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Fountzilas G.,Aristotle University of Thessaloniki | Ciuleanu E.,Ion Chiricuta Cancer Institute | Bobos M.,Aristotle University of Thessaloniki | Kalogera-fountzila A.,Aristotle University of Thessaloniki | And 12 more authors.
Annals of Oncology | Year: 2012

Background: Concomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial. Patients and methods: Totally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m. 2, epirubicin 75 mg/m. 2 and paclitaxel (Taxol) 175 mg/m. 2 (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m. 2 (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients). Results: Sixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT. Conclusion: IC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Fostira F.,National Diagnostics | Thodi G.,National Diagnostics | Sandaltzopoulos R.,Democritus University of Thrace | Fountzilas G.,Aristotle University of Thessaloniki | And 2 more authors.
BMC Cancer | Year: 2010

Background: Familial adenomatous polyposis, an autosomal dominant inherited disease caused by germline mutations within the APC gene, is characterized by early onset colorectal cancer as a consequence of the intrinsic phenotypic feature of multiple colorectal adenomatic polyps. The genetic investigation of Greek adenomatous polyposis families was performed in respects to APC and MUTYH germline mutations. Additionally, all available published mutations were considered in order to define the APC mutation spectrum in Greece.Methods: A cohort of 25 unrelated adenomatous polyposis families of Greek origin has been selected. Genetic testing included direct sequencing of APC and MUTYH genes. APC gene was also checked for large genomic rearrangements by MLPA.Results: Analysis of the APC gene performed in a Greek cohort of twenty five FAP families revealed eighteen different germline mutations in twenty families (80%), four of which novel. Mutations were scattered between exon 3 and codon 1503 of exon 15, while no large genomic rearrangements were identified.Conclusion: This concise report describes the spectrum of all APC mutations identified in Greek FAP families, including four novel mutations. It is concluded that the Greek population is characterized by genetic heterogeneity, low incidence of genomic rearrangements in APC gene and lack of founder mutation in FAP syndrome. © 2010 Fostira et al; licensee BioMed Central Ltd.


Koutras A.K.,University of Patras | Fountzilas G.,Aristotle University of Thessaloniki | Kalogeras K.T.,Aristotle University of Thessaloniki | Kalogeras K.T.,Hellenic Cooperative Oncology Group | And 3 more authors.
Critical Reviews in Oncology/Hematology | Year: 2010

The human epidermal growth factor receptor (HER) family comprises four homologous members. The activation of these receptors affects essential tumorigenic processes and plays a crucial role in the pathogenesis of breast cancer. Among HER family members, EGFR and HER2 are the most studied. However, accumulating data provide evidence for the significance of HER3 and HER4 alterations in breast carcinogenesis. The combination of HER2 and HER3 receptors may be critical in breast cancer growth and progression. Moreover, HER3 may provide a route for resistance to agents targeting EGFR or HER2. Although a number of studies have demonstrated that HER3 overexpression is associated with poor prognosis in patients with breast cancer, other studies have indicated that HER3 overexpression may be a positive prognostic factor. With respect to HER4 receptor, the existing evidence suggests that HER4 signalling promotes differentiation and growth inhibition of breast cancer cells. In addition, HER4 is more consistently related with a favourable prognosis in breast cancer. HER4 has multiple different activities in the breast, and many of these functions are mediated by a soluble HER4 intracellular domain. In addition, loss of HER4 expression may represent a marker for resistance to tamoxifen. Because of the functional interdependency among the HER receptors, it is possible that the effect on cell proliferation and tumor growth depends on receptor trans-signalling. Therefore, clarifying how and the extent to which these different signalling pathways interact in breast carcinogenesis, may lead to additional therapeutic opportunities. This review presents an update on the role of HER3 and HER4 receptors in breast cancer. Moreover, we provide current data relating to the prognostic significance of these receptors, as well as their impact on the activity of HER-targeting therapies in patients with breast cancer. © 2009 Elsevier Ireland Ltd.


Iliadis G.,Papageorgiou Hospital | Iliadis G.,Interbalkan Medical Center | Kotoula V.,Aristotle University of Thessaloniki | Chatzisotiriou A.,St Lukes Hospital | And 6 more authors.
BMC Cancer | Year: 2012

Background: In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O 6-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development.Methods: We prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material.Results: In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression-free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021).Conclusions: Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry could help not only to improve the prediction of outcome but also the outcome itself by identifying patients at high risk of treatment failure and, thus, seek alternative treatment for these patients. In this small series, MGMT protein was associated with less aggressive tumor characteristics. © 2011 Iliadis et al; licensee BioMed Central Ltd.


