Peter R Galle

Publications (255)1312.51 Total impact

• Article: Facing the dawn of immunotherapy for hepatocellular carcinoma.

  Martin F Sprinzl, Peter R Galle
  Journal of Hepatology 04/2013; · 9.26 Impact Factor
• Article: Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma.

  Anja Lautem, Michael Heise, Andreas Gräsel, Maria Hoppe-Lotichius, Nina Weiler, Daniel Foltys, Johanna Knapstein, Jörn M Schattenberg, Arno Schad, Anca Zimmermann, Gerd Otto, Hauke Lang, Peter R Galle, Marcus Schuchmann, Tim Zimmermann
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  ABSTRACT: Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long‑term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum‑based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor‑surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates.
  International Journal of Oncology 04/2013; 42(4):1297-304. · 2.40 Impact Factor
• Article: SIRT6 dependent genetic and epigenetic alterations are associated with poor clinical outcome in HCC patients.

  Jens U Marquardt, Kerstin Fischer, Katharina Baus, Anubha Kashyap, Shengyun Ma, Markus Krupp, Matthias Linke, Andreas Teufel, Ulrich Zechner, Dennis Strand, Snorri S Thorgeirsson, Peter R Galle, Susanne Strand
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  ABSTRACT: Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. So far the role of SIRT6 in development and progression of hepatocellular carcinoma is unknown. We first investigated SIRT6 expression in 153 primary human liver cancers, normal and cirrhotic livers using microarray analysis. SIRT6 was significantly downregulated in both cirrhotic livers and cancer. A Sirt6 knock out (KO) gene expression signature was generated from primary hepatoctyes isolated from three week old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed upregulation of established HCC-biomarkers Alpha-fetoprotein (Afp), Insulin-like growth factor 2 (Igf2), H19 and Glypican-3 (Gpc3). Furthermore decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes including global hypomethylation as well as metabolic changes including hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we could demonstrate that the Sirt6-KO signature possessed a predictive value for tumors other than HCC, i.e. breast and lung cancer. Conclusion: Loss of SIRT6 induces epigenetic changes which may be relevant to chronic liver diseases and HCC development. Downregulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype which ultimately has relevance for outcome of HCC and other cancer patients. (HEPATOLOGY 2013.).
  Hepatology 03/2013; · 11.66 Impact Factor
• Article: Delayed versus immediate treatment for patients with acute hepatitis C: a randomised controlled non-inferiority trial.

  Katja Deterding, Norbert Grüner, Peter Buggisch, Johannes Wiegand, Peter R Galle, Ulrich Spengler, Holger Hinrichsen, Thomas Berg, Andrej Potthoff, Nisar Malek, [......], Armin Koch, Helmut Diepolder, Stefan Lüth, Sandra Feyerabend, Maria Christina Jung, Magdalena Rogalska-Taranta, Verena Schlaphoff, Markus Cornberg, Michael P Manns, Heiner Wedemeyer
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  ABSTRACT: BACKGROUND: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy is very effective, with cure rates of greater than 85%. However, spontaneous clearance of HCV occurs in 10-50% of cases. We aimed to assess an alternative treatment strategy of delayed antiviral therapy in patients who do not eliminate the virus spontaneously compared with immediate treatment. METHODS: In our open-label phase 3 non-inferiority trial, we enrolled adults (≥18 years) with acute hepatitis C but no HIV or hepatitis B co-infection at 72 centres in Germany. We randomly allocated patients with symptomatic acute hepatitis C (1:1) to receive immediate pegylated interferon alfa-2b treatment for 24 weeks or delayed treatment with pegylated interferon alfa-2b plus ribavirin (for 24 weeks) starting 12 weeks after randomisation if HCV RNA remained positive. We used a computer-generated randomisation sequence and block sizes of eight, stratified by bilirubin concentration. We assigned all asymptomatic patients to immediate treatment with pegylated interferon alfa-2b for 24 weeks. The primary endpoint was sustained HCV RNA negativity in all randomly allocated participants who completed screening (intention-to-treat analysis), with a non-inferiority margin of 10%. For the primary analysis, we calculated the virological response of patients in the immediate and delayed treatment groups and an absolute risk difference stratified by bilirubin status. The trial was stopped early on advice from the study advisory committee because of slow recruitment of participants. This study is registered, number ISRCTN88729946. FINDINGS: Between April, 2004, and February, 2010, we recruited 107 symptomatic and 25 asymptomatic patients. 37 (67%) of 55 symptomatic patients randomly allocated to receive immediate treatment and 28 (54%) of 52 symptomatic patients randomly allocated to receive delayed treatment had a sustained virological response (difference 13·7%, 95% CI -4·6 to 32·0; p=0·071). 18 (72%) of 25 asymptomatic patients had a sustained virological response. 22 (42%) of 52 symptomatic patients allocated to receive delayed treatment did not complete follow-up compared with 20 (25%) of 80 symptomatic or asymptomatic patients assigned immediate treatment (p=0·037). 11 symptomatic patients (21%) assigned delayed treatment had spontaneous HCV clearance. 14 patients who received delayed pegylated interferon alfa-2b plus ribavirin treatment and completed follow-up achieved sustained virological response. INTERPRETATION: Delayed treatment is effective although not of equal efficacy to immediate treatment; coupled with the rate of spontaneous clearance it can reduce unnecessary treatment in closely monitored populations. Immediate treatment seems preferable in populations where loss to follow-up is great. FUNDING: German Network of Competence on Viral Hepatitis (HepNet, funded by the German Federal Ministry of Education and Research, grants 01KI0102, 01KI0401, and 01KI0601), MSD, Schering-Plough.
  The Lancet Infectious Diseases 03/2013; · 17.39 Impact Factor
• Article: Epigenetic regulation of methionine adenosyltransferase 1A; a role for microRNA-based treatment in liver cancer?

