Research Project: Molecular predictors of prognosis following curative treatment of hepatocellular carcinoma – the significance of liver stem/progenitor cells genes
Financing Authority: UEFISCDI.
Project Code: PN-II-ID-PCE-2011-3-0605
Contract Number: 125/2011
Project Director: Prof. Gheorghe Liliana, MD, PhD
Contractor: Fundeni Clinical Institute, Bucharest, Romania
Project duration: 2011-2016
Project budget: 1.437.500 RON
Abstract:
Hepatocellular carcinoma (HCC) is one of the most common and hard-to-treat cancers worldwide. Surgical tumor resection and liver transplantation, remain the only curative modalities for HCC, but recurrence rate is still high. In light of the dismal clinical outcome of this neoplasm, the development of effective systems that can predict the likelihood of recurrence is much needed. Classically, two general models of carcinogenesis have been debated: the stochastic model and the hierarchical model. The hierarchical model or cancer stem cell (CSC) model, postulates that a single CSC gives rise to a hierarchic organization containing varied downstream descendants, proliferates extensively, and initiates tumors at high frequency. The role of liver stem cells in HCC carcinogenesis has been illustrated experimentally. To date, it has been shown that CSCs in HCC can be identified by several cell surface antigens CD133, CD90, CD44, OV6 and the epithelial cell adhesion molecule (EpCAM), or by selecting for the side population cells in Hoechst dye-staining. The main objective of the proposed project is represented by the evaluation of liver stem/progenitor cells specific genes expression in HCC nodules as prognostic factor (overall and recurrence free survival) after curative surgical therapy. Our project will allow the identification of new diagnosis and prognosis markers for HCC, potentially adding novel markers to the molecular classifications.
The main objective of the proposed project is represented by the evaluation of liver stem/progenitor genes expression profile in hepatocarcinoma nodules as prognostic factors (overall and recurrence free survival) after curative surgical therapy (liver resection and liver transplantation).
Other objectives include:
-identification of combinations of markers that can help to differentiate stem/progenitor cells enriched tumor phenotype from other HCC molecular subtypes and the relationship with evolution following curative treatment.
-identification of stem/progenitor cells genes that can help to differentiate between early (<1 year) and late recurrence patterns after curative therapy, as well as between small HCC nodules (for tumors <2cm) and benign macronodules in cirrhosis
-identification of differences between gene expression of stem/progenitor genes in HCV vs HBV related HCC
-identification of the correlations between the histologic aspect and the immunohistochemical pattern of expression of liver stem/progenitor genes in HCC nodules.
Impact, relevance, applications.
The impact of the project will be assessed by:
The clinical impact – prediction of early recurrence leading to more aggressive follow-up after surgical therapy; potential identification of new molecular markers for targeted therapy; selection of patients for LT that have a low risk for recurrence according to identified significant markers.
The social impact – increase of the quality of life and survival of HCC patients; increase of the efficacy of treatment methods by their applicability in early stages; allow the best use of the scarce number of liver allografts available
The economic impact – decrease of the costs of medical assistance by optimizing the diagnostic and therapeutic act.
Current anticancer drugs kill differentiated cancer cells and cause a reduction in tumour mass. However, the cancer often recurs after treatment and this can be attributed to the presence of CSCs. Current research is now looking into a new generation of anticancer drugs or therapies that will selectively and specifically destroy various populations of CSCs while leaving the normal stem cell population unharmed, to allow for the complete regeneration of normal tissue. This is of even more importance in liver cirrhosis setting as are the majority of HCC patients that undergo resection.
Other potential application is the identification of a gene expression signature that could effectively predict early recurrence of HCC independent of microarray platforms and cohorts, and provide novel biological insights into the mechanisms of tumor recurrence in HBV and HCV related HCC.
