BibSonomy publications for /user/kanefendt/&Fri Feb 05 11:28:39 CET 2010J.Pharm.Biomed.Anal.182-96Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--part III452007& Analytical Calibration Chemistry Clinical France Laboratories Laboratory Medical Pharmaceutical Reference Reproducibility Research Results Societies Standards Techniques data methods numerical of standards statistics In the first two documents [Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewe, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, J. Pharm. Biomed. Anal. 36 (2004) 579-586; Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewe, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, E. Rozet, J. Pharm. Biomed. Anal., in press], a recent SFSTP Commission on the validation of analytical procedure has introduced a harmonized approach for the validation of analytical procedures. In order to complete this guide, the statistical methodology allowing to correctly conclude about the validity of a procedure is proposed in this third part of the guide. Indeed all the steps to obtain the decision tool namely the accuracy profile are described and illustrated step by step by a numerical example. This tool, based on the concept of total error (biasFri Feb 05 11:28:39 CET 2010Ann.Oncol.101745-1747Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome182007& A Aged Agents Antineoplastic Endothelial Factor Female Growth Humans Hypertension Indoles Middle Neurotoxicity Purpura Pyrroles Receptor-2 Syndromes Thrombocytopenic Thrombotic Vascular adverse antagonists chemically effects etiology induced inhibitors Fri Feb 05 11:28:39 CET 2010Microvasc.Res.2-372-84Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization742007& Angiogenesis Animals Blood Endothelial Factors Growth Humans Inhibitors Laboratories Neoplasms Neovascularization Pathologic Research Vascular Vessels antagonists blood cells drug inhibitors pathology supply therapeutic therapy use A solid tumor forms an organ-like entity comprised of neoplastic cells and non-transformed host stromal cells embedded in an extracellular matrix. Similar to normal tissues, blood vessels nourish cells residing in tumors. However, unlike normal blood vessels, tumor vasculature has abnormal organization, structure, and function. Tumor vessels are leaky and blood flow is heterogeneous and often compromised. Vascular hyperpermeability and the lack of functional lymphatic vessels inside tumors cause elevation of interstitial fluid pressure in solid tumors. Each of these abnormalities forms a physiological barrier to the delivery of therapeutic agents to tumors. Furthermore, elevated tumor interstitial fluid pressure increases fluid flow from the tumor margin into the peri-tumor area and may facilitate peri-tumor lymphatic hyperplasia and metastasis. Abnormal microcirculation in tumors also leads to a hostile microenvironment characterized by hypoxia and acidosis, which hinder the effectiveFri Feb 05 11:28:39 CET 2010Circ.Res.3268-276Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage1012007& Adhesion Albuminuria Angiotensin Animals Atherosclerosis B Blood C57BL Cardiovascular Cell Cells Chain Chloride Cultured Dietary Diseases Endothelial Ester Expression Factor-alpha Fusion Gene Humans Hypertension I-kappa II III Inbred Inflammation Intercellular Kidney Methyl Mice Models Molecule-1 NF-kappa NG-Nitroarginine Necrosis Nephritis Nitric Organ Oxide Polymerase Pressure Proteins Reaction Receptor Recombinant Regulation Research Reverse Signal Sodium Specificity Synthase TIE-1 Transcriptase Transduction Transgenic Tumor Type Vascular antagonists biosynthesis blood cells complications control etiology genetics inhibitors metabolism physiology physiopathology prevention protein toxicity Nuclear factor kappa B (NF-kappaB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappaB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappaB super-repressor IkappaBalphaDeltaN (Tie-1-DeltaN mice) overexpression. We confirmed cell-specific IkappaBalphaDeltaN expression and reduced NF-kappaB activity after TNF-alpha stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-l-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-DeltaN and control mice. In contrast to control mice, Tie-1-DeltaN mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-kappaB targets VCAM-1 and ICAM-1, compared with contrFri Feb 05 11:28:39 CET 2010J.Urol.51883-1887Sunitinib efficacy against advanced renal cell carcinoma1782007& Administration Adult Aged Agents Antineoplastic