  Jens U Marquardt, Peter R Galle
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  ABSTRACT: MicroRNAs (miRNAs) and methionine adenosyltransferase 1A (MAT1A) are dysregulated in Hepatocellular carcinoma (HCC), and reduced MAT1A expression correlates with worse HCC prognosis. Expression of miR-664, miR-485-3p, and miR-495, potential regulatory miRNAs of MAT1A, is increased in HCC. Knockdown of these miRNAs individually in Hep3B and HepG2 cells induced MAT1A expression, reduced growth, and increased apoptosis, while combined knockdown exerted additional effects on all parameters. Subcutaneous and intraparenchymal injection of Hep3B cells stably overexpressing each of this trio of miRNAs promoted tumorigenesis and metastasis in mice. Treatment with miRNA-664 (miR-664), miR-485-3p, and miR-495 siRNAs reduced tumor growth, invasion, and metastasis in an orthotopic liver cancer model. Blocking MAT1A induction significantly reduced the antitumorigenic effect of miR-495 siRNA, whereas maintaining MAT1A expression prevented miRNA-mediated enhancement of growth and metastasis. Knockdown of these miRNAs increased total and nuclear level of MAT1A protein, global CpG methylation, lin-28 homolog B (Caenorhabditis elegans) (LIN28B) promoter methylation, and reduced LIN28B expression. The opposite occurred with forced expression of these miRNAs. In conclusion, upregulation of miR-664, miR-485-3p, and miR-495 contributes to lower MAT1A expression in HCC, and enhanced tumorigenesis may provide potential targets for HCC therapy. (HEPATOLOGY 2013.).
  Hepatology 03/2013; · 11.66 Impact Factor
• Article: Prospective, open, multi-centre phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and oxaliplatin in patients with adenocarcinoma of the oesophagogastric junction.

  Markus Moehler, Ines Gockel, Hans-Peter Roessler, Dirk Arnold, Tanja Trarbach, Thomas Thomaidis, Gunther Klautke, Claus Rödel, Baruch Brenner, Hauke Lang, Peter R Galle, Carl C Schimanski, Heinz Schmidberger
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  ABSTRACT: BACKGROUND: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. METHODS: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). RESULTS: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. CONCLUSION: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction.Registered trial at clinical trials.gov: NCT00374985.
  BMC Cancer 02/2013; 13(1):75. · 3.01 Impact Factor
• Article: Late Consequences of Traumatic Rupture of the Diaphragm.

