[Show abstract][Hide abstract] ABSTRACT: Humans and dogs are affected by squamous cell carcinomas of the oral cavity (OSCC) in a considerably high frequency. The high mobility group A2 (HMGA2) protein was found to be highly expressed in human OSCC and its expression was suggested to act as a useful predictive and prognostic tool in clinical management of oral carcinomas. Herein the expression of HMGA2 and its sister gene HMGA1 were analysed within human and canine OSCC samples. Additionally, the HMGA negatively regulating miRNAs of the let-7 family as well as the let-7 regulating gene Lin28 were also comparatively analysed. Deregulations of either one of these members could affect the progression of human and canine OSCC.
BMC Cancer 09/2014; 14(1):694. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Caspase 14 is reduced in adenocarcinomas of the stomach and colon. In contrast, breast and lung adenocarcinomas frequently show an overexpression of caspase 14. Salivary gland adenocarcinomas have not been evaluated for potential aberrant caspase 14 expression.Materials and Methods
Samples from salivary gland carcinomas (n = 43) were analysed by immunohistochemistry (caspase 14, filaggrin, GATA3 and Ki67) and fluorescence in situ hybridization.ResultsCaspase 14 is not expressed in normal salivary glands, while in a subfraction of carcinomas (32%) an aberrant expression was found. Filaggrin could not be detected. Caspase 14 staining was not associated with tumour dedifferentiation, GATA3 expression or amplification of gene locus 19p13.Conclusion
In summary, aberrant expression of caspase 14 can be found in a subfraction of salivary gland carcinomas but could not be used as a biomarker for a specific carcinoma subtype of the salivary gland.
Journal of Oral Pathology and Medicine 09/2014; · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Routinely processed skin biopsies are still the mainstay for the diagnosis of melanocytic skin neoplasms (MSNs) and are considered the "gold standard" for individual patient management and clinical trials. The diagnostic challenge of melanocytic lesions of the skin prompts histopathologists to consider new diagnostic tools; among these, immunohistochemistry. We aimed to find putative new immunohistochemical markers, which can supplement the histological criteria used to detect dysplasia. In this immunohistochemical study, we chose a panel of promising biomarkers which could potentially differentiate between different MSN entities. These included α-methylacyl-coenzyme A racemase (AMACR; p504s), which is involved in the degradation of branched chained fatty acid derivates. We analysed a cohort of benign nevi and malignant melanomas. The design of the study included 78 melanocytic skin neoplasms (26 malignant melanomas and 52 benign nevi) in a tissue microarray. Immunohistochemistry of cyclin-dependent kinase inhibitor 2A (p16Ink4a), methylacyl-coenzyme A racemase (AMACR), cyclin D1, and E-cadherin was performed and assessed. We have observed that the p16Ink4a, AMACR, cyclin D1, and E-cadherin showed no exclusive staining for nevi or melanomas. However, a significant overexpression of AMACR was found in malignant melanomas compared to benign nevi. AMACR overexpression was also associated with an increased p16Ink4a staining. Our results suggest AMACR as an immunohistochemical marker for distinguishing malignant melanomas and dysplastic nevi from conventional melanocytic nevi.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 08/2014;
[Show abstract][Hide abstract] ABSTRACT: It is known that human papillomavirus (HPV) infection can cause squamous cell neoplasms at several sites, such as cervix uteri carcinoma and oral squamous carcinoma. There is little information on the expression of HPV and its predictive markers in tumours of the major and minor salivary glands of the head and neck. We therefore assessed oral salivary gland neoplasms to identify associations between HPV and infection-related epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) and tumour protein p53 (TP53). Formalin-fixed, paraffin-embedded tissue samples from oral salivary gland carcinomas (n=51) and benign tumours (n=26) were analysed by polymerase chain reaction (PCR) analysis for several HPV species, including high-risk types 16 and 18. Evaluation of EGFR, CDKN2A, TP53 and cytomegalovirus (CMV) was performed by immunohistochemistry. Epstein-Barr virus (EBV) was evaluated by EBV-encoded RNA in situ hybridisation. We demonstrated that salivary gland tumours are not associated with HPV infection. The expression of EGFR, CDKN2A and TP53 may be associated with tumour pathology but is not induced by HPV. CMV and EBV were not detectable. In contrast to oral squamous cell carcinomas, HPV, CMV and EBV infections are not associated with malignant or benign neoplastic lesions of the salivary glands.International Journal of Oral Science advance online publication, 11 July 2014; doi:10.1038/ijos.2014.28.
