Dimitrios Pectasides

Hippokration General Hospital, Athens, Athínai, Attica, Greece

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Publications (124)553.09 Total impact

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    ABSTRACT: To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62 % of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.
    Pathology oncology research : POR. 08/2014;
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    ABSTRACT: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet.
    BMC Cancer 07/2014; 14(1):515. · 3.33 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality attributed to traditional cardiovascular risk factors and/or the chronic systemic inflammation. We investigated the effect of a TNF antagonist (adalimumab-ADA) on aortic stiffness in RA patients. We studied 18 RA patients with active disease despite therapy with disease modifying antirheumatic drugs (DMARDs), treated with ADA (alone or in combination with DMARDs) for 12 weeks. Disease activity markers as well as aortic stiffness indices (carotid-femoral pulse wave velocity-PWV, augmentation index-AIx), were measured at baseline and at the end of treatment. Eighteen RA patients treated with methotrexate (MTX) were included as controls. Patients were categorized as responders (decrease of Disease Activity Score-DAS28 > 1.2) or nonresponders. There was a statistically significant decrease in PWV (from 8.18 ± 2.03 to 7.01 ± 1.78 m/s, p = 0.00006) and DAS28 (from 6.65 ± 1.22 to 4.69 ± 1.46, p = 0.00007) in RA patients treated with ADA. The decrease in PWV was observed both in responders (n = 12) and nonresponders (n = 6). Multivariate analysis showed that the decrease of PWV was independent of changes in disease activity or other parameters. There was no significant change in PWV in patients treated with MTX (from 8.87 ± 1.91 to 8.41 ± 2.17, p = 0.29). No significant change in AIx or traditional cardiovascular risk factors was observed. Treatment with ADA significantly reduced aortic stiffness in RA patients regardless of their response to therapy. These findings imply a direct protective effect of ADA in vascular wall in RA patients.
    Clinical rheumatology. 06/2014;
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    ABSTRACT: Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 226 patients with advanced or metastatic colorectal cancer that had been treated with cetuximab. Clinical information was collected retrospectively from the patients' medical records. After central evaluation, 147 cases with adequate material were eligible for further evaluation. EGFR and PTEN status was evaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Data were associated with cetuximab treatment outcome. Additional analysis was performed with previously published data on PIK3CA, BRAF and KRAS mutation status and EGFR ligand amphiregulin (AREG) and epiregulin intratumoral mRNA expression levels. PIK3CA mutation status and PTEN protein expression were also analyzed as a single complex parameter, to evaluate the predictive value of PI3K/PTEN axis dysfunction as one entity. Analysis showed a borderline association of overall response rate (ORR) and time to progression (TTP) with EGFR protein overexpression by IHC (p = 0.059 and p = 0.057, respectively) and a positive association of EGFR gain by FISH (found in only five cases) with longer TTP (p = 0.026). No association was found between ORR or TTP and PTEN IHC or FISH status. Comparative analysis with previously published data showed that PTEN protein expression is associated with longer TTP in patients with wild-type (WT) KRAS (p = 0.036) and especially in the ones with elevated AREG levels (p = 0.046), as well as in patients with both KRAS and BRAF WT (p = 0.019). Patients with both PIK3CA WT and PTEN protein expression had significantly longer TTP (p = 0.010) versus all others, in the absence of BRAF and KRAS mutations, a finding which persisted in the KRAS WT/AREG high subgroup (p = 0.046). In this cetuximab-treated colorectal cancer population, EGFR gain was associated with better outcome and PTEN protein expression with longer TTP in KRAS WT, KRAS WT/AREG high and KRAS/BRAF WT subpopulations. Cetuximab efficacy is greater with intact and activated EGFR signaling, without activating mutations of KRAS/BRAF and in the presence of preserved PTEN inhibitory activity upon the PI3K/AKT pathway. These results reflect a solid biological rationale and warrant further evaluation of the predictive role of PTEN in prospective studies.
