Hebron University

About: Hebron University is a education organization based out in Hebron, Palestinian Territory. It is known for research contribution in the topics: Population & Cancer. The organization has 2714 authors who have published 4180 publications receiving 163736 citations.

Sex effects across the lifespan in women with multiple sclerosis

Abstract: Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis.

Abstract: Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries. Metastasis is the major cause of endometrial cancer deaths. Therefore, there is a vital need for clinically relevant in vivo models allowing the elucidation of the molecular and cellular mechanisms underlying metastatic behavior. In this study, we describe an innovative experimental orthotopic model of human endometrial carcinoma. Implantation in the bifurcation of the uterine horns resulted in tumors integrated into the myometrial compartment, which can be used and further exploited for the study of in vivo angiogenesis, myometrial invasion, and the metastatic capacity of endometrial cancer cells. This orthotopic model also represents a suitable tool to analyze how tumorigenesis and distant metastasis of endometrial cancer might be influenced by gene alteration, by modulating its expression in the original cancer cell line. One of the candidate genes implicated in endometrial cancer is the transcription factor RUNX1. The over-expression of RUNX1 in the endometrial cancer cell line HEC1A and the transplantation of these cells to the uterus of nude mice were associated specifically with distant metastasis in the lung. RUNX1 plays a role in the establishment of metastases in endometrial cancer. Translated to the clinics, these models would be equivalent to an advanced undifferentiated carcinoma with node affectation (stage IIIC) and distant metastasis (stage IVB). These patients would be candidates for adjuvant therapy, not efficient until today, and therefore, our models are actually suitable for the design and evaluation of experimental therapies.

Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial

Abstract: Purpose: mTOR inhibition activates compensatory IGFR signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental design: In vitro and in vivo models, and a phase I study where advanced cancer patients received ridaforolimus (10-40 mg/day QD×5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg QOW) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main DLTs of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 breast cancer patients); 10/23 breast cancer patients and 6/11 ER+/high proliferative breast cancer patients showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high proliferative breast cancer.

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.

Abstract: Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature Updated OS analyses are reportedMethods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose) If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests Analyses adjusting for baseline prognostic factors and crossover were also performedResults: 296 women were randomized (148 per arm) The median number of prior trastuzumab-containing regimens for MBC treatment was 3 Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm At data cut-off for updated OS, 218 deaths (74%) had occurred Median OS following treatment with lapatinib plus trastuzumab was 607 weeks compared with 414 weeks for lapatinib alone A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 074; 95% CI: 057, 097; P=026) The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 071; 95% CI: 054, 093; P=012) A trend toward a clinically relevant 25% reduction in risk of death (P=080) was also observed after adjusting for crossoverConclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 61