- Email: [email protected]
AKt and ERK pathways in human Hep3B cancer cells
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260 OP-07
Initial RECIST tumour reduction as a prognostic parameter for transarterial chemoembolisation treatment success in patients with hepatocellular carcinoma D. Hasdemir 1 , N. Schweitzer 2 , A. Vogel 2 , C. von Falck 1 , F. Wacker 1 , B. Meyer 1 , T. Rodt ∗ ,1
S251
documented in only 12 of the patient charts. Data from literature shows concordant 1- and 2-year survival rates of 61–71% and 33–48% respectively for a comparable patient cohort. Conclusion: Despite a low-embolic TACE technique tumour response and overall survival in the analysed patient group was comparable to data from the literature where techniques applying additional embolic agents with potential adverse reactions were described.
1 Dept.
of Diagnostic and Interventional Radiology, Hannover Medical School; 2 Dept. of Gastroenterology, Hannover Medical School, Hannover, Germany
Introduction: In this study we investigate initial RECIST tumour reduction as a prognostic parameter for treatment success in patients with intermediate stage hepatocellular carcinoma receiving transarterial chemoembolisation (TACE). Method: All TACE procedures in our institution in three successive years (2006–2009) were reviewed using a custom-made database. Patients who had received previous chemoembolisation were excluded from the study. 63 patients with intermediate stage hepatocellular carcinoma who received initial chemoembolisation using a low-embolic technique were identified, in all patients RECIST follow-up was available. TACE procedures (n=198) were performed using doxorubicin and cisplatin as chemotherapeutic agents. Lipiodol was used as the only embolic agent. Individual RECIST response of the first five TACE procedures was correlated to overall survival and maximum treatment response based on RECIST criteria. Results: On average patients received 3.1 TACE procedures (SD 2.8). KaplanMeier analysis yielded a mean overall survival of 843 d (95% CI 682 – 1004 d). 19 patients (30.2%) did not show any response, 44 patients (69.8%) showed response. Maximum RECIST tumour response was assigned to the individual treatment intervals (TACE 1: 19 patients (30.2%); TACE 2: 6 patients (9.5%); TACE 3: 8 patients (12.7%); TACE 4: 5 patients (7.9%); TACE 5: 0 patients (0%); 6 patients TACE 6–17 (9.5%). A Pearson correlation was calculated between maximum tumour response and tumour response of the initial TACE procedures (TACE1: 0.606 (p<0.01); TACE 2: 0.701 (p<0.01); TACE 3: 0.498 (p<0.05). Conclusion: The initial RECIST tumour reduction significantly correlates to maximum tumour response and thus has potential to be applied as a prognostic parameter in TACE treatment.
OP-08
Results of transarterial chemoembolisation using a low-embolic technique in patients with intermediate stage hepatocellular carcinoma T. Rodt ∗ ,1 , D. Hasdemir 1 , N. Schweitzer 2 , A. Vogel 2 , C. von Falck 1 , H. Rosenthal 1 , F. Wacker 1 , B. Meyer 1 1 Dept. of Diagnostic and Interventional Radiology, Hannover Medical School; 2 Dept. of Gastroenterology, Hannover Medical School, Hannover, Germany