  Moritz Kaths, Maren Ebert, Peter R Galle, Annerose Keilmann, Hauke Lang, Ines Gockel
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  ABSTRACT: A 54-year-old man was admitted to our clinic due to elevated γ-glutamyltransferase, without any clinical symptoms. About 25 years ago, he had undergone blunt abdominal and thoracic trauma during an accident. No diagnostic measures or therapy had been performed at that time. Serum bilirubin was normal, but the values for alanine transaminase, aspartate transaminase, and alkaline phosphatase were slightly above the reference range. Sonography of the abdomen revealed dilated intrahepatic bile ducts up to 3 mm in diameter and steatosis of the liver grade I. CT scan and MRI of the thorax and abdomen showed a giant hiatal hernia with transposition of upper abdominal organs into the chest. As the patient presented clinically completely asymptomatic, without dyspnea, dysfunction of phonation or ingestion, we decided a conservative treatment with Ursodesoxycholic acid. The liver values resolved with this regimen gradually. At follow-up examination 1 year later, they had normalized. Spirometry showed a reduced lung capacity (3.44 L; 64.4% of the desired value) and a reduced FEV1 (forced expiratory volume in one second) of 2.84 L (70.2% of the desired value). Further diagnostics revealed normal otorhinolaryngological and phoniatric findings including stroboscopy of the vocal folds and voice range profile.
  The Thoracic and Cardiovascular Surgeon 01/2013; · 0.88 Impact Factor
• Article: No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: The ATRACTION study, a phase II randomised trial.

  Marcus Schuchmann, Jens M Kittner, Jörg F Schlaak, Dietmar M Klass, Christoph Eisenbach, Thomas Berg, Christian Trautwein, Rainer Günther, Stefan Zeuzem, Roger Gösseringer, Anne Ehrlich, Konrad Neumann, Daniel Wachtlin, Martin F Sprinzl, Tim Zimmermann, Wulf O Böcher, Peter R Galle
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  ABSTRACT: BACKGROUND: Preclinical data suggested all-trans retinoic acid (tretinoin) as a potential antiviral agent against chronic hepatitis C infection. AIMS: To assess efficacy, safety, and tolerability of tretinoin in combination with peg-interferon and ribavirin in genotype-1 infected patients with prior non-response. METHOD: We performed an open-label multicentre clinical trial. Patients were randomised to either receive additional tretinoin (45mg/m(2)/day) for 12 weeks (arm A), or peg-interferon and ribavirin alone (arm B). Primary endpoint was the slope of the third phase of viral decline (Mδ) as determined in an established kinetic model known to correlate with treatment outcome. Secondary endpoints were additional kinetic parameters, viral response rates, safety, and tolerability. RESULTS: 27 patients in arm A and 30 patients in arm B were treated per protocol until week 12. Viral kinetic parameters did not differ. Rates of early virological response (>2log(10) drop at week 12) were similar (10/27 versus 11/30 patients). In arm A, patients experienced a higher rate and intensity of adverse events, most commonly skin and mucosal dryness, and headache. CONCLUSION: Addition of tretinoin was safe and acceptably well tolerated. However, it did not influence viral kinetics and thus cannot be further considered as a treatment option.
  Digestive and Liver Disease 12/2012; · 3.05 Impact Factor
• Article: The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib.

  Marcus A Wörns, Sandra Koch, Ina M Niederle, Jens U Marquardt, Marc Nguyen-Tat, Thomas Gamstätter, Marcus Schuchmann, Henning Schulze-Bergkamen, Peter R Galle, Arndt Weinmann
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  ABSTRACT: BACKGROUND: Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. AIMS/METHODS: Univariate/multivariate analyses were conducted to identify retrospectively the impact of baseline characteristics on the survival of 110 patients with advanced HCC treated with sorafenib. RESULTS: Median survival of the whole cohort was 6.7 months, median survival in Child-Pugh A, B, C patients was 10.5, 6.1 and 3.0 months and median survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C/D was 6.8/2.6 months. Presence of ascites, presence of macrovascular invasion and BCLC stage D (mainly determined by Child-Pugh C status and Eastern Cooperative Oncology Group Performance Status>2) remained independent prognostic factors for the survival on multivariate analysis. Particularly, the presence of macrovascular invasion significantly influenced survival both in patients with liver cirrhosis Child-Pugh A and Child-Pugh B. CONCLUSION: Well maintained liver function and performance status are prerequisites for sorafenib treatment in patients with advanced HCC. Our findings do not support routine clinical use of sorafenib in Child-Pugh B patients. Evaluation of ascites and particularly macrovascular invasion might help to identify patients more likely to benefit from sorafenib treatment.
  Digestive and Liver Disease 11/2012; · 3.05 Impact Factor
• Article: Activation of the human immune system via toll-like receptors by the oncolytic parvovirus H-1.

