Publications by authors named "Jens U Marquardt"

104 Publications

The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis.

Hepatol Commun 2021 Dec 27. Epub 2021 Dec 27.

Precision Medicine-Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P = 2.9 × 10 ). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P = 3.1 × 10 ). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P = 0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P = 0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.
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http://dx.doi.org/10.1002/hep4.1886DOI Listing
December 2021

Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy.

Cancers (Basel) 2021 Nov 19;13(22). Epub 2021 Nov 19.

Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany.

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.
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http://dx.doi.org/10.3390/cancers13225817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616508PMC
November 2021

Acquired Resistance to Antiangiogenic Therapies in Hepatocellular Carcinoma Is Mediated by Yes-Associated Protein 1 Activation and Transient Expansion of Stem-Like Cancer Cells.

Hepatol Commun 2021 Nov 24. Epub 2021 Nov 24.

Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center Schleswig Holstein, Luebeck, Germany.

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor-initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long-term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere-forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor-initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule-positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes-associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro-oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC.
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http://dx.doi.org/10.1002/hep4.1869DOI Listing
November 2021

Tailored Systemic Therapy for Colorectal Cancer Liver Metastases.

Int J Mol Sci 2021 Oct 29;22(21). Epub 2021 Oct 29.

Department of Medicine I, University Medical Center Schleswig-Holstein-Campus Lübeck, 23558 Lübeck, Germany.

Liver metastases are the most common site of metastatic spread in colorectal cancer. Current treatment approaches involve effective systemic therapies in combination with surgical and/or interventional strategies. Multimodal strategies greatly improved clinical outcomes of patients with metastatic colorectal cancer over the last decades. Identification of predictive and prognostic biomarkers helped to comprehensively refine individual targeted treatment approaches and resulted in median overall survival rates of 30 months or longer. Current guidelines, thus, recommend treatment selection according to patients' performance status, tumor localization and stage as well as the tumor's molecular and genetic status. Here, we outline the latest developments in molecular decision-making for patients with upfront resectable, potentially or initially unresectable and non/never-resectable colorectal cancer liver metastases.
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http://dx.doi.org/10.3390/ijms222111780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584068PMC
October 2021

How COVID-19 kick-started online learning in medical education-The DigiMed study.

PLoS One 2021 21;16(9):e0257394. Epub 2021 Sep 21.

Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Background: The coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students' attitudes to online learning to provide a broad scientific basis to guide future development of medical education.

Methods: Overall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-point Likert scale, participants rated the online learning situation during the pandemic at their medical schools, technical and social aspects, and the current and future role of online learning in medical education.

Results: The majority of medical schools managed the rapid switch to online learning (78%) and most students were satisfied with the quantity (67%) and quality (62%) of the courses. Online learning provided greater flexibility (84%) and led to unchanged or even higher attendance of courses (70%). Possible downsides included motivational problems (42%), insufficient possibilities for interaction with fellow students (67%) and thus the risk of social isolation (64%). The vast majority felt comfortable using the software solutions (80%). Most were convinced that medical education lags behind current capabilities regarding online learning (78%) and estimated the proportion of online learning before the pandemic at only 14%. In order to improve the current curriculum, they wish for a more balanced ratio with at least 40% of online teaching compared to on-site teaching.

Conclusion: This study demonstrates the positive attitude of medical students towards online learning. Furthermore, it reveals a considerable discrepancy between what students demand and what the curriculum offers. Thus, the COVID-19 pandemic might be the long-awaited catalyst for a new "online era" in medical education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257394PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454930PMC
September 2021

Liver Resection for Intrahepatic Cholangiocarcinoma-Single-Center Experience with 286 Patients Undergoing Surgical Exploration over a Thirteen Year Period.

J Clin Med 2021 Aug 13;10(16). Epub 2021 Aug 13.

Department of General, Visceral and Transplant Surgery, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so far.

