Comparison of the diagnostic performance of 64-slice computed tomography coronary angiography in diabetic and non-diabetic patients with suspected coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Diabetics have high prevalence of subclinical coronary artery disease (CAD) with typical characteristics (diffuse disease, large calcifications). Although 64-slice multidetector computed tomography (MDCT) coronary angiography has high diagnostic accuracy to detect CAD, its diagnostic performance in diabetics with suspected CAD is unknown. To compare the diagnostic performance of 64-slice MDCT between diabetics and non-diabetics with suspected CAD scheduled for invasive coronary angiography (ICA).</p> <p>Methods</p> <p>We enrolled one hundred and five diabetic patients (92 men, age 65 +/- 9 years, Group 1) and 105 non-diabetic patients (63 men, age 63+/-5 years, Group 2) with indication to ICA for suspected CAD undergoing coronary 64-slice MDCT before ICA.</p> <p>Results</p> <p>In Group 1, the overall feasibility of coronary artery visualization was 93.8%. The most frequent artifact was blooming due to large coronary calcifications (54 artifacts, 67%). In Group 2, the overall feasibility was significantly higher vs. Group 1 (97%, p < 0.0001). In Group 1, the segment-based analysis showed a MDCT sensibility, specificity, positive predictive value, negative predictive value and accuracy for the detection of ≥50% luminal narrowing of 77%, 90%, 70%, 93% and 87%, respectively. In Group 2, all these parameters were significantly higher vs. Group 1. In the patient-based analysis, specificity, negative predictive value and accuracy were significantly lower in Group 1 vs. Group 2.</p> <p>Conclusions</p> <p>Although MDCT has high sensitivity for early identification of significant CAD in diabetics, its diagnostic performance is significantly reduced in these patients as compared to non-diabetics with similar clinical characteristics.</p

Coronary atherosclerosis in outlier subjects at the opposite extremes of traditional risk factors: Rationale and preliminary results of the Coronary Atherosclerosis in outlier subjects: Protective and novel Individual Risk factors Evaluation (CAPIRE) study

Although it is generally accepted that cardiac ischemic events develop when coronary atherosclerosis (coronary artery disease [CAD]) has reached a critical threshold, this is true only to a first approximation. Indeed, there are patients with severe CAD who do not develop ischemic events; conversely, at the other extreme, individuals with minimal CAD may do. Similar exceptions to this paradigm include patients with diffuse CAD with a low risk factor (RF) profile and others with multiple RFs who develop only mild or no CAD. Therefore, the CAPIRE project was designed to investigate whether the specific study of these extreme outlier populations could provide clues for identification of yet unknown risk or protective factors for CAD and ischemic events. In the CAPIRE study, 481 subjects without previous symptoms or history of ischemic heart disease and normal left ventricular systolic function undergoing coronary computed tomography angiography have been selected based on coronary computed tomography angiography findings and cardiovascular RF profile. Therefore, in the whole population, 2 extreme outlier populations have been identified: (1) subjects with no CAD despite multiple RFs, and (2) at the opposite extreme, subjects with diffuse CAD despite a low-risk profile. Each subject has been characterized by clinical, anatomical imaging variables of CAD and baseline circulating biomarkers. Blood samples were collected and stored in a biological bank for further advanced investigations. The project is designed as a prospective, observational, international multicenter study with an initial cross-sectional analysis of clinical, imaging, and biomolecular variables in the selected groups and a longitudinal 5-year follow-up

Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

The High-Level Interface Definitions in the ASTRI/CTA Mini Array Software System (MASS)

ASTRI (Astrofisica con Specchi a Tecnologia Replicante Italiana) is a Flagship Project funded by the Italian Ministry of Education, University and Research, and led by INAF, the Italian National Institute of Astrophysics. Within this framework, INAF is currently developing an end-to-end prototype, named ASTRI SST-2M, of a Small Size Dual-Mirror Telescope for the Cherenkov Telescope Array, CTA. A second goal of the project is the realization of the ASTRI/CTA mini-array, which will be composed of seven SST-2M telescopes placed at the CTA Southern Site. The ASTRI Mini Array Software System (MASS) is designed to support the ASTRI/CTA mini-array operations. MASS is being built on top of the ALMA Common Software (ACS) framework, which provides support for the implementation of distributed data acquisition and control systems, and functionality for log and alarm management, message driven communication and hardware devices management. The first version of the MASS system, which will comply with the CTA requirements and guidelines, will be tested on the ASTRI SST-2M prototype. In this contribution we present the interface definitions of the MASS high level components in charge of the ASTRI SST-2M observation scheduling, telescope control and monitoring, and data taking. Particular emphasis is given to their potential reuse for the ASTRI/CTA mini-array

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Molecular predictors of efficacy to anti-EGFR agents in colorectal cancer patients

Recent insights into the molecular pathogenesis of colorectal cancer (CRC) have given rise to specific target-directed therapies, including monoclonal antibodies (mAb) against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These drugs have been approved as first, second and third line therapies for metastatic CRC (mCRC) and the advent of target-specific cancer therapeutics has remarkably improved the outcomes of patients with CRC. The molecular mechanisms underlying the clinical response to these drugs are not fully understood, although recent studies have elucidated the effect of intracellular signaling pathways involving in particular RAS/RAF/MAPK signaling on the safety and efficacy of target-specific drugs. Activating mutations of KRAS and BRAF genes are genetic events in tumorigenesis and these mutations are implicated as predictive factors in determining response, in particular to anti-EGFR drugs, and additional data suggest that other EGFR downstream pathways such as PI3K/PTEN/Akt or JAK/STAT are also important when considering mechanisms of EGFR antibody resistance. Recently the European Medical Agency (EMEA) approved the use of the mAb Panitumumab (December 2007) and approved a license extension for the use of the mAb Cetuximab in combination with chemotherapy as first-line treatment (October 2008) in mCRC patients with no mutations in the codon 12 and 13 of KRAS gene. The predictive value of KRAS mutations in the treatment of CRC has been very useful to clinicians and patients in terms of decision making, avoiding toxicities, and decreasing financial burden. This success also encourages researchers to find new markers with the same strong predictive value. Future studies also need to identify patterns of multiple mutations to further increase the power of patient selection for anti-EGFR therapy. These advances allow us to truly enter a new and exciting era of individualized therapy in oncology. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatments conferred by KRAS and other gene mutations as well as the laboratory methods used to detect all these genetic variations