Project Team:
Project Director: Prof. Dr. Gheorghe Liana
Team Members: Prof. Dr. Irinel Popescu, Prof. Dr. Cristian Gheorghe, Iacob Speranta, Iacob Razvan, Cotruta Bogdan, Bancila Ion, Simionov Iulia, Vadan Roxana, Pirvulescu Iuliana, Croitoru Adina, Buica Florina, Gramaticu Iulia, Becheanu Gabriel, Herlea Vlad, Pechianu Nicolae, Grigorie Mihai, Stoica Luminita, Nastase Anca, Vagu Codruta, Ghetea Ligia Gabriela, Iliescu Laura Elena
Papers presented at National Meetings:
Gheorghe L, Iacob S, Ghidu C, Iacob R, Gheorghe C, Cerban R, Simionov I, Sporea I, Danila M, Croitoru A, Croitoru M, Hrehoret D and Popescu I. Management pattern of hepatocellular carcinoma at two tertiary centers in Romania. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2012. Paper presented at The XXXII’nd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Targu Mures 2012.
Iacob S, Hrehoret D, Matei E, Dorobantu B, Brasoveanu V, Dumbrava M, Becheanu G, Herlea V, Popescu I and Gheorghe L. Recurrent hepatitis c following liver transplantation in the romanian transplant program – treatment and outcome. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2012. Paper presented at The XXXII’nd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Targu Mures 2012.
Iacob S, Vagu C, Iacob R, Nastase A, Paslaru L, Popescu I, Ruta S, Gheorghe L. Recipi ent IL28B gene polymorphism and sustained viral response in Romanian patients with recurrent hepatitis C following liver transplantation. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2013. Paper presented at The XXXIII’rd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Timisoara 2013.
Iacob R, Vagu C, Nastase A, Iacob S, Grigorie M, Stoica L, Herlea V, Croitoru A, Dima SO, Coriu D, Paslaru L, Gheorghe L, Popescu I. Quantitative gene expression of liver progenitor cells specific genes in curatively treated hepatocellular carcinoma. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2013. Paper presented at The XXXIII’rd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Timisoara 2013.
Smira G, Matei E, Dorobantu B, Brasoveanu V, Gheorghe C, Gheorghe L and Popescu I. Donor outcomes in Right Lobe Adult Living Donor Liver Transplantation: a single center experience in Romania. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2013. Paper presented at The XXXIII’rd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Timisoara 2013.
Smira G, Cerban R, Ghidu C, Dumitru R, Grasu M, Gheorghe C, Popescu I and Gheorghe L. Impact of cytolysis after transarterial chemoembolization for hepatocellular carcinoma – a single center experience. Published Abstract in Journal of Gastrointestinal and Liver Diseases 2013. Paper presented at The XXXIII’rd National Congress Of Gastroenterology, Hepatology And Digestive Endoscopy, Timisoara 2013.
Iacob S, Cerban R, Gheorghe L. Which oligosaccharide to use for minimal hepatic encephalopathy in liver cirrhosis patients – oligofructose enriched-inulin or lactulose? J Hepatol 2014; 60(1): S1:S598. Poster presentation The International Liver Congress 2014, London, United Kingdom.
Gheorghe L, Iacob S, Ester C, Cerban R, Pietrareanu C, Tomescu D, Droc G, Hrehoret D, Brasoveanu V, Popescu I. Risk factors for 3 months mortality following liver transplantation in Romanian Transplant Program. J Hepatol 2014; 60(1): S1:S598. Poster presentation The International Liver Congress 2014, London, United Kingdom.
