Publications by authors named "Peter R Galle"

415 Publications

Ramucirumab in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: outcomes by treatment-emergent ascites.

Hepatol Res 2021 Mar 20. Epub 2021 Mar 20.

Massachusetts General Hospital Cancer Center and Jiahui International Cancer Center, Boston, MA, USA.

Aim: REACH and REACH-2 investigated ramucirumab versus placebo in patients with advanced hepatocellular carcinoma (HCC). Ascites is common in HCC and associated with poorer outcomes. This exploratory, pooled meta-analysis of patients with baseline alpha-fetoprotein (AFP) ≥400 ng/mL investigated outcomes by treatment-emergent (TE) ascites in REACH and REACH-2.

Methods: A pooled meta-analysis of independent patient data for participants (N=542) with baseline AFP ≥400 ng/mL (stratified by study) from REACH and REACH-2 was performed. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator, and OS further assessed by Cox models. The effect of TE ascites on OS was evaluated by multivariate Cox models.

Results: TE ascites developed in 66 patients (20.9%) in the ramucirumab group and 33 patients (14.8%) in the placebo group. When adjusted for treatment duration, the incidence rates per 100 patient-years of any grade TE ascites were 59.1 and 71.9 for the ramucirumab and placebo groups, respectively, and the incidence of grade ≥3 TE ascites were 13.4 and 19.6, respectively. TE ascites was associated with TE hypoalbuminemia (odds ratio 4.9, 95% CI 2.5-9.3), but not TE proteinuria or hypertension. One patient discontinued ramucirumab treatment due to TE ascites. Ramucirumab treatment improved OS and PFS compared with placebo, irrespective of TE ascites.

Conclusions: When adjusted for treatment duration, the incidence of TE ascites was no higher in patients who received ramucirumab than in those who received placebo. Ramucirumab was well tolerated and provided a survival benefit irrespective of the development of TE ascites. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13638DOI Listing
March 2021

Functional inhibition of Oct leads to HNF4α upregulation.

Exp Ther Med 2021 Apr 11;21(4):349. Epub 2021 Feb 11.

Department of Internal Medicine II, Hospital of Worms, D-67550 Worms, Germany.

Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibrosis were also detected in Oct3-knockout (FVB.Slc22a3tm10pb, Oct3) mice. To the best of our knowledge, no data exists on an interaction between Oct3 and Hnf4α. We hypothesised that loss of Oct3 may have an impact on Hnf4α expression. In the present study, gene expression analyses were performed in liver tissue from untreated Oct3 and wild type (FVB, WT) mice. C57BL/6, Oct3 and WT mice were treated with pro-fibrotic carbon tetrachloride (CCl) or thioacetamide (TAA) for 6 weeks to chemically induce liver fibrosis. Cholestasis-associated fibrosis was mechanically generated in Oct3 and WT mice by bile duct ligation (BDL). Finally, stably OCT1- and OCT3-transfected tumour cell lines and primary murine hepatocytes were treated with the non-selective OCT inhibitor quinine and Hnf4α expression was quantified by qPCR and immunofluorescence. The results revealed that Hnf4α is one of the top upstream regulators in Oct3 mice. Hnf4α mRNA expression levels were downregulated in Oct3 mice compared with in WT mice during cholestatic liver damage as well as fibrogenesis. The downregulation of Hnf4α mRNA expression in fibrotic liver tissue was reversible within 4 weeks. In stably OCT1- and OCT3-transfected HepG2 and HuH7 cells, and primary murine hepatocytes, functional inhibition of OCT led to the upregulation of Hnf4α mRNA expression. Hnf4α was revealed to be located in the cytosol of WT hepatocytes, whereas Oct3 hepatocytes exhibited nuclear Hnf4α expression. In conclusion, Hnf4α was downregulated in response to cholestasis and fibrosis, and functional inhibition of Oct may lead to the upregulation of Hnf4α.
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http://dx.doi.org/10.3892/etm.2021.9780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903485PMC
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

Assessing the impact of COVID-19 on liver cancer management (CERO-19).

JHEP Rep 2021 Feb 23:100260. Epub 2021 Feb 23.

BCLC group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS. CIBERehd. University of Barcelona. Spain.