    Journal of Cancer Research and Clinical Oncology 03/2014; · 2.91 Impact Factor
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    ABSTRACT: We investigated the utility of liver function breath tests [C-Aminopyrine Breath Test (C-ABT), C-Galactose Breath Test (C-GBT)], for the diagnosis of nonalcoholic steatohepatitis (NASH) among nonalcoholic fatty liver disease (NAFLD) patients. Liver biopsy is currently the gold standard for the differentiation between simple fatty liver (NAFL) and NASH in NAFLD patients. Thirty-six patients with histologically proven NAFLD (NAFL:16, NASH:20) underwent C-ABT and C-GBT. The results were expressed as the percentage of administered C dose recovered per hour (%dose/h) and as cumulative percentage of administered C dose recovered over time (%cumulative dose). Histologic lesions were scored according to Brunt and Kleiner's classifications. C-ABT results correlated inversely with activity grade (r=-0.650, P=0.001), NAFLD activity score (r=-0.473, P=0.026), and fibrosis stage (r=-0.719, P=0.001). Compared with NAFL, NASH patients had significantly lower %dose/h and %cumulative dose at 60, 90, and 120 minutes (always P<0.04) by C-ABT. C-ABT %dose/h and %cumulative dose at 120 minutes could predict the presence of NASH (area under the receiver operating characteristic curve: 0.762 and 0.741, respectively). In contrast, there was no significant association between C-GBT results and any patient characteristic. In the NAFLD patients, decreased and delayed liver microsomal function, as assessed by C-ABT, is associated with more severe necroinflammation and fibrosis, whereas C-ABT results at 120 minutes may be helpful for the diagnosis of NASH.
    Journal of clinical gastroenterology 01/2014; 48(1):59-65. · 2.21 Impact Factor
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    ABSTRACT: We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.
    PLoS ONE 01/2014; 9(6):e99131. · 3.73 Impact Factor
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    Gerasimos Aravantinos, Dimitrios Pectasides
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    ABSTRACT: As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.
    Journal of Ovarian Research 01/2014; 7:57. · 2.43 Impact Factor
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    ABSTRACT: Background The prognostic utility of VEGF-A splice variants in advanced breast cancer patients treated with bevacizumab (Bev) has not been studied. Patients and Methods 111 patients with metastatic breast cancer treated with weekly docetaxel or ixabepilone without bevacizumab (Cohort A) and 100 treated with weekly paclitaxel and bevacizumab (Cohort B) were studied. Formalin-fixed tumors were macrodissected for RT-qPCR relative quantification of VEGF-A165, 189, 206 isoforms spliced at exon 8 proximal site (VEGF-Axxxa) and at exon 8 distal splice site (VEGF-Axxxb). Results For high VEGF-Axxxa, the Hazard Ratio (HR) for progression was 1.08 (p=0.71) in non-Bev treated patients (Cohort A) and 0.66 (p=0.22) in Bev-treated patients (Cohort B), while the HR for death was 1.45 (p=0.13) and 0.50 (p=0.049) respectively. The interaction of VEGF-Axxxa with bevacizumab administration was significant (p=0.011) for OS. High tissue VEGF-Axxxb was not prognostic in Cohort A but was predictive for Bev benefit in Cohort B (HR for progression 0.57, p=0.04 and HR for death 0.51, p=0.02). Exploratory analyses done only in Cohort B suggested that abundance of VEGFR1 mRNA in peripheral blood and low VEGFR2 mRNA in tissue correlated with poor outcome. In multivariate analysis, high tissue mRNA of angiogenic VEGF-Axxxa in the presence of bevacizumab therapy predicted for favorable PFS (HR for progression 0.39, p=0.0227) and OS (HR for death 0.32, p=0.0140). Conclusions Tissue mRNA expression of angiogenic VEGF-Axxxa isoforms was retrospectively associated with adverse prognosis in the absence of bevacizumab and with favorable outcome when bevacizumab was administered in patients with advanced breast cancer.
    Clinical Breast Cancer 01/2014; · 2.42 Impact Factor
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    ABSTRACT: alphaB-crystallin is a small heat shock protein that has recently been characterized as an oncoprotein correlating with the basal core phenotype and with negative prognostic factors in breast carcinomas. The purpose of this study was to evaluate alphaB-crystallin with respect to clinicopathological parameters and the outcome of patients with operable high-risk breast cancer.
    BMC Clinical Pathology 01/2014; 14:28.