Iacob S, Ester C, Popescu I, Gheorghe L. Risk factors for death in cirrhotic patients with non-malignant portal vein thrombosis on the waiting list for liver transplantation. J Gastrointestin Liver Dis 2014. Suppl. Poster presentation The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Iacob S, Ester C, Simionov I, Gheorghe L. Liver stiffness measurement is influenced by type of autoimmune-related liver disease. J Gastrointestin Liver Dis 2014. Suppl. Poster presentation The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Iacob S, Greere M, Gheorghe L. Both cholestasis and portal hypertension predicted by liver stiffness, but not by spleen stiffness. J Gastrointestin Liver Dis 2014. Suppl. Poster presentation: The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Gheorghe L, Iacob S, Pietrareanu C, Hrehoret D, Brasoveanu V, Tomescu D, Droc G, Gheorghe C, Popescu I. Improved overall mortality on the Romanian waiting list for liver transplantation. J Gastrointestin Liver Dis 2014. Suppl. Poster presentation: The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Iacob R, Vagu C, Nastase A, Iacob S, Botea F, Grigorie R, Hrehoret D, Herlea V. Croitoru A, Dima S, Gheorghe L, Gheorghe C, Popescu I. Expression profile of stem/progenitor cells specific genes in hepatocellular carcinoma and potential prognostic significance. J Gastrointestin Liver Dis 2014. Suppl. Oral Presentation: The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Gheorghe L, Iacob S, Ester C, Cerban R, Pietrareanu C, Tomescu D, Droc G, Hrehoret D, Brasoveanu V, Popescu I. Predictors of short-term post-liver transplant mortality in the Romanian Transplant Program. J Gastrointestin Liver Dis 2014. Suppl. Oral Presentation: The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
Gheorghe L, Iacob S, Ester C, Cerban R, Pietrareanu C, Tomescu D, Droc G, Hrehoret D, Brasoveanu V, Popescu I. Predictors of short-term post-liver transplant mortality in the Romanian Transplant Program. J Gastrointestin Liver Dis 2014. Suppl. Oral Presentation: The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania.
S Iacob. Screening for hepatocellular carcinoma. The XXXVth National Congress of Gastrenterology, Hepatology and Digestive Endoscopy. Iasi 2015. J Gastrointestin Liver Dis 2015; 24 (Suppl 1). Oral Presentation.
Iacob R, Codruta Vagu, Anca Nastase, Ligia Ghetea, Speranta Iacob, Grigorie R, Botea F, Herlea V, Simona Dima, Gheorghe C, Popescu I, Liana Gheorghe. Recurrence risk stratification of patients with hepatocellular carcinoma following a potentially curative treatment using gene expression of liver stem/progenitor cells specific markers. The XXXVth National Congress of Gastrenterology, Hepatology and Digestive Endoscopy. Iasi 2015. J Gastrointestin Liver Dis 2015; 24 (Suppl 1): 10 (OP15). Oral Presentation.
Iacob R, Vagu C, Nastase A, Ghetea L, Iacob S, Botea F, Herlea V, Croitoru A, Dima S, Gheorghe C, Popescu I, Ott M, Gheorghe L. Hepatocyte reprogramming in a stem-cell-like phenotype. A potential mechanism of hepatocarcinogenesis. J Gastrointestin Liver Dis 2016; 25 (Suppl 2): 41 (OP54) Oral Presentation
Iacob Speranta, Iacob R, Cerban R, Gheorghe C, Gheorghe Liana. Staging of hepatocellular carcinoma in patients with liver cirrhosis enrolled in a screening program. J Gastrointestin Liver Dis 2016; 25 (Suppl 2): 42 (OP56) Oral Presentation
Cerban R, Iacob Speranta, Croitoru Adina, Dumitru Radu, Grasu Mugur, Ester Carmen, Gheorghe C, Gheorghe Liana. Transarterial chemoembolization in hepatocellular carcinoma – a single center experience from Romania. J Gastrointestin Liver Dis 2016; 25 (Suppl 2): 163 (IV148)
Iacob R, Becheanu G, Herlea V, Pechianu C, Dumbrava Mona, Iacob Speranta, Vagu Codruta, Nastase Anca, Ghetea Ligia, Gheorghe Liana, Popescu I. Hepatocyte telomerase expression in chronic liver disease and primary liver tumors – arguments for hepatocyte reprogramming. Journal of Tranlational Medicine and Research 2016. Poster presentation at the XIth Academician Nicolae Cajal National Symposium, march 17th-19th 2016, Bucharest
Papers presented at International Meetings:
Gheorghe L, Iacob S, Ghidu C, Iacob R, Cerban R, Simionov I, Croitoru A, Gheorghe C, Popescu I. Liver Stiffness Value Assessed by Transient Elastography Correlates With Nodule Size in Patients With Hepatocellular Carcinoma. Published Abstract in Gastroenterology 2012. Paper presented at Digestive Disease Week 2012, San Diego USA.
