A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

Despite an improved antitumor efficacy as noticed by an enhanced response rate and an improved progression-free survival, the hepatic intra-arterial fotemustine did not increase the overall survival of uveal melanoma patients with liver metastases only. We propose to consider intrahepatic treatment as an experimental approac

Trends of public health research output from India during 2001-2008

BACKGROUND: An understanding of how public health research output from India is changing in relation to the disease burden and public health priorities is required in order to inform relevant research development. We therefore studied the trends in the public health research output from India during 2001-2008 that was readily available in the public domain. METHODS: The scope and type of the published research from India in 2007 that was included in the PubMed database was assessed and compared with a previous similar assessment for 2002. Papers were classified based on the review of abstracts and original public health research papers were assessed in detail. Impact factors for the journals were used to compute quality-adjusted research output. The websites of governmental organizations, academic and research institutions and international organizations were searched in order to identify and review reports on original public health research produced in India from 2001 to 2008. The reports were classified based on the topics covered and quality and their trends over time were assessed. RESULTS: The number of original health research papers from India in PubMed doubled from 4494 in 2002 to 9066 in 2007. This included a 3.1-fold increase in public health research papers, but these comprised only 5% of the total papers in 2007. Within public health, the increase was lowest for the health system and policy category. Several major causes of disease burden in India continued to be underrepresented in the quality-adjusted public health research output in 2007. The number of papers evaluating population health interventions increased from 2002 to 2007, but there were none on the leading non-communicable causes of disease burden or on road traffic injuries. The number of identified original public health research reports increased by 64.7% from 204 in 2001-2004 to 336 in 2005-2008. The proportion of reports on reproductive and child health was very high but decreased slightly from 38.7% of the total in 2001-2004 to 31.5% in 2005-2008 (P = 0.09); those on the leading chronic non-communicable conditions and injuries increased from 6.4% to 13.4% (P = 0.01) but this was still much lower than their contribution to the disease burden. Health system/policy issues were the topic in 27.4% reports but health information issues were covered in a miniscule 0.6% reports. The proportion of reports that were evaluations increased slightly from 26% in 2001-2004 to 31.5% in 2005-2008, with this proportion being higher among the reports commissioned by international organizations (P < 0.001). The proportion of reports commissioned by Indian governmental organizations alone, or in collaboration with international organizations, doubled from 2001-2004 to 2005-2008 (P < 0.001). Only 25% of the total 540 reports had a quality score of adequate or better. The quality of reports produced by collaborations between Indian and international organizations was higher than those produced by Indian or international organizations alone (P < 0.001). CONCLUSION: This is the first analysis from India that includes research reports in addition to published papers. It provides the most up-to-date understanding of public health research output from India. The increase in available public health research output and the increase in commissioning of this research by Indian governmental organizations are encouraging. However, the distribution of research topics and the quality of research reports continue to be unsatisfactory. It is necessary for health policy to address these continuing deficits in public health research in order to reduce the very large disease burden in India.13 page(s

Isolation and characterization of equine endometrial mesenchymal stromal cells

Abstract Background Equine mesenchymal stromal/stem cells (MSCs) are most commonly harvested from bone marrow (BM) or adipose tissue, requiring the use of surgical procedures. By contrast, the uterus can be accessed nonsurgically, and may provide a more readily available cell source. While human endometrium is known to harbor mesenchymal precursor cells, MSCs have not been identified in equine endometrium. This study reports the isolation, culture, and characterization of MSCs from equine endometrium. Methods The presence of MSC and pericyte markers in endometrial sections was determined using immunohistochemistry. Stromal cells were harvested and cultured after separation of epithelial cells from endometrial fragments using Mucin-1-bound beads. For comparison, MSCs were also harvested from BM. The expression of surface markers in endometrial and BM-derived MSCs was characterized using flow cytometry and quantitative polymerase chain reaction. MSCs were differentiated in vitro into adipogenic, chondrogenic, osteogenic, and smooth muscle lineages. Results Typical markers of MSCs (CD29, CD44, CD90, and CD105) and pericytes (NG2 and CD146) were localized in the equine endometrium. Both endometrial and BM MSCs grew clonally and robustly expressed MSC and pericyte markers in culture while showing greatly reduced or negligible expression of hematopoietic markers (CD45, CD34) and MHC-II. Additionally, both endometrial and BM MSCs differentiated into adipogenic, osteogenic, and chondrogenic lineages in vitro, and endometrial MSCs had a distinct ability to undergo smooth muscle differentiation. Conclusions We have demonstrated for the first time the presence of cells in equine endometrium that fulfill the definition of MSCs. The equine endometrium may provide an alternative, easily accessible source of MSCs, not only for therapeutic regeneration of the uterus, but also for other tissues where MSCs from other sources are currently being used therapeutically

The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographicaly diverse populations

Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report

Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms

International audienceWeight variation has been reported as a side effect of chemotherapy treatment in early breast cancer patients and has been identified as a factor of poor prognosis. Causes of weight variation during chemotherapy and mechanisms involved in the poor prognosis have been little studied. Here is reviewed the current knowledge about the main causes and mechanisms involved in body weight change. Special emphasis is placed on factors associated with weight variation which could potentially be involved in the risk of relapse in breast cancer survivors. In recent decades, some studies have investigated the causes of weight variation by studying energy balance of breast cancer patients during chemotherapy. Weight gain or loss may be the consequence of energy imbalance through different factors linked with chemotherapy, such as poor treatment tolerance, decreased muscle mass and function, or hormonal alterations. This results in body composition modifications in favour of fat gain and/or lean body mass loss. Increased adipose tissue, especially in the abdominal region, could induce metabolic disturbances such as insulin resistance, through various pathways involving adipokines. These molecules have growth properties and could therefore play a role in cancer relapse. Understanding such mechanisms is key to developing preventive strategies for improving the prognosis of early-stage breast cancer patients