International Journal of Oral Science 07/2014; · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in the cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes are associated with an elevated risk for chronic pancreatitis, which is a known risk factor for pancreatic cancer (PC). Therefore, we analyzed whether PRSS1, CFTR, SPINK1, and/or CTRC mutations are associated with pancreatic adenocarcinoma.
[Show abstract][Hide abstract] ABSTRACT: The tumour suppressor gene RB1 is frequently silenced in many different types of human cancer including hepatocellular carcinoma (HCC). However, mutations of the RB1 gene are relatively rare in HCC. A systematic screen for the identification of imprinted genes deregulated in human HCC revealed that RB1 shows imprint abnormalities in a high proportion of primary patient samples. Altogether 40% of the HCC specimens (16/40) showed hyper -or hypomethylation at the CpG island in intron 2 of the RB1 gene. Re-analysis of publicly available genome-wide DNA methylation data confirmed these findings in two independent HCC cohorts. Loss of correct DNA methylation patterns at the RB1 locus leads to the aberrant expression of an alternative RB1-E2B transcript as measured by quantitative real-time PCR.Demethylation at the intron 2 CpG island by DNMT1 knockdown or aza-deoxycytidine (DAC) treatment stimulated expression of RB1-E2B transcript accompanied by diminished RB1 main transcript expression. No aberrant DNA methylation was found at the RB1 locus in hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5) and their corresponding adjacent liver tissue specimens. Deregulated RB1 expression due to hyper- or hypomethylation in intron 2 of the RB1 gene is found in tumours without loss of heterozygosity and is associated with a decrease in overall survival (p = 0.032) if caused by hypermethylation of CpG85. This unequivocally demonstrates that loss of imprinting represents an important additional mechanism for RB1 pathway inactivation in human HCC complementing well-described molecular defects.
The Journal of Pathology 05/2014; · 7.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clear cell renal cell carcinomas (ccRCC) have aberrant signalling pathways which affect vascular endothelial growth factor and are related to increased tumour angiogenesis. Little is known about other angiogenesis-associated genes in primary tumours and metastases. Quantitative PCR of 45 angiogenesis-associated gene transcripts was performed on formalin-fixed and paraffin-embedded tissues from primary ccRCC (n = 18) and their metastases (n = 17; in 8/17 cases the corresponding primary tumour could be analysed). In metastases, a significant increase was found in the expression of 15 pro-angiogenic (such as prostaglandin-endoperoxide synthase 1) and also anti-angiogenic (such as TIMP metallopeptidase inhibitor 2) factors. Comparison of a primary with its metastasis performed on eight cases showed that even without preceding anti-angiogenic therapy in metastases expression of angiogenic factors is increased. In ccRCC, the effects of anti-angiogenic factors are superimposed by pro-angiogenic factors. Increased expression of angiogenic factors in metastases might be related to development of resistance after anti-angiogenic therapy but might also be an inherent biological characteristic.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2014; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV)-associated post-transplant smooth muscle tumours (PTSMT), are rare complications following organ/stem cell transplantation. Despite the mainly benign behaviour of PTSMT, alternative therapies are needed for those patients with progressive tumours. In tumours not approachable by surgery or reduction of immunosuppression, the angiogenic microenvironment might be a potential target of therapy, an approach that is well utilised in other soft tissue neoplasms. In a previous study, we evaluated the expression of EBV-related genes and the microRNA profile in PTSMT, but so far the characteristics of angiogenesis in PTSMT are not known. Therefore, the aim of this study was to evaluate the expression pattern of angiogenesis-related genes in PTSMT, in order to identify potential target molecules for anti-angiogenic therapy.PTSMT (n = 5 tumours) were compared with uterine leiomyomas (n = 7). Analyses included real-time PCR of 45 angiogenesis-associated genes, immunohistochemistry (CD31, prostaglandin endoperoxide synthase 1/PTGS1) and assessment of tumour vascularisation by conventional histopathology.PTSMT showed similar or fewer vessels than leiomyomas. Of the genes under investigation, 23 were down-deregulated (pro-angiogenic and some anti-angiogenic factors) and five were up-regulated (e.g. PTGS1 which is expressed at very low levels in leiomyomas but moderately higher levels in PTSMT).In summary, no particular target molecule could be identified, because tumour angiogenesis in PTSMT is characterised by low levels of major pro-angiogenic factors and there is no prominent increase in tumour vascularisation. EBV can induce angiogenesis via its viral late membrane protein 1 (LMP1) but PTSMT frequently do not express LMP1, which could be an explanation why, despite EBV infection, PTSMT show no exaggerated tumour angiogenesis.