Methods: Between January 2008 to December 2020, a total of 286 patients underwent 307 surgical explorations for intended liver resection of iCCA at our department. Data were analyzed with regard to (1) preoperative treatment of tumor, (2) operative details, (3) perioperative morbidity and mortality, (4) histopathology, (5) outcome measured by tumor recurrence, treatment of recurrence and survival and (6) prognostic factors for overall and disease-free survival.

Results: the resectability rate was 74.6% (229/307). In total, 202 primary liver resections, 21 repeated, 5 re-repeated, and 1 re-re-repeated liver resections were performed. In primary liver resections there were 77% (155/202) major hepatectomies. In 39/202 (20%) of patients additional hepatic wedge resections and in 87/202 (43%) patients additional 119 other surgical procedures were performed next to hepatectomy. Surgical radicality in first liver resections was 166 R0-, 33 R1- and 1 R2-resection. Following the first liver resection, the calculated 1-, 3- and 5-year-survival is 80%, 39%, and 22% with a median survival of 25.8 months. Until the completion of data acquisition, tumors recurred in 123/202 (60.9%) patients after a median of 7.5 months (range 1-87.2 months) after resection. A multivariate cox regression revealed tumor size ( < 0.001), T stage ( < 0.001) and N stage ( = 0.003) as independent predictors for overall survival. N stage ( = 0.040), preoperative therapy ( = 0.005), T stage ( = 0.004), tumor size ( = 0.002) and M stage ( = 0.001) were independent predictors for recurrence-free survival.

Conclusions: For complete surgical removal, often extended liver resection in combination with complex vascular or biliary reconstruction is required. However, despite aggressive surgery, tumor recurrence is frequent and long-term oncological results are poor. This indicated that surgery alone is unlikely to make great strides in improving prognosis of patients with iCCA, instead clearly suggesting that liver resection should be incorporated in multimodal treatment concepts.
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http://dx.doi.org/10.3390/jcm10163559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396970PMC
August 2021

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis.

JCI Insight 2021 09 8;6(17). Epub 2021 Sep 8.

Department of Medicine I, University Medical Center Mainz, Mainz, Germany.

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.
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http://dx.doi.org/10.1172/jci.insight.146196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492348PMC
September 2021

Acute esophageal tear in eosinophilic esophagitis.

Oxf Med Case Reports 2021 Jul 21;2021(7):omab056. Epub 2021 Jul 21.

Department of Internal Medicine I, University Hospital Schleswig-Holstein - Campus Lübeck, Lübeck, Germany.

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http://dx.doi.org/10.1093/omcr/omab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297642PMC
July 2021

Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma.

J Clin Med 2021 Jun 25;10(13). Epub 2021 Jun 25.

Department of Medicine I, University Medical Center Schleswig-Holstein-Campus Lübeck, 23562 Lübeck, Germany.

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.
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http://dx.doi.org/10.3390/jcm10132803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269161PMC
June 2021

The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico.

Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature ( and ) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis.
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http://dx.doi.org/10.3390/cancers13071721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038696PMC
April 2021

High pretreatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

United European Gastroenterol J 2021 Mar 11. Epub 2021 Mar 11.

Department of Internal Medicine I, Johannes Gutenberg University, Mainz, Germany.

Background: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein (AFP) is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion.

Objective: We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort.

Methods: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg University Mainz between 1998 and 2014 and two available pretreatment AFP-values (AFP-slope) were retrospectively analysed. Clinicopathological baseline parameters, pretreatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models.

Results: High static and dynamic AFP variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic AFP variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static AFP values.

Conclusion: Static and dynamic AFP variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.
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http://dx.doi.org/10.1177/2050640620972611DOI Listing
March 2021

The Co-mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion-Driven Cholangiocarcinoma.

Hepatology 2021 09 26;74(3):1357-1370. Epub 2021 Aug 26.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background And Aims: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion-positive ICC. Response rates of up to 35% indicate that FGFR-targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or response to FGFR-targeted therapies in patients with ICC.

