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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.


Markou A.,National and Kapodistrian University of Athens | Yousef G.M.,Li Ka Shing Knowledge Institute | Stathopoulos E.,University General Hospital of Heraklion | Georgoulias V.,University General Hospital of Heraklion | Lianidou E.,National and Kapodistrian University of Athens
Clinical Chemistry | Year: 2014

BACKGROUND: Stability of microRNAs (miRNAs) in formalin-fixed paraffin-embedded (FFPE) tissues enables their reliable analysis in archived FFPE tissue samples, which are an invaluable source for the evaluation of novel biomarkers. Especially in breast cancer, for which late relapses occur in many cases, analysis of miRNAs in FFPE tissues holds great potential, because it can lead to the discovery of novel biomarkers suitable for future routine clinical diagnostics for breast cancer. We investigated the prognostic significance of 6 metastasis-related miRNAs that can critically regulate various stages of migration and invasion and play critical roles in the multistep metastatic process. METHODS: We quantified the expression of 6 mature miRNAs (namely miR-21, miR-205, miR-10b, miR- 210, miR-335, and let-7a) by reverse- transcription quantitative PCR in FFPE tissues of 84 patients with early breast cancer and a long follow-up and 13 cancerfree breast tissue FFPE samples that were used as the control group. We further correlated individual miRNA over- or underexpression with the disease-free interval (DFI) and overall survival (OS). RESULTS: Univariate analysis revealed that both miR-21 and miR-205 were significantly associated with DFI and only miR-205 with OS. Multivariate analysis demonstrated that miR-205 and miR-21 were independent factors associated with early disease relapse, whereas only miR-205 overexpression was associated with OS. CONCLUSIONS: Our results clearly indicate that deregulation of metastasis-associated miRNAs in primary tumors is associated with clinical outcome in patients with early breast cancer and can differentiate patients with higher risk in well-characterized subgroups. © 2013 American Association for Clinical Chemistry.


Gioulbasanis I.,University General Hospital of Heraklion | Gioulbasanis I.,University General Hospital of Larissa | Baracos V.E.,University of Alberta | Giannousi Z.,University General Hospital of Heraklion | And 4 more authors.
Annals of Oncology | Year: 2011

Background: Cancer cachexia adversely affects survival and quality of life but its timely recognition is problematic. Nutritional questionnaires, like the Mini Nutritional Assessment (MNA), could identify early those patients at risk. The aim of the study was to compare MNA with 5% weight loss, a common criterion used in oncologic evaluation. Patients and methods: The nutritional status of 171 chemotherapy-naive patients with metastatic lung cancer was evaluated by both methods. The results were compared and correlated with clinical and laboratory values and with clinical outcome. Results: The incidence of malnourished or patients at risk was higher according to the MNA (P < 0.001). Both methods correlated with the performance status (P < 0.001) but MNA was further correlated with the number of metastatic sites (P = 0.007) and the presence of brain metastasis (P = 0.022). Of 14 laboratory values studied, 9 were correlated with MNA and 5 with the weight loss history. Both methods were correlated with response to first-line therapy, time to progression and survival but MNA had a better predictive (P < 0.001) and prognostic (P < 0.001) value. Conclusions: MNA outperforms weight loss history as a baseline nutritional screening method in patients with metastatic lung cancer and could further refine prognostication. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Pallis . A.G.,University General Hospital of Heraklion | Gridelli C.,Sg Moscati Hospital
Cancer Treatment Reviews | Year: 2010

As a result of an increasing life expectancy, the incidence of non-small-cell lung cancer (NSCLC) in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for NSCLC. The current evidence supports the safety and efficacy of treatment for NSCLC cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger counterparts and that chronological age per se is not a negative prognostic factor. However, it should be noted that these data are derived from retrospective studies which are likely to suffer from selection bias. Prospective data support the use of third generation single-agent (vinorelbine, gemcitabine, docetaxel) as first-line treatment for older NSCLC patients. Although cisplatin-based doublets represent the cornerstone of chemotherapy treatment for advanced/metastatic NSCLC their role in the treatment of older patients needs to be further elucidated. Despite a growing body of data, further work is still needed to establish optimal strategies to care for this special population and prospective specific trials for older NSCLC patients are clearly needed. © 2010 Elsevier Ltd.


Valachis A.,University General Hospital of Heraklion | Polyzos N.P.,PACMeR | Polyzos N.P.,University General Hospital of Larisa | Patsopoulos N.A.,Harvard University | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2010

Abstract:: Numerous studies have demonstrated that angiogenesis and in particular VEGF over-expression play an essential role in the progression and metastatic potential of breast cancer. Bevacizumab is a humanized recombinant monoclonal antibody that specifically blocks the binding of VEGF to high-affinity receptors and it has been recently used for the treatment of metastatic breast cancer. We conducted a meta-analysis to synthesize available evidence for use of bevacizumab in metastatic breast cancer patients. Systematic review and meta-analysis of available trials. Primary outcomes were overall survival, progression free survival (PFS) and objective response rate (ORR). Five trials were identified with 3,163 eligible patients. Combination of bevacizumab and chemotherapy resulted in a statistically significant improvement in PFS (HR = 0.70, 95% CI 0.60-0.82, P = 9.3 × 10-6) and ORR (RR = 1.26, 95% CI 1.17-1.37, P = 9.96 × 10-9) compared with chemotherapy alone. Differences in objective response rates were substantial independently by the type of chemotherapy used, while PFS advantages were observed only for taxanes. The pooled HR for overall survival did not show significant advantage for the use of bevacizumab compared to placebo arm (HR = 0.90, 95% CI 0.80-1.03, P = 0.119). This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in patients with metastatic breast cancer. Bevacizumab treatment might be suggested for treatment of 1st line metastatic breast cancer, but more data are needed until statistical overall survival differences will be documented and firm guideline recommendation could be given. © 2010 Springer Science+Business Media, LLC.