[Show abstract][Hide abstract] ABSTRACT: Seit 13 Jahren werden Ringversuche zur Qualitätssicherung der Bestimmung tumorbiologischer Parameter beim Mammakarzinom (Östrogenrezeptor [ER], Progesteronrezeptor [PR] und epithelialer Wachstumsfaktorrezeptor 2 [HER2]) in Deutschland durchgeführt. Als erster Ringversuch weltweit wurden ,,tissue micro arrays“ mit 20 verschiedenen Gewebeproben von Mammakarzinomen hierfür eingesetzt. Eine weitere Innovation bedeutet die Aufteilung in einen zertifikatsrelevanten Test- und einen schwierige Grenzfälle anreichernden, auf latente Schwächen hinweisenden Trainingsteil. Wie bei NordiQC und UKNequas erfolgen eine externe Begutachtung der Färbequalität und eine getrennte Bewertung von Färbe- und Auswertequalität. Seit 2010 wird zusätzlich ein internetbasierter Ringversuch ohne Evaluation der Färbungen für den immunhistochemischen Nachweis von ER und PR angeboten. Seit Einführung der Ringversuche sind die Teilnehmerzahlen (n = 200–250) und Erfolgsraten stetig gestiegen. Der Mammakarzinomringversuch stellt damit den größten regelmäßigen Ringversuch in Deutschland dar. Eine regelmäßige laborinterne Überprüfung der Qualität der immunhistochemischen Färbungen von ER, PR und HER2 sowie eine Teilnahme an Ringversuchen führen zu einer nachweisbaren Verbesserung reproduzierbarer Färbungen und sind daher für eine Qualitätssicherung in der Brustkrebsdiagnostik notwendig. Der Einsatz von Vollautomaten für die immunhistochemischen Färbungen ist ständig angestiegen und beträgt mittlerweile annähernd 50 % der Teilnehmer.
Der Pathologe 01/2014; 35(1). · 0.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rare Epstein–Barr virus (EBV)+ smooth muscle tumours (SMT) manifest typically under immunosuppression. Three major subtypes are known: human immunodeficiency virus-associated (HIV-SMT), after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT).
So far, there are no analyses which compare the clinico-pathological characteristics of all three subtypes.
Case reports and case series on these three tumour types were collected (1990–2012). Meta-data analysis was performed for identification of similarities and differences.
A total of 73 HIV-SMT, 66 PTSMT and 9 CI-SMT were evaluated. There was a slight female predominance (55–67%). Children were affected nearly equally in HIV-SMT (33%) and PTSMT (35%), while all CI-SMT occurred in children. HIV-SMT manifested preferentially in the central nervous system, gut/liver, skin, lungs/larynx/pharynx and adrenal glands. PTSMT were predominantly found in the liver, lungs/larynx/pharynx, gut/spleen and brain. CI-SMT were often found in lungs/larynx, brain, liver, adrenal glands and spleen. Antecedent EBV+ lymphoproliferations manifested more often in PTSMT.
In all three tumour subtypes, survival analyses did not show any significant differences regarding surgical therapeutic approaches, the occurrence of multiple tumours, tumour size or sarcoma-like histological features. HIV-SMT had the poorest overall survival, which might be attributed to HIV-associated infectious complications.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to analyze the efficacy of two different biopsy forceps with respect to their functionality and quality for histological assessment of upper urinary tract biopsies.
We compared flow rates, active deflection angle and histological quality of specimens taken from upper urinary tract biopsies of 40 consecutively treated patients between October 2011 and October 2012. Two different biopsy forceps [group A = 20 patients: "Piranha (®) " (Boston Scientific, Natick, USA) versus group B = 20 patients: "EF-120-00-3F" (Euromedical GmbH, Siegsdorf, GER)] were assessed.
The specimens obtained with the "EF-120-00-3F" were superior in terms of tissue preservation such as intact urothelium/tissue fragmentation and the prevention of artifacts due to tissue compression (existence of artifacts/nucleus evaluation). Furthermore, due to superiority of tissue preservation, tissues obtained with the "EF-120-00-3F" showed better tissue orientation in the sense of anatomic evaluation of invasion and deep layer involvement. Irrigation flow rates did not differ significantly while deflection angle was more impaired with the "Piranha" biopsy forceps. No difference was observed with the handling of both biopsy forceps.