Iacob S, Iacob R, Grigorie M, Hrehoret D, Brasoveanu V, Herlea V, Gheorghe C, Gheorghe L, Popescu I. Outcome of Liver Transplantation for Hepatocellular Carcinoma - a Single Center Experience. Published Abstract in Transplantation 2012. Paper presented at the ILTS 18TH Internation Annual Congress, 2012, San Francisco USA.
Iacob S, Cicinnati V.R, Wu G, Lindemann M, Heinemann F.M, Rebmann V, Horn P.A, Kabar I, Schmidt H.H, Beckebaum S. Soluble Ligands for Activating Natural Killer Receptor (NKG2D) Are Biomarkers for Progression of Hepatic Fibrosis after Liver Transplantation. Published Abstract in Transplantation 2012. Paper presented at the ILTS 18TH Internation Annual Congress, 2012, San Francisco USA.
Iacob S, Cicinnati V.R, Wu G, Xu L, Kabar I, Schmidt H.H, Beckebaum S. Role of ATP-Binding Cassette Transporter Gene Polymorphisms and Metabolic Risk Factors for Allograft Fibrosis after Liver Transplantation. Published Abstract in Transplantation 2012. Paper presented at the ILTS 18TH Internation Annual Congress, 2012, San Francisco USA.
Iacob R, Vagu C, Nastase A, Iacob S, Grigorie M, Stoica L, Herlea V, Croitoru A, Dima SO, Coriu D, Paslaru L, Gheorghe L, Popescu I. Quantitative gene expression of liver progenitor cells specific genes in curatively treated hepatocellular carcinoma. Published Abstract in Hepatology International 2013. Paper presented at 23rd Conference of the Asian Pacific Association for the Study of the Liver – APASL 2013. Singapore.
Iacob S, Ester C, Popescu I, Gheorghe L. Risk Factors For Death On The Waiting List For Liver Transplantation in Patients With Non-Malignant Portal Vein Thrombosis. Tranplantation 2014: Suppl 98 1:905. Poster Presentation The World Transplant Congress 2014, San Francisco, US:
Iacob S, Cicinnati V, Kabar I, Schmidt H, Beckebaum S. ABC-Transporter Gene Polymorphisms - Risk Factor for Biliary Complications in Liver Transplant Recipients. Tranplantation 2014: Suppl 98 1:905. Poster Presentation The World Transplant Congress 2014, San Francisco, USA
Iacob S, Cicinnati V, Lindemann M, Heinemann F, Radtke A, Kaiser G, Kabar I, Schmidt H, Baba H, Beckebaum S. Donor Specifi c Antibodies Against HLA Class II and C4d-Positivity: Risk Factors for Liver Allograft Fibrosis. Tranplantation 2014: Suppl 98 1:905. Oral Presentation The World Transplant Congress 2014, San Francisco, USA
Iacob R, Iacob S, Vagu C, Nastase A, Botea F, Herlea V, Croitoru A, Dima S, Gheorghe C, Gheorghe L, Popescu I. Quantitative Gene Expression of Stem/Liver Progenitor Cells Specific Genes Could Be Used to Predict the Absence of Early Recurrence of Hepatocellular Carcinoma After a Potentially Curative Treatment. Tranplantation 2014: Suppl 98 1:905. Oral Presentation The World Transplant Congress 2014, San Francisco, USA
Gheorghe L, Iacob R, Vagu C, Nastase A, Iacob S, Botea F, Herlea V, Croitoru A, Dima S, Gheorghe C, Popescu I. A predictive score using quantitative gene expression of stem/liver progenitor cells specific genes can be used to identify patients at risk for tumor recurrence in curatevily treated hepatocellular carcinoma. Gastroenterology 2014; 146 (5). S1-S1099. Poster Presentation . Digestive Disease Week 2014, Chicago, USA.
Iacob S, Cerban R, Gheorghe L. Which oligosaccharide to use for minimal hepatic encephalopathy in liver cirrhosis patients – oligofructose enriched-inulin or lactulose? J Hepatol 2014; 60(1): S1:S598. Poster presentation The International Liver Congress 2014, London, United Kingdom.
