title: Examinations of Factors Influencing Survival of Liver Transplantation for Hepatocellular Carcinoma: A Single-Center Experience From Budapest.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Orthotopic liver transplantation (OLT) is the best therapy of choice for early, unresectable HCC. The Hungarian Liver Transplantation Program was launched in 1995 at the Department of Transplantation and Surgery, Semmelweis University, Budapest. From that time more than 60 patients underwent OLT for hepatic tumors, which in most cases were HCC. Our clinical examination was undertaken to analyze the possible influential factors of outcomes for our series of patients who received OLT for HCC.
  
  
  METHODS
  We performed a review of all patients who underwent OLT for HCC at our department from 1996 to October 1, 2013. Disease extent was determined by preoperative computed tomography or magnetic resonance images. All explants were examined and categorized based on tumor number, size, distribution, HCC histologic grade, and vascular invasion. Patients with HCC were classified as having tumors either meeting Milan criteria, beyond Milan criteria but within UCSF criteria, or exceeding UCSF criteria. OLT was performed using standard techniques including orthotopic implantation with cross-clamp technique or with the piggyback technique. Postoperative immunosuppression included a triple drug regimen of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone. mTOR inhibitors have been available since 2004.
  
  
  RESULTS
  HCC most commonly occurs in the presence of cirrhosis as a result of longstanding chronic liver disease. Most of our patients who underwent OLT for HCC are 56 to 60 years old, and most also had underlying HCV cirrhosis. As of October 1, 2013, 21 of 49 (42.85%) patients had died after OLT for HCC. The main cause was the recurrence of the HCC in 38%, followed by sepsis in 33%, and HCV recurrence in 19%. One death each (4.7% of the total number of deaths) was caused by primary nonfunction of the graft, acute myocardial infarct, and de novo malignancy, respectively. Overall survival for the entire group at 1, 3, and 5 years after transplantation was 73.48%, 65.2%, and 50.08%, respectively. Using pretransplant imaging, 34 tumors (69.3%) were within Milan criteria, 8 (16.3%) were beyond Milan but within UCSF criteria, and 7 (14.3%) exceeded UCSF criteria. Based on explant pathology, 30 tumors (61.2%) were within Milan criteria, 7 (14,3%) were beyond Milan but within UCSF criteria, and 12 (24.3%) exceeded UCSF criteria. New onset, non-HCC malignant tumor developed in 2 cases (4%). There was no significant difference between the surgical techniques or the immunosuppressive strategies. Using the Cox analysis in our series, it can be seen that mortality was higher with tumors exceeding Milan criteria but within UCSF criteria compared with tumors within Milan criteria (Coef. = 0.5749 in Setting 1 and 0.1226 in Setting 2), and even higher with tumors beyond UCSF criteria compared with tumors within Milan criteria (Coef. = 0.7228 in Setting 1 and 0.1456 in Setting 2). Recurrence of the tumor causes higher mortality (Coef. = 1.709 in Setting 1 and 1.0256 in Setting 2). It seems that using an mTOR inhibitor has a beneficial impact on mortality (Coef. = -1.409 in Setting 1). Vascular invasion was associated with higher mortality (Coef. = 0.6581in Setting 1). Higher AFP levels correlated with higher mortality but not significantly (Coef. = 0.0002 in Setting 2). In our series, survival after OLT for HCC was best with tumors within Milan criteria comparing those exceeded Milan criteria (odds ratio = 4.000).
  
  
  CONCLUSIONS
  According to our findings, the Milan criteria are still the safest criteria system; however, slightly expanded criteria do not have significantly worse results. Preoperative imaging methods sometimes show fewer or smaller tumors, and the explant histology reports the exact staging of HCC at the time of OLT. Histological examination especially of the lymphovascular invasion is mandatory to assess the estimated prognosis. Extremely high levels of AFP mean higher risk. HCC recurrence is an important factor on the outcome; therefore, continuous oncologic screening is mandatory. Immunosuppressant agents are chiefly responsible not just for higher risk of recurrence but for higher risk to develop de novo malignancies. Viral serology must be done periodically to catch HCV recurrence in time and begin adequate antiviral therapy. Potentially, mTOR inhibitors could be potent immunosuppressive agents after OLT for HCC due to this antiproliferative effect.
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary. Electronic address: pirosl666@hotmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Piros
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Fehérvári
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Görög
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Nemes
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: J
authors.initials: J
authors.lastname: Szabó
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Gerlei
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Végső
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Kóbori
authors.affiliation: Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Máthé
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000601:surgery*; D005260:Female; D006801:Humans; D006814:Hungary; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000150:complications* / Q000601:surgery; D008113:Liver Neoplasms / Q000601:surgery*; D016031:Liver Transplantation / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: D007166:Immunosuppressive Agents