P = 0.006). In a multivariate Cox model for overall survival, including all known prognostic variables and stratified for HPV type, the level of E6/E7 mRNA expression was an independent prognostic indicator, second only to lymph node status. No correlation was observed between DNA copy number and the level of HPV E6/E7 mRNA expression, which reflects that not all DNA copies are equally transcriptionally active. Conclusions: Cervical cancer patients with high HPV E6/E7 oncogene mRNA expression have a worse survival independently from established prognostic factors