42 results on '"Filippos Koinis"'
Search Results
2. Data from MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer
- Author
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Alexandra Drakaki, Dennis J. Slamon, Dimitrios Iliopoulos, Vassilis Georgoulias, Allan J. Pantuck, Shawnt Issakhanian, Tong Luo, Artin Soroosh, Christina Vorvis, Swapna Mahurkar-Joshi, Filippos Koinis, Neil O'Brien, Hsiao-Wang Chen, and Marina Koutsioumpa
- Abstract
Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR-21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21–induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A–ERK network in mice. Mol Cancer Ther; 17(7); 1430–40. ©2018 AACR.
- Published
- 2023
3. Lung cancer and annual mean exposure to outdoor air pollution in Crete, Greece. Reflections from a two decades big-database
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Dimitra Sifaki-Pistolla, Christos Lionis, Filippos Koinis, Dimitrios Mavroudis, and Nikos Tzanakis
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General Earth and Planetary Sciences ,General Environmental Science - Published
- 2022
4. Dynamic changes of CTCs in patients with metastatic HR(+)/HER2(−) breast cancer receiving salvage treatment with everolimus/exemestane
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Nefeli Georgoulia, Nikolaos Tsoukalas, Maria Spiliotaki, Galatea Kallergi, Filippos Koinis, Eleni Politaki, Dora Hatzidaki, Nikolaos Xenidis, Vassilis Georgoulias, Stella Apostolaki, A. Kotsakis, and Christos Nikolaou
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Salvage treatment ,Toxicology ,03 medical and health sciences ,chemistry.chemical_compound ,Cytokeratin ,0302 clinical medicine ,Breast cancer ,Exemestane ,Internal medicine ,medicine ,Effective treatment ,Pharmacology (medical) ,In patient ,Pharmacology ,Everolimus ,business.industry ,medicine.disease ,Metastatic breast cancer ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Detection of CTCs represents a poor prognostic factor in patients with early and metastatic breast cancer (mBC) and treatment with everolimus–exemestane (E/E) is an established effective treatment in hormone receptor-positive/HER2-negative mBC patients. The effect of E/E on CTCs in mBC patients was prospectively investigated. CTCs from 50 pre-treated patients with mBC receiving E/E were analyzed using the CellSearch (CS) platform and triple immunofluorescence (IF) staining for cytokeratin, M30 and Ki67 expression to assess their proliferative and apoptotic status. CTCs (by CS) were detected in 64% of patients before treatment and E/E administration resulted in their decreased prevalence [(n = 18; 36%, p = 0.004) and (n = 7; 19.4%, p = 0.019) post-1st and post-3rd treatment cycle, respectively] whereas it was significantly increased at disease progression (PD: 61%) compared to post-1st and post-3rd cycle (p = 0.049 and p = 0.021, respectively). Ki67-positive CTCs were detected in 60%, 60%, 17% and 50% of patients before treatment, post-1st, post-3rd cycle and at PD, respectively, while the opposite was observed for M30-positive CTCs (0% at baseline, 10% after the 1st cycle, 50% after the 3rd cycle and 0% at PD). The detection of even ≥ 1 CTC/5 ml after one cycle was associated with decreased PFS (3.3 vs 9.0 months, p = 0.025) whereas the detection of even ≥ 2 CTCs at PD was associated with decreased OS (32.4 vs 19.5 months; p = 0.009). The combination of E/E resulted in early elimination of proliferating CTCs in mBC patients and this effect was associated with a favorable clinical outcome.
- Published
- 2021
5. Phenotypic Characterization of Circulating Tumor Cells Isolated from Non-Small and Small Cell Lung Cancer Patients
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Argyro Roumeliotou, Evangelia Pantazaka, Anastasia Xagara, Foteinos-Ioannis Dimitrakopoulos, Angelos Koutras, Athina Christopoulou, Theodoros Kourelis, Nada H. Aljarba, Saad Alkahtani, Filippos Koinis, Athanasios Kotsakis, and Galatea Kallergi
- Subjects
Cancer Research ,circulating tumor cells ,non-small-cell lung cancer ,small-cell lung cancer ,lung cancer ,JUNB ,CXCR4 ,Oncology - Abstract
In the present study, we evaluated the expression of JUNB and CXCR4 in circulating tumor cells (CTCs) of lung cancer patients and investigated whether these proteins have prognostic clinical relevance. Peripheral blood from 30 patients with non-small-cell lung cancer (NSCLC) was filtered using ISET membranes, and cytospins from 37 patients with small-cell lung cancer (SCLC) were analyzed using confocal and VyCAP microscopy. Both JUNB and CXCR4 were expressed in the vast majority of lung cancer patients. Interestingly, the phenotypic patterns differed between NSCLC and SCLC patients; the (CK+/JUNB+/CXCR4+) phenotype was present in 50% of NSCLC vs. 71% of SCLC patients. Similarly, the (CK+/JUNB+/CXCR4–) was present in 44% vs. 71%, the (CK+/JUNB–/CXCR4+) in 6% vs. 71%, and the (CK+/JUNB–/CXCR4–) phenotype in 38% vs. 84%. In NSCLC, the presence of ≥1 CTCs with the (CK+/JUNB+/CXCR4+) phenotype was associated with worse progression-free survival (PFS) (p = 0.007, HR = 5.21) while ≥2 with poorer overall survival (OS) (p < 0.001, HR = 2.16). In extensive stage SCLC patients, the presence of ≥4 CXCR4-positive CTCs was associated with shorter OS (p = 0.041, HR = 5.01). Consequently, JUNB and CXCR4 were expressed in CTCs from lung cancer patients, and associated with patients’ survival, underlying their key role in tumor progression.
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- 2022
6. Emerging Role of YAP and the Hippo Pathway in Prostate Cancer
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Filippos Koinis, Evangelia Chantzara, Michael Samarinas, Anastasia Xagara, Zisis Kratiras, Vasiliki Leontopoulou, and Athanasios Kotsakis
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Medicine (miscellaneous) ,General Biochemistry, Genetics and Molecular Biology - Abstract
The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. YAP overexpression and nuclear localization has been linked to poor prognosis and resistance to treatment, highlighting a therapeutic potential that may suggest innovative strategies to treat cancer. This review aimed to summarize available data on the biological function of the dysregulated Hippo pathway in PCa and identify knowledge gaps that need to be addressed for optimizing the development of YAP-targeted treatment strategies in patients likely to benefit.
- Published
- 2022
7. Prostate Cancer: Quo Vadis?
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Christopher J. Logothetis, Filippos Koinis, Paul G. Corn, Eleni Efstathiou, and Ana Aparicio
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Male ,medicine.medical_specialty ,business.industry ,Urology ,030232 urology & nephrology ,MEDLINE ,Prostatic Neoplasms ,medicine.disease ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Intervention (counseling) ,Humans ,Medicine ,business ,Intensive care medicine - Abstract
Utility measures are urgently needed for clinical application of new, more sensitive diagnostics to reduce the risk of excessive intervention.
- Published
- 2019
8. 'The Oizys Study': Prevalence and impact of scan-related anxiety on QoL among Greek cancer patients and their caregivers
- Author
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Filippos Koinis, Vasiliki Leontopoulou, Evangelia Chantzara, and Athanasios Kotsakis
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Cancer Research ,Oncology - Abstract
e24118 Background: Diagnostic imaging may be a major source of distress in patients with advanced cancer, a condition known as “scanxiety”. Scanxiety represents a complex array of negative and stressful emotions linked with cancer scans, and the uncertainties and fears that may accompany them. We aimed to evaluate the prevalence and characterize risk factors for scanxiety among cancer patients and their caregivers and evaluate the impact of scanxiety on quality of life (QoL), during the COVID-era. Methods: We conducted a cross-sectional survey study of metastatic cancer patients treated at the University Hospital of Larisa and their caregivers. Eligible patients met the following inclusion criteria: age > 18 years old, ability to speak and write fluently in Greek, having had at least one imaging study during the period of the study ( seven days before the survey), approval of the patient’s oncologist to approach the patient. Patients/caregivers with pre-existing (prior to cancer diagnosis anxiety disorder) were excluded from the study. After completion of the informed consent process, patients/caregivers completed all survey items. We used a modified version of the Greek version of the Impact of Event Scale-Revised (IES-R-Gr) to specifically assess distress associated with scans, and QoL was measured using the EORTC QLQ-C30 questionnaire. Results: 218 patients with metastatic cancer and their caregivers were included in the study. Patient's mean age was 66 years (range 35-88). The majority were men (61%) and were diagnosed with Non-Small-Cell Lung Cancer. 71% had an IES-R-Gr score that was suggestive of scanxiety. Their symptoms were more severe symptoms while waiting for the results. Patients with a recent diagnosis (< 6 months) had higher levels. Interestingly, 16% of the patients had postponed a check-up due to scanxiety, while 77% reported that stress does not decrease over time. The majority of caregivers (81%) reported scanxiety, without a strong correlation with the score of the respective patients. Unlike patients, the majority of caregivers reported an increase in stress during the COVID-19 period. The presence of scanxiety was associated with decreased QoL in patients (p = 0.004). Conclusions: Scanxiety is a common problem among patients with metastatic cancer and is associated with impaired QoL. To our knowledge this is the first study implying that caregivers also experience scanxiety and may be a persistent problem.