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    ABSTRACT: The 13C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function which has been shown to correlate inversely to the Child-Pugh score. The aim of the study was to determine the utility of CBT in the assessment of cirrhosis and its correlation to the model for end-stage liver disease (MELD) score. Thirty-nine patients, 29 with cirrhosis and 10 with chronic liver disease without cirrhosis, and 8 healthy volunteers were included. Cirrhotic patients were graded according to Child-Pugh and MELD scores. All participants underwent CBT and laboratory tests on the same day. The results of the CBT were expressed as percentages of changes over baseline values (Δ‰) per 100 mg caffeine. The mean single 15-min, 30-min, 45-min and 1-h CBT results, as well as cumulative CBT values differed significantly between healthy controls or chronic liver disease patients and cirrhotics (1-h CBT: 3.22±1.06 or 3.56±2.80 vs. 1.69±2.52, P≤0.01). In contrast, the CBT results at any time point or cumulative values did not correlate with MELD or Child-Pugh scores. Receiver operating characteristics (ROC) analysis showed that the 30-min CBT values were more accurate in differentiating cirrhotics from chronic liver disease patients (area under ROC curve: 0.871). CBT can reliably differentiate the patients with decompensated cirrhosis from non-cirrhotic patients with chronic liver diseases. However, in patients with decompensated cirrhosis, CBT results do not seem to be associated with the Child-Pugh and MELD scores.
    Annals of Gastroenterology 01/2014; 27(1):53-59.
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    ABSTRACT: Triple negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study (GWAS) of TN breast cancer (stage 1: 1,529 TN cases, 3,399 controls; stage 2: 2,148 cases, 1,309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (p<5x10(-8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the SNPs analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (p<0.05). Associations with TN breast cancer were confirmed for ten loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (p<0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 (rs12525163 Odds Ratio (OR)=1.15, p=4.9x10(-4)) and 19p13.1 (rs1864112 OR=0.84, p=1.8x10(-9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR=4.03, 95% CI 3.46-4.70, p=4.8x10(-69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
    Carcinogenesis 12/2013; · 5.64 Impact Factor
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    ABSTRACT: Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit. Formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 (IGFBP2), insulin growth factor receptor 1 (IGF1R), cMET, EphA2, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR). Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin (AREG) mRNA levels in KRAS wild-type tumors (HR, 0.17; P < .0001), and high epiregulin (EREG) mRNA levels (HR, 0.38; P = .006). High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC.
    Clinical Colorectal Cancer 09/2013; · 1.80 Impact Factor
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    ABSTRACT: Serum HBsAg levels might represent an important predictor of sustained off-treatment response in HBeAg-negative chronic hepatitis B (CHB). We evaluated the changes of HBsAg and interferon-inducible protein 10 (IP10) serum levels in HBeAg-negative CHB patients treated with entecavir. 114 patients received entecavir for a median of 4.3 years. HBsAg levels were determined at baseline, 6 and 12 months and every year thereafter until year-4. IP10 levels were measured at baseline and annually until year-4 in 76 patients. Virological remission rates were high (year-1: 94%, after year-2: 97-98%). Compared to baseline, HBsAg levels decreased by a median of 0.03, 0.13, 0.17, 0.22, and 0.32 log10 IU/mL at 6 months and 1, 2, 3 and 4 years, respectively (P⩽0.001 for all comparisons). The proportions of patients with HBsAg decline of ⩾0.5 or ⩾1 log10 IU/mL were 9% or 6% at year-1 and 21% or 10% at the last visit. Median IP10 levels (pg/mL) did not change from baseline to year-1 or -2 (245 vs 229 or 251), but increased at year-3 and -4 (275 and 323, P<0.030). HBsAg drop ⩾0.5 log10 was associated with baseline IP10 or IP10 >350 pg/mL (P⩽0.002). HBsAg loss occurred in 4/114 (3.5%) patients or in 1/2, 3/21 and 0/91 patients with baseline HBsAg <100, 100-1000 and >1000 IU/mL, respectively (P<0.001). In HBeAg-negative CHB patients, 4-year entecavir therapy decreases serum HBsAg levels, but the rate of decline is rather slow. Serum IP10 levels represent a promising predictor of HBsAg decline in this setting.
    Journal of Hepatology 09/2013; · 9.86 Impact Factor
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    ABSTRACT: BACKGROUND: The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >=2.2 and >=2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated. RESULTS: HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death. CONCLUSION: HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy.Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202.