Background: The coronavirus 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). This project has evaluated if the schedule of LC screening or procedures has been interrupted /delayed because of the COVID-19 pandemic.

Material And Methods: An international survey evaluated the impact of COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave.

Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia and Africa (73.7%, 17.1%, 5.3%, 2.6% and 1.3% per continent, respectively). Eighty-seven per cent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening program, 50% cancelled curative and/or palliative treatments for LC, and 44.0% cancelled the liver transplantation program. Forty-five out 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service prior to COVID-19 pandemic (n=19/37).

Conclusion: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with LC. Modifications in screening, diagnostic and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision making.
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http://dx.doi.org/10.1016/j.jhepr.2021.100260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901294PMC
February 2021

Impact of Non-Alcoholic Fatty Liver Disease on Metabolic Comorbidities in Type 2 Diabetes Mellitus.

Exp Clin Endocrinol Diabetes 2021 Feb 18. Epub 2021 Feb 18.

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

Objective: Type 2 Diabetes (T2D) is a major risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The published prevelance in epidemiological studies in this high risk population exceeds 70%. The aim of this analysis was to investigate the impact of NAFLD on T2D patients in Germany.

Methods: Using the Disease Analyzer Database (IQVIA), T2D patients with NAFLD diagnosed in Germany were matched to a cohort without NAFLD controlling for age, sex, physician, index year and metabolic comorbidities and assessed for their risk of developing myocardial infarction, stroke, peripheral arterial disease (PAD) or chronic kidney disease, as well as the type of T2D treatment on NAFLD.

Results: 2633 T2D patients with NAFLD were matched to 2633 T2D patients without liver disease. The ICD coded prevalence of NAFLD in patients with T2D in primary care in Germany was 7.8%. On regression analysis of patients with T2D , the presence of NAFLD was associated with a higher risk of renal failure during follow-up (HR 1.17, 95% CI 1.02-1.34, p=0.027). No association with the development of myocardial infarction, stroke, PAD or initiation of insulin therapy was observed. NAFLD patients were more frequently treated with DDP-4 inhibitors (+/-metformin) and less frequently with insulin within the first year of T2D diagnosis. The metabolic control (HbA1c range 6.5-7.5%) during follow-up did not differ between both groups.

Conclusion: The coded prevalence of NAFLD in T2D patients is low, which is in contrast to published series. Enhancing disease awareness of NAFLD and screening recommendations in high risk populations will be beneficial for the active management of these patients.
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http://dx.doi.org/10.1055/a-1378-4679DOI Listing
February 2021

No Evidence for Classic Thrombotic Microangiopathy in COVID-19.

J Clin Med 2021 Feb 9;10(4). Epub 2021 Feb 9.

Institute of Clinical Chemistry and Laboratory medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death.

Materials And Methods: Patients ( = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data.

Results: COVID-19 patients ( = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels.

Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.
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http://dx.doi.org/10.3390/jcm10040671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916239PMC
February 2021

Tumor Incidence in Patients with Non-Alcoholic Fatty Liver Disease.

Dtsch Arztebl Int 2020 Oct;117(43):719-724

Department of Medicine I, University Medical Center MainzMetabolic Liver Diseases, Department of Medicine I, University Medical Center MainzEpidemiology, IQVIA, Frankfurt.

Background: The incidence of cancer is increasing worldwide. The role of comorbidities in this development is debated. The aim of this study was to investigate the significance of non-alcoholic fatty liver disease (NAFLD) for the incidence of cancer of various kinds in Germany.

Methods: Between 2000 and 2015, data on 31 587 patients with established NAFLD were collected for analysis. A control group (n = 31 587) assembled for comparison was matched for sex, age, treating physician, and Charlson Comorbidity Index (CCI).

Results: By 10 years after the index date, 15.3% of patients with NAFLD and 13.4% of patients in the control group had been diagnosed with cancer (p <0.001). Patients with NAFLD exhibited significantly higher rates of male genital cancers (HR 1.26; 95% confidence interval [1.06; 1.5]; p = 0.008), skin cancer (HR 1.22 [1.07; 1.38]; p = 0.002) and breast cancer (HR 1.2 [1.01; 1.43]; p = 0.036). In this analysis, the rate of hepatocellular carcinoma did not differ between patients with NAFLD and patients without NAFLD (0.19% vs. 0.12%; p = 0.204).