- Published
- 2022
9. Dynamic changes of CTCs in patients with metastatic HR(+)/HER2(-) breast cancer receiving salvage treatment with everolimus/exemestane
- Author
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Maria, Spiliotaki, Galatea, Kallergi, Christos, Nikolaou, Nikolaos, Xenidis, Eleni, Politaki, Stella, Apostolaki, Nefeli, Georgoulia, Filippos, Koinis, Nikolaos, Tsoukalas, Dora, Hatzidaki, Athanasios, Kotsakis, and Vassilis, Georgoulias
- Subjects
Adult ,Aged, 80 and over ,Salvage Therapy ,Receptor, ErbB-2 ,Breast Neoplasms ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,Androstadienes ,Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Female ,Everolimus ,Prospective Studies ,Neoplasm Metastasis ,Aged - Abstract
Detection of CTCs represents a poor prognostic factor in patients with early and metastatic breast cancer (mBC) and treatment with everolimus-exemestane (E/E) is an established effective treatment in hormone receptor-positive/HER2-negative mBC patients. The effect of E/E on CTCs in mBC patients was prospectively investigated.CTCs from 50 pre-treated patients with mBC receiving E/E were analyzed using the CellSearch (CS) platform and triple immunofluorescence (IF) staining for cytokeratin, M30 and Ki67 expression to assess their proliferative and apoptotic status.CTCs (by CS) were detected in 64% of patients before treatment and E/E administration resulted in their decreased prevalence [(n = 18; 36%, p = 0.004) and (n = 7; 19.4%, p = 0.019) post-1st and post-3rd treatment cycle, respectively] whereas it was significantly increased at disease progression (PD: 61%) compared to post-1st and post-3rd cycle (p = 0.049 and p = 0.021, respectively). Ki67-positive CTCs were detected in 60%, 60%, 17% and 50% of patients before treatment, post-1st, post-3rd cycle and at PD, respectively, while the opposite was observed for M30-positive CTCs (0% at baseline, 10% after the 1st cycle, 50% after the 3rd cycle and 0% at PD). The detection of even ≥ 1 CTC/5 ml after one cycle was associated with decreased PFS (3.3 vs 9.0 months, p = 0.025) whereas the detection of even ≥ 2 CTCs at PD was associated with decreased OS (32.4 vs 19.5 months; p = 0.009).The combination of E/E resulted in early elimination of proliferating CTCs in mBC patients and this effect was associated with a favorable clinical outcome.
- Published
- 2020
10. MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer
- Author
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Swapna Mahurkar-Joshi, Allan J. Pantuck, Tong Luo, Marina Koutsioumpa, Alexandra Drakaki, Shawnt Issakhanian, Filippos Koinis, Hsiao-Wang Chen, Vassilis Georgoulias, Dimitrios Iliopoulos, Dennis J. Slamon, Christina Vorvis, Neil A. O'Brien, and Artin Soroosh
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Carcinogenesis ,MAP Kinase Signaling System ,Regulator ,Transcriptome ,Mice ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Protein Phosphatase 2 ,Gene ,Cell Proliferation ,Chemistry ,Cell growth ,Protein phosphatase 2 ,Oligonucleotides, Antisense ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Urinary Bladder Neoplasms ,Oncology ,Cell culture ,Cancer research - Abstract
Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR-21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21–induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A–ERK network in mice. Mol Cancer Ther; 17(7); 1430–40. ©2018 AACR.
- Published
- 2018
11. A Comparison of Three Methods for the Detection of Circulating Tumor Cells in Patients with Early and Metastatic Breast Cancer
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Giannis Stoupis, Maria Spiliotaki, Dimitrios Mavroudis, Stella Apostolaki, M. Perraki, Vassilis Georgoulias, Filippos Koinis, Eleni Politaki, Galatea Kallergi, Evi Lianidou, Georgia Saloustrou, Dora Hatzidaki, Areti Strati, Tereza Skaltsi, and Sofia Agelaki
- Subjects
0301 basic medicine ,CA15-3 ,Oncology ,Physiology ,medicine.medical_treatment ,Immunofluorescence ,Kaplan-Meier Estimate ,lcsh:Physiology ,0302 clinical medicine ,Circulating tumor cell ,lcsh:QD415-436 ,Neoplasm Metastasis ,Real Time RT-qPCR ,Aged, 80 and over ,lcsh:QP1-981 ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,Metastatic breast cancer ,030220 oncology & carcinogenesis ,Female ,Cell Search System ,Adjuvant ,Adult ,medicine.medical_specialty ,Concordance ,CA 15-3 ,Breast Neoplasms ,Real-Time Polymerase Chain Reaction ,lcsh:Biochemistry ,03 medical and health sciences ,Breast cancer ,Cell Line, Tumor ,Internal medicine ,Breast Cancer ,medicine ,Humans ,RNA, Messenger ,Aged ,Keratin-19 ,Chemotherapy ,Keratin-18 ,business.industry ,Keratin-8 ,medicine.disease ,Early Diagnosis ,030104 developmental biology ,Microscopy, Fluorescence ,Leukocyte Common Antigens ,business ,Circulating Tumor Cells - Abstract
Background: We directly compared CTC detection rates and prognostic significance, using three different methods in patients with breast cancer (BC). Methods: Early (n=200) and metastatic (n=164) patients were evaluated before initiating adjuvant or first-line chemotherapy, using the CellSearchTM System, an RT-qPCR for CK-19 mRNA detection and by double immunofluorescence (IF) microscopy using A45-B/B3 and CD45 antibodies. Results: Using the CellSearchTM System, 37% and 16.5% of early BC patients were CTC-positive (at ≥1 and ≥2 CTCs/23 ml of blood), 18.0% by RT-qPCR and 16.9% by IF; no agreement was observed between methods. By the CellSearchTM 34.8% and 53.7% (at≥ 5 and ≥ 2 CTCs/7.5 ml) of metastatic patients were CTC-positive, 37.8% by RT-qPCR and 28.5% by IF. A significant agreement existed only between the CellSearchTM and RT-qPCR. In 60.8% of cases, differential EpCAM and CK-19 expression on CTCs by IF could explain the discrepancies between the CellSearchTM and RT-qPCR. CTC-positivity by either method was associated with decreased overall survival in metastatic patients. Conclusion: A significant concordance was observed between the CellSearchTM and RT-qPCR in metastatic but not in early BC. Discordant results could be explained in part by CTC heterogeneity. CTC detection by all methods evaluated had prognostic relevance in metastatic patients.
- Published
- 2017
12. CD8 PD-1 T-cells and PD-L1 circulating tumor cells in chemotherapy-naïve non-small cell lung cancer: towards their clinical relevance?
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Athanasios Kotsakis, Galatea Kallergi, Despoina Aggouraki, Zaharoula Lyristi, Filippos Koinis, Eleni Lagoudaki, Anastasios Koutsopoulos, Vassilis Georgoulias, and Eleni-Kyriaki Vetsika
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0301 basic medicine ,biology ,business.industry ,medicine.medical_treatment ,Immunosuppression ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Ligand (biochemistry) ,lcsh:RC254-282 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Circulating tumor cell ,Oncology ,030220 oncology & carcinogenesis ,PD-L1 ,Cancer research ,medicine ,biology.protein ,Clinical significance ,Lung cancer ,business ,CD8 - Abstract
Background: Since tumor cells may escape from immune surveillance through the programmed cell death 1 (PD-1)/programmed death ligand (PD-L)1 axis, this study was designed in order to evaluate whether there is a correlation between the levels of PD-1+ and PD-L1+-expressing immune cells (ICs) and circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC). Patients and methods: Peripheral blood was obtained from 37 chemotherapy-naïve patients with metastatic NSCLC before treatment. PD-1 and PD-L1 expression was evaluated (1) on ICs with anti-tumor function (CD4+ and CD8+ T-cells, B-cells, monocytes/dendritic cells) using flow cytometry, (2) on CTCs by immunofluorescence and (3) on cells from tumor tissues by immunohistochemistry. The levels of PD-1+ and PD-L1+-expressing ICs were correlated with progression-free survival (PFS). Results: The presence of PD-1+ CD8+ cells, with reduced interferon (IFN)-γ expression, but not other ICs, were positively correlated with PD-L1+ CTCs ( p < 0.04). Increased percentages of PD-1+ CD8+ T-cells, were associated with a worse response to treatment ( p = 0.032) and shorter PFS ( p = 0.023) which, in multivariate analysis, was revealed as an independent predictor for decreased PFS [hazard ratio (HR): 4.1, p = 0.0007]. Conclusion: The results of the current study, for first time, provide evidence for a possible interaction between ICs and CTCs in NSCLC patients via the PD-1/PD-L1 axis and strongly support that the levels of PD-1+ CD8+ in these patients may be of clinical relevance.
- Published
- 2019
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13. Machine learning and data mining frameworks for predicting drug response in cancer: An overview and a novel in silico screening process based on association rule mining
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Leonidas G. Alexopoulos, Vassilis Georgoulias, Theodore Sakellaropoulos, George-Romanos P Foukas, Aristotelis Tsirigos, Vassilis G. Gorgoulis, Konstantinos Vougas, Andreas Ntargaras, Russell D. Petty, Petros P. Sfikakis, Jiri Bartek, Filippos Koinis, Paul A. Townsend, Alexander Polyzos, Vassilios Myrianthopoulos, Rebecca C. Fitzgerald, Dimitris Thanos, Athanassios Kotsinas, Iannis Aifantis, Hua Zhou, and Sonali Narang
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0301 basic medicine ,Association rule learning ,Process (engineering) ,Computer science ,Context (language use) ,Machine learning ,computer.software_genre ,Field (computer science) ,Task (project management) ,Machine Learning ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Web application ,Animals ,Data Mining ,Humans ,Pharmacology (medical) ,Computer Simulation ,Pharmacology ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Precision medicine ,Pipeline (software) ,ComputingMethodologies_PATTERNRECOGNITION ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Artificial intelligence ,Data mining ,business ,computer - Abstract
A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs on a personalized basis. The success of such a task largely depends on the ability to develop computational resources that integrate big "omic" data into effective drug-response models. Machine learning is both an expanding and an evolving computational field that holds promise to cover such needs. Here we provide a focused overview of: 1) the various supervised and unsupervised algorithms used specifically in drug response prediction applications, 2) the strategies employed to develop these algorithms into applicable models, 3) data resources that are fed into these frameworks and 4) pitfalls and challenges to maximize model performance. In this context we also describe a novel in silico screening process, based on Association Rule Mining, for identifying genes as candidate drivers of drug response and compare it with relevant data mining frameworks, for which we generated a web application freely available at: https://compbio.nyumc.org/drugs/. This pipeline explores with high efficiency large sample-spaces, while is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. We conclude with future prospects and challenges of applying machine learning based drug response prediction in precision medicine.
