Helena Venizelou Hospital

Athens, Greece

Helena Venizelou Hospital

Athens, Greece
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Markou A.,National and Kapodistrian University of Athens | Strati A.,National and Kapodistrian University of Athens | Malamos N.,Helena Venizelou Hospital | Georgoulias V.,University General Hospital of Heraklion | Lianidou E.S.,National and Kapodistrian University of Athens
Clinical Chemistry | Year: 2011

BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) is crucial to identify novel diagnostic and therapeutic targets for individualized therapies. We developed a multiplexed PCR-coupled liquid bead array to detect the expression of multiple genes in CTCs. METHODS: mRNA isolated from immunomagnetically enriched CTCs was subjected to multiplex PCR for KRT19 (keratin 19; also known as CK19), ERBB2 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian); also known as HER2], SCGB2A2 (secretoglobin, family 2A, member 2; also known as MGB1, mammaglobin A), MAGEA3 (melanoma antigen family A, 3), TWIST-1 [twist homolog 1 (Drosophila)], and HMBS (hydroxymethylbilane synthase; also known as PBGD). Biotinylated amplicons were hybridized against fluorescent microspheres carrying gene-specific capture probes and incubated with streptavidin-phycoerythrin. Wequantified the captured labeled amplicons and decoded the beads by Luminex flow cytometry. The assay was validated for limit of detection, specificity, and comparison with reverse-transcription quantitative PCR (RT-qPCR), and its clinical performance was evaluated in 64 patients with operable breast cancer, 20 patients with metastasis, and 17 healthy individuals. RESULTS: The assay was specific for each gene in complex multiplexed formats and could detect the expression of each gene at the level of a single SK-BR-3 cell. The assay produced results comparable to those for RT-qPCR for each gene. None of the genes tested was detected in the CTC fraction of healthy donors. We detected KRT19, ERBB2, MAGEA3, SCGB2A2, and TWIST1 in 26.6%, 12.5%, 18.7%, 10.9%, and 31.2% of operable breast cancer patients, respectively, and detected the corresponding genes in 65%, 20%, 30%, 20%, and 20% of patients with verified metastasis, respectively. CONCLUSIONS: The expression of 6 genes in CTCs can be measured simultaneously and reliably, thereby saving precious sample and reducing the costs and time of analysis. © 2010 American Association for Clinical Chemistry.


Thomopoulos C.,Helena Venizelou Hospital | Skalis G.,Helena Venizelou Hospital | Michalopoulou H.,Helena Venizelou Hospital | Tsioufis C.,National and Kapodistrian University of Athens | Makris T.,Helena Venizelou Hospital
Clinical Cardiology | Year: 2015

This analysis investigated the extent of different outcome reductions from low-density lipoprotein cholesterol (LDL-C) lowering following ezetimibe/simvastatin treatment and the proportionality of outcome to LDL-C reductions. The authors searched PubMed between 1997 and mid-June 2015 (any language) and the Cochrane Library to identify all randomized controlled trials comparing ezetimibe/simvastatin with placebo or less intensive LDL-C lowering. Risk ratios (RR) and 95% confidence intervals (CIs), standardized to 20 mg/dL LDL-C reduction, were calculated for 5 primary outcomes (fatal and nonfatal) and 4 secondary outcomes (non-cardiovascular [CV] death, cancer, myopathy, and hepatopathy). Five ezetimibe/simvastatin RCTs (30 051 individuals) were eligible, 2 comparing ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment. Outcomes reduced almost to the same extent were stroke (RR: -13%, 95% CI: -21% to -3%), coronary heart disease (CHD; RR: -12%, 95% CI: -19% to -5%), and composite of stroke and CHD (RR: -14%, 95% CI: -20% to -8%). Absolute risk reductions: 5 strokes, 10 CHD events, and 16 stroke and CHD events prevented for every 1000 patients treated for 5 years. Residual risk was almost 7× higher than absolute risk reduction for all the above outcomes. All death outcomes were not reduced, and secondary outcomes did not differ between groups. Logarithmic risk ratios were not associated with LDL-C lowering. Our meta-analysis provides evidence that, in patients with different CV disease burden, major CV events are safely reduced by LDL-C lowering with ezetimibe/simvastatin, while raising the hypothesis that the extent of LDL-C lowering might not be accompanied by incremental clinical-event reduction. © 2015 Wiley Periodicals, Inc.