Conclusion: NAFLD slightly increases the risk of breast cancer in women, genital cancer in men, and skin cancer irrespective of sex. Thus, NAFLD can be considered a marker of increased cancer risk.
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http://dx.doi.org/10.3238/arztebl.2020.0719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871444PMC
October 2020

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

Br J Cancer 2021 Feb 3. Epub 2021 Feb 3.

Kindai University, Osaka, Japan.

Background: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).

Methods: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.

Results: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001).

Conclusions: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.

Clinical Trial Registration: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).
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http://dx.doi.org/10.1038/s41416-021-01260-wDOI Listing
February 2021

Multidisciplinary approach to the complex treatment for non-cirrhotic portal hypertension - case-report-based discussion.

Z Gastroenterol 2021 Jan 11;59(1):43-49. Epub 2021 Jan 11.

I. Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Germany.

Non-cirrhotic portal vein thrombosis (PVT) in patients with antiphospholipid syndrome (APS) is a rare complication, and the management has to be determined individually based on the extent and severity of the presentation. We report on a 37-year-old male patient with non-cirrhotic chronic PVT related to a severe thrombophilia, comprising APS, antithrombin-, factor V- and factor X-deficiency. Three years after the initial diagnosis of non-cirrhotic PVT, the patient presented with severe hemorrhagic shock related to acute bleeding from esophageal varices, requiring an emergency transjugular intrahepatic portosystemic stent shunt (TIPSS). TIPSS was revised after a recurrent bleeding episode due to insufficient reduction of the portal pressure. Additionally, embolization of the dilated V. coronaria ventriculi led to the regression of esophageal varices but resulted simultaneously in a left-sided portal hypertension (LSPH) with development of stomach wall and perisplenic varices. After a third episode of acute esophageal varices bleeding, a surgical distal splenorenal shunt (Warren shunt) was performed to reduce the LSPH. Despite anticoagulation with low molecular weight heparin and antithrombin substitution, endoluminal thrombosis led to a complete Warren shunt occlusion, aggravating the severe splenomegaly and pancytopenia. Finally, a partial spleen embolization (PSE) was performed. In the postinterventional course, leukocyte and platelet counts increased rapidly and the patient showed no further bleeding episodes. Overall, this complex course demonstrates the need for individual assessment of multimodal treatment options in non-cirrhotic portal hypertension. This young patient required triple modality porto-systemic pressure reduction (TIPSS, Warren shunt, PSE) and involved finely balanced anticoagulation and bleeding control.
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http://dx.doi.org/10.1055/a-1330-9827DOI Listing
January 2021

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

JHEP Rep 2021 Apr 13;3(2):100215. Epub 2020 Nov 13.

Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC.

Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle.

Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]).

Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade.

Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.
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http://dx.doi.org/10.1016/j.jhepr.2020.100215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772786PMC
April 2021

Potential Impact of IMbrave150 Results in the Evolving Treatment Landscape of Advanced Hepatocellular Carcinoma: A Multidisciplinary Expert Opinion.

J Hepatocell Carcinoma 2020 21;7:423-433. Epub 2020 Dec 21.

University Medical Centre Mainz, Mainz, Germany.

A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.
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http://dx.doi.org/10.2147/JHC.S274930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762763PMC
December 2020

Treatment of cytokine storm syndrome with IL-1 receptor antagonist anakinra in a patient with ARDS caused by COVID-19 infection: A case report.

Clin Case Rep 2020 Dec 15;8(12):2990-2994. Epub 2020 Sep 15.

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

The biological anakinra appears promising to halt cytokine storm syndrome seen in severe courses of COVID-19. However, immunosuppression with anakinra may facilitate sepsis, necessitating continuous screening for bacterial superinfections.
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http://dx.doi.org/10.1002/ccr3.3307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752410PMC
December 2020

Proton pump inhibitor use is associated with a variety of infections in patients with liver cirrhosis.

Medicine (Baltimore) 2020 Dec;99(50):e23436

Department of General Practice and Family Medicine, Philipps-University, Marburg.