Carcinoma Cell Disease Disease-Free Female Follow-Up Humans Indoles Kidney Laboratories Male Method Middle Neoplasm Neoplasms Oral Outcome Progression Pyrroles Rate Renal Research Retrospective Single-Blind Staging States Studies Survival Treatment Tyrosine United administration dosage drug epidemiology methods mortality pathology response therapy PURPOSE: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). RESULTS: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to pFri Feb 05 11:28:39 CET 2010Cancer Res.2593-599Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth672007& Animals Antibodies Antitumor Assays BALB Binding C Cell D Endothelial Factor Growth Human Humans Immunohistochemistry Inbred Ligands Mice Model Monoclonal Neoplasms Neovascularization Nude Pathologic Processes Receptor-3 Research Vascular Xenograft analysis antagonists blood immunology inhibitors metabolism pharmacology supply therapy Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3-treated tumors was significantly decreased and hypoxic and necrotic tumor tissue waFri Feb 05 11:28:39 CET 2010Lancet96042011-2019Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib3702007& Aged Agents Animals Antineoplastic Arteries Artery Blood Carcinoma Coronary Disease Failure Female Gastrointestinal Heart Humans Hypertension Indoles Kinase Kinases Male Mice Middle Multicenter Pressure Protein-Tyrosine Pyrroles Rats Research Retrospective Safety Stroke Stromal Studies Topic Tumors Tyrosine Volume adverse antagonists as blood chemically drug effects induced inhibitors methods therapeutic therapy toxicity use BACKGROUND: Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. METHODS: We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiFri Feb 05 11:28:39 CET 2010Int.J.Biol.Markers1 Suppl 4S10-S23Surrogate predictive biomarkers for response to anti-EGFR agents: state of the art and challenges222007& Antibodies Biological Carcinoma Dosage Drug Epidermal Factor Gene Growth Human Humans Immunohistochemistry Inhibitors Kinase Kinases Lung Markers Monoclonal Mutation Neoplasm Neoplasms Non-Small-Cell Phosphoproteins Predictive Protein Protein-Tyrosine Proteins Proto-Oncogene Quinazolines Receptor Resistance Tests Tyrosine Value analysis antagonists c-akt drug effects erbB-2 erbB-3 genetics identify inhibitors of protein response therapeutic therapy use The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clinical and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs,Fri Feb 05 11:28:39 CET 2010Clin.Res.Cardiol.11829-830Severe cardiomyopathy in a patient with renal cell carcinoma after treatment with the novel tyrosine kinase inhibitor sunitinib962007& Aged Agents Angiogenesis Antineoplastic Carcinoma Cardiomyopathies Cell Dysfunction Echocardiography Female Humans Illness Index Indoles Inhibitors Kidney Kinase Kinases Left Neoplasms Protein-Tyrosine Pyrroles Renal Severity Tyrosine Ventricular adverse antagonists chemically contraindications drug effects induced inhibitors of therapy Fri Feb 05 11:28:39 CET 2010AAPS.J.2E260-E267Appropriate calibration curve fitting in ligand binding assays92007& Algorithms Analytical Binding Calibration Chemistry Dose-Response Drug Ligands Models Pharmaceutical Pharmacokinetics Preparations Protein RANGE Relationship Reproducibility Research Results Sensitivity Specificity Statistical analysis and data metabolism methods numerical of response statistics Calibration curves for ligand binding assays are generally characterized by a nonlinear relationship between the mean response and the analyte concentration. Typically, the response exhibits a sigmoidal relationship with concentration. The currently accepted reference model for these calibration curves is the 4-parameter logistic (4-PL) model, which optimizes accuracy and precision over the maximum usable calibration range. Incorporation of weighting into the model requires additional effort but generally results in improved calibration curve performance. For calibration curves with some asymmetry, introduction of a fifth parameter (5-PL) may further improve the goodness of fit of the experimental data to the algorithm. Alternative models should be used with caution and with knowledge of the accuracy and precision performance of the model across the entire calibration range, but particularly at upper and lower analyte concentration areas, where the 4- and 5-PL algorithms generally outpFri Feb 05 11:28:39 CET 2010Nat.Rev.Cancer5332-344Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition72007& Adaptor