  Maike Sieben, Petra Schäfer, Christiane Dinsart, Peter R Galle, Markus Moehler
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  ABSTRACT: This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV) induced human immune responses. Firstly the role of TLRs in the activation of the NFκB transcription factor was characterized, secondly the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFκB translocation to the nucleus.and a reduced cytoplasmic IκB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFκB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFκB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-α was determined. Here H-1PV-induced TCL significantly enhanced the TNF-α level by DCs after co-culture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy. © 2012 Wiley Periodicals, Inc.
  International Journal of Cancer 11/2012; · 5.44 Impact Factor
• Article: Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation.

  Martin F Sprinzl, Arndt Weinmann, Nikola Lohse, Hanna Tönissen, Sandra Koch, Jörn Schattenberg, Maria Hoppe-Lotichius, Tim Zimmermann, Peter R Galle, Torsten Hansen, Gerd Otto, Marcus Schuchmann
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  ABSTRACT: The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS-associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ≥5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56-8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69-10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46-14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid dosage after OLT (5.2 ± 2.4 mg/day vs. 7.1 ± 4.7 mg/day, P = 0.014), and was linked to NAFLD (P = 0.001) via obesity (OR = 4.67, CI = 1.55-14.1, P = 0.006) and dyslipidemia (OR = 4.23, CI = 1.35-13.3, P = 0.013) post-OLT. In conclusion, we were able to identify low threshold HbA1c as a novel risk factor for MetS after OLT and described a link of MetS with NAFLD in transplant organs. This study also indicated that steroid treatment is associated with MetS rates after OLT.
  Transplant International 11/2012; · 2.92 Impact Factor
• Article: CellLineNavigator: a workbench for cancer cell line analysis.

  Markus Krupp, Timo Itzel, Thorsten Maass, Andreas Hildebrandt, Peter R Galle, Andreas Teufel
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  ABSTRACT: The CellLineNavigator database, freely available at http://www.medicalgenomics.org/celllinenavigator, is a web-based workbench for large scale comparisons of a large collection of diverse cell lines. It aims to support experimental design in the fields of genomics, systems biology and translational biomedical research. Currently, this compendium holds genome wide expression profiles of 317 different cancer cell lines, categorized into 57 different pathological states and 28 individual tissues. To enlarge the scope of CellLineNavigator, the database was furthermore closely linked to commonly used bioinformatics databases and knowledge repositories. To ensure easy data access and search ability, a simple data and an intuitive querying interface were implemented. It allows the user to explore and filter gene expression, focusing on pathological or physiological conditions. For a more complex search, the advanced query interface may be used to query for (i) differentially expressed genes; (ii) pathological or physiological conditions; or (iii) gene names or functional attributes, such as Kyoto Encyclopaedia of Genes and Genomes pathway maps. These queries may also be combined. Finally, CellLineNavigator allows additional advanced analysis of differentially regulated genes by a direct link to the Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources.
  Nucleic Acids Research 10/2012; · 8.03 Impact Factor
• Article: Next generation sequencing of HCC from European and Asian HCC cohorts. Back to p53 and Wnt/β-Catenin.

  Andreas Teufel, Jens U Marquardt, Peter R Galle
  Journal of Hepatology 10/2012; · 9.26 Impact Factor
• Article: Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft-no benefit of combination therapy.

  Thomas C Wehler, Swaantje Hamdi, Annett Maderer, Claudine Graf, Ines Gockel, Irene Schmidtmann, Michael Hainz, Martin R Berger, Matthias Theobald, Peter R Galle, Markus Moehler, Carl C Schimanski
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  ABSTRACT: BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. RESULTS: In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45β. In resistant cell lines, pp53 and GADD45β levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFRβ expression intensity. CONCLUSIONS: In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect.
  International Journal of Colorectal Disease 09/2012; · 2.38 Impact Factor
• Article: Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large german cohort.

  Ina M Niederle, Marcus-Alexander Wörns, Sandra Koch, Marc Nguyen-Tat, Christoph Düber, Gerd Otto, Marcus Schuchmann, Peter R Galle, Arndt Weinmann
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  ABSTRACT: : Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. : We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. : Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fibrolamellar carcinoma was more frequent in young versus old patients (20% vs. 0.7%; P<0.001). There was a trend toward more potentially curative treatment options in young patients, and overall survival was longer in the young group compared with older patients (56.0 vs. 15.2 mo; P=0.048). : This western cohort of young patients is distinctly different from described Asian cohorts, especially with regard to a lower rate of underlying liver disease and particularly hepatitis B virus. Young patients had a better overall survival than older patients.
  Journal of clinical gastroenterology 08/2012; 46(9):775-8. · 2.21 Impact Factor
• Article: Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC.