Markou A.,National and Kapodistrian University of Athens | Farkona S.,National and Kapodistrian University of Athens | Schiza C.,National and Kapodistrian University of Athens | Efstathiou T.,National and Kapodistrian University of Athens | And 4 more authors.
Clinical Cancer Research | Year: 2014

Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while PIK3CA somatic mutations play a crucial role in therapy response. We investigated the presence of PIK3CA mutations in CTC and whether this is associated with clinical outcome.We developed and validated an ultrasensitive methodology for the detection of PIK3CA mutations that is based on a combination of allele-specific, asymmetric rapid PCR and melting analysis. We analyzed PIK3CA hotspot mutations in: (i) a training group consisting of EpCAM-positive CTC fraction from 37 patients with clinically confirmed metastasis, and 26 healthy female volunteers and 15 primary breast tumor tissues and (ii) an independent group consisting of EpCAM-positive CTC fraction from 57 metastatic and 118 operable breast cancer patients and 76 corresponding primary tumors.The assay could detect 0.05% of mutated dsDNA in the presence of 99.95% wtDNA for both exons (9 and 20) and was highly specific (0/26 healthy donors). PIK3CA mutations were identified in EpCAM-positive CTC in 20 of 57(35.1%) and in 23 of 118 (19.5%) patients with metastatic and operable breast cancer, and in 45 of 76(59.2%) corresponding FFPEs. Our data indicate that PIK3CA mutational status in CTCs can change during disease progression and is associated with worse survival (P ? 0.047).PIK3CA hotspot mutations are present at a relatively high frequency in CTCs and their presence is associated with worse survival in patients with breast cancer with metastasis. Evaluation of PIK3CA mutational status in CTCs is a strategy with potential clinical application. Clin Cancer Res; 20(22); ©-2014 American Association for Cancer Research.


Zanchetti A.,Instituto Auxologico Italiano | Zanchetti A.,University of Milan | Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Instituto Auxologico Italiano | Parati G.,University of Milan Bicocca
Circulation Research | Year: 2015

Sixty-eight blood pressure (BP)-lowering randomized controlled trials (defined as randomized controlled trials comparing active treatment with placebo, or less active treatment, achieving a BP difference, performed between 1966 and end 2013 in cohorts with ≥40% hypertensive patients, and exclusive of trials in acute myocardial infarction, heart failure, acute stroke, and dialysis) were identified and meta-analyzed grouping the randomized controlled trials on the basis of clinically relevant questions: (1) does BP lowering reduce all types of cardiovascular outcome? (2) Is prevention of all outcomes proportional to the extent of systolic, diastolic, and pulse BP? (3) Have all classes of BP-lowering drugs been shown capable of reducing all types of cardiovascular outcome? (4) Is BP lowering beneficial when intervention is initiated at any grade (or stage) of hypertension? (5) Do BP-lowering randomized controlled trials provide evidence about systolic BP and diastolic BP targets of treatment? (6) Should BP-lowering treatment be preferentially addressed to patients in higher risk categories promising larger absolute treatment benefits? The results of these meta-analyses provide further support to current hypertension treatment guidelines by showing that BP lowering can significantly reduce major cardiovascular outcomes largely independent of the agents used, significant risk reduction is found at all hypertension grades (stages), and when systolic BP is lowered below a cut off of 140 mm Hg with some further reduction limited to stroke at systolic BP values just <130 mm Hg. Absolute risk reduction progressively increases higher is total cardiovascular risk, but this greater benefit is associated with a progressively higher residual risk, ie, higher treatment failures. © 2015 American Heart Association, Inc.