Kalyva E.,City College | Malakonaki E.,City College | Eiser C.,University of Sheffield | Mamoulakis D.,University General Hospital of Heraklion
Pediatric Diabetes | Year: 2011

Kalyva E, Malakonaki E, Eiser C, Mamoulakis D. Health-related quality of life (HRQoL) of children with type 1 diabetes mellitus (T1DM): self and parental perceptions. The aim of the study was to evaluate health-related quality of life (HRQoL) in children and adolescents with type 1 diabetes mellitus (T1DM) in Greece compared with healthy controls and to identify the effect of age, gender, age of onset of disease, and metabolic control on perceptions of HRQoL. A total of 117 children and adolescents with T1DM aged 5-18, their parents, and 128 matched healthy children and adolescents participated. Children and adolescents completed PedsQL™ 4.0 Generic Core Scales. Children and adolescents with T1DM also completed the PedsQL™ 3.0 Diabetes Module, while their parents completed the proxy-reports of both the PedsQL™ 4.0 Generic Core Scales and the PedsQL™ 3.0 Diabetes Module. The results demonstrated that children and adolescents with T1DM had lower general HRQoL compared with healthy matched children and adolescents. Parents of children and adolescents with diabetes reported that the illness has a greater affect on their children's lives than the children themselves. Finally, the results indicated that later age of onset of diabetes, less hyperglycemic episodes, lower glycosylated hemoglobin (HbA1c), older age, and male gender were associated with better general HRQoL and diabetes-specific HRQoL. The findings have implications for designing effective therapeutic interventions aimed at improving the HRQoL of children and adolescents with T1DM. © 2010 John Wiley & Sons A/S.


Voutsina A.,University of Crete | Tzardi M.,University General Hospital of Heraklion | Kalikaki A.,University of Crete | Zafeiriou Z.,University General Hospital of Heraklion | And 5 more authors.
Modern Pathology | Year: 2013

Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations. PIK3CA exon 9 mutations in primary tumors and loss of PTEN nuclear expression in metastases correlated with KRAS mutations. KRAS wild-type status in primary tumors was associated with loss of PTEN cytoplasmic expression and high gene copy number of MET. Survival and clinical data were available for 68 patients. The multiple regression analysis revealed that the right-sided tumor localization and overexpression of MET were associated with shorter overall survival. © 2013 USCAP, Inc. All rights reserved.


Pallis A.G.,University General Hospital of Heraklion
Cancer and Metastasis Reviews | Year: 2010

Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include strand breaks (double or single strand), crosslinks (inter-strand, intra-strand, DNA-protein crosslinks), and interference with nucleotide metabolism and DNA synthesis. On the other hand, cancer cells activate various DNA repair pathways and repair DNA damages induced by cytotoxic drugs. The purpose of the current review is to present the major types of DNA damage induced by cytotoxic agents, DNA repair pathways, and their role as predictive agents, as well as evaluate the future perspectives of the novel DNA repair pathways inhibitors in cancer therapeutics. © 2010 Springer Science+Business Media, LLC.


Pallis A.G.,University General Hospital of Heraklion
European Respiratory Disease | Year: 2011

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. For patients with early-stage disease, surgery followed by adjuvant chemotherapy is the optimal treatment. For patients with locally advanced disease, the standard approach is chemoradiotherapy, since it offers a small but statistically significant prolongation in survival compared with the sequential approach. It should be noted, however, that this approach is associated with significant toxicity and it only applies to patients with good performance status. For patients with metastatic disease, chemotherapy represents the cornerstone of treatment and results in a median survival of approximately 10 months. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets and the use of gefitinib and erlotinib has improved the outcome in selected patients with advanced NSCLC. Hopefully, advances in understanding the molecular biology of cancer and mechanisms of tumourigenesis will facilitate the discovery and development of novel 'targeted agents' and will further improve outcomes for these patients. © 2011 Touch Briefings.


Detorakis E.T.,University General Hospital of Heraklion
Acta medica (Hradec Králové) / Universitas Carolina, Facultas Medica Hradec Králové | Year: 2012

Sometimes intraorbital foreign bodies lead to unexpected findings. A 16-year old boy was referred due to ocular surface trauma. A conjunctival laceration was detected at the level of the left caruncle with associated left exotropia, reduced adduction as well as a preretinal hemorrhage along the nasal periphery of the fundus. A blow-out fracture of the medial orbital wall was suspected and a CT scan of the orbits was scheduled which revealed the presence of a large intraorbital foreign body. The removal of the intraorbital foreign body (which proved to be a bullet) and precautionary laser photocoagulation along the nasal periphery of the left eye were performed. Ocular surface trauma may reveal unexpected findings, such as an intraorbital foreign body, requiring investigation by a CT scan.

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