Introduction: We report on the results of transarterial chemoembolisation (TACE) using a low embolic technique in patients with intermediate stage hepatocellular carcinoma and compare the outcome to data on alternative chemoembolisation techniques from the literature. Method: All patients receiving initial TACE treatment in our institution between 2006 and 2009 were reviewed using a custom-made database. Patients with prior TACE were excluded. 75 patients with intermediate stage hepatocellular carcinoma receiving initial TACE treatment were identified. TACE (n=209) was performed using doxorubicin and cisplatin as chemotherapeutic agents in combination with lipiodol. For this low-embolic technique no additional embolic agent was used. Results: The patients received an average of 2.8 TACE procedures (SD 2.7). Best RECIST tumour response was assessed (mean value 23.9%, SD 27%). When TACE was terminated several patients were treated with second line therapies. Kaplan-Meier analysis yielded a mean overall survival (OS) of 806 d (95% CI 658–954 d). 23 patients were censored (liver transplant n=12). 1-year survival and 2-year survival rates were 68.8 and 40.6% respectively (patients with liver transplantation were excluded). Adverse reactions were
OP-09
Pharmacokinetic characteristics of the new treatment combination of sorafenib and resminostat, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced hepatocellular carcinoma (HCC): The SHELTER study B. Hauns ∗ ,1 , A. Mais 1 , R. Doblhofer 1 , S.W. Henning 1 , B. Hentsch 1 , M. Bitzer 2 , SHELTER Study Group 1 4SC
AG, Planegg-Martinsried, Germany; 2 Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany Introduction: Resminostat (4SC-201), a novel pan-HDAC inhibitor, was investigated in a clinical Phase I/II study (SHELTER) aiming to evaluate safety, efficacy and pharmacokinetics (PK) in HCC patients exhibiting progressive disease under first-line treatment with sorafenib. Clinical efficacy of resminostat was demonstrated in combination with sorafenib and in mono-therapy with median PFS of 5.4 and 3.2 months and median OS of 8.1 and 4.2 months, respectively. Method: Resminostat was administered at oral doses of 200, 400 or 600 mg in combination treatment with sorafenib or alone (600 mg) in a once-daily, repeated-dose schedule for 5 days followed by a 9-day drug-free period. Sorafenib was given twice-daily at total daily doses (TDD) of 400 or 800 mg. Blood samples were taken from 56 patients to investigate PK parameters of resminostat and sorafenib on Cycle 1 Day 1 (C1D1), C1D5 and C3D5. Individual plasma concentration-time data and descriptive statistics of PK characteristics were evaluated by non-compartmental analysis using WinNonlin software. Results: Plasma exposure to resminostat increased dose-dependently for all doses and at different days. Median tmax was obtained 1–2 h post dose. Plasma exposure following single (C1D1) and multiple (C1D5) dosing was comparable with geometric mean Cmax values of 2.57 and 2.07 mg/L (400 mg) and 3.67 and 3.18 mg/L (600 mg), respectively. AUC0–6 h values were 4.86 and 5.13 mgh/L (400 mg) and 8.65 and 8.54 mgh/L (600 mg), respectively. No induction or inhibition of absorption/elimination processes of resminostat and no accumulation or reduction in resminostat plasma exposure were detected. Terminal plasma elimination half-life (t1/2 ) remained constant at around 2 h. Plasma exposure to sorafenib increased dose-proportionally from 400 to 800 mg TDD. After multiple dosing (C1D5), geometric mean Cmax values were 4.37 mg/L (400 mg TDD) and 14.4 mg/L (800 mg TDD); AUC0–6 h values 20.5 mgh/L and 53.6 mgh/L. Importantly, co-administration of resminostat did not relevantly affect the exposure to sorafenib. Conclusion: Plasma concentrations of both drugs correlated well with administered doses and remarkably were in the expected range without obvious influence of preexisting liver disease. No indication for a drug–drug interaction was observed further supporting the promising treatment combination of resminostat and sorafenib.