    BMC Cancer 03/2013; 13(1):163. · 3.33 Impact Factor
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    ABSTRACT: Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23–24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.
    PLoS ONE 03/2013; · 3.73 Impact Factor
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    ABSTRACT: BACKGROUND: Spontaneous bacterial peritonitis (SBP) is historically caused by Gram-negative bacteria (GNB) almost exclusively Enterobacteriaceae. Recently, an increasing rate of infections with Gram-positive cocci (GPC) and multidrug-resistant (MDR) microorganisms was demonstrated. AIMS: To assess possible recent changes of the bacteria causing SBP in cirrhotic patients. METHODS: We retrospectively recorded 47 cases (66% males) during a 4-year-period (2008-2011). RESULTS: Twenty-eight (60%) patients had healthcare-associated infections while 15 (32%) received prophylactic quinolone treatment. GPC were found to be the most frequent cause (55%). The most prevalent organisms in a descending order were Streptococcus spp (n = 10), Enterococcus spp (n = 9), Escherichia coli (n = 8), Klebsiella pneumonia (n = 5), methicillin-sensitive Staphylococcus aureus (n = 4) and coagulase-negative Staphylococcus spp (n = 3). Nine of the isolated bacteria (19%) were MDR, including carbapenemase-producing K. pneumonia (n = 4), followed by extended-spectrum beta-lactamase-producing E. coli (n = 3) and Pseudomonas aeruginosa (n = 2). MDR bacteria were more frequently isolated in healthcare-associated than in community-acquired infections (100% vs 50%, P = 0.006), in patients receiving long-term quinolone prophylaxis (67% vs 24%, P = 0.013) and in those with advanced liver disease as suggested by higher MELD score (28 vs 19, P = 0.012). More infections with GNB than GPC were healthcare-associated (81% vs 42%, P = 0.007). Third-generation cephalosporin resistance was observed in 49% and quinolone resistance in 47%. CONCLUSIONS: GPC were the most frequent bacteria in culture-positive SBP and a variety of drug-resistant microorganisms have emerged. As a result of high rates of resistance in currently recommended therapy and prophylaxis, the choice of optimal antibiotic therapy is vital in the individual patient.
    Liver international: official journal of the International Association for the Study of the Liver 03/2013; · 3.87 Impact Factor
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    ABSTRACT: BACKGROUND: More than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy. METHODS: Previously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA. RESULTS: Only PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20--35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25--35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15--26). CONCLUSIONS: BRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.
    BMC Cancer 02/2013; 13(1):49. · 3.33 Impact Factor
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    ABSTRACT: Local recurrence is the major manifestation of treatment failure in patients with operable laryngeal carcinoma. Established clinicopathological factors cannot sufficiently predict patients that are likely to recur after treatment. Additional tools are therefore required to accurately identify patients at high risk for recurrence. This study attempts to identify and independently validate gene expression models, prognostic of disease-free survival (DFS) in operable laryngeal cancer. Using Affymetrix U133A Genechips, we profiled fresh-frozen tumor tissues from 66 patients with laryngeal cancer treated locally with surgery. We applied Cox regression proportional hazards modeling to identify multigene predictors of recurrence. Gene models were then validated in two independent cohorts of 54 and 187 patients (fresh-frozen and formalin-fixed tissue validation sets, respectively). We focused on genes univariately associated with DFS (p<0.01) in the training set. Among several models comprising different numbers of genes, a 30-probe set model demonstrated optimal performance in both the training (log-rank, p<0.001) and 1(st) validation (p = 0.010) sets. Specifically, in the 1(st) validation set, median DFS as predicted by the 30-probe set model, was 34 and 80 months for high- and low-risk patients, respectively. Hazard ratio (HR) for recurrence in the high-risk group was 3.87 (95% CI 1.28-11.73, Wald's p = 0.017). Testing the expression of selected genes from the above model in the 2(nd) validation set, with qPCR, revealed significant associations of single markers, such as ACE2, FLOT1 and PRKD1, with patient DFS. High PRKD1 remained an unfavorable prognostic marker upon multivariate analysis (HR = 2.00, 95% CI 1.28-3.14, p = 0.002) along with positive nodal status. We have established and validated gene models that can successfully stratify patients with laryngeal cancer, based on their risk for recurrence. It seems worthy to prospectively validate PRKD1 expression as a laryngeal cancer prognostic marker, for routine clinical applications.
