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Ymittos Athens, Greece

Wang E.,U.S. National Institutes of Health | Zhao Y.,U.S. National Institutes of Health | Monaco A.,U.S. National Institutes of Health | Uccellini L.,U.S. National Institutes of Health | And 5 more authors.
PLoS ONE | Year: 2012

Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed.

Gogas H.,National and Kapodistrian University of Athens | Dafni U.,National and Kapodistrian University of Athens | Koon H.,University Hospital Case Medical Center | Spyropoulou-Vlachou M.,National Tissue Typing Center | And 13 more authors.
Journal of Translational Medicine | Year: 2010

Purpose: Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.Experimental design: 286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.Results: No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.Conclusion: No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients. © 2010 Gogas et al; licensee BioMed Central Ltd.

Lionaki S.,Laiko Hospital | Panagiotellis K.,Laiko Hospital | Iniotaki A.,National Tissue Typing Center | Boletis J.N.,Laiko Hospital
Clinical and Developmental Immunology | Year: 2013

Kidney transplantation has evolved over more than half a century and remarkable progress has been made in patient and graft outcomes. Despite these advances, chronic allograft dysfunction remains a major problem. Among other reasons, de novo formation of antibodies against donor human leukocyte antigens has been recognized as one of the major risk factors for reduced allograft survival. The type of treatment in the presence of donor specific antibodies (DSA) posttransplantation is largely related to the clinical syndrome the patient presents with at the time of detection. There is no consensus regarding the treatment of stable renal transplant recipients with circulating de novo DSA. On the contrast, in acute or chronic allograft dysfunction transplant centers use various protocols in order to reduce the amount of circulating DSA and achieve long-term graft survival. These protocols include removal of the antibodies by plasmapheresis, intravenous administration of immunoglobulin, or depletion of B cells with anti-CD20 monoclonal antibodies along with tacrolimus and mycophenolate mofetil. This review aims at the comprehension of the clinical correlations of de novo DSA in kidney transplant recipients, assessment of their prognostic value, and providing insights into the management of these patients. © 2013 Sophia Lionaki et al.

Vasiliades G.,General Hospital of Athens G. Gennimatas | Kopanakis N.,General Hospital of Athens G. Gennimatas | Vasiloglou M.,General Hospital of Athens G. Gennimatas | Zografos G.,General Hospital of Athens G. Gennimatas | And 4 more authors.
International Journal of Biological Markers | Year: 2012

Background: Previous studies have demonstrated altered levels of hematopoietic cytokines in the serum of patients with different types of cancer. Methods: We measured the serum levels of the hematopoietic cytokines stem cell factor (SCF), interleukin 3 (IL-3), macrophage- colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) in 40 pancreatic and ampullary cancer patients and 40 healthy volunteers, using ELISA. We also assessed the most widely used pancreatic tumor markers, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), in both groups. We then correlated the concentrations of the cytokines and the tumor markers in the patients' serum and we estimated their diagnostic ability by calculating diagnostic sensitivity and specificity, positive and negative predictive values and the receiver operating characteristic (ROC) curve. Results: The SCF and IL-3 levels were significantly lower and the M-CSF levels significantly higher in pancreatic cancer patients than in controls. There were significant positive correlations between the serum levels of CEA and M-CSF, GM-CSF and SCF, and between GM-CSF and IL-3. The area under the ROC curve and diagnostic sensitivity of M-CSF were greater than those of SCF and IL-3. The diagnostic sensitivity of the combined use of SCF and M-CSF reached 97.5%. Conclusion: The diagnostic ability of M-CSF and SCF in pancreatic and ampullary cancer should stimulate further studies evaluating their clinical usefulness as tumor markers. © 2012 Wichtig Editore.

Gogas H.,National and Kapodistrian University of Athens | Kirkwood J.M.,University of Pittsburgh | Falk C.S.,German Cancer Research Center | Dafni U.,National and Kapodistrian University of Athens | And 6 more authors.
Cancer | Year: 2010

BACKGROUND: Interferon is approved for adjuvant treatment of patients with stage IIB/III melanoma. The identification of predictive markers that would permit selection of patients would be beneficial. Specific human leukocyte antigen (HLA) class I and II antigens have previously shown an association with response to therapy or overall survival of patients with metastatic melanoma. METHODS: A total of 284 high-risk melanoma patients participating in a randomized trial and 246 healthy controls were molecularly typed for HLA class I and II. Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated. RESULTS: No significant differences were found between the distribution of HLA genotype in the melanoma population compared with healthy controls. Correlations between nonrecurrence and the presence of HLA-Cw*06 allele were noted present in 19.3% of melanoma patients. The median relapse-free survival of the Cw*06-positive cohort was 100.2 months versus 37.3 months in the Cw*06-negative cohort (P =.013).The median overall survival for the Cw*06-positive cohort has not yet been reached, versus 78.9 months in the Cw*06-negative cohort (P = .025). HLA-Cw*06 was present in 29.79% of patients in the autoimmunity group and 15.38% of patients in the nonautoimmunity group (P =.049). CONCLUSIONS: No allele was associated with absence of recurrence in patients receiving adjuvant interferon with the exception of HLA-Cw*06, an allele correlated with psoriasis. HLA-Cw*06-positive patients have better relapse-free and overall survival. © 2010 American Cancer Society.

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