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- 2019
14. Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy
- Author
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L. Giannikaki, Maria Sfakianaki, Z. Saridaki, Maria Tzardi, Spyros Pontikakis, A Kalykaki, N Malamos, Filippos Koinis, Maria Trypaki, E. Kontopodis, Eleni Lagoudaki, Chara Papadaki, V. Georgoulias, and John Souglakos
- Subjects
Bridged-Ring Compounds ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Drug resistance ,Carcinoma, Ovarian Epithelial ,Biology ,Carboplatin ,Thrombospondin 1 ,03 medical and health sciences ,Thioredoxins ,0302 clinical medicine ,Predictive Value of Tests ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,medicine ,Carcinoma ,Humans ,Neoplasms, Glandular and Epithelial ,Ovarian Neoplasms ,Pharmacology ,Chemotherapy ,Taxane ,Hazard ratio ,Middle Aged ,Prognosis ,medicine.disease ,Confidence interval ,Repressor Proteins ,Regimen ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Predictive value of tests ,Immunology ,Molecular Medicine ,Female ,Taxoids - Abstract
To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P
- Published
- 2016
15. Effect of First-Line Treatment on Myeloid-Derived Suppressor Cells’ Subpopulations in the Peripheral Blood of Patients with Non–Small Cell Lung Cancer
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Eleni-Kyriaki Vetsika, Vassilis Georgoulias, Athanasios Kotsakis, Marianthi Gkioulmpasani, Eleftheria Skalidaki, Despoina Aggouraki, Anna Koutoulaki, and Filippos Koinis
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Myeloid ,Bevacizumab ,medicine.medical_treatment ,Lipopolysaccharide Receptors ,Lewis X Antigen ,Flow cytometry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,Aged ,Aged, 80 and over ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Myeloid-Derived Suppressor Cells ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Myeloid-derived Suppressor Cell ,Cancer research ,Female ,Reactive Oxygen Species ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Introduction Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells of myeloid origin whose expression is induced by, among others things, vascular endothelial growth factor. We have previously identified two monocytic and one granulocytic MDSC subpopulations associated with the clinical outcome in patients with non–small cell lung cancer (NSCLC). The aim of the present study was to evaluate the effect of chemotherapy on these MDSC subpopulations. Methods Circulating immune cells from 46 patients with unresectable NSCLC were analyzed by flow cytometry before the initiation of chemotherapy and after three cycles. Changes in the frequencies of the MDSC subpopulations were correlated with clinical outcome. Results Chemotherapy had no uniform effect on either the number or the functionality of monocytic and granulocytic MDSCs. However, three cycles of bevacizumab-containing regimens significantly reduced the percentage of the granulocytic-MDSCs compared with non–bevacizumab-based regimens ( p = 0.0086). At the time of evaluation of response, disease progression was associated with significantly higher levels of all three MDSC subpopulations compared with in patients with disease control. Ιn patients with disease progression after three cycles of chemotherapy, the percentage of CD15-positive monocytic MDSCs was significantly increased compared with baseline. Conclusions In the peripheral blood of patients with NSCLC, bevacizumab-based chemotherapy significantly reduced the levels of granulocytic MDSCs. An increase in the levels of CD15-positive monocytic MDSCs was associated with poor response to treatment and disease progression, providing evidence of their clinical relevance in patients with NSCLC.
- Published
- 2016
16. CD8
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Athanasios, Kotsakis, Galatea, Kallergi, Despoina, Aggouraki, Zaharoula, Lyristi, Filippos, Koinis, Eleni, Lagoudaki, Anastasios, Koutsopoulos, Vassilis, Georgoulias, and Eleni-Kyriaki, Vetsika
- Subjects
PD-L1 ,immune cells ,immunosuppression ,PD-1 ,circulating tumor cells ,Original Research - Abstract
Background: Since tumor cells may escape from immune surveillance through the programmed cell death 1 (PD-1)/programmed death ligand (PD-L)1 axis, this study was designed in order to evaluate whether there is a correlation between the levels of PD-1+ and PD-L1+-expressing immune cells (ICs) and circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC). Patients and methods: Peripheral blood was obtained from 37 chemotherapy-naïve patients with metastatic NSCLC before treatment. PD-1 and PD-L1 expression was evaluated (1) on ICs with anti-tumor function (CD4+ and CD8+ T-cells, B-cells, monocytes/dendritic cells) using flow cytometry, (2) on CTCs by immunofluorescence and (3) on cells from tumor tissues by immunohistochemistry. The levels of PD-1+ and PD-L1+-expressing ICs were correlated with progression-free survival (PFS). Results: The presence of PD-1+ CD8+ cells, with reduced interferon (IFN)-γ expression, but not other ICs, were positively correlated with PD-L1+ CTCs (p < 0.04). Increased percentages of PD-1+ CD8+ T-cells, were associated with a worse response to treatment (p = 0.032) and shorter PFS (p = 0.023) which, in multivariate analysis, was revealed as an independent predictor for decreased PFS [hazard ratio (HR): 4.1, p = 0.0007]. Conclusion: The results of the current study, for first time, provide evidence for a possible interaction between ICs and CTCs in NSCLC patients via the PD-1/PD-L1 axis and strongly support that the levels of PD-1+ CD8+ in these patients may be of clinical relevance.
- Published
- 2018
17. Therapeutic strategies for chemotherapy-induced neutropenia in patients with solid tumors
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Vassilis Georgoulias, George Nintos, Filippos Koinis, and Athanasios Kotsakis
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Risk ,medicine.medical_specialty ,Neutropenia ,MEDLINE ,Antineoplastic Agents ,Cochrane Library ,Quality of life (healthcare) ,Neoplasms ,Granulocyte Colony-Stimulating Factor ,Health care ,Epidemiology ,Ambulatory Care ,Humans ,Medicine ,Pharmacology (medical) ,Intensive care medicine ,Adverse effect ,Febrile Neutropenia ,Pharmacology ,business.industry ,General Medicine ,medicine.disease ,Anti-Bacterial Agents ,Surgery ,Quality of Life ,Drug Therapy, Combination ,business ,Risk assessment - Abstract
Chemotherapy-induced neutropenia (CIN) is a common adverse event during treatment of cancer patients, associated with increased morbidity, mortality, health care costs and impairment of patients' quality of life which necessitate dose reductions.A computerized systematic literature search was performed through Medline, PubMed, Google Scholar and the Cochrane Library to identify peer reviewed publications relevant to CIN, pathophysiology and epidemiology, patient risk-assessment and existing treatment approaches. Additionally, emerging issues such as alternative therapeutic options and implications in elderly care were addressed.Although CIN represents a common adverse event in the management of patients with solid tumors, the heterogeneity in clinical practice across different settings underlines the need to improve existing tools for accurate patient classification. Moreover, the definition of the optimal implementation of out-patient treatment and the use of colony-stimulating factor as add-on treatment together with antibiotics should be further investigated in order to accumulate more solid data. Finally, physician education is required to ensure that scientific knowledge is implemented in the daily clinical practice.
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- 2015
18. Lung cancer and annual mean exposure to outdoor air pollution in Crete, Greece
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Vassilis Georgoulias, Filippos Koinis, Dimitra Sifaki-Pistolla, Nikos Tzanakis, and Christos Lionis
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Cancer Research ,Lung Neoplasms ,Epidemiology ,Air pollution ,010501 environmental sciences ,medicine.disease_cause ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Environmental risk ,Environmental protection ,Environmental health ,Air Pollution ,Medicine ,Humans ,030212 general & internal medicine ,Registries ,Lung cancer ,0105 earth and related environmental sciences ,Greece ,business.industry ,Public Health, Environmental and Occupational Health ,Follow up studies ,Environmental Exposure ,medicine.disease ,Oncology ,Particulate Matter ,business ,Follow-Up Studies - Abstract
The increasing burden of lung cancer (LC) in Crete, Greece, has raised certain concerns about the potential association of environmental risk factors with LC. The aim of this study was to assess outdoor air pollution (OAP) and the risk for LC mortality for the first time in Crete using LC primary data. 5057 LC cases (diagnosed from 1992 to 2013) were obtained from the Cancer Registry of Crete (http://www.crc.uoc.gr) and followed up until 2014. The age-standardized incidence and mortality rates (ASIR) were calculated. Data on OAP indicators [particulate matter (PM)2.5, between 2.5 and 10 μm (PM2.5-10), PM10, PM2.5 absorbance (black carbon measure), nitrogen dioxide (NO2), and nitrogen oxides (NOx)] were collected. Spatial statistics were calculated and the binary logistic regression model was constructed at α=0.05 in IBM SPSS 24 and ArcMap 10.3.1. LC in Crete accounts for 40.2 new cases/100 000/year for both sexes (ASIRmales=73.1 new cases/100 000/year; ASIRfemales=11.8 new cases/100 000/year). Annual median estimates of environmental concentrations in Crete were as follows: PM2.5=20.7 (±1.5) µg/m, PM10=38.9 (±2.5) µg/m, PM2.5-10=59.6 (±3.7) µg/m, PM2.5 absorbance=1.2 (±0.3)×10/m, NO2=15.2 (±3.8) µg/m, and NOx=20.1 (±4.9) µg/m. A statistically significant association was observed between OAP and LC mortality (mean correlation coefficient=0.75; P0.05). The highest risk for 5-year LC mortality was found in the major urban centers and several south-east and north-west rural regions of Crete (relative risk=3.2, 95% confidence interval=1.6-4.7). OAP seems to be an important determinant of LC mortality. Targeted interventions should be performed in the high-risk areas.