Lazaridis G.,Aristotle University of Thessaloniki | Lambaki S.,Aristotle University of Thessaloniki | Karayannopoulou G.,Aristotle University of Thessaloniki | Eleftheraki A.G.,Hellenic Cooperative Oncology Group | And 6 more authors.
Strahlentherapie und Onkologie | Year: 2014

Background and purpose. There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer. Patients and methods. Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 997 patients participating in two adjuvant phase III trials were assessed for EGFR, PTEN, p-Akt, p-mTOR protein expression, and PIK3CA mutational status. These markers were evaluated for associations with each other and with selected patient and tumor characteristics, immunohistochemical subtypes, disease-free survival (DFS), and overall survival (OS). Results. p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN, with p-Akt473, and with the presence of PIK3CA mutations. EGFR expression was positively associated with p-Akt473, p-Akt308, and PIK3CA wild-type tumors. Finally, p-Akt308 was positively associated with p-Akt473 expression. In univariate analysis, EGFR (p=0.016) and the coexpression of EGFR and p-mTOR (p=0.015) were associated with poor OS. Among patients with p-Akt308-negative or low-expressing tumors, those treated with hormonal therapy were associated with decreased risk for both relapse and death (p=0.013 and p<0.001, respectively). In the subgroup of patients with locoregional relapse, positive EGFR and mTOR protein expression was found to be associated with increased (p=0.034) and decreased (p<0.001) risk for earlier relapse, respectively. In multivariate analysis, low levels of p-Akt308 and the coexpression of EGFR and p-mTOR retained their prognostic value. Conclusion. Low protein expression of p-Akt308 was associated with improved DFS and OS among patients treated with hormonal therapy following adjuvant chemotherapy. Coexpression of EGFR and p-mTOR was associated with worse OS. © 2014 Springer-Verlag.


PubMed | Hellenic Cooperative Oncology Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

18590 Background: Combinations of -lactam antibiotics and aminoglycosides are considered standard therapy for febrile neutropenia. Monotherapies have been proposed as standard treatments, demonstrating equal efficacy and better safety.This is a prospective, multi-centre, randomized clinical trial. Cancer patients with absolute neutrophil count (ANC) <1,000/mmOne hundred twenty-seven febrile episodes were treated (group A: 66, group B: 61). Patient characteristics were well balanced in terms of age, underlying malignancies, ANC, and granulocyte-colony stimulating factor (G-CSF) support. Both treatments were well tolerated. No significant differences were seen in terms of success to treatment. Complete success was achieved in 45 (68%) of patients in group A and 40 (66%) in group B, while another 8 patients in group A (12%) and 6 in group B (10%) required addition of pre-defined anti-staphyloccocci antibiotic.Empirical treatment of febrile neutropenic episodes with piperacillin/tazobactam monotherapy appears to be as effective as the standard ceftazidime/amikacin combination. No significant financial relationships to disclose.


PubMed | Hellenic Cooperative Oncology Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

5074 Background: Carboplatin combined with paclitaxel are considered treatment of choice as initial chemotherapy for AOC. We compared this combination with a regimen combining cisplatin plus paclitaxel and doxorubicin. In the pre-taxane era the addition of doxorubicin to the cisplatin-based regimens appeared to improve survival. Therefore, there was a significant interest in assessing the role of a taxane/platinum/ anthracycline combination therapy in a randomized study.Patients with AOC after the initial cytoreductive surgery were stratified according to the FIGO stage and the presence of residual disease and randomized to either 6 courses of paclitaxel 175 mg/mIntent to treat analysis was performed on 432 patients (group A: 210, B: 222). The treatment groups were well balanced in terms of major patient and tumor characteristics. 70% of the patients had stage III and 23% stage IV disease. Significantly more patients developed febrile neutropenia in group B (p = 0.01). No other significant differences were observed in terms of severe toxicity and no difference was found between the two groups in complete and overall response rate. With a median follow up of 44 months, median survival was 37.2 months in group A and 45.2 months in group B (p = 0.33).Both regimens are well tolerated and effective as first line chemotherapy of AOC. Combination of cisplatin, paclitaxel and doxorubicin does not seem to improve survival as compared with the standard carboplatin/paclitaxel regimen. No significant financial relationships to disclose.