Antibodies Benzenesulfonates Biological Delivery Diseases Drug Enzyme Heart Human Humans Indoles Inhibitors Kinase Kinases Models Monoclonal Mutation Neoplasms Protein Protein-Tyrosine Proteins Proto-Oncogene Pyridines Pyrroles Quinazolines Research Signal Systems Transducing Tyrosine adverse antagonists c-abl cells chemically development drug effects growth induced inhibitors physiology protein response therapy toxicity Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cellsFri Feb 05 11:28:39 CET 2010Proc.Natl.Acad.Sci.U.S.A4317069-17074Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy1042007& A Administration Agents Angiogenesis Animals Antineoplastic Antitumor Assays Blood Cell Dose-Response Drug Endothelial Factor Female Growth Humans Hypoxia Indoles Inducing Line Mice Model Neoplasms Organ Outcome Placenta Pregnancy Proteins Pyrroles RANGE Receptor-2 Relationship Research Schedule Scid Specificity Treatment Tumor Tyrosine Vascular Xenograft administration blood dosage drug effects metabolism pathology pharmacology protein response therapy toxicity Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibility of their exploitation as surrogate biomarkers for pharmacodynamic drug activity/exposure and patient benefit. A postulated mechanism for these changes is that they are tumor-dependent, resulting from drug-induced decreases in vascular function, increases in tumor hypoxia, and changes in hypoxia-regulated genes. However, here we report that an identical pattern of change is observed in normal nontumor-bearing mice treated with SU11248/sunitinib, a small-molecule inhibitor of VEGF and PDGF RTKs. The changes were dose-dependent, plateaued after 4 days of consecutive treatment, reversed after discontinuation of therapy, and correlated with antitumor activity. Altered proteiFri Feb 05 11:28:39 CET 2010Nat.Rev.Drug Discov.9734-745Molecular basis for sunitinib efficacy and future clinical development62007& A Angiogenesis Animals Carcinoma Clinical Design Drug Endothelial Factor France Growth Humans Indoles Inhibitors Kinase Kinases Neoplasm Neoplasms Protein-Tyrosine Pyrroles Receptors Resistance Topic Trials Tyrosine Vascular adverse antagonists as biosynthesis blood drug effects enzymology inhibitors metabolism pharmacology response supply therapeutic therapy use Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitorsFri Feb 05 11:28:39 CET 2010EXS96223-268Molecular regulation of tumor angiogenesis: mechanisms and therapeutic implications2006& Angiogenesis Capillaries Human Humans Inhibitors Neoplasms Neovascularization Pathologic Research blood control drug metabolism pathology pharmacology prevention supply therapeutic therapy use Angiogenesis, the process of new capillary formation from a pre-existing vessel plays an essential role in both embryonic and postnatal development, in the remodeling of various organ systems, and in several pathologies, particularly cancer. In the last 20 years of angiogenesis research, a variety of angiogenic regulators, both positive and negative, have been identified. The discovery of several anti-angiogenic factors has led to the development of novel cancer therapies based on targeting a tumor's vascular supply. A number of these new therapies are currently being tested in clinical trials in the U.S.A. and elsewhere. A major advance in the field of anti-angiogenic therapy occurred recently when the FDA approved Avastin (bevacizumab), the first solely anti-angiogenesis therapy approved for treatment of human cancer. While it has long been appreciated that tumor growth and progression are dependent on angiogenesis, it is only recently that progress has been made in elucidating the mFri Feb 05 11:28:39 CET 2010Eur.J.Cancer183127-3139The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review422006& A Angiogenesis Antibodies Endothelial Factor Growth Humans Inhibitors Kinase Kinases Medical Monoclonal Neoplasms Neovascularization Oncology Pathologic Protein Protein-Tyrosine Receptors Tyrosine Vascular adverse antagonists blood control drug effects inhibitors prevention protein supply therapy toxicity Clinical experience with vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors is rapidly increasing, and some compounds have already been approved for regular anticancer treatment. Apart from their activity, much attention has been focussed on the clinical toxicity profile of these compounds. This review describes the most frequently occurring side-effects of both antibodies and tyrosine kinase