OP-10
Grifola frondosa water extract induces autophagy and leads to apoptotic cell death through the inhibition of PI3K/AKt and ERK pathways in human Hep3B cancer cells C.-H. Lin ∗ ,1 , L. Wan 2 1 Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan; 2 School of Chinese Medicine, China Medical University, Taichung, Taiwan
Introduction: Mushrooms are used in traditional Chinese medicine. For many years Grifola frondosa have been used empirically in traditional medicine to
S252
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260
treat several diseases. In particular, a major biological activity of G. frondosa is its antitumor activity, which has been a target for scientific and clinical research. G. frondosa is a mushroom indigenous to many Asian countries; it is an edible fungus with a large fruiting body characterized by overlapping caps. Liver cancer is a leading cause of cancer deaths, for which there is currently no successful chemotherapy. The aim of this study is to investigate the chemopreventive effects of G. frondosa in a liver cancer cell-line, Hep3B. Recent studies have revealed that G. frondosa inhibits tumor growth by inducing apoptosis. Methods: To investigate the inhibition of cell growth and ability by GFW treatment, we used a MTT assay, colony formation assay, soft agar assay and wound healing assay. Further, we also made use of phase contrast microscopy, flow cytometry and Western blot to detect autophagy and apoptosis. We next examined the ability of GFW to modulate tumor growth in xenograft mouse model. Results: This study examined the effect of G. frondosa on viability and apoptosis of human liver cancer cells Hep3B. We found that treatment with water extract of G. frondosa (GFW) (15.6 or 7.8 μg/mL) significantly reduced Hep3B cancer cells growth by 95% and 90% respectively, and induced cytoplasmic vacuolations. The autophagy-associated proteins LC3A, LC3B, ATG3, ATG5, ATG7, and Beclin-1 were also increased in Hep3B cancer cells treated with GFW. GFW inhibited the phosphorylation of PI3K (Tyr458/Tyr199) an important maker in autophagy signaling pathway, in addition, GFW increased the phosphorylation of JNK (Thr183/Tyr185), and down-regulation of Bcl-2. Moreover, prolonged exposure of Hep3B cells to GFW eventually caused apoptosis which was associated with suppression of phosphorylated Akt (Ser473) and ERK (Thr202/Tyr204), and activation of caspase-3 and -9, and concomitant degradation of PARP. We also demonstrated a GFW-induced therapeutic effect on Hep3B tumor development in nude mice. The feeding of GFW (50 mg kg–1 day–1 ) significantly inhibited tumor growth by 77.4%, as compared with the control group, in nude mice inoculated with Hep3B cancer cells. Conclusion: In conclusion, our results demonstrated that the PI3K signaling pathway promotes autophagy in GFW treated Hep3B cells. On the other hand, we also found that inhibition of ERK and of the PKC-delta signaling pathway promotes apoptosis in GFW-treated Hep3B cells. These findings implied that GFW may be used as a novel therapeutic reagent for the treatment of hepatocellular carcinoma.
OP-11
Serum C-reactive protein (CRP) as biomarker for overall survival in patients with sorafenib therapy with hepatocellular carcinoma S. Koch ∗ , M.A. Wörns, I. Niederle, M. Schuchmann, P.R. Galle, A. Weinmann Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany Introduction: C-reactive protein (CRP) belongs to the inflammatory acute phase proteins and is synthesized by hepatocytes. These are related to the prognosis of different tumor entities, including HCC. Methods: Retrospective analysis of all patients with advanced HCC who were treated with sorafenib between 2007 and 2012 at the University Medical Center of the Johannes Gutenberg University Mainz whose serum CRP levels at initiation of sorafenib therapy were available. All patients had no noticeable infection at this date. 1 mg/dl was used as a cutoff value for CRP levels. The overall survival (OS) was appraised by Kaplan-Meier method. Results: 109 patients (median age: 63.9 years; 85.3% men) were included to this study. 72 patients (median age: 63.8 years) showed high CRP levels (≥1 mg/dl) at begin of Sorafenib, and 37 (median age: 64.1 years) showed low CRP levels (<1 mg/dl). Child-Pugh score: no cirrhosis and A/B/C was 50%/36.1%/8.3% in patients with high CRP levels vs. 64.9%/27%/5.4% in patients with low CRP levels. There was no significant difference in the BCLC classification, in the presence of portal vein thrombosis (41.7% vs. 21.6%, p=0.1571) or in the presence of ascites at beginning of sorafenib (73.6% vs. 59.5%, p=0.3837). Median levels of alphafetoprotein (AFP) at initiation of sorafenib therapy were three times higher in patients with high CRP levels (309 vs. 89 ng/ml, p=0.1114). The median tumor size was significantly higher
in patients with increased CRP levels: 8 vs. 4.3 cm (p<0.05). A low CRP level at initiation of sorafenib therapy was associated with a significant better OS (9.1 months vs. 3.3 months, p<0.05). Conclusion: The presence of high CRP levels at initiation of sorafenib in patients with advanced HCC affects the OS adversely. Further studies have shown that CRP is an independent predictor for the OS in patients with sorafenib therapy.