Approach And Results: In this study, we use an autochthonous murine model of ICC to demonstrate that FGFR2 fusions are potent drivers of malignant transformation. Furthermore, we provide preclinical evidence that the co-mutational spectrum acts not only as an accelerator of tumor development, but also modifies the response to targeted FGFR inhibitors. Using pharmacologic approaches and RNA-interference technology, we delineate that Kirsten rat sarcoma oncogene (KRAS)-activated mitogen-activated protein kinase signaling causes primary resistance to FGFR inhibitors in FGFR2 fusion-positive ICC. The translational relevance is supported by the observation that a subset of human FGFR2 fusion patients exhibits transcriptome profiles reminiscent of KRAS mutant ICC. Moreover, we demonstrate that combination therapy has the potential to overcome primary resistance and to sensitize tumors to FGFR inhibition.

Conclusions: Our work highlights the importance of the co-mutational spectrum as a significant modifier of response in tumors that harbor potent oncogenic drivers. A better understanding of the genetic underpinnings of resistance will be pivotal to improve biomarker-guided patient selection and to design clinically relevant combination strategies.
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http://dx.doi.org/10.1002/hep.31799DOI Listing
September 2021

Echocardiographic evidence of an intrapulmonary shunt in a patient with severe liver cirrhosis.

Clin Res Cardiol 2021 07 23;110(7):1128-1131. Epub 2021 Feb 23.

Klinik Für Innere Medizin II, Kardiologie, Angiologie Und Internistische Intensivmedizin, Universitäres Herzzentrum Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, Lübeck, Germany.

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http://dx.doi.org/10.1007/s00392-021-01817-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238719PMC
July 2021

Ribavirin Improves NK Cell IFNγ Response During Sofosbuvir-based DAA Therapy in HCV-infected Liver Transplant Recipients.

Transplantation 2021 10;105(10):2226-2238

Department of Surgery, University Hospital Regensburg, Regensburg, Germany.

Background: Chronic hepatitis C virus (HCV) infection is characterized by activation of natural killer (NK) cells. Here, we asked whether HCV elimination by sofosbuvir-based direct-acting antivirals (DAAs) and the addition of ribavirin (RBV) improve NK cell function in liver transplant (LTx) recipients.

Methods: We analyzed NK cell degranulation and interferon (IFN)γ-response along with STAT1 and STAT4 phosphorylation in 29 HCV-infected LTx recipients and 17 HCV-infected patients during DAA treatment.

Results: Compared with uninfected LTx recipients, NK cells from HCV-infected LTx recipients were polarized toward cytotoxicity with increased CD107a-degranulation (10.1% versus 14.6%; P = 0.0263) and reduced capacity to produce IFNγ (43.0% versus 26.7%; P = 0.0002). The altered phenotype of NK cells in HCV-infected LTx recipients was accompanied by increased STAT1 (44.6% versus 87.4%; P < 0.0001) and STAT1 phosphorylation (0.7% versus 8.9%; P = 0.0005) compared with pSTAT4 IFNα-induction (29.9% versus 17.6%; P = 0.0014). Successful DAA therapy did not affect CD107a-degranulation but decreased STAT1. RBV cotreatment with DAA therapy for HCV increased CD56Bright NK cell IFNγ-responses in LTx recipients (70.9% versus 89.2%; P = 0.002), and this correlated to an increase in the inducibility of pSTAT4 (MFI 157 versus 173; P = 0.0002).

Conclusions: RBV cotreatment of HCV infection improved pSTAT4-dependent IFNγ-production in NK cells. This is relevant especially for immunocompromised patients such as LTx recipients or patients with end-stage liver disease.
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http://dx.doi.org/10.1097/TP.0000000000003612DOI Listing
October 2021

p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model.

Cell Mol Gastroenterol Hepatol 2021 21;11(5):1387-1404. Epub 2021 Jan 21.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address:

Background & Aims: A coordinated stress and regenerative response is important after hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the checkpoint kinase 2/transformation-related protein 53 (p53)/cyclin-dependent kinase inhibitor 1A (p21) pathway in a murine model of metabolic liver injury.

Methods: Nitisinone was reduced or withdrawn in Fah mice lacking Chk2, p53, or p21, and survival, tumor development, liver injury, and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas antibody Jo2.