PubMed | Hellenic Cooperative Oncology Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

9024 Background: Immunotherapies with beneficial effect in advanced melanoma have been shown to induce the collateral appearance of autoimmune responses, as thyroid autoantibodies and depigmentation. We have previously reported that the appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with adjuvant interferon is associated with statistically significant improvements in relapse-free and overall survival (RFS and OS) in patients with melanoma. In the current report, follow-up data were updated on October 1st 2007.Two hundred patients were included in the study. Peripheral blood was obtained prior to initiation of adjuvant interferon at completion of 1 month of intravenous interferon and at 3, 6, 9 months. Serum samples were tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin antibodies by enzyme linked immunosorbant assay (ELISA). Patients were examined for the appearance of vitiligo or other clinical manifestations of autoimmune diseases. The simultaneous prognostic effect of various factors was determined in a multivariate analysis with use of the Cox proportional-hazards model. Autoimmune status was included in the models as a time- dependent variable.At a median follow up of 72 months (95% C.I., 66.8 - 76.3) 128 patients had a relapse and 105 have died. The previously reported median follow-up was 46 months with 115 observed relapses and 82 deaths. The median RFS was 28 months and the median OS was 63 months. Among patients without autoimmunity, the median RFS was 16 months (112 of 148 had a relapse) while among patients with autoimmunity 115 months (16 of 52 had a relapse). Nine out of the 16 relapses in the group with autoimmunity were late relapses observed at the additional follow-up period. The median OS was 37 months among patients without autoimmunity (98 of 148 died) and was not reached among patients with autoimmunity (7 of 52 died). In the univariate and multivariate Cox regression analysis autoimmunity was an independent prognostic factor for improved RFS and OS (p<0.001).The detection of autoantibodies and the appearance of clinical manifestations of autoimmunity remain a significant prognostic marker for RFS and OS with additional follow- up. [Table: see text].


PubMed | Hellenic Cooperative Oncology Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

9054 Background: Attempts to identify patients who benefit from adjuvant treatment with interferon alfa-2b (IFN) have been disappointing. The development of autoimmunity during adjuvant therapy with IFN cannot assist selection of patients for therapy at baseline. Multiple polymorphisms within the CTLA-4 gene have been found to be associated with autoimmune diseases. We therefore evaluated six CTLA- 4 single nucleotide polymorphisms (SNPs) in high-risk melanoma patients enrolled in a study of two regimens of high-dose IFN and compared the distribution of SNPs found in healthy controls.We genotyped DNA from peripheral blood of 203 stage IIb, IIc and III melanoma patients and 288 healthy controls for 49 A/G, 60 C/T, 318 C/T, JO27, JO30 and JO31 using PCR and pyrosequencing technology (Biotage, Uppsala, Sweden).At a median follow up of 57.3 months (95% CI 50.14-64.76), 115 patients have recurred and 58 have died. The median DFS was 42 months and the median OS has not been reached yet (mean OS: 65 months). There were no statistical significant differences in the incidence of CTLA-4 polymorphisms between melanoma patients and healthy controls. The tabular distribution of these polymorphisms in melanoma patients is presented below. RFS and OS did not differ significantly between patients with the alleles represented by these polymorphisms (p=0.90 and p=0.28 for 49 A/G, p=0.89 and p=0.9 for 60 C/T, p=0.63 and p=0.72 for 318 C/T, p=0.88 and p=0.69 for JO27, p=0.74 and p=0.97 for JO30, p=0.6 and p=0.92 for JO31 respectively). High association between the different polymorphisms was found (Fishers exact p-values <.001 for all associations).No polymorphism of CTLA4 defined by the SNPs studied was correlated with improved RFS or OS in this high-risk group of melanoma patients. [Table: see text] [Table: see text].


PubMed | Hellenic Cooperative Oncology Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

13500 Background: Cetuximab is an anti-EGFR monoclonal antibody with activity in colorectal cancer. Patients most likely to benefit should be identified using molecular markers.A retrospective analysis was performed on patients treated with cetuximab who had paraffin embedded tissue available for testing. Tumor specimens were tested for EGFR (31G7, Zymed), PTEN (28H6, Novocastra) and pAkt 1/2/3 (Thr 308, Santa Cruz) expression by IHC. The EGFR gene status was investigated by FISH (Vysis).Seventy-two patients were identified. EGFR expression was detected in 32/68 patients tested. PTEN was positive in all cases tested (64/64) and pAkt in 52 of 64 patients, in >70% of cells in 21/64 cases. Most patients were treated with cetuximab in various combinations, three patients received it as a single agent and 7 patients in more than one line of therapy. Median follow-up from diagnosis was 30.7 months and from Cetuximab initiation 6.9 months. Median survival from diagnosis has not been reached yet but from initiation of Cetuximab it is 13.6 months. 19 patients achieved a PR and 1 a CR. Most patients with PR were treated in first or second line however, 6 patients achieved a PR in 3Overexpression of pAkt may correlate with response to Cetuximab in colorectal cancer. No significant financial relationships to disclose.

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