OP-12
Results of surgical management of cholangiocarcinoma of the extrahepatic bile ducts A. Frena ∗ , S. Patauner, F. Martin Hepatobiliary Surgery Unit, Department of General Surgery, Central Hospital of Bolzano, Bolzano, Italy Introduction: Carcinoma of the mid or distal third of the common bile duct is a fairly rare nosological entity in the Western world, accounting for 13–23% of tumours of the extrahepatic bile ducts. The surgical treatment varies in relation to the site: in the case of carcinomas of the distal common bile duct the operation of choice is duodeno-pancreatectomy, whereas for tumours of the mid common bile duct there is still no unanimous consensus of opinion regarding the type of surgery. The prognosis of these tumours is, on the whole, better than that of carcinomas of the proximal choledochus. Method: We retrospectively assessed 37 patients with non-hilar extra-hepatic bile duct tumours observed in our surgery department from 2002 to 2012. The patient series comprised 21 men and 16 women, with a mean age of 71 years. The presenting symptom was jaundice in 95% of cases. In 23 cases the carcinoma affected the distal common bile duct and in 14 cases the mid common bile duct. Results: 15 patients were treated with a radial intent by either duodenopancreatectomy (13 cases) or by resection of the common bile duct (2 cases). Ten patients with local inoperability or liver metastases were treated with a palliative biliodigestive anastomosis. Twelve patients were excluded from surgery and treated endoscopically. Postoperative staging identified 1 patient as stage Ia, 2 patients as stage Ib, 8 patients as stage IIa, 3 patients as stage IIb, and 1 patient as stage III according to the new TNM classification. There was no operative mortality. Survival at 1, 2 and 5 years was 51%, 27% and 14%, respectively. Conclusion: Carcinoma of the mid or distal portion of the common bile duct is a tumour that offers fairly good prospects of survival. Surgical radicality is achieved essentially by obtaining ductal and radial margins which are free of microscopic infiltration and by means of a thorough lymphadenectomy. These conditions can be achieved more easily in carcinomas of the distal portion of the duct owing to the extent of the duodeno-pancreatectomy they require. In carcinomas of the mid common bile duct the anatomical contiguity with the portal vein is responsible for a lower resectability rate.
OP-13
Liver resection for cholangiocarcinoma: A single-center experience of the first decade of the new millennium A. Nickkholgh ∗ ,1 , A. Mehrabi 1 , M. Hafezi 1 , A. Edalatpour 1 , B. Göppert 2 , T. Bruckner 3 , P. Schemmer 1 , M.W. Büchler 1 1 Dept.