We conclude that the "EF-120-00-3F" biopsy forceps represent a valuable modification of antegradely insertable instruments that qualifies for improved and correct staging as well as diagnosis of upper urinary specimens in comparison with standard biopsy forcipes.
World Journal of Urology 12/2013; · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human primary breast cancers and breast cancer cell lines are classified by microarray-defined molecular subtypes, which reflect differentiation characteristics. Estrogen receptor (ER) expression is indicative of the luminal molecular subtype. We have previously established IPH-926, the first well-characterized cell line from infiltrating lobular breast cancer. IPH-926 displays an ER/PR/ErbB2 triple-negative immunophenotype, which is due to a loss of ER expression in its in vivo clonal ancestry. Loss of ER might indicate a fundamental change of cellular differentiation and it is unclear whether a luminal subtype is preserved beyond ER conversion. Using Affymetrix microarray analysis, seven different classifier gene lists (PAM305, DISC256, TN1288, PAM50, UNC1300, LAB704, INT500) and a background population of 50 common mammary carcinoma cell lines, we have now determined the molecular subtype of IPH-926. Strikingly, the IPH-926 expression profile is highly consistent with a luminal subtype. It is nearest to luminal/ER-positive breast cancer cell lines and far apart from basal breast cancer cell lines. Quantitative real-time RT-PCR confirmed enhanced expression of luminal marker genes (AGR2, CLU, CA12, EMP2, CLDN3) and low or absent expression of basal marker genes (KRT5, CD44, CAV1, VIM). Moreover, IPH-926 lacked androgen receptor (AR) expression, a transcription factor previously associated with luminal-like gene expression in a subset of triple-negative or molecular apocrine breast cancers. In conclusion, IPH-926 is triple-negative but belongs to the luminal subtype. Luminal differentiation characteristics can be preserved beyond ER conversion and might not require a compensatory expression of AR.
Cancer Science 12/2013; 104(12):1726-1730. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABO incompatibility is no longer a barrier in kidney transplantation. C4d is frequently positive in ABO-incompatible (iABO) biopsies without further signs of microcirculation injury. This phenomenon is assumed to represent graft accommodation. However, ultrastructural examination of glomerular and peritubular capillary endothelium might reveal subtle endothelial damage.
We studied the ultrastructural appearance of the endothelium in 67 biopsies from 21 patients with iABO allografts and compared it with 20 patients (29 biopsies) with ABO-compatible (cABO) grafts with C4d positivity and 25 ABO-compatible control patients (25 biopsies) without serological or histological evidence of humoral rejection (C4d negative). Ten ultrastructural parameters indicative of chronic and acute glomerular and peritubular capillary damage in transmission electron microscopy (TEM) were semi-quantitatively graded and expressed in a sum score. Clinico-pathological data were compared as well as graft function at the time of biopsy and follow-up.
Ultrastructural parameters did not significantly differ between iABO and controls. In contrast, C4d-positive cABO had the highest TEM sum score (P = 0.001 versus iABO, P = 0.002 versus controls). The sum score did not differ between C4d-positive and C4d-negative iABO but did differ between patients with and without anti-HLA donor-specific antibodies (DSA). Graft function in iABO at the time of biopsy and at follow-up was similar to controls.
Our ultrastructural observations support the concept of endothelial accommodation in iABO renal transplants. C4d positivity in the ABO-incompatible situation does not indicate injurious activation of the complement cascade and does not seem to impact on the graft function, in contrast to C4d deposition in cABO with antibody-mediated rejection.
[Show abstract][Hide abstract] ABSTRACT: Post-transplant lymphoproliferative disease (PTLD) is the most frequent malignant complication of transplantation in childhood. Even with modern post-transplant immunosuppressive strategies, 1-2 % of all kidney transplant recipients will develop PTLD within the first 5 years after transplantation, and the risk remains high even thereafter as long as immunosuppression is required. In addition to PTLD, adult kidney transplant recipients have an increased incidence of other immunosuppression-related malignancies, such as non-melanoma skin cancer or Kaposi's sarcoma. It is foreseeable that pediatric transplant recipients will face similar complications during their adult life. Not only immunosuppression but also other risk factors have been identified for some of these malignancies. Strategies addressing these risk factors during childhood may contribute to life-long cancer prevention. Furthermore, early recognition and regular screening may facilitate early diagnosis and treatment, thereby reducing transplant-related morbidity. In this review we focus on malignant complications after renal transplantation and discuss known risk factors. We also review current screening strategies for malignancies during post-transplant follow-up.