Results: In a model of metabolic liver injury, loss of p53, but not Chk2, impairs the oxidative stress response and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell-cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, showing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the distinct phenotypes associated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on proliferation and the anti-oxidative stress response.

Conclusions: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage-response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, is related to the level at which the cascade is interrupted. Accession numbers of repository for expression microarray data: GSE156983, GSE156263, GSE156852, and GSE156252.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024980PMC
January 2021

High pre-treatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

United European Gastroenterol J 2020 Nov 23:2050640620972611. Epub 2020 Nov 23.

Department of Internal Medicine I, Johannes Gutenberg University, Mainz, Germany.

Background: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static alpha-fetoprotein values is limited and the clinical potential is a matter of ongoing scientific discussion.

Objective: We here evaluated the prognostic impact of pre-treatment static and dynamic alpha-fetoprotein variables on overall survival of hepatocellular carcinoma patients in a Western cohort.

Methods: Patients with confirmed hepatocellular carcinoma ( = 809) treated at the Johannes Gutenberg-University Mainz between 1998 and 2014 and two available pre-treatment alpha-fetoprotein-values (AFP-slope) were retrospectively analysed. Clinico-pathological baseline parameters, pre-treatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models.

Results: High static and dynamic alpha-fetoprotein variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B ( < 0.01) and C stage ( < 0.001), portal vein thrombosis ( < 0.001) and extrahepatic spread ( < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic alpha-fetoprotein variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static alpha-fetoprotein values.

Conclusion: Static and dynamic alpha-fetoprotein variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.
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http://dx.doi.org/10.1177/2050640620972611DOI Listing
November 2020

GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells.

J Cell Physiol 2021 05 10;236(5):4076-4090. Epub 2020 Nov 10.

Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor-suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor-suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma-derived cell lines were exposed to GDF11 (50 ng/ml), RNA-seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum-related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real-time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.
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http://dx.doi.org/10.1002/jcp.30151DOI Listing
May 2021

Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany.

Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.
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http://dx.doi.org/10.3390/cancers12092495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563159PMC
September 2020

Impact of non-selective ß-blockers on hepatic encephalopathy in patients with liver cirrhosis.

Eur J Intern Med 2020 12 29;82:83-89. Epub 2020 Aug 29.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address:

Background: Non-selective β-blockers (NSBB) are frequently used for the treatment of portal hypertension and gastroesophageal varices in patients with liver cirrhosis; however prospective studies investigating the potential association between NSBB use and hepatic encephalopathy (HE) are still scarce. We investigated the potential association between NSBB use and the presence of covert HE (CHE) as well as the development of overt HE (OHE).

Methods: 224 patients with liver cirrhosis were included into this cohort study at two German centers and followed for a median of 364 days. CHE was diagnosed by pathological results in the PHES. Predictors for the presence of CHE or the development of OHE were analyzed using logistic-regression or cox-regression models.

Results: 39% of patients were treated with NSBB and CHE was detected in 34% of patients at study inclusion. In logistic regression analysis, NSBB use, higher MELD score and a history of OHE were independently associated with the presence of CHE. Cumulative incidence of OHE was considerably higher in NSBB users than in non-users (p<0.001). In Cox-regression models NSBB use, presence of CHE, lower albumin and higher MELD score were independently associated with the development of OHE in the whole cohort as well as in the subgroup of patients with decompensated liver cirrhosis. NSBB use was independently associated with higher risk of mortality or need for liver transplantation in decompensated patients but not in the total cohort.

Conclusion: NSBB use seems to be associated with the presence of CHE as well as the development of OHE in patients with decompensated liver cirrhosis.
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http://dx.doi.org/10.1016/j.ejim.2020.08.022DOI Listing
December 2020

Determination of primary microRNA processing in clinical samples by targeted pri-miR-sequencing.

RNA 2020 11 15;26(11):1726-1730. Epub 2020 Jul 15.

Aarhus University, Department of Molecular Biology and Genetics, 8000 Aarhus, Denmark.

MicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in diseases such as cancer. The processing of primary microRNA transcripts is an important regulatory step in microRNA biogenesis. Due to low expression level and association with chromatin, primary microRNAs are challenging to study in clinical samples where input material is limited. Here, we present a high-sensitivity targeted method to determine processing efficiency of several hundred primary microRNAs from total RNA that requires relatively few RNA sequencing reads. We validate the method using RNA from HeLa cells and show the applicability to clinical samples by analyzing RNA from normal liver and hepatocellular carcinoma. We identify 24 primary microRNAs with significant changes in processing efficiency from normal liver to hepatocellular carcinoma, among those the highly expressed miRNA-122 and miRNA-21, demonstrating that differential processing of primary microRNAs is occurring and could be involved in disease. With our method presented here we provide means to study pri-miRNA processing in disease from clinical samples.
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http://dx.doi.org/10.1261/rna.076240.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566579PMC
November 2020

Outcome Prediction of Covert Hepatic Encephalopathy in Liver Cirrhosis: Comparison of Four Testing Strategies.

Clin Transl Gastroenterol 2020 06;11(6):e00172

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Introduction: Despite the negative impact of covert hepatic encephalopathy on the outcome of patients with liver cirrhosis, data regarding the ability of different testing strategies to predict overt hepatic encephalopathy (OHE) development and mortality are limited. This study aimed to compare the ability of Psychometric Hepatic Encephalopathy Score (PHES), critical flicker frequency (CFF), simplified animal naming test (S-ANT1), and clinical covert hepatic encephalopathy (CCHE) score to predict OHE development and mortality.

Methods: A total of 224 patients with liver cirrhosis were tested with different testing strategies and prospectively followed up regarding clinically relevant outcomes (OHE or death/liver transplantation).

Results: Prevalence of pathological results varied among the testing strategies: PHES 33.9%, CFF 17.9%, S-ANT1 41.5%, and CCHE score 33.9%. All testing strategies were independent predictors of OHE development after adjusting for model of end-stage liver disease (MELD) score and history of OHE. The predictive performances of PHES (area under the receiver operating characteristic curve, 0.742) and CCHE (area under the receiver operating characteristic curve, 0.785) regarding OHE development during the next 180 days were significantly better than those of CFF and S-ANT1. In multivariable analysis, pathological results in PHES, S-ANT1, and CCHE score were independently associated with higher mortality. CFF did not correlate with mortality in the whole cohort. In the subgroup of patients with a MELD score <15, pathological results in PHES, CFF, or CCHE score were independent predictors of higher mortality.

Discussion: PHES and CCHE score predict OHE development and mortality in patients with liver cirrhosis. In particular, in patients with low MELD score, both testing strategies could help to identify patients who might benefit from liver transplantation.
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http://dx.doi.org/10.14309/ctg.0000000000000172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339190PMC
June 2020

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin.

Int J Cancer 2020 11 23;147(9):2564-2577. Epub 2020 Jun 23.

First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2-mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4β1 (very late antigen-4, VLA-4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA-4 β1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis-promoting role in the absence of Merlin.
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http://dx.doi.org/10.1002/ijc.33144DOI Listing
November 2020

BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC.

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Institute for Biochemistry and Molecular Biology, University of Freiburg, 79104 Freiburg, Germany.

Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.
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http://dx.doi.org/10.3390/cancers12061437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352885PMC
May 2020

Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

EBioMedicine 2020 Apr 21;54:102699. Epub 2020 Apr 21.

Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. Electronic address:

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed.

Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients.

Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues.

Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.
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http://dx.doi.org/10.1016/j.ebiom.2020.102699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182727PMC
April 2020

Validation of prognostic accuracy of MESH, HKLC, and BCLC classifications in a large German cohort of hepatocellular carcinoma patients.

United European Gastroenterol J 2020 05 29;8(4):444-452. Epub 2020 Jan 29.

Department of Medicine I, University Medical Center, Mainz, Germany.

Background And Aim: The Barcelona Clinic Liver Cancer (BCLC) staging system is commonly used to classify hepatocellular carcinoma (HCC) patients. However, other staging classification schemes have been proposed. We aimed to compare the prognostic accuracy of the Hong Kong Liver Cancer Staging (HKLC), the Model to Estimate Survival for HCC (MESH), and the BCLC staging systems using a Western cohort of HCC patients.