of General, Visceral and Transplant Surgery; 2 Institute of Pathology; of Medical Biometry and Informatics, Ruprecht-Karls-University, Heidelberg, Germany 3 Institute
Background: Cholangiocarcinoma (CCC) arises from the biliary epithelium anywhere from the intrahepatic ducts down to the distal common bile duct. Liver resection constitutes the only therapeutic option for the intrahepatic and hilar CCC, as well as the locally advanced gallbladder carcinoma. The aim of this work was to present our single-center cohort of patients undergoing liver resection for CCC within the last decade. Methods: Demographic, topographic, clinical, operative, surgical pathologic and follow-up data from all consecutive patients (n=231) undergoing surgical management for CCC between December 2001 and May 2011 was prospec-
Initial RECIST tumour reduction as a prognostic parameter for transarterial chemoembolisation treatment success in patients with hepatocellular carcinoma D. Hasdemir 1 , N. Schweitzer 2 , A. Vogel 2 , C. von Falck 1 , F. Wacker 1 , B. Meyer 1 , T. Rodt ∗ ,1
S251
documented in only 12 of the patient charts. Data from literature shows concordant 1- and 2-year survival rates of 61–71% and 33–48% respectively for a comparable patient cohort. Conclusion: Despite a low-embolic TACE technique tumour response and overall survival in the analysed patient group was comparable to data from the literature where techniques applying additional embolic agents with potential adverse reactions were described.
1 Dept.
of Diagnostic and Interventional Radiology, Hannover Medical School; 2 Dept. of Gastroenterology, Hannover Medical School, Hannover, Germany
Introduction: In this study we investigate initial RECIST tumour reduction as a prognostic parameter for treatment success in patients with intermediate stage hepatocellular carcinoma receiving transarterial chemoembolisation (TACE). Method: All TACE procedures in our institution in three successive years (2006–2009) were reviewed using a custom-made database. Patients who had received previous chemoembolisation were excluded from the study. 63 patients with intermediate stage hepatocellular carcinoma who received initial chemoembolisation using a low-embolic technique were identified, in all patients RECIST follow-up was available. TACE procedures (n=198) were performed using doxorubicin and cisplatin as chemotherapeutic agents. Lipiodol was used as the only embolic agent. Individual RECIST response of the first five TACE procedures was correlated to overall survival and maximum treatment response based on RECIST criteria. Results: On average patients received 3.1 TACE procedures (SD 2.8). KaplanMeier analysis yielded a mean overall survival of 843 d (95% CI 682 – 1004 d). 19 patients (30.2%) did not show any response, 44 patients (69.8%) showed response. Maximum RECIST tumour response was assigned to the individual treatment intervals (TACE 1: 19 patients (30.2%); TACE 2: 6 patients (9.5%); TACE 3: 8 patients (12.7%); TACE 4: 5 patients (7.9%); TACE 5: 0 patients (0%); 6 patients TACE 6–17 (9.5%). A Pearson correlation was calculated between maximum tumour response and tumour response of the initial TACE procedures (TACE1: 0.606 (p<0.01); TACE 2: 0.701 (p<0.01); TACE 3: 0.498 (p<0.05). Conclusion: The initial RECIST tumour reduction significantly correlates to maximum tumour response and thus has potential to be applied as a prognostic parameter in TACE treatment.
OP-08
Results of transarterial chemoembolisation using a low-embolic technique in patients with intermediate stage hepatocellular carcinoma T. Rodt ∗ ,1 , D. Hasdemir 1 , N. Schweitzer 2 , A. Vogel 2 , C. von Falck 1 , H. Rosenthal 1 , F. Wacker 1 , B. Meyer 1 1 Dept. of Diagnostic and Interventional Radiology, Hannover Medical School; 2 Dept. of Gastroenterology, Hannover Medical School, Hannover, Germany