Peitsidis P.,Helena Venizelou Hospital
Expert Opinion on Pharmacotherapy | Year: 2012

The use of selective progesterone modulators (SRMs) has been investigated extensively over the last few years. Ulipristal acetate (UPA) is an selective progesterone receptor modulator (SPRM) which has been in use since 2010 as an effective alternative emergency contraception (EC) regimen to Levonorgestrel (LNG). It acts by inhibiting ovulation and delaying implantation. Its effectiveness is active up to 120 h after sexual intercourse. UPA is safe and has a good tolerability profile. Health care practitioners should inform women of all reproductive ages that UPA is an effective alternative agent for those who are dissatisfied with other means of EC, and its activity of up to 120 h after sexual intercourse should also be highlighted. © 2012 Informa UK, Ltd.


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,San Luca Hospital | Parati G.,University of Milan Bicocca | Zanchetti A.,Instituto Auxologico Italiano IRCCS | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Randomized controlled trials (RCTs) of blood pressure (BP) lowering lend themselves to be meta-analyzed to help providing evidence-based recommendations for hypertension treatment. Objectives: To investigate whether relative or absolute risk reductions increase at increasing levels of baseline cardiovascular risk and whether BP-lowering treatment should be addressed to patients in risk categories promising larger absolute treatment benefits. Methods: Sixty-eight RCTs of intentional and nonintentional BP lowering were classified in four strata of increasing average 10-year incidence of cardiovascular death in the placebo or less active treatment group: lowto- moderate risk (<5%; 23 RCTs, 81 675 individuals), high risk (5% to <10%; 11 RCTs, 46 162 individuals), very high risk (10% to <20%; 19 RCTs, 91 152 individuals), and very very high risk (≥20%; 16 RCTs, 26 881 individuals). Risk ratios and 95% confidence intervals (CIs; random-effects model) standardized to 10/5mmHg SBP/DBP reduction, absolute risk reduction, and residual risk of seven major fatal/nonfatal outcomes were calculated. Relative and absolute risk reductions in the cardiovascular risk strata were compared by the trend analysis, residual risk by calculating odds ratio (OR) relative to low-to-moderate risk. Results: Relative reductions of all outcomes did not differ in the risk strata, but absolute reductions significantly increased with increasing cardiovascular risk (P for trend <0.001 except for CHD): a 10/5mmHg SBP/DBP reduction reduced the incidence of major cardiovascular events by 7 (95% CI 3-10), 30 (9-50), 56 (35-76), and 87 (62-112) events every 1000 patients treated 5 years, with increasing cardiovascular risk. However, also residual risk significantly (P < 0.001) increased with increasing cardiovascular risk [up to an OR 9.43 (8.60-10.35) for cardiovascular death]. The increase in residual risk with increasing level of cardiovascular risk persisted when RCTs with average initial age at least 65 years were excluded, and mean ages at the different cardiovascular risk levels were comparable. Conclusion: BP-lowering treatment induces greater absolute risk reductions the higher the cardiovascular risk level, but a higher risk level is also associated with higher absolute residual risk, independent of age. Whereas reserving antihypertensive treatment to high-risk hypertensive patients maximizes the cost-benefit ratio, only treatment of low-to-moderate risk hypertensive patients may prevent the increasing number of treatment failures when treatment is initiated at higher risk. Copyright © Lippincott Williams & Wilkins.


