The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver metastases of B16F1 melanoma cells

Matrix metalloproteinases (MMPs) have been shown to contribute functionally to tumor metastasis. MMP inhibitors are thus being assessed for clinical utility as anti-metastatic therapeutics. Batimastat (BB-94) is a synthetic MMP inhibitor that has been shown to inhibit tumor growth and metastasis in mice. Here we assessed the ability of batimastat to inhibit liver metastases of murine B16F1 cells, after injection of cells in mice via mesenteric vein to target the liver. We then determined which of the sequential steps in metastasis were affected by batimastat, in order to identify its mechanism of action in vivo. Intravital videomicroscopy was used to assess the effect on extravasation, and a cell accounting procedure was used to determine the effect on initial survival of cells. Stereological quantification of functional blood vessels was used to determine the effect on tumor vascularity, thereby avoiding problems associated with immunohistochemical detection of liver sinusoidal endothelial cells. We found that batimastat (50 mg/kg i.p. 5 h prior to and after cell injection, daily thereafter) resulted in a 23% reduction in mean diameter of liver metastases (equivalent to a 54% reduction in tumor volume), while not reducing the number of metastases. Extravasation of cells from the liver circulation was not affected: at 8, 24 and 48 h after injection of cells, the same proportion of cells had extravasated from treated vs. control mice. Batimastat also did not inhibit early survival of cells. However, batimastat-treated mice had a significantly reduced percentage vascular volume within liver metastases, indicating inhibition of angiogenesis. This study demonstrates in vivo that the mechanism by which batimastat limits growth of B16F1 metastases in liver is not by affecting extravasation, but by inhibiting angiogenesis within metastases. This finding suggests that MMP inhibitors may be appropriate for use in patients with metastatic cells that have already extravasated in secondary sites.     

Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing

Mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer in carrier women. An understanding of behavioral responses to BRCA1 mutation testing by mutation carriers and non-carriers is important to guide the clinical application of this new technology. This study examined the utilization of genetic testing for a BRCA1 mutation in high-risk individuals and the response of tested women with respect to interventions for early cancer detection and prevention. This study assessed the utilization of genetic testing for both men and women in a large kindred and the behavioral responses by women with respect to use of health care interventions during the 2 years following testing. Participants were offered BRCA1 mutation testing. Surveillance behaviors related to breast and ovarian cancer were assessed by computer-assisted telephone interviews at baseline (prior to genetic counseling and testing), 1-2 weeks, 4-6 months, 1 and 2 years after the provision of test results. Mutation carriers, non-carriers, and individuals of unknown mutation status were compared to determine the impact of test results. Utilization of genetic testing for both men and women are reported and, for women, mammography, breast self-exam, clinical breast exam, mastectomy, oophorectomy, transvaginal ultrasound, and CA125 screening were assessed. Of those fully informed of the opportunity for testing, 55% of the women and 52% of the men pursued genetic testing. With respect to mammography for women 40 years and older, 82% of mutation carriers obtained a mammogram in each year following testing compared to 72% of non-carrier women the first year and 67% the second year. This mammography utilization represents a significant increase over baseline for both mutation carriers and non-carriers. Younger carrier women also significantly increased their mammography utilization from baseline. Overall, 29% of the carrier women did not obtain a single mammogram by 2 years post-testing. At 2 years, 83% of the carrier women and 74% of the non-carriers reported adherence to recommendations for breast self-exam and over 80% of carrier women had obtained a clinical breast examination each year following testing. None of the carrier women had obtained a prophylactic mastectomy by 2 years after testing, although 11% were considering this procedure. Of carrier women 25 years of age and older who had at least one intact ovary at the time of testing, 46% of carriers had obtained an oophorectomy 2 years after testing, including 78% of women 40 years of age and older. The majority of carrier women (73%) had discussed their genetic test results with a medical doctor or health care provider. Our results indicate utilization of genetic testing by a majority of high-risk individuals who received information about testing. Both carriers and non-carriers increased their utilization of mammography and breast self-exam following testing. Oophorectomy was obtained by a large proportion of carrier women in contrast to mastectomy which was not utilized within the first 2 years following testing.     