Introduction: We report on the results of transarterial chemoembolisation (TACE) using a low embolic technique in patients with intermediate stage hepatocellular carcinoma and compare the outcome to data on alternative chemoembolisation techniques from the literature. Method: All patients receiving initial TACE treatment in our institution between 2006 and 2009 were reviewed using a custom-made database. Patients with prior TACE were excluded. 75 patients with intermediate stage hepatocellular carcinoma receiving initial TACE treatment were identified. TACE (n=209) was performed using doxorubicin and cisplatin as chemotherapeutic agents in combination with lipiodol. For this low-embolic technique no additional embolic agent was used. Results: The patients received an average of 2.8 TACE procedures (SD 2.7). Best RECIST tumour response was assessed (mean value 23.9%, SD 27%). When TACE was terminated several patients were treated with second line therapies. Kaplan-Meier analysis yielded a mean overall survival (OS) of 806 d (95% CI 658–954 d). 23 patients were censored (liver transplant n=12). 1-year survival and 2-year survival rates were 68.8 and 40.6% respectively (patients with liver transplantation were excluded). Adverse reactions were
OP-09
Pharmacokinetic characteristics of the new treatment combination of sorafenib and resminostat, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced hepatocellular carcinoma (HCC): The SHELTER study B. Hauns ∗ ,1 , A. Mais 1 , R. Doblhofer 1 , S.W. Henning 1 , B. Hentsch 1 , M. Bitzer 2 , SHELTER Study Group 1 4SC
AG, Planegg-Martinsried, Germany; 2 Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany Introduction: Resminostat (4SC-201), a novel pan-HDAC inhibitor, was investigated in a clinical Phase I/II study (SHELTER) aiming to evaluate safety, efficacy and pharmacokinetics (PK) in HCC patients exhibiting progressive disease under first-line treatment with sorafenib. Clinical efficacy of resminostat was demonstrated in combination with sorafenib and in mono-therapy with median PFS of 5.4 and 3.2 months and median OS of 8.1 and 4.2 months, respectively. Method: Resminostat was administered at oral doses of 200, 400 or 600 mg in combination treatment with sorafenib or alone (600 mg) in a once-daily, repeated-dose schedule for 5 days followed by a 9-day drug-free period. Sorafenib was given twice-daily at total daily doses (TDD) of 400 or 800 mg. Blood samples were taken from 56 patients to investigate PK parameters of resminostat and sorafenib on Cycle 1 Day 1 (C1D1), C1D5 and C3D5. Individual plasma concentration-time data and descriptive statistics of PK characteristics were evaluated by non-compartmental analysis using WinNonlin software. Results: Plasma exposure to resminostat increased dose-dependently for all doses and at different days. Median tmax was obtained 1–2 h post dose. Plasma exposure following single (C1D1) and multiple (C1D5) dosing was comparable with geometric mean Cmax values of 2.57 and 2.07 mg/L (400 mg) and 3.67 and 3.18 mg/L (600 mg), respectively. AUC0–6 h values were 4.86 and 5.13 mgh/L (400 mg) and 8.65 and 8.54 mgh/L (600 mg), respectively. No induction or inhibition of absorption/elimination processes of resminostat and no accumulation or reduction in resminostat plasma exposure were detected. Terminal plasma elimination half-life (t1/2 ) remained constant at around 2 h. Plasma exposure to sorafenib increased dose-proportionally from 400 to 800 mg TDD. After multiple dosing (C1D5), geometric mean Cmax values were 4.37 mg/L (400 mg TDD) and 14.4 mg/L (800 mg TDD); AUC0–6 h values 20.5 mgh/L and 53.6 mgh/L. Importantly, co-administration of resminostat did not relevantly affect the exposure to sorafenib. Conclusion: Plasma concentrations of both drugs correlated well with administered doses and remarkably were in the expected range without obvious influence of preexisting liver disease. No indication for a drug–drug interaction was observed further supporting the promising treatment combination of resminostat and sorafenib.