  Diana Becker, Ioannis Sfakianakis, Markus Krupp, Frank Staib, Aslihan Gerhold-Ay, Anja Victor, Harald Binder, Maria Blettner, Thorsten Maass, Snorri Thorgeirsson, Peter R Galle, Andreas Teufel
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  ABSTRACT: Multiple activations of individual genes during embryonic liver and HCC development have repeatedly prompted speculations about conserved embryonic signatures driving cancer development. Recently, the emerging discussion on cancer stem cells and the appreciation that generally tumors may develop from progenitor cells of diverse stages of cellular differentiation has shed increasing light on the overlapping genetic signatures between embryonic liver development and HCC. However there is still a lack of systematic studies investigating this area. We therefore performed a comprehensive analysis of differentially regulated genetic signaling pathways in embryonic and liver cancer development and investigated their biological relevance.Genetic signaling pathways were investigated on several publically available genome wide microarray experiments on liver development and HCC. Differentially expressed genes were investigated for pathway enrichment or underrepresentation compared to KEGG annotated pathways by Fisher exact evaluation. The comparative analysis of enrichment and under representation of differentially regulated genes in liver development and HCC demonstrated a significant overlap between multiple pathways. Most strikingly we demonstrated a significant overlap not only in pathways expected to be relevant to both conditions such as cell cycle or apoptosis but also metabolic pathways associated with carbohydrate and lipid metabolism. Furthermore, we demonstrated the clinical significance of these findings as unsupervised clustering of HCC patients on the basis of these metabolic pathways displayed significant differences in survival.These results indicate that liver development and liver cancer share similar alterations in multiple genetic signaling pathways. Several pathways with markedly similar patterns of enrichment or underrepresentation of various regulated genes between liver development and HCC are of prognostic relevance in HCC. In particular, the metabolic pathways were identified as novel prognostically relevant players in HCC development.
  Molecular Cancer 08/2012; 11(1):55. · 3.99 Impact Factor
• Article: Preservation of HUGL-1 expression as a favourable prognostic factor in pancreatic carcinoma.

  Stefan Biesterfeld, Alexander Kauhausen, Carmen Kost, Ines Gockel, Christoph C Schimanski, Peter R Galle
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  ABSTRACT: The expression of the human homologue of Drosophila tumour suppressor gene lgl (HUGL-1) in pancreatic cancer was retrospectively assessed in 97 patients with surgically treated pancreatic cancer in order to correlate the HUGL-1 profile with patients' survival. Immunohistochemistry was performed on 4-μm-thick paraffin sections from representative tumour blocks using a standard protocol. The expression of HUGL-1 was evaluated semiquantitatively as negative (0), weak (1), medium (2) or strong (3). The results were correlated with clinicopathological parameters and with patients' survival, considering an observation period of 17 (mean) ± 16 (SD) months. In normal and inflammatory tissue, a uniform and relatively strong staining was observed in ductal epithelium, ganglion cells and some acinar epithelia. The endocrine islets exhibited a weak positivity. Human pancreatic cancer revealed variable intensities of HUGL-1 expression. A total of 69 tumour specimens were classified as negative and 28 as positive. The HUGL-1 expression was not correlated with clinical variables (age, gender), staging or tumour grading. HUGL-1 positivity proved to be prognostically favourable (p=0.0241) conferring a higher survival rate, especially for patients who had survived more than 12 months. The presence of distant metastases (M1) at diagnosis had a weak significant influence on survival (p=0.0474). The other staging parameters (T, N, UICC stage), tumour grading and clinical variables (age, gender) gave no significant prognostic information. In a multivariate Cox model, only HUGL-1 expression passed the entry limits. Preservation of HUGL-1 expression in pancreatic adenocarcinoma is a good prognostic factor that contributes to a better overall survival.
  Anticancer research 08/2012; 32(8):3153-9. · 1.73 Impact Factor
• Article: Molecular in vivo imaging of gastric cancer in a human-murine xenograft model: targeting epidermal growth factor receptor.