Methods: We retrospectively analyzed 918 patients diagnosed with HCC treated at the University Medical Center of Mainz between 2005 and 2014. We compared the predictive power of survival time of the BCLC, HKLC, and MESH. Predictive ability was tested using the integrated Brier score (IBS) and Harrell's C index.

Results: Kaplan-Meier analyses showed significant differences in survival between stages defined by the BCLC, HKLC, and MESH. The HKLC classification demonstrated a more robust classification concordance and lower prediction error compared to the BCLC and MESH. In addition, we found that the BCLC offers superior predictive ability to the MESH in the first four years, whereas the MESH is superior for long-term predictions.

Conclusion: Our analyses confirm the prognostic value of three different HCC scoring systems. When compared, the HKLC provides superior prognostication ability.
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http://dx.doi.org/10.1177/2050640620904524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226688PMC
May 2020

NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis.

Oncogene 2020 04 13;39(15):3128-3144. Epub 2020 Feb 13.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

NOTCH receptor signaling plays a pivotal role in liver homeostasis and hepatocarcinogenesis. However, the role of NOTCH pathway mutations and the NOTCH target gene HES5 in liver tumorigenesis are poorly understood. Here we performed whole-exome sequencing of 54 human HCC specimens and compared the prevalence of NOTCH pathway component mutations with the TCGA-LIHC cohort (N = 364). In addition, we functionally characterized the NOTCH target HES5 and the patient-derived HES5-R31G mutation in vitro and in an orthotopic mouse model applying different oncogenic backgrounds, to dissect the role of HES5 in different tumor subgroups in vivo. We identified nonsynonymous mutations in 14 immediate NOTCH pathway genes affecting 24.1% and 16.8% of HCC patients in the two independent cohorts, respectively. Among these, the HES5-R31G mutation was predicted in silico to have high biological relevance. Functional analyses in cell culture showed that HES5 reduced cell migration and clonogenicity. Further analyses revealed that the patient-derived HES5-R31G mutant protein was non-functional due to loss of DNA binding and greatly reduced nuclear localization. Furthermore, HES5 exhibited a negative feedback loop by directly inhibiting the NOTCH target HES1 and downregulated the pro-proliferative MYC targets ODC1 and LDHA. Interestingly, HES5 inhibited MYC-dependent hepatocarcinogenesis, whereas it promoted AKT-dependent liver tumor formation and stem cell features in a murine model. Thus, NOTCH pathway component mutations are commonly observed in HCC. Furthermore, the NOTCH target gene HES5 has both pro- and anti-tumorigenic functions in liver cancer proposing a driver gene dependency and it promotes tumorigenesis with its interaction partner AKT.
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http://dx.doi.org/10.1038/s41388-020-1198-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142020PMC
April 2020

[Monocentric experiences of stereotactic body radiation therapy (SBRT) for advanced hepatocellular carcinomas (BCLC-C)].

Z Gastroenterol 2020 Jan 13;58(1):39-47. Epub 2020 Jan 13.

I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland.

Hepatocellular carcinomas (HCCs) are highly malignant primary liver cancers with poor prognosis and limited treatment options in advanced stages of disease. Treatment of HCC requires interdisciplinary discussion and multimodal therapy approaches. Beside established loco-regional and systemic therapies, stereotactic body radiation therapy (SBRT) gained increasing importance over recent years. First results of early clinical studies indicate high rates of local control with a good safety profile. In the present work, we evaluated our single center experiences with SBRT in patients with advanced HCCs.Ten patients with 16 SBRTs were included and retrospectively analyzed in this case collection. All patients presented in advanced tumor stages with vascular invasion and/or metastases, but preserved liver function. Two patients were treated only with SBRT, two after TACE and six patients received SBRT in addition to systemic therapy. In most of the cases SBRT were applied to intrahepatic lesions. Large tumor thromboses, lymph nodes as well as bone metastases were irradiated in one, three and five fractions with a median overall dose of 38 Gy. We observed a good local tumor control with a good safety profile in all cases. No severe complications occurred in combination to sequential as well as additive approach to loco-regional or systemic treatments.In conclusion, our experiences confirm results of early clinical studies indicating safe use and good local control rates also in advanced stages of HCC with preserved liver function.
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http://dx.doi.org/10.1055/a-1072-6683DOI Listing
January 2020

Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies.