inhibitors and discusses some of the underlying mechanisms. Some practical guidelines for treatment of the side-effects are givenFri Feb 05 11:28:39 CET 2010Oncologist.7753-764Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions112006& A Angiogenesis Clinical Endothelial Factor Growth Human Humans Inhibitors Kinase Kinases Lung Neoplasms Piperidines Protein Protein-Tyrosine Proteins Quinazolines Receptors Research Safety Topic Trials Tyrosine Vascular antagonists as drug inhibitors metabolism protein therapeutic therapy use Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For othFri Feb 05 11:28:39 CET 2010Genes Dev.243347-3365Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway202006& Adaptation Animals Cardiac Cardiomegaly Cell Contraction Differentiation Diseases Failure Growth Heart Humans Hypertension Myocardial Myocytes Neovascularization Physiologic Physiological Proteins Proto-Oncogene Signal Sports Transduction c-akt cytology development embryology genetics growth metabolism pathology physiology physiopathology protein Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinase-dependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussedFri Feb 05 11:28:39 CET 2010Trends Cell Biol.6293-300Notch signaling in the regulation of tumor angiogenesis162006& Agents Angiogenesis Animals Binding Biological Blood Carcinogens Cells Endothelial Genes Humans Inducing Inhibitors Laboratories Ligands Models Neoplasms Neovascularization Notch Pathologic Receptors Signal Suppressor Transduction Tumor Vessels blood cells development growth metabolism physiology supply therapy The Notch signaling pathway is conserved in vertebrates and invertebrates and is involved in many developmental processes. Notch receptors and ligands are expressed on the cell surface enabling interactions between adjacent cells upon receptor-ligand binding. Notch signaling molecules have an important well-documented role in vascular development, differentiation, proliferation, apoptosis and tumorigenesis. Recently, several groups have identified the importance of Notch signaling in tumor angiogenesis. Notch activity increases specifically in tumor endothelium and in various tumors types and, in some studies, Notch signaling suppresses angiogenic processes. Because the Notch signaling pathway can mediate communication between various cell types in the tumor microenvironment, interactions between tumor cells and endothelial cells might promote angiogenesis, therefore targeting the Notch pathway might provide a novel strategy for anti-angiogenic therapies. Here, we discuss recent insighFri Feb 05 11:28:39 CET 2010Nat.Rev.Cancer6475-485Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition72007& A Administration Agents Angiogenesis Antineoplastic Biological Blood Clinical Coagulation Drug Endothelial Factor Function Growth Humans Hypertension Inhibitors Left Models Neoplasm Platelets Research Resistance Schedule Signal Thrombosis Topic Transduction Trials Vascular Ventricular administration adverse antagonists as chemically dosage drug effects etiology induced inhibitors physiology toxicity Contrary to initial expectations, angiogenesis inhibitors can cause toxicities in patients with cancer. The toxicity profiles of these inhibitors reflect the disturbance of growth factor signalling pathways that are important for maintaining homeostasis. Experiences with angiogenesis inhibitors in clinical trials indicate that short-term toxicities are mostly manageable. However, these agents will also be given in prolonged treatment strategies, so we need to anticipate possible long-term toxicities. In addition, understanding the molecular mechanisms involved in the toxicity of angiogenesis inhibition should allow more specific and more potent inhibitors to be developedFri Feb 05 11:28:39 CET 2010Pharmacogenomics.4319-327Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan82007& A Adult Aged Antibodies Antineoplastic Biological Camptothecin Chemotherapy Colorectal Combined Disease Endothelial Factor Female Growth Humans Male Markers Medical Middle Monoclonal Neoplasms Oncology Outcome Progression Prospective Protocols Rate Studies Survival Treatment Tumor Vascular administration analogs antagonists blood derivatives dosage drug inhibitors methods mortality response therapeutic therapy trends use OBJECTIVE: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. METHODS: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. RESULTS: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion