Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous-intraperitoneal (IV-IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy

Pharmacokinetics and pharmacogenetics of metronomic chemotherapy.

Despite the numerous preclinical and clinical studies that have been conducted on metronomic chemotherapy in the past 10 years, few pharmacokinetic and pharmacogenetics data on this dosing regimen are available. Indeed, only the pharmacokinetics of metronomically administered drugs, such as irinotecan, UFT, and vinorelbine, have been described in patients, but no data are available on the most widely explored agents in such an approach like cyclophosphamide or capecitabine. Methodological issues and the neglected importance of the relationship between plasma concentrations of metronomically administered chemotherapeutic drugs (and their active metabolites) contributed to the absence of data on the commonly used 50 mg/day cyclophosphamide schedule. Moreover, few data are available on the pharmacogenetics of metronomic chemotherapy, and, although some objective responses have been obtained in various tumors, it remains largely unknown which genetic backgrounds could affect or predict the clinical response of patients. Trials integrating pharmacokinetic and pharmacogenetics research are necessary to better evaluate the clinical benefit of metronomic chemotherapy

Pharmacokinetics and Pharmacogenetics of Metronomic Chemotherapy

Despite the numerous preclinical and clinical studies that have been conducted on metronomic chemotherapy in the past 10 years, few pharmacokinetic and pharmacogenetics data on this dosing regimen are available. Indeed, only the pharmacokinetics of metronomically administered drugs, such as irinotecan, UFT, and vinorelbine, have been described in patients, but no data are available on the most widely explored agents in such an approach like cyclophosphamide or capecitabine. Methodological issues and the neglected importance of the relationship between plasma concentrations of metronomically administered chemotherapeutic drugs (and their active metabolites) contributed to the absence of data on the commonly used 50 mg/day cyclophosphamide schedule. Moreover, few data are available on the pharmacogenetics of metronomic chemotherapy, and, although some objective responses have been obtained in various tumors, it remains largely unknown which genetic backgrounds could affect or predict the clinical response of patients. Trials integrating pharmacokinetic and pharmacogenetics research are necessary to better evaluate the clinical benefit of metronomic chemotherapy

Clinical outcome of patients with malignant ventricular tachyarrhythmias and a multiprogrammable implantable cardioverter-defibrillator implanted with or without thoracotomy: an international multicenter study

Objectives. The long term efficacy and safety of a third-generation implantable cardioverter-defibrillator implanted with thoracotomy and nonthoracotomy lead systems was evaluated in a multicenter international study. Background. The clinical impact of transvenous leads for nonthoracotomy implantation and pacing for bradyarrhythmias and tachyarrhythmias in implantable cardioverter defibrillator systems is not well defined. Methods. The safety of the implantation procedure and clinical outcome of 1,221 patients with symptomatic and life-threatening ventricular tachyarrhythmias who underwent implantation of a third generation cardioverter defibrillator using either a thoracotomy approach with epicardial leads (616 patients) or a nonthoracotomy approach with endocardial leads (605 patients) in a nonrandomized manner was analyzed. The implantable cardioverter defibrillator system permitted pacing, cardioversion, defibrillation, arrhythmia event memory and noninvasive tachycardia induction. Results. Successful implantation of an endocardial lead system was achieved in 605 (88.2%) of 686 patients and an epicardial system in 614 (99.7%) of 616 (p 0.2). Conclusions. Third-generation cardioverter defibrillators with monophasic waveforms can be successfully implanted with epicardial (99.7%) and endocardial (88.2%) lead systems. We conclude that endocardial leads should be the implant technique of first choice. Improved patient management and tolerance for device therapy is achieved with the addition of antitachycardia pacemaker capability in these systems