    PLoS ONE 01/2013; 8(8):e70429. · 3.73 Impact Factor
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    ABSTRACT: [This corrects the article on p. e58182 in vol. 8.].
    PLoS ONE 01/2013; 8(4). · 3.73 Impact Factor
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    ABSTRACT: Discrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer. Formalin-fixed paraffin-embedded tumor blocks were collected from women with early breast cancer participating in two HeCOG adjuvant trials. Messenger RNA was studied by quantitative PCR, ER protein expression was centrally assessed using immunohistochemistry (IHC) and ESR1 gene copy number by dual fluorescent in situ hybridization probes. In a total of 1010 women with resected node-positive early breast adenocarcinoma, the tumoral ESR1/CEP6 gene ratio was suggestive of deletion in 159 (15.7%), gene gain in 551 (54.6%) and amplification in 42 cases (4.2%), with only 30 tumors (3%) harboring five or more ESR1 copies. Gene copy number ratio showed a significant, though weak correlation to mRNA and protein expression (Spearman's Rho <0.23, p = 0.01). ESR1 clusters were observed in 9.5% (57 gain, 38 amplification) of cases. In contrast to mRNA and protein expression, which were favorable prognosticators, gene copy number changes did not obtain prognostic significance. When ESR1/CEP6 gene ratio was combined with function (as defined by ER protein and mRNA expression) in a molecular classifier, the Gene Functional profile, it was functional status that impacted on prognosis. In univariate analysis, patients with functional tumors (positive ER protein expression and gene ratio normal or gain/amplification) fared better than those with non-functional tumors with ESR1 gain (HR for relapse or death 0.49-0.64, p = 0.003). Significant interactions were observed between gene gain/amplification and paclitaxel therapy (trend for DFS benefit from paclitaxel only in patients with ESR1 gain/amplification, p = 0.066) and Gene Functional profile with HER2 amplification (Gene Functional profile prognostic only in HER2-normal cases, p = 0.029). ESR1 gene deletion and amplification do not constitute per se prognostic markers, instead they can be classified to distinct prognostic groups according to their protein-mediated functional status.
    PLoS ONE 01/2013; 8(7):e70634. · 3.73 Impact Factor

Publication Stats

1k Citations
553.09 Total Impact Points


  • 2011–2014
    • Hippokration General Hospital, Athens
      Athínai, Attica, Greece
    • University of Southern California
      • Department of Preventive Medicine
      Los Angeles, CA, United States
  • 2013
    • Νοσοκομείο Σωτηρία
      Athínai, Attica, Greece
  • 2011–2013
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, Minnesota, United States
  • 2008–2013
    • University Hospital of Ioannina
      Yannina, Epirus, Greece
  • 2004–2013
    • Attikon University Hospital
      • Department of Internal Medicine IV
      Athínai, Attica, Greece
  • 2012
    • Hygeia Hospital
      Athínai, Attica, Greece
    • National Center for Scientific Research Demokritos
      • Molecular Diagnostics and Cytogenetics Laboratory
      Athínai, Attica, Greece
  • 2010–2011
    • Laiko Hospital
      Athínai, Attica, Greece
  • 2008–2011
    • Alexandra Regional General Hospital
      Athínai, Attica, Greece
  • 2004–2011
    • Athens State University
      Athens, Alabama, United States
  • 2007–2010
    • University of Patras
      • School of Medicine
      Patrís, Kentriki Makedonia, Greece
  • 2009
    • Metropolitan Hospital
      Athínai, Attica, Greece
    • Εθνική Σχολή Δημόσιας Υγείας
      Athínai, Attica, Greece
  • 2006–2008
    • Hellenic Cooperative Oncology Group
      Athínai, Attica, Greece
  • 2005–2007
    • Aristotle University of Thessaloniki
      • • Laboratory of Ecology
      • • Faculty of Medicine
      Saloníki, Central Macedonia, Greece
    • Metaxa Cancer Hospital
      Le Pirée, Attica, Greece