Gheorghe L, Iacob S, Ester C, Cerban R, Pietrareanu C, Tomescu D, Droc G, Hrehoret D, Brasoveanu V, Popescu I. Risk factors for 3 months mortality following liver transplantation in Romanian Transplant Program. J Hepatol 2014; 60(1): S1:S598. Poster presentation The International Liver Congress 2014, London, United Kingdom
Gheorghe L, Iacob S, Ester C, Iacob R, Popescu I, Gheorghe C. Safety and efficacy of anticoagulation therapy for portal/splanhnic vein thrombosis in patients with liver cirrhosis on the waiting list for liver transplantation. Gastroenterology 2015. 148, 4, Suppl 1: S1-S1196. Poster presentation, Digestive Disease Week 2015, Washington DC, USA.
Iacob S, Ester C, Iacob R, Gheorghe C, Popescu I and Gheorghe L. Risk factors associated with overall and bleeding-related mortality in patients with portal vein thrombosis on the waiting list for liver transplantation. Gastroenterology 2015. 148, 4, Suppl 1: S1-S1196. Poster presentation, Digestive Disease Week 2015, Washington DC, USA.
Iacob S, Gheorghe L, Tabacelia D, Iacob R, Gheorghe C, Popescu I. New organ allocation score predicting both pre and post-transplant survival in the romanian national transplant program. Digestive Disease Week 2015. Gastroenterology 2015. 148, 4, Suppl 1: S1-S1196. Poster presentation, Digestive Disease Week 2015, Washington DC, USA.
Iacob S, Wu G, Kabar I, Huesing A, Schmidt HJ, Beckebaum S and Cicinnati V. Post-liver transplant fibrosis allograft progression is associated with increased levels of soluble NKG2D ligands. Journal of Hepatology 2015. 62, S2: S187-S931. Poster Presentation, 50th Annual Meeting of the EASL (European Association for the Study of the Liver) 2015, Vienna Austria.
Iacob S, Maschmeier M, Wu G, Kabar I, Huesing A, Schmidt HJ, Cicinnati V and Beckebaum S. Single nucleotide polymorphisms of CYP3A subfamily and p-glycoprotein influence pharmacokinetics of once-daily extended release tacrolimus in liver transplant recipients. Transplant International 2015. 28, S4: 1-822. Poster Presentation, ESOT (European Society for Organ Transplantation) 2015, Brussels, Belgium.
Iacob S, Popescu I, Gheorghe L. Efficacy of new antivirals in liver transplant recipients with severe recurrent hepatitis C in a large volume transplantation centre in a limited resource setting. Transplant International 2015. 28, S4: 1-822. Poster Presentation, ESOT (European Society for Organ Transplantation) 2015, Brussels, Belgium.
Iacob S, Iacob R, Vagu C, Ruta S, Gheorghe C, Paslaru L, Popescu I and Gheorghe L. rs199508964 Deletion in exon 6 of IRF5 gene is correlated with IL28B gene SNP rs12980275 and predicts sustained virological response in patients with recurrent hepatitis C following liver transplantation. Transplant International 2015. 28, S4: 1-822. Poster Presentation, ESOT (European Society for Organ Transplantation) 2015, Brussels, Belgium.
Iacob R, Vagu C, Nastase A, Iacob S, Botea F, Grigorie R, Stoica L, Herlea V, Croitoru A, Dima S, Gheorghe C, Gheorghe L, Ott M, Popescu I. Significance of liver enriched transcription factors as molecular markers for hepatocellular carcinoma recurrence after a potentially curative treatment. Transplantation 2015. 99, Suppl 7S, 1-340. Poster Presentation, 21st Annual International Congress of the ILTS (International Liver Transplantation Society) 2015, Chicago IL, USA.