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- 2017
19. Smoking behaviour of lung and colorectal cancer patients during and after diagnosis. Which factors hinder smoking cessation?
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Vasiliki-Eirini Chatzea, Vasilis Georgoulias, Dimitra Sifaki-Pistolla, Nikos Tzanakis, Christos Lionis, Georgia Pistolla, and Filippos Koinis
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Oncology ,medicine.medical_specialty ,Health (social science) ,Epidemiology ,Colorectal cancer ,medicine.medical_treatment ,colorectal cancer ,Health Professions (miscellaneous) ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,tobacco smoking ,Lung cancer ,Cancer Diagnosis ,030505 public health ,Lung ,business.industry ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,medicine.disease ,smoking cessation ,3. Good health ,lung cancer ,medicine.anatomical_structure ,Smoking cessation ,0305 other medical science ,business - Abstract
Introduction To assess the smoking behaviour of Lung Cancer (LC) and Colorectal (CRC) patients at the time of diagnosis and one year after diagnosis. Material and Methods The study took place in the island of Crete, Greece. Data (LC patients=4,421; CRC patients=3,609) were derived from the Cancer Registry of Crete (1992-2010). Participants with I-III stage primary cancer and confirmed diagnosis (histologically/cytologically) were included. Patients with unknown stage were excluded after testing for potential statistical bias. Kruskal-Wallis (one-way analyses of variance) and logistic regression models estimated the risk of not quitting smoking after diagnosis. All tests were two-tailed (a=0.05). Results Overall, 75.1% of LC and 51.4% of CRC patients were current smokers at the time of diagnosis. One year after diagnosis 49.5%% of the LC and 38.1% of the CRC patients were still smoking. Males, public insurance, high number of pack/years, not receiving chemotherapy/radiotherapy, not undergoing surgery, higher number of co-morbidities, advanced cancer stage (III) and alcohol consumption were significant predictors of not quitting smoking one year after diagnosis (p
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- 2017
20. Deprivation and smoking trends among lung cancer patients before and after the Greek economic crisis. Insights from the Cancer Registry of Crete
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Filippos Koinis, Vasiliki-Eirini Chatzea, Nikos Tzanakis, Vasilis Georgoulias, Christos Lionis, and Dimitra Sifaki-Pistolla
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medicine.medical_specialty ,Health (social science) ,Epidemiology ,cigarette smoking ,economic crisis ,Health Professions (miscellaneous) ,deprivation ,03 medical and health sciences ,0302 clinical medicine ,Cigarette smoking ,risk factors ,Medicine ,030212 general & internal medicine ,Lung cancer ,030505 public health ,business.industry ,lcsh:Public aspects of medicine ,1. No poverty ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,medicine.disease ,3. Good health ,Cancer registry ,lung cancer ,Emergency medicine ,Medical emergency ,0305 other medical science ,business - Abstract
Introduction Τo provide insights on Lung Cancer (LC) and the associated risk factors before-after the economic crisis in Crete, Greece. To assess the smoking habits of LC patients during the austerity period. Material and Methods The study was conducted in Crete, Greece. Data (5,057 LC cases) were obtained from the Cancer Registry of Crete (CRC). Age-Standardized Incidence and Mortality Rates (ASIR, ASMR/100,000/year), adjusted Charlson’s Comorbidity Index (CCI%), deprivation index (HPI-2) and exposure to Outdoor Air Pollution (OAP) were estimated. The analysis was performed for two time periods (Period A: 1992-2008; Period B: 2009-2013). Results ASIR presented a significant increase during the economic crisis, while even higher increase was observed in ASMR (Period A: ASMR=30.5/100,000/year; Period B: ASMR=43.8/100,000/year; p
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- 2017
21. Nab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group
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Lambros Vamvakas, Kostas Kalbakis, Efthimios Prinarakis, Aris Polyzos, Nikolaos Kentepozidis, Marios Bakogeorgos, Ioannis Varthalitis, John Souglakos, Filippos Koinis, Nikolaos Vardakis, Ioannis Boukovinas, Panagiotis Katsaounis, Athanasios Kotsakis, and Vassilis Georgoulias
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Oncology ,medicine.medical_specialty ,Phases of clinical research ,Nab-paclitaxel ,Gastroesophageal Junction Adenocarcinoma ,Neutropenia ,chemotherapy regimen ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Carcinoma ,030212 general & internal medicine ,Taxane ,business.industry ,gastric cancer ,Gastroenterology ,medicine.disease ,Chemotherapy regimen ,Docetaxel ,Fluorouracil ,030220 oncology & carcinogenesis ,second-line treatment ,Original Article ,business ,medicine.drug - Abstract
Background This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma. Methods Thirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days). Results Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22). Conclusion Nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.
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- 2017
22. A Circulating Subpopulation of Monocytic Myeloid-Derived Suppressor Cells as an Independent Prognostic/Predictive Factor in Untreated Non-Small Lung Cancer Patients
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Vassilis Georgoulias, Despoina Aggouraki, Athanasios Kotsakis, Dimitris Mavroudis, Marianthi Gioulbasani, Eleni-Kyriaki Vetsika, Eirini Skalidaki, Anna Koutoulaki, and Filippos Koinis
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lcsh:Immunologic diseases. Allergy ,Male ,Lung Neoplasms ,Article Subject ,CD14 ,Sialic Acid Binding Ig-like Lectin 3 ,Immunology ,CD33 ,Lipopolysaccharide Receptors ,Lewis X Antigen ,Nitric Oxide Synthase Type II ,CD15 ,Biology ,Disease-Free Survival ,Monocytes ,Immunophenotyping ,Flow cytometry ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Immunology and Allergy ,Myeloid Cells ,Aged ,Aged, 80 and over ,CD11b Antigen ,medicine.diagnostic_test ,Monocyte ,Cancer ,HLA-DR Antigens ,General Medicine ,Middle Aged ,Flow Cytometry ,Prognosis ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,Multivariate Analysis ,Myeloid-derived Suppressor Cell ,Cancer research ,Female ,lcsh:RC581-607 ,Reactive Oxygen Species ,Research Article - Abstract
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of cells with immunosuppressive properties and might confer to worse prognosis in cancer patients. The presence of phenotypically newly described subpopulations of MDSCs and their association with the clinical outcome were investigated in non-small cell lung cancer (NSCLC) patients. The percentages and correlation between MDSCs and distinct immune cells in the peripheral blood of 110 chemotherapy-naive patients before treatment and healthy controls were investigated using flow cytometry. Two monocytic [CD14+CD15−CD11b+CD33+HLA-DR−Lin−and CD14+CD15+CD11b+CD33+HLA-DR−Lin−] and a granulocytic [CD14−CD15+CD11b+CD33+HLA-DR−Lin−] subpopulations of MDSCs were identified, expressing inducible nitric oxide synthase, and reactive oxygen species, respectively. Increased percentages of both monocytic-MDSCs’ subpopulations were inversely correlated to dendritic/monocyte levels(P≤0.04), while granulocytic-MDSCs were inversely correlated to CD4+T cells(P=0.006). Increased percentages of monocytic-MDSCs were associated with worse response to treatment(P=0.02)and patients with normal levels of CD14+CD15+CD11b+CD33+HLA-DR−Lin−had longer overall survival and progression free-survival compared to those with high levels(P=0.008andP=0.005, resp.). Multivariate analysis revealed that the increased percentages of CD14+CD15+CD11b+CD33+HLA-DR−Lin−MDSCs were independently associated with decreased progression free-survival and overall survival. The data provide evidence that increased percentages of new monocytic-MDSCs’ subpopulations in advanced NSCLC patients are associated with an unfavourable clinical outcome.
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- 2014
23. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one
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Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle
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Pharmacology ,0303 health sciences ,Cancer Research ,Side effect ,business.industry ,medicine.drug_class ,Immunology ,Phases of clinical research ,Monoclonal antibody ,Phase i study ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunology and Allergy ,Medicine ,In patient ,Programmed death 1 ,business ,030304 developmental biology - Published
- 2016
24. Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment
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Michail Nikolaou, Eleni Lagoudaki, Athanasios Kotsakis, Ippokratis Messaritakis, Eleni Politaki, Vassilis Georgoulias, Anastasios Koutsopoulos, and Filippos Koinis
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Cancer Research ,Chemotherapy ,Circulating tumor cell ,Oncology ,business.industry ,medicine.medical_treatment ,Cancer research ,medicine ,In patient ,Front line ,Clinical significance ,Non small cell ,business - Abstract
e20086 Background: The aim of the study was to characterize and evaluate the presence of DLL3-positive Circulating Tumor Cells (CTCs) in SCLC patients receiving front-line chemotherapy and assess their clinical relevance. Methods: Peripheral blood was obtained from treatment-naïve patients with SCLC (n = 108 patients), after one-etoposide/platinum cycle (n = 68 patients) and on disease progression (n = 48 patients). CTCs were detected after immunofluorescence staining using antibodies against the DLL3, cytokeratins (CK), CD45 and vimentin (Vim). Results: Before treatment, 74.1% of patients had detectable CTCs (DLL3+/CD45-). One-treatment cycle significantly decreased both the detection rate of DLL3+/CD45- CTCs ( p< 0.001) and their absolute number ( p< 0.001). Triple immunofluorescence staining using anti-CK, anti-Vim and anti-DLL3 antibodies revealed an important CTC heterogeneity since DLL3 could be detected in Vim+, Vim-, CK+ and CK- CTCs. On disease progression, both the detection rate of DLL3+/CD45- CTCs as well as their number were significantly increased compared to post-1st cycle values ( p< 0.001 and p= 0.002, respectively). In addition, 22.7% of patients had detectable DLL3+/CD45- cells which could not be captured by the CellSearch assay. In multivariate analysis, the detection of DLL3+/CD45- CTCs at baseline was significantly associated with decreased progression-free survival (HR = 10.8; p= 0.005) whereas their detection on disease progression was associated with decreased overall survival (HR: 28.2; p= 0.016). Conclusions: These findings demonstrate an important heterogeneity of CTCs, based on the expression of CK, Vim and DLL3, in patients with SCLC and the changes of DLL3+/CD45- CTCs during treatment seem to be a dynamic biomarker associated with treatment efficacy and patients’ clinical outcome.