Front Oncol 2019 13;9:1421. Epub 2019 Dec 13.

Heisenberg Research Group "Regulation von Bcl-2-Proteinen Durch Konformationelle Flexibilität," Institute for Biochemistry and Molecular Biology, University of Freiburg, Freiburg, Germany.

Hepatocellular carcinoma (HCC) ranks among the most rapidly evolving cancers in the Western world. The majority of HCCs develop on the basis of a chronic inflammatory liver damage that predisposes liver cancer development and leads to deregulation of multiple cellular signaling pathways. The resulting dysbalance between uncontrolled proliferation and impaired predisposition to cell death with consecutive failure to clear inflammatory damage is a key driver of malignant transformation. Therefore, resistance to death signaling accompanied by metabolic changes as well as failed immunological clearance of damaged pre-neoplastic hepatocytes are considered hallmarks of hepatocarcinogenesis. Hereby, the underlying liver disease, the type of liver damage and individual predisposition to apoptosis determines the natural course of the disease as well as the therapeutic response. Here, we will review common and individual aspects of cell death pathways in hepatocarcinogenesis with a particular emphasis on regulatory networks and key molecular alterations. We will further delineate the potential of targeting cell death-related signaling as a viable therapeutic strategy to improve the outcome of HCC patients.
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http://dx.doi.org/10.3389/fonc.2019.01421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923252PMC
December 2019

Improved Prediction of Survival by a Risk Factor-Integrating Inflammatory Score in Sorafenib-Treated Hepatocellular Carcinoma.

Liver Cancer 2019 Oct 4;8(5):387-402. Epub 2018 Oct 4.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background And Aims: Inflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy.

Methods: Overall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses.

Results: Patients receiving sorafenib ( = 120) for advanced HCC (Barcelona Clinic Liver Cancer stage C) were explored by retrospective analysis. Findings were subsequently validated by a second HCC cohort ( = 113) receiving sorafenib at two independent treatment centers. Multivariable assessment across these HCC cohorts confirmed a stable association of CAR ( ≤ 0.001), GPS ( ≤ 0.01) and mGPS ( ≤ 0.004) with OS. This study also identified Eastern Cooperative Oncology Group (ECOG) performance score ( < 0.001) and portal thrombosis ( = 0.002) as prognostic factors and uncovered an inconsistent OS association of NLR and PLR in HCC patients. Additional combined analysis of ECOG, portal thrombosis and GPS within an extended score (GPS-EP) was associated with OS ( = 0.021), which was confirmed within the validation cohort ( = 0.001). In sorafenib-treated HCC, the ROC-AUC value for the prediction of 12-month survival was 0.761 (CAR >/≤0.37 cut-off, < 0.001), 0.766 (GPS, < 0.001) and 0.754 (mGPS, < 0.001), respectively. In comparison to this, GPS-EP achieved a higher AUC of 0.826 (0.746-0.907) for the 12-month survival prediction, resulting in a 64.4% sensitivity and 83.3% specificity at a > 2 point cut-off.

Conclusions: Inflammatory scores obtained before sorafenib treatment initiation are associated with OS in advanced HCC. Their combination with other risk factors improves prediction of 3- and 12-month survival, which could guide treatment decisions in selected patient subgroups.
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http://dx.doi.org/10.1159/000492628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873091PMC
October 2019

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Hepatology 2020 07 20;72(1):88-102. Epub 2020 May 20.

Departments of Gastroenterology and Hepatology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.

Background And Aims: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC.

Approach And Results: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (OR , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10 ).

Conclusions: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
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http://dx.doi.org/10.1002/hep.30996DOI Listing
July 2020
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