OP-10
Grifola frondosa water extract induces autophagy and leads to apoptotic cell death through the inhibition of PI3K/AKt and ERK pathways in human Hep3B cancer cells C.-H. Lin ∗ ,1 , L. Wan 2 1 Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan; 2 School of Chinese Medicine, China Medical University, Taichung, Taiwan
Introduction: Mushrooms are used in traditional Chinese medicine. For many years Grifola frondosa have been used empirically in traditional medicine to
S252
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260
treat several diseases. In particular, a major biological activity of G. frondosa is its antitumor activity, which has been a target for scientific and clinical research. G. frondosa is a mushroom indigenous to many Asian countries; it is an edible fungus with a large fruiting body characterized by overlapping caps. Liver cancer is a leading cause of cancer deaths, for which there is currently no successful chemotherapy. The aim of this study is to investigate the chemopreventive effects of G. frondosa in a liver cancer cell-line, Hep3B. Recent studies have revealed that G. frondosa inhibits tumor growth by inducing apoptosis. Methods: To investigate the inhibition of cell growth and ability by GFW treatment, we used a MTT assay, colony formation assay, soft agar assay and wound healing assay. Further, we also made use of phase contrast microscopy, flow cytometry and Western blot to detect autophagy and apoptosis. We next examined the ability of GFW to modulate tumor growth in xenograft mouse model. Results: This study examined the effect of G. frondosa on viability and apoptosis of human liver cancer cells Hep3B. We found that treatment with water extract of G. frondosa (GFW) (15.6 or 7.8 μg/mL) significantly reduced Hep3B cancer cells growth by 95% and 90% respectively, and induced cytoplasmic vacuolations. The autophagy-associated proteins LC3A, LC3B, ATG3, ATG5, ATG7, and Beclin-1 were also increased in Hep3B cancer cells treated with GFW. GFW inhibited the phosphorylation of PI3K (Tyr458/Tyr199) an important maker in autophagy signaling pathway, in addition, GFW increased the phosphorylation of JNK (Thr183/Tyr185), and down-regulation of Bcl-2. Moreover, prolonged exposure of Hep3B cells to GFW eventually caused apoptosis which was associated with suppression of phosphorylated Akt (Ser473) and ERK (Thr202/Tyr204), and activation of caspase-3 and -9, and concomitant degradation of PARP. We also demonstrated a GFW-induced therapeutic effect on Hep3B tumor development in nude mice. The feeding of GFW (50 mg kg–1 day–1 ) significantly inhibited tumor growth by 77.4%, as compared with the control group, in nude mice inoculated with Hep3B cancer cells. Conclusion: In conclusion, our results demonstrated that the PI3K signaling pathway promotes autophagy in GFW treated Hep3B cells. On the other hand, we also found that inhibition of ERK and of the PKC-delta signaling pathway promotes apoptosis in GFW-treated Hep3B cells. These findings implied that GFW may be used as a novel therapeutic reagent for the treatment of hepatocellular carcinoma.
OP-11
Serum C-reactive protein (CRP) as biomarker for overall survival in patients with sorafenib therapy with hepatocellular carcinoma S. Koch ∗ , M.A. Wörns, I. Niederle, M. Schuchmann, P.R. Galle, A. Weinmann Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany Introduction: C-reactive protein (CRP) belongs to the inflammatory acute phase proteins and is synthesized by hepatocytes. These are related to the prognosis of different tumor entities, including HCC. Methods: Retrospective analysis of all patients with advanced HCC who were treated with sorafenib between 2007 and 2012 at the University Medical Center of the Johannes Gutenberg University Mainz whose serum CRP levels at initiation of sorafenib therapy were available. All patients had no noticeable infection at this date. 1 mg/dl was used as a cutoff value for CRP levels. The overall survival (OS) was appraised by Kaplan-Meier method. Results: 109 patients (median age: 63.9 years; 85.3% men) were included to this study. 72 patients (median age: 63.8 years) showed high CRP levels (≥1 mg/dl) at begin of Sorafenib, and 37 (median age: 64.1 years) showed low CRP levels (<1 mg/dl). Child-Pugh score: no cirrhosis and A/B/C was 50%/36.1%/8.3% in patients with high CRP levels vs. 64.9%/27%/5.4% in patients with low CRP levels. There was no significant difference in the BCLC classification, in the presence of portal vein thrombosis (41.7% vs. 21.6%, p=0.1571) or in the presence of ascites at beginning of sorafenib (73.6% vs. 59.5%, p=0.3837). Median levels of alphafetoprotein (AFP) at initiation of sorafenib therapy were three times higher in patients with high CRP levels (309 vs. 89 ng/ml, p=0.1114). The median tumor size was significantly higher
in patients with increased CRP levels: 8 vs. 4.3 cm (p<0.05). A low CRP level at initiation of sorafenib therapy was associated with a significant better OS (9.1 months vs. 3.3 months, p<0.05). Conclusion: The presence of high CRP levels at initiation of sorafenib in patients with advanced HCC affects the OS adversely. Further studies have shown that CRP is an independent predictor for the OS in patients with sorafenib therapy.