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- 2019
25. P3.02c-103 Effect of Anti-PD-1 Therapy on Immune Cells in the Peripheral Blood of Non-Small Cell Lung Cancer (NSCLC) Patients
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Filippos Koinis, Zacharoula Lyristi, Vassilis Georgoulias, Despoina Aggouraki, Eleni-Kyriaki Vetsika, and Athanasios Kotsakis
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Immune system ,business.industry ,Internal medicine ,Anti pd 1 ,Medicine ,non-small cell lung cancer (NSCLC) ,business ,medicine.disease ,Peripheral blood - Published
- 2017
26. Abstract 1587: Detection of PD-L1 and PD-1 positive circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab
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Galatea Kallergi, Vassilis Georgoulias, Despoina Agouraki, Anastasia Voumvouraki, Anastasios Koutsopoulos, Stuart S. Martin, Filippos Koinis, Christos Stournaras, Eleni Lagoudaki, Athanasios Kotsakis, and Eleni-Kiriaki Vetsika
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,medicine.drug_class ,non-small cell lung cancer (NSCLC) ,Cancer ,medicine.disease ,Monoclonal antibody ,Circulating tumor cell ,Internal medicine ,PD-L1 ,medicine ,biology.protein ,Antibody ,Liquid biopsy ,Nivolumab ,business - Abstract
Introduction: Circulating tumor cells (CTCs) are considered as a “liquid biopsy” that allows the assessment of tumor changes over time. Tumor cells may escape from the immune system through the activation of PD-1/PD-L1 axis. Targeting these molecules with monoclonal antibodies has shown encouraging results at many types of cancers, including NSCLC. In the current study we investigated the expression of PD-1/PD-L1 molecules on the CTCs isolated from NSCLC patients treated with Nivolumab. Methods: CTCs were isolated based on their size using the ISET platform from 27 patients before treatment, after 1 cycle and 3 cycles. CTCs were detected with Giemsa staining and immunofluorescence (IF) experiments, using either pancytokeratin (A45-B/B3) (CK7)/PD-1/CD45 or (A45-B/B3)(CK7)/PD-L1/CD45 combination of antibodies and analysis with the ARIOL system. Spiking experiments using the NSCLC cell lines: H460, H1299, HCC827 and SKMES in normal blood were used to evaluate the detection method. Results: Giemsa evaluation in Nivolumab-treated patients at baseline (25 evaluable samples), after the 1st (9 evaluable samples) and the 3rd (8 evaluable patients) cycle of treatment showed that CTCs could be detected in 48% (12/25), 33.3% (3/9) and 50% (4/8) of patients, respectively. IF could also reveal the presence of CK-positive cells in 44.4% (12/27), 22% (2/9) and 75% (6/8) patients, respectively. PD-1 (+) CTCs were detected in 33.3% (4/12) of patients at baseline, in, 0% after the 1 and 16.7% (1/6) of patients after the 3rd cycle. The same percentages were identified for PD-L1 expression in the same cohort of patients. The expression of PD-1 at baseline was associated with poorer OS (p=0.022) and PFS (p=0.011), while the expression of PD-L1 was associated with shorter PFS (p=0.011). Multivariate analysis revealed that the presence of CK-positive cells is an independent prognostic factor for OS (p=0.028) Conclusion: Nivolumab reduced the number of PD-1- and PD-L1-expressing CTCs in advanced NSCLC patients. Furthermore the expression of both markers at baseline is associated with the clinical outcome. Citation Format: Galatea Kallergi, Anastasios Koutsopoulos, Eleni Lagoudaki, Despoina Agouraki, Eleni-Kiriaki Vetsika, Anastasia Voumvouraki, Stuart S. Martin, Filippos Koinis, Christos Stournaras, Vassilis Georgoulias, Athanasios Kotsakis. Detection of PD-L1 and PD-1 positive circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1587.
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- 2018
27. Prognosis in advanced lung cancer--A prospective study examining key clinicopathological factors
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Jo Bowden, Claribel Simmons, Ioannis Gioulbasanis, Marie Fallon, Filippos Koinis, Barry Laird, Bjørn Henning Grønberg, Tora Skeidsvoll Solheim, Kenneth C. H. Fearon, and Donald C. McMillan
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Oncology ,Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Cancer Research ,Multivariate analysis ,Cachexia ,Lung Neoplasms ,medicine.medical_treatment ,Weight loss ,Internal medicine ,Weight Loss ,medicine ,Humans ,Prospective Studies ,Lung cancer ,Prospective cohort study ,Aged ,Neoplasm Staging ,Inflammation ,Chemotherapy ,Performance status ,Proportional hazards model ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Surgery ,Female ,medicine.symptom ,business ,CRP - Abstract
ObjectivesIn patients with advanced incurable lung cancer deciding as to the most appropriate treatment (e.g. chemotherapy or supportive care only) is challenging. In such patients the TNM classification system has reached its ceiling therefore other factors are used to assess prognosis and as such guide treatment. Performance status (PS), weight loss and inflammatory biomarkers (Glasgow Prognostic Score (mGPS)) predict survival in advanced lung cancer however these have not been compared. This study compares key prognostic factors in advanced lung cancer.Materials and methodsPatients with newly diagnosed advanced lung cancer were recruited and demographics, weight loss, other prognostic factors (mGPS, PS) were collected. Kaplan-Meier and Cox regression methods were used to compare these prognostic factors.Results390 patients with advanced incurable lung cancer were recruited; 341 were male, median age was 66 years (IQR 59-73) and patients had stage 4 non-small cell (n = 288) (73.8%) or extensive stage small cell lung cancer (n = 102) (26.2%). The median survival was 7.8 months. On multivariate analysis only performance status (HR 1.74 CI 1.50-2.02) and mGPS (HR 1.67, CI 1.40-2.00) predicted survival (p < 0.001). Survival at 3 months ranged from 99% (ECOG 0-1) to 74% (ECOG 2) and using mGPS, from 99% (mGPS0) to 71% (mGPS2). In combination, survival ranged from 99% (mGPS 0, ECOG 0-1) to 33% (mGPS2, ECOG 3).ConclusionPerformance status and the mGPS are superior prognostic factors in advanced lung cancer. In combination, these improved survival prediction compared with either alone.
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- 2014
28. Evaluation of proliferation and apoptosis markers in circulating tumor cells of women with early breast cancer who are candidates for tumor dormancy
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Maria Spiliotaki, Galatea Kallergi, Kyriaki Kapranou, Vassilis Georgoulias, Dimitris Mavroudis, Sofia Agelaki, Kostas Kalbakis, Harris Markomanolaki, and Filippos Koinis
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Adult ,CA15-3 ,Oncology ,medicine.medical_specialty ,Proliferation index ,Population ,Apoptosis ,Breast Neoplasms ,Peripheral blood mononuclear cell ,Disease-Free Survival ,Circulating tumor cell ,Breast cancer ,Surgical oncology ,Cell Line, Tumor ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,education ,Aged ,Cell Proliferation ,Neoplasm Staging ,Medicine(all) ,education.field_of_study ,Keratin-18 ,biology ,Carcinoma, Ductal, Breast ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,medicine.disease ,Peptide Fragments ,Carcinoma, Lobular ,Ki-67 Antigen ,biology.protein ,Keratins ,Female ,Antibody ,Research Article - Abstract
Introduction Clinical dormancy is frequently observed in breast cancer. In the present study, we aimed to characterize circulating tumor cells (CTCs) in dormancy candidates (DC) with early breast cancer in terms of proliferation and apoptosis. Methods Cytospins of peripheral blood mononuclear cells (PBMCs) were obtained from DC (n = 122) who were disease-free for at least 5 years and from metastatic patients (n = 40) who relapsed more than 5 years after surgery. Sequential samples from eight DC (n = 36) who maintained a prolonged disease-free status and from eight DC (n = 27) presenting late relapse during follow-up, were also analyzed. PBMCs were triple stained with a pancytokeratin, antibody along with anti-Ki67 and anti-M30 antibodies as proliferation and apoptosis markers, respectively. Results CTCs were identified in 40 (33%) of 122 DC and in 15 (37.5%) of 40 metastatic patients. In total, twenty-five (62.5%) DC had exclusively dormant (Ki67(-)/M30(-)), seven (17.5%) had proliferative Ki67(+)/M30(-), four (10%) had apoptotic Ki67(-)/M30(+) and four (10%) had both phenotypes of proliferative and apoptotic CTCs. In comparison, 53.4% of CTC-positive metastatic patients had exclusively dormant and 46.6% had proliferative CTCs; none had apoptotic CTCs (P = 0.039). Among all CTCs detected in DC patients, 82.4% were dormant, whereas in the nondormant population, 32.5% were proliferative and 67.5% apoptotic. The respective percentages in metastatic patients were 59.1%, 100% and 0% (P
- Published
- 2014
29. Abstract 1726: Evaluation of PD-L1/PD-1 on circulating tumor cells (CTCs) and on primary tumor in advanced non-small cell lung cancer (NSCLC)
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Christos Stournaras, Maria Trypaki, Vassilis Georgoulias, Anastasios Koutsopoulos, Filippos Koinis, Galaktea Kallergi, Panagiotis Katsarlinos, Athanasios Kotsakis, Despoina Aggouraki, Eleni Lagoudaki, and Eleni-Kyriaki Vetsika
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,biology ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,non-small cell lung cancer (NSCLC) ,Cancer ,medicine.disease ,Primary tumor ,Metastasis ,Circulating tumor cell ,PD-L1 ,Internal medicine ,biology.protein ,Medicine ,business - Abstract