  Michael S Hoetker, Ralf Kiesslich, Mustafa Diken, Markus Moehler, Peter R Galle, Yanqing Li, Martin Goetz
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  ABSTRACT: The prognosis of gastric cancer depends on early diagnosis. Targeted therapies against epidermal growth factor receptors (EGFRs) are currently emerging for the treatment of gastric cancer. To specifically visualize gastric cancer by using monoclonal antibodies targeting EGFR1 as molecular probes for in vivo molecular confocal laser endomicroscopy (mCLE) in a human-murine xenograft model. Prospective in vivo animal study. Animal laboratory. Human gastric carcinoma xenografts were examined in 26 nude mice by using mCLE after injection of fluorescently labeled antibodies. Nine mice received low-dose anti-EGFR1 antibodies, 7 mice cetuximab, and 7 control mice isotype antibodies. Three mice were screened for autofluorescence without injection. Macroscopic fluorescence was evaluated in 2 additional mice. Molecular imaging of gastric cancer with confocal laser endomicroscopy. Fluorescence intensity in the anti-EGFR1 (P = .0145) and cetuximab group (P = .0047) was significantly higher than in isotype control mice. The same protocol allowed macroscopic fluorescence detection of tumor xenografts. Animal model. In vivo microscopic and macroscopic molecular imaging of gastric cancer is feasible in a human-murine xenograft model with both diagnostic and therapeutic antibodies targeting EGFR1. In perspective, mCLE could help diagnose and molecularly characterize gastric cancer during ongoing gastroscopy and may even assist in the prediction of response to therapy.
  Gastrointestinal endoscopy 07/2012; 76(3):612-20. · 6.71 Impact Factor
• Article: Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.

  Jörn M Schattenberg, Michael Nagel, Yong Ook Kim, Tobias Kohl, Marcus A Wörns, Tim Zimmermann, Arno Schad, Thomas Longerich, Detlef Schuppan, You-Wen He, Peter R Galle, Marcus Schuchmann
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  ABSTRACT: Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl(4)) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP (flip(-/-)). Acute liver injury from CCl(4) and TAA were enhanced in flip(-/-) mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH(2)-terminal kinase 2 (JNK2) in flip(-/-) mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip(-/-) mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease.
  AJP Gastrointestinal and Liver Physiology 06/2012; 303(4):G498-506. · 3.43 Impact Factor
• Article: Identification of RARRES1 as a core regulator in liver fibrosis.

  Andreas Teufel, Diana Becker, Susanne N Weber, Steven Dooley, Katja Breitkopf-Heinlein, Thorsten Maass, Katrin Hochrath, Markus Krupp, Jens U Marquardt, Martin Kolb, Bernhard Korn, Christof Niehrs, Tim Zimmermann, Patricio Godoy, Peter R Galle, Frank Lammert
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  ABSTRACT: Genetic factors contribute to progression and modulation of hepatic fibrosis. High throughput genomics/transcriptomics approaches aiming at identifying key regulators of fibrosis development are tainted with the difficulty of separating essential biological "driver" from modifier genes. We applied a comparative transcriptomics approach and investigated fibrosis development in different organs to identify overlapping expression changes, since these genes may be part of core pathways in fibrosis development. Gene expression was analysed on publicly available microarray data from liver, lung and kidney fibrosis. RARRES1, AGER and S100A2 were differentially regulated in all fibrosis experiments. RARRES1 was extensively analysed by means of advanced bioinformatics analyses and functional studies. Microarray and Western Blot analysis of a standard liver fibrosis model (CCl(4)) demonstrated an early induction of RARRES1 mRNA and protein expression. In addition, quantitative RT-PCR in tissue samples from patients with advanced liver fibrosis showed higher expression as compared to non-fibrotic biopsies. Microarray analysis of RARRES1 overexpressing cells identified an enrichment of a major signature associated with fibrosis. Furthermore, RARRES1 expression increased during in vitro activation of hepatic stellate cells. To further verify the pro-fibrogenic role across organs, we demonstrated an increase in RARRES1 expression in a rat lung fibrosis model induced by adenoviral TGF-β1 induction. We have performed a comparative transcriptomics analysis in order to identify core pathways of liver fibrogenesis, confirmed a candidate gene and enlightened the up- and downstream mechanisms of its action leading to fibrosis across organs and species.
  Journal of Molecular Medicine 06/2012; · 4.67 Impact Factor