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,San Luca Hospital | Parati G.,University of Milan Bicocca | Zanchetti A.,Instituto Auxologico Italiano IRCCS | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Relevant clinical questions not approached by randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment can be explored by meta-analyses stratified by clinical criteria. Objectives: Investigating whether all grades of hypertension benefit from BP-lowering treatment and which are the target BP levels to maximize outcome reduction. Methods: Of the 68 RCTs of intentional and nonintentional BP-lowering, those without baseline antihypertensive drugs were stratified by the average baseline SBP and DBP (hypertension grades 1, 2, and 3). RCTs with or without baseline treatment were considered for investigating the effects of mean achieved SBP/DBP across three SBP cutoffs and two DBP cutoffs. Risk ratios (RR) and 95% confidence interval (CI) (random-effects model), standardized to 10/5mmHg SBP/DBP reduction, and absolute risk reductions of seven fatal and nonfatal outcomes were calculated. Differences between relative and absolute risk reductions in the different strata of baseline or achieved SBP/DBP were evaluated by trend or heterogeneity analyses. Results: In 32 RCTs (104 359 individuals), significant outcome reductions were found independently of the hypertension grade, with no trend toward risk ratio changes with increasing baseline BP. A secondary analysis limited to RCTs on grade 1 hypertension at low-to-moderate risk showed significant outcome reductions [risk ratio: stroke 0.33 (0.11-0.98), coronary events 0.68 (0.48-0.95), and death 0.53 (0.35-0.80)]. In 32 RCTs (128 232 individuals), relative and absolute outcome reductions were significant for the SBP differences across 150 and 140mmHg cutoffs. Below 130 mmHg, only stroke and all-cause death were significantly reduced. Absolute outcome reduction showed a significant trend to decrease, the lower the SBP cutoff considered. In 29 RCTs (107 665 individuals), outcomes were significantly reduced across DBP cutoffs of 90 and 80 mmHg. After excluding RCTs with baseline DBP less than 90 mmHg, only stroke reduction was significant at achieved DBP less than 80 mmHg. Conclusion: Meta-analyses favor BP-lowering treatment even in grade 1 hypertension at low-to-moderate risk, and lowering SBP/DBP to less than 140/90 mmHg. Achieving less than 130/80mmHg appears safe, but only adds further reduction in stroke. Copyright © Lippincott Williams & Wilkins.


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,San Luca Hospital | Parati G.,University of Milan Bicocca | Zanchetti A.,Instituto Auxologico Italiano IRCCS | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Antihypertensive treatment is based on randomized controlled trials (RCTs) started since 1966. Meta-analyses comprehensive of all RCTs but limited to RCTs investigating blood pressure (BP) lowering in hypertensive patients are lacking. Objectives: Two clinical questions were investigated: the extent of different outcome reductions by BP lowering in hypertensive patients, and the proportionality of outcome reductions to SBP, DBP, and pulse pressure (PP) reductions. Methods: PubMed between 1966 and December 2013 (any language), Cochrane Collaboration Library and previous overviews were used as data sources for identifying and selecting all RCTs comparing the antihypertensive drugs with placebo or less intense BP lowering (intentional BP-lowering RCTs); comparing BP-lowering drugs with placebo without BP-lowering intention, but with BP difference (nonintentional BPlowering RCTs); and enrolling at least 40% hypertensive patients. RCTs on acute myocardial infarction, heart failure, acute stroke, and dialysis were excluded. RCT quality was assessed by scoring. Risk ratios and 95% confidence interval (CI), standardized to 10/5mmHg SBP/DBP reduction, of seven fatal and nonfatal outcomes were calculated (random-effects model). The relationships of different outcome reductions to SBP, DBP, and PP reductions were investigated by meta-regressions. Results: A total of 68 RCTs (245 885 individuals) were eligible, of which 47 (153 825 individuals) were 'intentional' RCTs. All outcomes were reduced (P < 0.001) by BP lowering, stroke [-36% (-29, -42)], and heart failure [-43% (-28, -54)] to a greater extent, with smaller reductions for coronary events [coronary heart disease (CHD): -16% (-10, -21)], cardiovascular [-18% (-11, -24)], and all-cause mortality [-11% (-5, -16)]. Absolute risk reductions were 17 (14, 20) strokes, 28 (19, 35) cardiovascular events, and 8 (4, 12) deaths prevented every 1000 patients treated for 5 years. Logarithmic risk ratios were related to SBP, DBP, and PP reductions (P = 0.001-0.003) for stroke and composite cardiovascular events, but not for CHD. Conclusion: Meta-analyses of all BP-lowering RCTs involving hypertensive patients provide precise estimates of benefits (larger for stroke and heart failure, but also significant for CHD and mortality). Absolute risk reductions are substantial. Relationships of logarithmic risk ratios with BP reductions imply risk reduction increases progressively to a smaller extent the larger the BP reduction. Copyright © Lippincott Williams & Wilkins.