Introduction: Circulating tumour cells (CTCs) are responsible for the metastatic dissemination of the tumor. They have been shown to express Programmed Death-Ligand1 (PD-L1) to escape from the immune system surveillance through its ligation with the PD-1receptor on the surface of effector immune cells. We investigated the expression of PD-1/PD-L1 on CTCs isolated from NSCLC patients treated with chemotherapy. Methods: CTCs were isolated based on their size using the ISET platform from 30 stage IV chemo-naïve NSCLC patients (before and after chemotherapy). CTCs were detected after staining with Giemsa and immunofluorescence (IF). Double and triple staining experiments with different combination of antibodies: [Cytokeratins(CK)/PD-1/CD45 and CK/PD-L1/CD45] were performed and the samples were analyzed with the ARIOL system. Results Giemsa staining showed that twenty-three (77%) out of 30 and six (54.5%) out of 11 patients had detectable CTCs at baseline and after the 3rd cycle of front-line chemotherapy. IF staining revealed seventeen out of 30 (56.7%) patients positive for CTCs at baseline level and 8 out of 11 (72.7%) samples after the 3rd cycle of treatment. PD-1 and PD-L1 expression was observed in 53% (9/17) and in 47% of the CTC-positive patients at baseline; in addition, 13% (1/8) and 63% (5/8) patients had PD-1 and PD-L1, respectively after the 3rd cycle. Among the total number of detected CTCs, 67% were PD-1(+) at baseline and 25% after the 3rd cycle (p=0.069). In addition, 26% and 80% were PD-L1(+) at baseline and after the 3rd cycle, respectively. Patients with more than 3 PD-1 positive CTCs showed shorter PFS (p=0.022). Primary tissue from ten of the examined patients was also available. More than 5% of PD-L1 (+) tumor infiltrating lymphocytes (TILs) were observed in 20% (2/10) of the patients. More than 5% PD-L1 positive cells in the primary tumor were observed in 20%. However the two group of the patients were different. In addition both patients with PD-L1 (+) TILs harvested CTCs with PD-1 expression and one of them had also PD-L1 positive CTCs. Conclusion: PD-1- and PD-L1-positive CTCs could be detected before and during 1st line treatment in metastatic NSCLC. This expression was related to patients’ prognosis, implying that these molecules can be served as targets for metastasis restoration. Furthermore the expression of PD-1 on CTCs suggests a bilateral cross-talk between tumor and immune cells. Citation Format: Galaktea Kallergi, Eleni Kyriaki Vetsika, Despoina Aggouraki, Eleni Lagoudaki, Anastasios Koutsopoulos, Filippos Koinis, Panagiotis Katsarlinos, Maria Trypaki, Christos Stournaras, Vassilis Georgoulias, Athanasios Kotsakis. Evaluation of PD-L1/PD-1 on circulating tumor cells (CTCs) and on primary tumor in advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1726. doi:10.1158/1538-7445.AM2017-1726
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- 2017
30. Abstract 619: Effect of anti-PD-1 therapy on immune cells in the peripheral blood of non-small cell lung cancer patients
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Vassilis Georgoulias, Eleni-Kyriaki Vetsika, Filippos Koinis, Athanasios Kotsakis, Despoina Aggouraki, Aristeidis Koukos, Zaharoula Lyristi, Despoina Kourougkiaouri, and Galatea Kallergi
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,biology ,business.industry ,medicine.medical_treatment ,T cell ,FOXP3 ,medicine.disease ,Cell therapy ,Immune system ,medicine.anatomical_structure ,Internal medicine ,Cancer research ,medicine ,biology.protein ,Antibody ,Lung cancer ,business ,CD8 - Abstract
Background: Programmed cell death-1 (PD-1), an inhibitory immune check-point, plays a pivotal role in tumor immune escape. The interaction of PD-1 with its ligand (PD-L1) results in T cells exhaustion, and the blockade of this interaction can partially restore T cell function. Recently, antibodies targeting PD-1 and PD-L1 have been approved for treatment of advanced Non Small Cell Lung Cancer (NSCLC). In this pilot study, we aimed to investigate the effect of anti-PD1 treatment or chemotherapy on the frequencies of circulating PD-1+ T cells and PD-L1+ immunosuppressive cells in NSCLC patients. Patients & Methods: Peripheral blood samples were collected from 35 advanced NSCLC patients before initiation of treatment and after 3 cycles. Twelve treatment-naïve patients received front-line chemotherapy, whereas 23 patients received anti-PD1 treatment in the second-line setting. Flow cytometry was used to quantify PD-1- and PD-L1-expressing immune cells. Changes in the frequencies of these cells were compared between the two settings and correlated with the clinical outcome. Results: Chemotherapy had no effect on the percentages of PD-1+CD4+ and PD-1+CD8+ T cells after 3 cycles, whereas there was a significant decrease in PD-1+CD4+ and PD-1+CD8+ T cells in patients who received 3 administrations of anti-PD1 antibody (p=0.007 and p=0.05, respectively). Moreover, the levels of PD-1-CD4+ (p=0.009) and PD-1-CD8+ (p=0.009) were augmented in response to anti-PD-1 therapy. The frequencies of both peripheral CD4+ Tregs (CD3+CD4+CD25highCD127-/lowCD152+FoxP3+) and granulocytic MDSCs (G-MDSC; CD14-CD15+CD33+CD11b+HLA-DR-Lin-) expressing PD-L1 were decreased following anti-PD1 therapy (p=0.01 and p=0.02, respectively). In contrast, chemotherapy affected only the PD-L1+CD4+ Tregs, but not the PD-L1+G-MDSC, by increasing their levels after 3 cycles (p=0.04). Anti-PD-1 treatment induced a superior reduction of the PD-1+CD4+, PD-1+CD8+ T cells, PD-L1+CD4+ Tregs and PD-L1+G-MDSCs percentages compared to the effect of first line chemotherapy (p=0.04, p=0.05, p=0.002 and p=0.01, respectively). Furthermore, a significant decrease in PD-1+CD8+ T cells, PD-L1+CD4+ Tregs and PD-L1+G-MDSCs after 3 doses of anti-PD-1 was observed in patients who experienced stable disease compared to baseline (p=0.006, p=0.05 and p=0.03, respectively). At the time of response evaluation to chemotherapy, the percentage of the PD-L1+CD4+ Tregs after 3 cycles was significantly inferior compared to baseline, in disease progressors (p=0.04). Conclusion: These data indicate that although chemotherapy affected the levels of PD-L1+CD4+ Tregs, anti-PD1 therapy seems to exert an effect on both PD1+ T cells and PD-L1+ immunosuppressive cells. Additional studies are needed in a larger cohort in order to document its impact on their clinical relevance in NSCLC patients. This study is ongoing and updated data will be presented at the meeting. Citation Format: Eleni-Kyriaki Vetsika, Galatea Kallergi, Despoina Aggouraki, Zaharoula Lyristi, Aristeidis Koukos, Despoina Kourougkiaouri, Filippos Koinis, Vassilis Georgoulias, Athanasios Kotsakis. Effect of anti-PD-1 therapy on immune cells in the peripheral blood of non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 619. doi:10.1158/1538-7445.AM2017-619
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- 2017
31. Corrigendum to 'Prognosis in advanced lung cancer – A prospective study examining key clinicopathological factors' [Lung Cancer 88 (2015) 304–309]
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Kenneth C. H. Fearon, Ioannis Gioulbasanis, Donald C. McMillan, Claribel Simmons, Filippos Koinis, Tora Skeidsvoll Solheim, Marie Fallon, Bjørn Henning Grønberg, Barry Laird, and Jo Bowden
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,020205 medical informatics ,business.industry ,02 engineering and technology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Key (cryptography) ,business ,Prospective cohort study ,Lung cancer - Published
- 2017
32. Prognostic value of PD-L1+CD4+ T cells in non-small cell lung cancer (NSCLC) patients treated with a PD-1 inhibitor
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Vassilis Georgoulias, Despoina Aggouraki, Kiriaki E. Vetsika, Zacharoula Lyristi, Athanasios Kotsakis, and Filippos Koinis
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Cancer Research ,biology ,business.industry ,Cell ,non-small cell lung cancer (NSCLC) ,medicine.disease ,Clinical trial ,medicine.anatomical_structure ,Immune system ,Oncology ,Programmed cell death 1 ,PD-L1 ,biology.protein ,Cancer research ,medicine ,Antibody ,business ,Receptor - Abstract
58 Background: One of the tumour escape mechanisms is the expression of programmed cell death-1 (PD-1) receptor on immune cells. Clinical trials have demonstrated that antibodies against PD-L1 or PD-1 molecules induce objective clinical responses in pre-treated patients with NSCLC. In this study, we evaluated the levels of PD-1+ and PD-L1+expressing- immune cells and their association with the clinical outcome in NSCLC patients. Methods: Peripheral blood was collected from 32 advanced/metastatic pre-treated NSCLC patients before anti-PD-1 therapy (Nivolumab). Flow cytometry was performed to identify and quantify PD-1 and PD-L1 expression on circulating immune cells with anti-tumor function (CD4+ and CD8+ T cells, B cells, Dendritic cells) , as well as on immunosuppressivecells [(CD4+ and CD8+ Treg cells, Bregs, Myeloid-derived Suppressor cells (MDSC)]. Correlation between the levels of PD-1+ and PD-L1+-expressing immune cells, as well as their association with overall (OS) and progression-free survival (PFS) was evaluated; high expression of immune cells was defined as the percentage of the cells above the mean value. Results: PD-1 and PD-L1 expression was detected on all tested immune cells with anti-tumor activity. PD-1 expression was found on all immunosuppressive cells, whereas only CD4+ and CD8+ Treg cells and Granulocytic -MDSCs expressed PD-L1. No PD-L1 expression was observed on Bregs and monocytic-MDSCs. There was no correlation of PD-1 or PD-L1-expressing cells with response to anti-PD1 treatment. A significantly decreased PFS was observed in the low CD4+ PD-L1+ T cells group compared with the high CD4+ PD-L1+ group (3.4 months vs. 5.2 months, p=0.03). Univariate analysis for PFS revealed that the low percentages of CD4+ PDL-1+ T cells were prognostic for shorter PFS (HR= 3.1, p=0.04). On the multivariate analysis, low PD-L1+ CD4+T cells were independently associated with decreased PFS (HR: 3.3, p=0.03). Conclusions: These data provide evidence that PD-L1+ expression on peripheral CD4+ T cells was a significant predictor of better PFS in NSCLC patients. Therefore, PD-L1 expression could be used for the selection of patients who might benefit from PD-1/PD-L1 inhibitors.