What Goes Around: the process of building a community-based harm reduction research project

Background

Often, research takes place on underserved populations rather than with underserved populations. This approach can further isolate and stigmatize groups that are already made marginalized. What Goes Around is a community-based research project that was led by community members themselves (Peers).

Case presentation

This research aimed to implement a community-based research methodology grounded in the leadership and growing research capacity of community researchers and to investigate a topic which community members identified as important and meaningful. Chosen by community members, this project explored how safer sex and safer drug use information is shared informally among Peers. Seventeen community members actively engaged as both community researchers and research participants throughout all facets of the project: inception, implementation, analysis, and dissemination of results. Effective collaboration between community researchers, a community organization, and academics facilitated a research process in which community members actively guided the project from beginning to end.

Conclusions

The methods used in What Goes Around demonstrated that it is not only possible, but advantageous, to draw from community members’ involvement and direction in all stages of a community-based research project. This is particularly important when working with a historically underserved population. Purposeful and regular communication among collaborators, ongoing capacity building, and a commitment to respect the experience and expertise of community members were essential to the project’s success. This project demonstrated that community members are highly invested in both informally sharing information about safer sex and safer drug use and taking leadership roles in directing research that prioritizes harm reduction in their communities.

     

Evaluating Facility-Based Decision-Making in Women with a Prior Cesarean Delivery and Association with Maternal and Perinatal Outcomes

Objective To describe facility-based decision-making for women with one prior cesarean delivery (CD) in a resource-limited setting and to characterize maternal and perinatal outcomes in these groups. Methods One year retrospective study of women with one prior CD delivering at Korle-Bu Teaching Hospital (KBTH), Ghana. Women were categorized into three groups based on initial plan of management on admission [trial of labor after cesarean (TOLAC), emergency repeat CD (EMCD) or non-emergent repeat CD (RCD)]. Characteristics and outcomes across these groups were then compared. Results During the study period, 1247 women with one prior CD delivered at KBTH, of which 377 (30.2%) were triaged to RCD, 439 (35.2%) to EMCD and 431 (34.6%) to TOLAC. Twelve uterine ruptures and no maternal deaths occurred. Perinatal mortality was 4.2% (n?=?52). Compared to the RCD group, the TOLAC group had a lower risk for maternal adverse events (aOR 0.3, 95% CI 0.1–1.0; p?=?0.04) and non-significant higher risk of perinatal adverse events (aOR 1.6, 95% CI 0.7–3.3; p?=?0.25). Compared to women triaged to RCD, the EMCD group had a non-significant increase in risk of maternal adverse events (aOR 1.6, 95% CI 0.8–3.5; p?=?0.2) and a significantly higher rate of perinatal adverse events (aOR 2.4, 95% CI 1.2–4.9; p?=?0.01). Conclusions for Practice Women triaged to EMCD at admission are different when compared to women allowed a TOLAC or offered a non-emergent RCD. These women bear increased rates of adverse outcomes and should be considered as a separate group for analysis in future studies conducted in similar settings.     

Radiological aspects of Gaucher disease

Advances in imaging and the development of commercially available enzyme therapy have significantly altered the traditional radiology of Gaucher disease. The cost of treatment and need for monitoring response to therapy have magnified the importance of imaging. There are no recent comprehensive reviews of the radiology of this relatively common lysosomal storage disease. This article describes the modern imaging, techniques and radiological manifestations of Gaucher disease.     

Determinants of mortality in non-neutropenic ICU patients with candidaemia

Introduction  

Candidaemia in critically-ill intensive care unit (ICU) patients is associated with high crude mortality. Determinants of mortality – particularly those amenable to potential modification – are incompletely defined.