Iacob R, Vagu Codruta, Nastase Anca, Iacob Speranta, Botea F, Herlea V, Croitoru Adina, Dima Simona, Gheorghe C, Popescu I, Ott M and Gheorghe Liana. Hepatocyte Reprogramming to a Progenitor-Cell Phenotype Is a Potential Mechanism of Hepatocarcinogenesis - The Role of Reprogramming Factors: OCT4, SOX2 and NANOG. Gastroenterology 2016, Vol. 150, Issue 4, S296–S297 (Sa1367). Poster presentation at Digestive Disease Week 2016, San Diego, CA, USA
Iacob Speranta, Popescu I, Gheorghe Liana. 100% virological response with 3D regimen and significant short-term liver stiffness improvement in patients with recurrent hepatitis C following liver transplantation. Hepatology 2016;64(Suppl 1):809A(1635). Poster Presentation at AASLD, The Liver Meeting 2016, Boston, MA, USA
Iacob Speranta, Gheorghe Liana, Trifan Aanca, Stanciu C, Sirli Roxana, Sporea I, Lupusoru R, Cijevschi Cristina, Arama Victoria, Brisc C, Rogoveanu I, Iacob R, Gheorghe C. Dynamics of AFP in cirrhotic patients with virological response following 3D therapy and severe necro-inflammation at Fibromax. Hepatology 2016;64(Suppl 1):982A(1979). Poster Presentation at AASLD, The Liver Meeting 2016, Boston, MA, USA
Prizes and Distinctions:
SRGH Prize for best oral presentation: Expression profile of stem/progenitor cells specific genes in hepatocellular carcinoma and potential prognostic significance, The XXXIVth National Symposium of Gastroenterology, Hepatology and Digestive Endoscopy, Oradea, Romania
Best Poster Presentation Award. Hepatocyte telomerase expression in hepatocellular carcinoma and chronic liver disease. Iacob R, Becheanu G, Herlea V, Pechianu C, Dumbrava Mona, Iacob Speranta, Vagu Codruta, Nastase Anca, Ghetea Ligia, Popescu I, Gheorghe Liana. 3rd UpDate on Hepatology, Course Bucharest 2016, Romania, 28-29 April 2016, Bucuresti, Romania.
Published articles:
Gheorghe L, Iacob S, Iacob R, Smira G, Pietrareanu C, Hrehoret D, Brasoveanu V, Gheorghe C and Popescu I. Dynamics of the Romanian waiting list for liver transplantation after changing organ allocation policy. Journal of Gastrointestinal and Liver Diseases 2013 Sep;22(3):299-303
Iacob S, Gheorghe L, Tabacelia D, Iacob R, Gheorghe C, Popescu I. A new score to predict outcome after liver transplantation. J Transl Med Res 2015; 20(3):123-131
Iacob R, Herlea V, Popa C, Nastase A, Ghetea L, Iacob S, Botea F, Pechianu C, Grigorie R, Croitoru A, Dima S, Gheorghe C, Gheorghe L and Popescu I. Prognostic significance of CD44 expression in hepatocellular carcinoma following a potentially curative treatment. J. Transl. Med. Res 2016;21(4):267-273
Upcoming Papers:
Hepatocyte telomerase expression in hepatocellular carcinoma and chronic liver disease. Iacob R, Herlea V, Becheanu G, Pechianu C, Dumbrava Mona, Iacob Speranta, Vagu Codruta, Nastase Anca, Ghetea Ligia, Ott M, Popescu I, Gheorghe Liana.
Expression of transcription factors OCT4 and SOX2 in hepatocellular carcinoma and liver cirrhosis - arguments for hepatocyte reprogramming. Iacob R, Vagu Codruta, Herlea V, Nastase Anca, Iacob Speranta, Ghetea Ligia, Botea F, Croitoru Adina, Dima Simona, Gheorghe C, Ott M, Popescu I, Gheorghe Liana.
Significance of stem cell specific genes as molecular markers for hepatocellular carcinoma recurrence after a potentially curative treatment. Iacob R, Vagu Codruta, Nastase Anca, Iacob Speranta, Ghetea Ligia, Botea F, Grigorie R, Herlea V, Stoica L, Croitoru Adina, Dima Simona, Gheorghe C, Ott M, Popescu I, Gheorghe Liana.