[Show abstract][Hide abstract] ABSTRACT: The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.
Proceedings of the National Academy of Sciences 08/2013; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Human T-cell lymphotropic virus type 1 (HTLV-1) screening of blood and organ donors is not mandatory in Germany because of its low prevalence (about 7/100,000). An HTLV-1 transmission event caused by a multiple organ donor was investigated. Validity of diagnostic procedures and HTLV-1 disease association in immunosuppressed organ recipients were analyzed. Methods. Two screening immunoassays and an immunoblot (confirmatory assay) were used for detection of HLTV-1/2 antibodies. Proviral DNA was quantified in blood and biopsies of organ recipients by HTLV-1 real-time polymerase chain reaction (RT-PCR). Results. Proviral HTLV-1-DNA was detected in all blood samples of three organ recipients (1 to 100 copies/10(2)cells) but seroconversion was delayed for up to 2 years in screening assays and more than 6 years in the confirmatory assay. In two of three organ recipients a cutaneous T-cell lymphoma was diagnosed 2 and 3 years after infection, respectively. Proviral HTLV-1 DNA concentration was almost 100 copies/10(2)cells in cutaneous lymphoma biopsies whereas in biopsies of other tissues ≤3.0 copies/10(2)cells were found. The third organ recipient did not suffer from lymphoma but detailed clinical data on this patient were not available to us. Conclusions. Biopsy results support an etiological role for HTLV-1 in these cases of primary cutaneous T cell lymphoma after solid organ transplantation. HTLV-1 associated lymphoma can arise quickly in immunocompromised transplant recipients. The diagnosis of potentially HTLV-1 associated disease in organ recipients may require PCR because of delayed seroconversion.
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV)-associated post-transplant smooth muscle tumours (PTSMT) are rare complications. In our previous molecular analysis, we have evaluated the expression of regulatory microRNA which are known to be EBV-related (miR-146a and miR-155) but found no deregulation in PTSMT. In this current analysis, we aimed to characterize the expression profiles of several hundred microRNA. Tissue samples from PTSMT and uterine leiomyomas were analysed by quantitative real-time PCR for the expression of 365 mature microRNA. PTSMT and leiomyomas share a highly similar microRNA profile, e.g. strong expression of miR-143/miR-145 cluster and low expression of miR-200c. Among EBV-related microRNA (miR-10b, miR-21, miR-29b, miR-34a, miR-127, miR-146a, miR-155, miR-200b, miR-203 and miR-429) only miR-10b and miR-203 were significantly deregulated. The expression pattern of microRNA in PTSMT is not associated with EBV infection but reflects the leiomyomatous differentiation of the tumour cells.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Fibrinogen storage disease (FSD) is a rare autosomal-dominant hereditary disorder characterized by hypofibrinogenemia and accumulation of fibrinogen aggregates within the hepatocellular endoplasmatic reticulum (ER). Some FSD patients present with elevated amino-transferases and fibrosis/cirrhosis similar to alpha-1-antitrypsin deficiency (ATD), also an ER storage disease. Pharmacological stimulation of autophagy has been shown to mediate clearance of protein aggregates and halt progression of liver fibrosis in in vivo models of ATD. Our aim was to evaluate the presence of autophagy and a possible response to autophagy-enhancing therapy in patients with FSD. METHODS: Hepatic fibrosis was assessed by transient elastography in 2 newly identified FSD families with fibrinogen Aguadilla and Brescia mutations, encompassing 8 affected members. Available liver biopsies were assessed for autophagy. 2 patients, who had had elevated alanine amino-transaminases (2-5 above upper limit of normal), were treated with the autophagy enhancer carbamazepine (CBZ). RESULTS: Transient elastography did not show evidence of significant fibrosis in any affected family members. Quantitative electron microscopy of one patient showed a 5.15-fold increase of late stage autophagocytic vacuoles compared to control livers. CBZ at low anticonvulsive treatment levels led to rapid normalization of alanine- aminotransferase and decrease of caspase-cleaved and uncleaved cytokeratin-18 fragments (M30 and M65). These effects reversed after discontinuation of treatment. CONCLUSIONS: Response to CBZ may be mediated by pharmacologically enhanced autophagy resulting in reduction of aggregate-related toxicity in FSD. These results suggest clinical applicability of pharmacological stimulation of autophagy in FSD, but potentially also in other related disorders.
Journal of Hepatology 05/2013; · 9.86 Impact Factor