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- 2017
33. Abstract P1-01-06: Ki67-positive CTCs are associated with early disease relapse in patients with early breast cancer undergoing adjuvant chemotherapy
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Maria Spiliotaki, Filippos Koinis, D. Mavroudis, Eleni Politaki, Sophia Agelaki, A Spanaki, V. Georgoulias, and L Kassiou
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Adjuvant chemotherapy ,Internal medicine ,Early disease ,Medicine ,In patient ,business ,Early breast cancer - Abstract
Background: The determination of Ki67 in the primary tumor has prognostic value in early breast cancer (BC). We evaluated Ki67 expression in circulating tumor cells (CTCs) from patients with early BC undergoing adjuvant chemotherapy and correlated Ki67 positivity with patient outcome. Methods: Ki67 expression in CTCs was evaluated by immunofluorescent analysis in paired blood samples of patients with early BC (n=166) obtained before and after adjuvant chemotherapy. Ki67 expression was also evaluated in CTC-positive patients at 6 - 24 months after the end of chemotherapy (n=31). Cytospins of peripheral blood mononuclear cells were double stained with A45-B/B3 cytokeratin and Ki67 antibodies. The proliferation index (PI) of CTCs was defined as the ratio of Ki67-positive CTCs/total CTCs. Results: CTCs were detected in 53 (32%) patients before and/or after chemotherapy. Ki67-positive [Ki67(+)] CTCs were identified in 79% of CTC-positive patients, 25% presenting exclusively Ki67(+) CTCs and 21%, exclusively Ki67(-) CTCs. The mean value of Ki67(+) CTCs/patient remained unchanged pre- and post-chemotherapy [(mean±SE): pre- vs post-chemotherapy 2.5±0.7 vs 4.2±2, respectively; p= 0.900]. Similarly, the PI among the total CTCs detected pre- and post-chemotherapy was 59% and 60%, respectively. Ten (19%) of 53 CTC-positive and 9 (8%) of 113 CTC-negative patients relapsed (p = 0.039). In addition, all CTC-positive patients who relapsed harbored Ki67(+) CTCs before and/or after chemotherapy. Interestingly, 70% of them experienced early disease recurrence, ranging from 6-29 months after the initiation of adjuvant chemotherapy. Furthermore, 38.5% of patients with exclusively Ki67(+) CTCs relapsed compared to none among patients with exclusively Ki67(-) CTCs (p = 0.041). Of the 31 CTC-positive patients evaluated during follow-up, 39% remained CTC-positive. However, only 33.3% of them harbored Ki67(+) CTCs, 8.3% had exclusively Ki67(+) CTCs and 66.7% exclusively Ki67(-) CTCs. The mean value of Ki67(+) CTCs/patient was significantly reduced on the follow-up samples [(mean±SE): follow-up vs pre-chemotherapy, 1.35±1.3 vs 2.5±0.7, respectively; p=0.014 and follow-up vs post-chemotherapy, 1.35±1.3 vs 4.2±2, respectively; p= 0.026]. Conclusions: Ki67 expression on CTCs is predictive of early relapse in patients with early BC. Ki67 expression is not decreased by adjuvant chemotherapy, whereas it is reduced early during follow-up, possibly due to adjuvant hormone therapy and/or anti-HER2 therapy. The above results suggest that additional therapy is needed for patients with early BC and Ki67(+) CTCs to prevent early disease recurrence. Citation Format: Agelaki S, Spiliotaki M, Politaki E, Spanaki A, Kassiou L, Koinis F, Georgoulias V, Mavroudis D. Ki67-positive CTCs are associated with early disease relapse in patients with early breast cancer undergoing adjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-06.
- Published
- 2017
34. Salvage chemotherapy with docetaxel and pegylated liposomal doxorubicin in pretreated patients with platinum- and taxane-sensitive ovarian cancer: a multicenter phase II trial of the Hellenic Oncology Research Group (HORG)
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Christos Emmanouilidis, Zafeiris Zafeiriou, Antonia Kalykaki, Vassilis Georgoulias, Kostas Kalbakis, Elisavet Papadimitraki, Filippos Koinis, Aristidis Polyzos, George Samonis, and Athina Christopoulou
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Docetaxel ,Neutropenia ,Carcinoma, Ovarian Epithelial ,Toxicology ,Carboplatin ,Polyethylene Glycols ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Neoplasms, Glandular and Epithelial ,Prospective Studies ,Aged ,Pharmacology ,Ovarian Neoplasms ,Salvage Therapy ,Taxane ,business.industry ,Middle Aged ,medicine.disease ,Clinical trial ,Regimen ,Doxorubicin ,Toxicity ,Female ,Taxoids ,Neoplasm Recurrence, Local ,Ovarian cancer ,business ,Febrile neutropenia ,medicine.drug - Abstract
To evaluate the safety and antitumor activity of docetaxel (DOC) and pegylated liposomal doxorubicin (PLD) combination in patients with platinum- and taxane-sensitive ovarian cancer.Twenty-three patients were enrolled. DOC was administered at the dose of 40 mg/m(2) intravenously (i.v.) and PLD at 20 mg/m(2) i.v. on days 1 and 15 in cycles of 28 days. The study was closed prematurely due to slow accrual.Seven (30.4 %) patients achieved objective response (three complete, four partial), while five (21.7 %) others experienced stable disease (overall disease control rate 52.1 %). The median progression-free survival was 4.8 months and the median overall survival 18.8 months. Grade 3-4 neutropenia occurred in two (8.7 %) and one (4.3 %) patients, respectively. Febrile neutropenia occurred in two patients. The most common non-hematological grade 3 toxicity was hand-foot syndrome (13 % of patients). There was no treatment-related death.The combination of pegylated liposomal doxorubicin and docetaxel is a well tolerated and a relatively active regimen in pretreated patients with platinum- and taxane-sensitive advanced ovarian cancer.
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- 2014
35. Effect of 2nd line pazopanib (PZN) on the number and phenotype of CTCs in patients with small cell lung cancer
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Ippokratis Messaritakis, Vassilis Georgoulias, Filippos Koinis, Stella Apostolaki, Nikolaos Vovolinis, Eleni Politaki, Eleftheria Kleio Dermitzaki, Athanasios Kotsakis, and Maria Plataki
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Pazopanib ,Cancer Research ,Oncology ,business.industry ,Cancer research ,Medicine ,In patient ,Non small cell ,Line (text file) ,business ,Phenotype ,respiratory tract diseases ,medicine.drug - Abstract
8562Background: To investigate the effect of 2nd line PZN on the number and phenotype of CTCs in patients with SCLC. Methods: CTCs were detected in58 pts using the CelleSearch assay (CS) and double...
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- 2016
36. Salvage treatment of relapsed/refractory small cell lung cancer with pazopanib: A Hellenic Oncology Research Group’s (HORG) phase II study
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Epaminontas Samantas, E Hartabilas, Charalampos Christofyllakis, Stavros D. Peroukidis, Efthimios Prinarakis, Nikolaos K. Kentepozidis, Athanasios Kotsakis, Vasilis Karavasilis, George Fountzilas, Vassilis Georgoulias, Filippos Koinis, Eleftheria Kleio Dermitzaki, and Sofia Agelaki
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Oncology ,Cancer Research ,medicine.medical_specialty ,Research groups ,integumentary system ,biology ,business.industry ,Angiogenesis ,Salvage treatment ,Phases of clinical research ,Pazopanib ,Internal medicine ,embryonic structures ,cardiovascular system ,biology.protein ,medicine ,Non small cell ,business ,Tyrosine kinase ,Platelet-derived growth factor receptor ,medicine.drug - Abstract
8561Background: Pazopanib (PZB) is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and c-kit. Several studies have shown that angiogenesis is of ...
