Conclusion: Endothelial progenitor cells positive for CD-34 and kinase domain receptor (KDR) predict occurrence of death from cardiovascular causes and cardiovascular events. Summary: Endothelial progenitor cells can differentiate into endothelial cells and proliferate. They may be candidates for mediating vascular regeneration. These cells, derived from the bone marrow, are thought to support vascular endothelium integrity. Levels of endothelial progenitor cells correlate inversely with cardiovascular risk factors. The authors sought to study the prognostic value associated with circulating endothelial progenitor cells. Endothelial progenitor cells positive for CD-34 and KDR were determined using flow cytometry. Five hundred and nineteen patients with coronary artery disease confirmed by angiography were studied. After twelve months of follow-up, association between death from cardiovascular causes, the occurrence of a first major cardiovascular event (defined as myocardial infarction, hospitalization, revascularization, or death from cardiovascular cause), revascularization, hospitalization, and death from all causes was correlated with baseline levels of endothelial progenitor cells. Two hundred and fourteen patients had a first major cardiovascular event, 43 participants died, with 23 of these deaths from cardiovascular causes. Adjusting for age, vascular risk factors, sex, and other variables relevant to cardiovascular disease, increased levels of endothelial progenitor cells were associated with a reduced risk of a first major cardiovascular event (Hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.62 to 0.89; P ϭ .002), death from cardiovascular causes, (HR 0.31; 95% CI 0.16 to 0.63; P ϭ .001), hospitalization (HR 0.76; 95% CI 0.63 to 0.94; P ϭ .01), and revascularization (HR 0.77; 95% CI 0.62 to 0.95; P ϭ .02). Myocardial infarction and death from all causes were not predicted by endothelial progenitor-cell levels. Comment: The role of endothelial progenitor cells in rejuvenation of vascular endothelium is currently an area of intensive investigation. It appears these immature cells may modify the pathogenesis of atherosclerotic disease. Measurement of endothelial progenitor cells may improve risk stratification in patients with cardiovascular disease.

In chronic inflammatory conditions, endothelial cells actively recruit immune cells from the circulation into the underlying tissue and participate in angiogenesis to support the continuous demand for oxygen and nutrients. They do so in response to activation by cytokines and growth factors such as tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), and fibroblast growth factors (FGFs). Receptor triggering initiates intracellular signal transduction leading to activation of nuclear factor kappaB (NFkappaB), mitogen activated protein kinase (MAPK) activity, and nitric oxide and reactive oxygen species production, among others. As a result, adhesion molecules, cytokines and chemokines, and a variety of other genes are being expressed that mediate and control the inflammatory process. In recent years, different classes of drugs have been developed that interfere with selected enzymes involved in the intracellular signalling cascades. In endothelial cell cultures, they exert potent inhibitory effects on the expression of genes, while several studies also report on in vivo effectiveness to confine the inflammatory responses. To prevent undesired toxicity and to improve drug behaviour and efficacy, drug carrier systems have been developed that selectively deliver the therapeutics into the activated endothelial cells. The above subjects are recapitulated to give an overview on the status of development of endothelial cell directed therapeutic strategies to pharmacologically interfere with chronic inflammatory diseases.

ALK rearrangement detection using FISH is the standard test to identify patients with non-small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH. Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH-positive advanced NSCLC from four other hospitals were used for validation. Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, = 0.01, respectively]. Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. .

A first-inhuman phase I trial of Vvax001, an alphavirusbased therapeutic cancer vaccine against human papillomavirus (HPV)-induced cancers was performed assessing immunological activity, safety, and tolerability. Vvax001 consists of replication-incompetent Semliki Forest virus replicon particles encoding HPV16-derived antigens E6 and E7. Twelve participants with a history of cervical intraepithelial neoplasia were included. Four cohorts of three participants were treated per dose level, ranging from 5 Â 10 5 to 2.5 Â 10 8 infectious particles per immunization. The participants received three immunizations with a 3-week interval. For immune monitoring, blood was drawn before immunization and 1 week after the second and third immunization. Immunization with Vvax001 was safe and well tolerated, with only mild injection site reactions, and resulted in both CD4 + and CD8 + T cell responses against E6 and E7 antigens. Even the lowest dose of 5 Â 10 5 infectious particles elicited E6/E7-specific interferon (IFN)-g responses in all three participants in this cohort. Overall, immunization resulted in positive vaccine-induced immune responses in 12 of 12 participants in one or more assays performed. In conclusion, Vvax001 was safe and induced immune responses in all participants. These data strongly support further clinical evaluation of Vvax001 as a therapeutic vaccine in patients with HPV-related malignancies.