OP-12
Results of surgical management of cholangiocarcinoma of the extrahepatic bile ducts A. Frena ∗ , S. Patauner, F. Martin Hepatobiliary Surgery Unit, Department of General Surgery, Central Hospital of Bolzano, Bolzano, Italy Introduction: Carcinoma of the mid or distal third of the common bile duct is a fairly rare nosological entity in the Western world, accounting for 13–23% of tumours of the extrahepatic bile ducts. The surgical treatment varies in relation to the site: in the case of carcinomas of the distal common bile duct the operation of choice is duodeno-pancreatectomy, whereas for tumours of the mid common bile duct there is still no unanimous consensus of opinion regarding the type of surgery. The prognosis of these tumours is, on the whole, better than that of carcinomas of the proximal choledochus. Method: We retrospectively assessed 37 patients with non-hilar extra-hepatic bile duct tumours observed in our surgery department from 2002 to 2012. The patient series comprised 21 men and 16 women, with a mean age of 71 years. The presenting symptom was jaundice in 95% of cases. In 23 cases the carcinoma affected the distal common bile duct and in 14 cases the mid common bile duct. Results: 15 patients were treated with a radial intent by either duodenopancreatectomy (13 cases) or by resection of the common bile duct (2 cases). Ten patients with local inoperability or liver metastases were treated with a palliative biliodigestive anastomosis. Twelve patients were excluded from surgery and treated endoscopically. Postoperative staging identified 1 patient as stage Ia, 2 patients as stage Ib, 8 patients as stage IIa, 3 patients as stage IIb, and 1 patient as stage III according to the new TNM classification. There was no operative mortality. Survival at 1, 2 and 5 years was 51%, 27% and 14%, respectively. Conclusion: Carcinoma of the mid or distal portion of the common bile duct is a tumour that offers fairly good prospects of survival. Surgical radicality is achieved essentially by obtaining ductal and radial margins which are free of microscopic infiltration and by means of a thorough lymphadenectomy. These conditions can be achieved more easily in carcinomas of the distal portion of the duct owing to the extent of the duodeno-pancreatectomy they require. In carcinomas of the mid common bile duct the anatomical contiguity with the portal vein is responsible for a lower resectability rate.
OP-13
Liver resection for cholangiocarcinoma: A single-center experience of the first decade of the new millennium A. Nickkholgh ∗ ,1 , A. Mehrabi 1 , M. Hafezi 1 , A. Edalatpour 1 , B. Göppert 2 , T. Bruckner 3 , P. Schemmer 1 , M.W. Büchler 1 1 Dept.
of General, Visceral and Transplant Surgery; 2 Institute of Pathology; of Medical Biometry and Informatics, Ruprecht-Karls-University, Heidelberg, Germany 3 Institute
Background: Cholangiocarcinoma (CCC) arises from the biliary epithelium anywhere from the intrahepatic ducts down to the distal common bile duct. Liver resection constitutes the only therapeutic option for the intrahepatic and hilar CCC, as well as the locally advanced gallbladder carcinoma. The aim of this work was to present our single-center cohort of patients undergoing liver resection for CCC within the last decade. Methods: Demographic, topographic, clinical, operative, surgical pathologic and follow-up data from all consecutive patients (n=231) undergoing surgical management for CCC between December 2001 and May 2011 was prospec-