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,San Luca Hospital | Parati G.,University of Milan Bicocca | Zanchetti A.,Instituto Auxologico Italiano IRCCS | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2015

Background and objectives: In 68 randomized controlled trials (RCTs), blood pressure (BP) lowering was obtained by using drugs of different classes. We have investigated whether BP lowering by any of the major drug classes is effective in reducing the cardiovascular outcomes. Methods: A total of 55 RCTs (195 267 individuals) were suitable for drug-class meta-analyses. Risk ratios and their 95% confidence intervals of seven fatal and nonfatal outcomes were estimated by a random-effects model. Results: Twelve RCTs (48 898 patients) compared a diuretic with no treatment. SBP/DBP differences of about -12/-5 mmHg were accompanied by significant reductions of all outcomes, including mortality. The same results were obtained by limiting analyses to eight RCTs using low-dose diuretics. Separate analyses for thiazides, chlorthalidone and indapamide (all low dose) showed each subclass was associated with significant reduction of some major outcome. Five RCTs (18 724 patients; SBP/DBP difference -10.5/-7 mmHg) showed beta-blockers significantly reduced stroke, heart failure and major cardiovascular events. In RCTs comparing calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with placebo smaller SBP/DBP differences were achieved, mostly because in the majority of these later RCTs the antihypertensive drug and placebo were added on a background treatment with other antihypertensive agents. Nonetheless, significant reductions of stroke, major cardiovascular events, cardiovascular and all-cause death were obtained with calcium antagonists (10 RCTs, 30 359 patients); stroke, coronary heart disease, heart failure and major cardiovascular events by ACE inhibitors (12 RCTs, 35 707 patients); and stroke, heart failure and major cardiovascular events by ARBs (13 RCTs, 65 256 patients). Conclusion: BP lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular events. This supports the concept that reduction of these events is because of BP lowering per se rather than specific drug properties. However, evidence of risk reduction of other events and particularly mortality was obtained so far with some drug classes only. As a result of marked differences in the trial design, total cardiovascular risk, SBP/DBP differences and statistical power, comparisons of meta-analyses of different drug-specific placebo-controlled RCTs appear unwarranted. © 2015 Wolters Kluwer Health, Inc.


Thomopoulosa C.,Helena Venizelou Hospital | Paratib G.,San Luca Hospital | Paratib G.,University of Milan Bicocca | Zanchettic A.,University of Milan
Journal of Hypertension | Year: 2015

Background and objectives: We have recently published an overview and meta-analysis of the effects of the five major classes of blood pressure-lowering drugs on cardiovascular outcomes when compared with placebo. However, possible differences in effectiveness of the various classes can correctly be estimated only by head-tohead comparisons of different classes of agents. This has been the objective of a new survey and meta-analysis. Methods: A database search between 1966 and August 2014 identified 50 eligible randomized controlled trials for 58 two-drug comparisons (247 006 patients for 1 029 768 patient-years). Risk ratios and their 95% confidence intervals of seven outcomes were estimated by a randomeffects model. Results: The effects of all drug classes are not significantly different on most outcomes when their blood pressure effect is equivalent. However, there are also significant differences involving almost all classes of drugs. When compared to all other classes together, diuretics are superior in preventing heart failure; beta-blockers less effective in preventing stroke; calcium antagonists superior in preventing stroke and all-cause death, but inferior in preventing heart failure; angiotensin-converting enzyme inhibitors more effective in preventing coronary heart disease and less in preventing stroke; angiotensin receptor blockers inferior in preventing coronary heart disease; and renin-angiotensin system blockers more effective in preventing heart failure. When stratifying randomized controlled trials according to total cardiovascular risk, no drug class was found to change in effectiveness with the level of risk. Conclusions: The results of all available evidence from head-to-head drug class comparisons do not allow the formulation of a fixed paradigm of drug choice valuable for all hypertensive patients, but the differences found may suggest specific choices in specific conditions, or preferable combinations of drugs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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