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- 2016
37. Abstract P2-02-16: The proliferation index of circulating tumor cells (CTCs) is not influenced by the administration of adjuvant chemotherapy in early breast cancer (BC) and seems to reflect Ki67 expression of the primary tumor
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Sophia Agelaki, Maria Spiliotaki, A Spanaki, D. Mavroudis, Maria Kafousi, Filippos Koinis, M Tzardi, L Kassiou, and V. Georgoulias
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Oncology ,Cancer Research ,Pathology ,medicine.medical_specialty ,Chemotherapy ,Proliferation index ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Primary tumor ,Peripheral blood mononuclear cell ,Cytokeratin ,Breast cancer ,Circulating tumor cell ,Internal medicine ,Medicine ,business - Abstract
Background: The assessment of Ki67 in the primary tumor represents a prognostic marker with potential predictive implications in early BC. We evaluated Ki67 expression in CTCs from patients with early BC and assessed the effect of adjuvant chemotherapy as well as Ki67 expression in the primary tumor. Methods: Ki67 was evaluated in CTCs of 97 patients with early BC pre- and post- adjuvant chemotherapy by the use of immunofluorescence analysis. Cytospins of peripheral blood mononuclear cells were double stained with A45-B/B3 cytokeratin mouse antibody and a Ki67 rabbit antibody. Ki67 staining of the primary tumor was also performed for 13 CTC-positive patients. A proliferation index (PI) in CTCs was considered as the ratio of Ki67-positive CTCs/total CTCs. A PI of up to 14% was defined as 'low' whereas a PI above 14% was defined as 'high'. Results: CTCs were detected in 26 (26.8%) patients before and/or after chemotherapy. Seven (27%) of 26 CTC-positive and 8 (11%) of 74 CTC-negative patients relapsed (p = 0.047). Ki67-positive CTCs were identified in 20 (76.9%) of 26 patients, whereas in 1 (3.9%) and 5 (19.2%) patients, exclusively Ki67-positive and Ki67-negative CTCs, respectively, were detected. Seven (33%) of 21 Ki67-positive patients relapsed in contrast to none among the exclusively Ki67-negative patients (p = 0.13). A total of 154 and 161 CTCs were detected pre- and post-chemotherapy, respectively; the PI in CTCs was 56% and 55%, respectively. In 8 patients with detectable CTCs at both time points, the PI was 65% and 49% pre- and post-chemotherapy, respectively. In 5 (62.5%) out of 8 patients, the PI remained high, in 2 (25%) increased and in 1 patient no Ki67–positive CTCs were detected post-chemotherapy. Seventeen patients were CTC-positive at baseline [HER2 positive, n=5; triple negative, n=1; hormone receptor positive, n=11]. A concordance in Ki67 staining between the primary tumor and CTCs was recorded in 10 (77%) out of 13 patients. Moreover, in 2 (67%) of 3 patients with exclusively Ki67-negative CTCs, low Ki67 expression was also observed in the primary tumor. Interestingly, 2 out of 5 patients with HER2 positive primary relapsed and both had high PI in their CTCs, whereas 2 out the 3 HER2 positive patients that did not relapse had low CTC proliferation index. Similarly, the triple negative patient had low PI in her CTCs and has not relapsed after 4 years of follow up. Conclusions: Adjuvant chemotherapy fails to decrease the proliferation index in CTCs. Ki67 expression in CTCs seems to reflect Ki67 expression in the primary tumor and could be predictive of patient outcome. Citation Format: Agelaki S, Spiliotaki M, Spanaki A, Kassiou L, Tzardi M, Koinis F, Kafousi M, Georgoulias V, Mavroudis D. The proliferation index of circulating tumor cells (CTCs) is not influenced by the administration of adjuvant chemotherapy in early breast cancer (BC) and seems to reflect Ki67 expression of the primary tumor. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-16.
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- 2016
38. Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pretreated with a non-platinum-based regimen in the first-line setting: A randomized phase II study of the Hellenic Oncology Research Group (HORG)
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Filippos Koinis, Leonidas Chelis, Panagiota Economopoulou, C. Christophyllakis, Christos Nikolaou, Nikolaos Vardakis, Aristidis Polyzos, Nikolaos K. Kentepozidis, Vassilis Georgoulias, and Athanasios Kotsakis
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Cisplatin ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,digestive, oral, and skin physiology ,Phases of clinical research ,medicine.disease ,female genital diseases and pregnancy complications ,respiratory tract diseases ,Irinotecan ,Regimen ,Pemetrexed ,Internal medicine ,medicine ,Non small cell ,Lung cancer ,business ,medicine.drug - Abstract
e19044 Background: Platinum-based chemotherapy is the standard front-line treatment for patients with advanced Non Small Cell Lung Cancer (NSCLC). However, third generation non-platinum combination...
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- 2015
39. Effect of chemotherapy on the myeloid-derived suppressor cells percentages in the peripheral blood of advanced non-small cell lung cancer patients (TUM6P.965)
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E. Vetsika, Marianthi Gioulmpasani, Eirini Skalidaki, Afroditi Katsarou, Filippos Koinis, Despoina Aggouraki, Anna Koutoulaki, Dimitris Mavroudis, Vassilis Georgoulias, and Athanasios Kotsakis
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Immunology ,Immunology and Allergy - Abstract
In our previous study, high levels of one granulocytic (G-MDSC) and two monocytic (M-MDSCs) subpopulations of immunosuppressive MDSCs were found and their overexpression was correlated with worse prognosis in NSCLC patients. Using flow cytometry, the impact of chemotherapy on the percentages and functionality of M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin- and CD14+CD15+CD11b+ CD33+HLA-DR-Lin-) and G-MDSC (CD14-CD15+CD11b+CD33+HLA-DR-Lin-) was evaluated in the peripheral blood of patients (n=141) prior to chemotherapy and after the 3rd and 6th cycle of treatment. The M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased post chemotherapy compared to baseline, whereas chemotherapy had no effect on CD14+CD15+CD11b+CD33+HLA-DR-Lin- M-MDSCs. In contrast, the production of iNOS by M-MDSCs was significantly increased compared to the baseline. Both G-MDSC levels and their ROS expression were not affected by chemotherapy. In addition, both subtypes of MDSCs, when co-cultured with CD3+ T cells, were able to significantly suppress IFN-γ secretion by T cells. Finally, the M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased in patients that did not develop progressive disease during or after treatment completion, compared to patients with disease progression. Chemotherapy seems to have an impact on MDSC expression and functionality, hence targeting these cells may lead to a better clinical outcome in NSCLC patients.
- Published
- 2015
40. Abstract 3664: High frequency of a circulating monocytic subpopulation of myeloid-derived suppressor cells predicts worst clinical outcome in untreated non-small lung cancer patients
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Eleni-Kyriaki Vetsika, Athanasios Kotsakis, Marianthi Gioulmpasani, Filippos Koinis, Despoina Aggouraki, Anna Koutoulaki, Vassilis Georgoulias, Eirini Skalidaki, and Dimitris Mavroudis
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Cancer Research ,medicine.diagnostic_test ,business.industry ,CD14 ,CD33 ,Cancer ,medicine.disease ,Flow cytometry ,Immune system ,Oncology ,Immunology ,medicine ,Myeloid-derived Suppressor Cell ,Lung cancer ,business ,CD8 - Abstract
Background: The immune system can either prevent and control the tumor growth or promote tumor escape. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature cells with immune suppressive properties and their overexpression seems to confer a worse prognosis in cancer patients. Objective: The aim of the study was to investigate the presence of new phenotypically immature subpopulations of MDSCs which could be associated with advanced/metastatic NSCLC patients' clinical outcome. Materials & Methods: Circulating subtypes of MDSCs (monocytic and granulocytic), as well as the CD4+ , CD8+ , dendritic (DC), monocytes and B cells were assessed in peripheral blood of of chemotherapy-naive patients with advanced/metastatic NSCLC (n=134) and healthy controls (n=28) were analyzed using flow cytometry. The phenotypic characterization of MDSCs subpopulations was determined in strictly immature myeloid cells. A correlation between the levels of MDSCs and other tested immune cells as well as their association with overall (OS) and progression- free survival (PFS) was evaluated; high expression of MDSCs was defined as the percentage of the cells above the 90% percentile of the controls. Results: Two monocytic [M-MDSC: CD14+CD15-CD11b+CD33+HLA-DR-Lin- and CD14+CD15+CD11b+CD33+HLA-DR-Lin-] and a granulocytic [G-MDSC: CD14-CD15+CD11b+CD33+HLA-DR-Lin-] subpopulation of MDSCs were significantly increased (p Conclusion: The data provide evidence that the increased frequency of two new M-MDSC subpopulations in patients with advanced/metastatic NSCLC is associated with an unfavorable clinical outcome. Citation Format: Eleni Kyriaki Vetsika, Filippos Koinis, Marianthi Gioulmpasani, Despoina Aggouraki, Anna Koutoulaki, Eirini Skalidaki, Dimitris Mavroudis, Vassilis Georgoulias, Athanasios Kotsakis. High frequency of a circulating monocytic subpopulation of myeloid-derived suppressor cells predicts worst clinical outcome in untreated non-small lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3664. doi:10.1158/1538-7445.AM2014-3664
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- 2014
41. Phase II Trial of Mfoliri Plus Bevacizumab as 1st Line Treatment in Elderly Patients with Metastatic Colorectal Cancer
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John Souglakos, Lambros Vamvakas, Vassilis Georgoulias, Filippos Koinis, Athina Christopoulou, Nikolaos Kentepozidis, Athanasios Karampeazis, Elisavet Papadimitraki, Dora Hatzidaki, and Kostas Kalbakis
- Subjects
Oncology ,medicine.medical_specialty ,Bevacizumab ,business.industry ,Colorectal cancer ,Internal medicine ,Medicine ,Hematology ,Line (text file) ,business ,medicine.disease ,medicine.drug - Published
- 2013
42. A data mining framework for predicting drug response in cancer
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Konstantinos Vougas, Theodore Sakelaropoulos, Filippos Koinis, Alexander Polyzos, Athanassios Kotsinas, Vassilis Myrianthopoulos, Moss, Tyler J., Sarina Piha-Paul, Hua Zhou, Sonali Narang, Foukas, George-Romanos P., Andreas Ntargaras, Vassilis Georgoulias, Leonidas Alexopoulos, Iannis Aifantis, Paul Townsend, Petros Sfikakis, Rebecca Fitzgerald, Dimitris Thanos, Mills Shaw, Kenna R., Jiri Bartek, Russell Petty, Aristotelis Tsirigos, and Vasileios Gorgoulis
- Subjects
Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc - Abstract
Defining therapeutically “vulnerable” genes that modulate anti-cancer drug response is of paramount importance in precision cancer treatment. The success of such a task largely depends on the ability to develop computational resources that integrate big “omic” data into effective drug-response models. Herein, based on the pharmacogenomic profile of 1,001 cancer cell lines we constructed a novel in silico screening process based on Association Rule Mining for identifying genes as candidate drivers of drug response. Our computational pipeline explores with high efficiency large sample-spaces, is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. The selection algorithm was validated by in silico and experimental means. Within this context, we identified experimentally novel targets related with responsiveness to: i) Doxorubicin treatment, and ii) MAPK and PI3K inhibitor administration. The presented data mining scheme provides evidence for potential practical applications and a proof-of-concept for the implementation of precision medicine in everyday clinical practice.
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