A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000–1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35–80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation

Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential.

Expression of a recently identified murine gene, nm23, has been previously proposed to be inversely correlated to tumor metastatic potential in rodent model systems. The present study was designed to investigate whether nm23 RNA was detectable in human tumor tissue, and if it was differentially expressed. nm23 RNA levels in 27 human primary infiltrating ductal breast carcinomas were determined by using Northern blots or in situ hybridization. These data were compared to traditional histopathological indicators of metastatic potential, including the number of involved (tumor bearing) lymph nodes, grade of differentiation, and hormone receptor status. A striking consistency was observed in all tumors from patients with involved lymph nodes. Using Northern blot or in situ hybridizations, all of these tumors expressed low levels of nm23 RNA. Quantitative in situ hybridization on tumors from patients with 0 involved lymph nodes identified two groups: (a) approximately 75% contained high nm23 RNA levels, and (b) 25% contained significantly (alpha = 0.05) lower nm23 RNA levels. Low nm23 RNA levels in the 0 involved lymph node tumors were accompanied by two additional histopathological indicators of high metastatic potential, low nuclear and cytoplasmic estrogen receptor content, and poorly differentiated histological grade. In contrast, none of the high nm23 RNA level tumors were both receptor negative and poorly differentiated. We conclude that nm23 RNA levels are differentially expressed in human breast tumors, and that low nm23 RNA levels are associated with histopathological indication of high metastatic potential. Short term (median follow-up of 16 months) clinical course data were consistent with nm23 RNA levels, in that 2 of 11 low nm23 RNA content patients (including one from the 0 involved lymph node group) developed metastases, while none of the high nm23 RNA patients have experienced recurrent disease

A novel function for the nm23-H1 gene: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest

BACKGROUND: We have developed a culture system using reconstituted basement membrane components in which normal human mammary epithelial cells exhibit several aspects of the development and differentiation process, including formation of acinar-like structures, production and basal deposition of basement membrane components, and production and apical secretion of sialomucins. Cell lines and cultures from human breast carcinomas failed to recapitulate this process. The data indicate the importance of cellular interactions with the basement membrane in the regulation of normal breast differentiation and, potentially, its loss in neoplasia. PURPOSE: Our purpose was to use this assay to investigate the role of the putative metastasis suppressor gene nm23-H1 in mammary development and differentiation. METHODS: The metastatic human breast carcinoma cell line MDA-MB-435, clones transfected with a control pCMVBamneo vector, and clones transfected with pCMVBamneo vector containing nm23-H1 complementary DNA (the latter of which exhibited a substantial reduction in spontaneous metastatic potential in vivo) were cultured within a reconstituted basement membrane. Clones were examined for formation of acinus-like spheres, deposition of basement membrane components, production of sialomucin, polarization, and growth arrest. RESULTS: In contrast to the parental cell line and control transfectants, MDA-MB-435 breast carcinoma cells overexpressing Nm23-H1 protein regained several aspects of the normal phenotype within reconstituted basement membrane. Nm23-H1 protein-positive cells formed organized acinus-like spheres, deposited the basement membrane components type IV collagen and, to some extent, laminin to the outside of the spheres, expressed sialomucin, and growth arrested. Growth arrest of Nm23-H1 protein-positive cells was preceded by and correlated with formation of a basement membrane, suggesting a causal relationship. CONCLUSION: The data indicate a previously unidentified cause-and-effect relationship between nm23-H1 gene expression and morphological–biosynthetic–growth aspects of breast differentiation in this model system. IMPLICATIONS: While the basement membrane microenvironment is capable of directing the differentiation of normal human breast cells, neoplastic transformation abrogates this relationship, suggesting that intrinsic cellular events are also critical to this process. The data identify nm23-H1 gene expression as one of these events, suggesting an important role in the modulation of cellular responsiveness to the microenvironment. The data also identify previously unknown growth inhibitory effects of nm23-H1 gene overexpression

Environmental Security and Pastoralism

Pastoral areas are home for more than 200 million people and provide essential environmental, economic and social services at global level. Despite the key role of grasslands for many emerging economies, these areas are historically affected by intensifying challenges, like droughts, desertification, burgeoning populations and extreme poverty. As a result of these conditions many countries in Africa, Middle East and Asia are host to a disproportionate number of the world's violent conflicts, where vulnerable pastoralist communities play a key role. The main aim of this paper is to provide an overview of the importance of pastoral areas for the security and an analysis of the role of Geomatic tools to support environmental security analysis in pastoral areas, with special consideration for the activities carried out by ILRI as part of its global mandate to eradicate poverty and insecurity through sustainable livestock production

Brain metastases.

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve