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In pre-clinical safety studies, drug-induced vascular injury is an issue of concern because there are no obvious diagnostic markers for pre-clinical or clinical monitoring and there is an intellectual gap in our understanding of the pathogenesis of this lesion. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary targets, smooth muscle and endothelial cells are unknown. However, evaluation of novel markers for potential clinical monitoring with a mechanistic underpinning would add value in risk assessment and management. This mini review focuses on the progress to identify diagnostic markers of drug-induced vascular injury. Von Willebrand factor (vWF), released upon perturbation of endothelial cells, is transiently increased in plasma prior to morphological evidence of damage in dogs or rats treated with vascular toxicants. Therefore, vWF might be a predictive biomarker of vascular injury. However, vWF is not an appropriate biomarker of lesion progression or severity since levels return to baseline values when there is morphological evidence of injury. A potential mechanistically linked biomarker of vascular injury is caveolin-1. Expression of this protein, localized primarily to smooth muscle and endothelial cells, decreases with the onset of vascular damage. Since vascular injury involves multiple mediators and cell types, evaluation of a panel rather than a single biomarker may be more useful in monitoring early and severe progressive vascular injury.

number 1: The futility of transvaginal ultrasound in type II endometrial cancer C. Billingsley, K. Kenne, C. Cansino, D. O'Malley, D. Cohn, J. Fowler, E. Eisenhauer, L. Copeland, F. Backes, R. Salani, The Ohio State University, Columbus, OH, USA, University of California Davis, Sacramento, CA, USA, University of Cincinnati, UC Health Medical Arts Building, Cincinnati, OH, USA Objectives: To determine the utility of transvaginal ultrasound (TVUS) in women with type II endometrial cancer, including serous, clear cell, and high-grade carcinomas. Methods: A retrospective review was conducted in women with pathology proven type II endometrial cancer that underwent preoperative TVUS. The following data were obtained: endometrial stripe (EMS) measurement, presence of intracavitary fluid or lesion, myometrial and/or adnexal masses, uterine size and volume. Pathology reports were reviewed and clinicopathologic factors were abstracted. Descriptive analyses were performed to assess demographic and comparative data. Results: Sixty-three women comprised the study cohort and the median age was 65 years. The most commonly reported symptom was postmenopausal bleeding in 51 patients (80.9%). The EMS was reported as thin (b5 mm) or indistinct in 18 patients (28.6%). Approximately 60% of patients were noted to have one or more ultrasound abnormalities: intracavitary lesion (18, 28.6%), intracavitary fluid (8, 12.7%), myometrial lesion (19, 30.2%), and adnexal mass (8, 12.7%). Poorly differentiated endometrioid cancer (33; 52.4%) represented the predominant histology. Of the 28% of women with a thin/indistinct EMS, seven women did not have an ultrasound abnormality, representing 11% of women with type II endometrial cancer who had no abnormal ultrasound findings whatsoever. Conclusions: Women with type II endometrial cancer were found to have a thin/indistinct EMS on TVUS in approximately 25% of cases. Furthermore, lack of any ultrasound abnormality, including a thickened EMS, were noted in 11% of patients. The use of TVUS, which has been of diagnostic and triaging value for women with type I cancer, is of limited utility in type II endometrial cancer. Therefore, endometrial sampling should be included in the evaluation of all women with postmenopausal bleeding, regardless of EMS thickness. doi:10.1016/j.ygyno.2014.04.019 Abstract number 2: Durationof intra-chemotherapy anemia is associatedwith prognosis and survival in epithelial ovarian cancer R. Brightwell, K. Eng, S. Lele, K. Odunsi, Roswell Park Cancer Institute,number 2: Durationof intra-chemotherapy anemia is associatedwith prognosis and survival in epithelial ovarian cancer R. Brightwell, K. Eng, S. Lele, K. Odunsi, Roswell Park Cancer Institute

Many hydrocarbons are environmental pollutants that, due to their lipophilicity and chemical stability, accumulate in biological systems including milk and body fat. A number of investigations have demonstrated that many organochlorine compounds can act as tumour promoters in vivo and inhibit gap junctional intercellular communication between cells in culture. In the present study we have investigated the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), different polychlorinated biphenyls, chlorinated paraffins and the pesticide endosulfan. Using techniques of scrape loading dye/transfer and Western blot analysis the function, expression and phosphorylation of different connexins in vitro and in vivo were studied. The results show a good correlation between the ability to act as a tumour promoter and to interfere with gap junctional intercellular communication. All tested compounds inhibited the intercellular communication in a liver derived cell line (IAR 20). However, the results show that the time to inhibition varies between the different agents. Endosulfan and chlorinated paraffins inhibit the communication within one hour, whereas dioxin like substances need to expose the cells for 48 hours before the communication is affected.

Deoxyribonucleoside triphosphate (dNTP) pool sizes were determined in cell strains derived from patients with the genetic diseases ataxia telangiectasia (GM2052), Bloom's syndrome (GM1492), and Fanconi's anemia (GM368), and were compared to the dNTP pools in a normal human fibroblast cell strain (253/79). In addition, the effect of deoxythymidine on both dNTP pool levels and cell growth was examined. The three mutant cell strains differed only slightly from the normal cell strain. The cellular characteristics of the cell strains, such as chromosome instability, are apparently not an effect of dNTP pool imbalance.

The ability of crocidolite fibers to induce point mutations and mitotic abnormalities in Chinese hamster ovary (CHO) cells was examined in cell cultures. The purpose has been to study the possibilities for establishing in vitro test methods to quantify genetic damage induced by asbestos and other mineral fibers. Results obtained with the CHO/hypoxanthine guanine phosphoribosyl transferase system indicated that crocidolite fibers per se do not significantly increase the number of thioguanine-resistant mutants. Crocidolite fibers also failed to potentiate the mutagenicity of benzo[a]pyrene. Time-lapse cinematography and microscopy showed that asbestos (crocidolite) fibers were markedly cytotoxic. Among surviving cells some underwent abnormal cell divisions which resulted in multi- and micronucleate cells. Many cells that contained a few asbestos fibers, however, underwent mitosis and successfully formed two mononucleate daughter cells capable of further divisions. Individual, fiber-containing cells were examined by time-lapse television recordings for 4-5 days. During this time period some cells underwent six divisions and generated an almost normal number of daughter cells. Cells which contained fibers that were longer or equivalent to the diameter of the mitotic cell (20 microns), showed different forms of mitotic abnormalities. The frequency of multinucleate cells was drastically increased following exposure to asbestos fibers. Only rarely, however, did these cells divide to produce viable daughter cells capable of continued cell multiplication. The frequency of multinucleate cells was dependent on the dose of exposure to asbestos fibers and could possibly be used as an index of the degree of mitotic disturbances induced by mineral fibers.