There is evidence that intake of proton pump inhibitors (PPI) increases the risk for spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis. However, data regarding the impact of PPI intake on occurrence of infections other than SBP are still lacking.We hypothesized that PPI use is associated with a higher rate of infections other than SBP in patients with liver cirrhosis.The current case-control study sample included patients with liver cirrhosis from the Disease Analyzer database (IQVIA), which compiles data such as risk factors, drug prescriptions and diagnoses obtained from general practitioners and specialists in Germany. In total, 2,823 patients with infections were matched with 2,823 patients without infections by propensity scores. For quantification of PPI use the prescribed quantity of PPI during the past 12 months before index date was analyzed.Frequency of PPI users was significantly higher in patients with infections than in patients without infections (47.9% vs 37.9%). In regression analysis, PPI use was significantly associated with the occurrence of infections overall (OR 1.55, 95% CI 1.39-1.72, P < .001), and associated with the occurrence of lower respiratory tract infections, urinary tract infections and infectious gastroenteritis. There was no association between PPI use and skin infections. Pantoprazole and omeprazole were the most frequently prescribed PPIs and were both independently associated with the occurrence of infections.PPI use may be associated with infections other than SBP in patients with liver cirrhosis. Prescription of PPI should be limited to patients with a clear indication.
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http://dx.doi.org/10.1097/MD.0000000000023436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738005PMC
December 2020

Systemic therapy of advanced hepatocellular carcinoma.

Future Oncol 2021 Apr 14;17(10):1237-1251. Epub 2020 Dec 14.

Hannover Medical School, Hannover, Germany.

For a decade, sorafenib remained the only approved first-line treatment and standard of care for advanced hepatocellular carcinoma. The treatment landscape has been evolving rapidly over the past 2 years with the approval of additional first-and second-line systemic treatments, most of which are targeted therapies. The expected approval of immunotherapies constitutes a paradigm shift: for the first time in years, a checkpoint inhibitor in combination with a VEGF antibody recently outperformed sorafenib with regards to efficacy. The wider availability of systemic therapies increases the chance for longer overall survival but raises new questions concerning the role of local options, treatment choice and sequential treatment. Following an expert discussion at the German Cancer Congress 2020 in Berlin, this article aims to summarize the current evidence on and experience of treatment choice and sequence in first- and second-line therapy.
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http://dx.doi.org/10.2217/fon-2020-0758DOI Listing
April 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

Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab.

Liver Int 2021 Mar 5;41(3):598-607. Epub 2020 Dec 5.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.

Background & Aims: Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo.

Methods: Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival.

Results: Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population.

Conclusions: The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.
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http://dx.doi.org/10.1111/liv.14731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898500PMC
March 2021

Pilot Study on Malnutrition and DNA Damage in Patients with Newly Diagnosed Gastrointestinal Tumors: Is DNA Damage Reversible by Early Individualized Nutritional Support?

J Gastrointestin Liver Dis 2020 Oct 27;29(4):569-577. Epub 2020 Oct 27.

1 st Clinic and Polyclinic of Internal Medicine, University Medical Center Mainz; Medical Clinic 2, Dept. of Diabetology and Endocrinology, Clinic of Worms, Germany.

Background And Aims: Nutritional support (NS) in patients with malignancies and malnutrition improves outcome and treatment tolerance. The underlying mechanisms are not completely understood. We aimed to investigate for the first time the influence of an early individualized NS in newly diagnosed patients with gastrointestinal/hepato-pancreatic malignancies and malnutrition on DNA damage, oxidative stress and subclinical inflammation.

Methods: This prospective case-control study included 43 patients with newly diagnosed malignancies and malnutrition. At baseline (F0), we documented patients' data, oncological diagnosis, comorbidities, alcohol/ nicotine consume. Nutritional parameters, DNA damage [histone-variant H2AX phosphorylated on the 139-serine residue (γ-H2AX) foci/cell], oxidative status, subclinical inflammation were measured. During diagnostic workup, patients received an individualized NS, and got a follow-up before the start of treatment (F1), (n=21). Healthy controls (n=21) were included for comparison of DNA damage at baseline.

Results: γ-H2AX-values at baseline were higher than in controls (p<0.001) and higher than after the NS at F1 (p=0.011). Patients with severe gastrointestinal symptoms (SGS) had higher baseline foci compared to patients with mild gastrointestinal symptoms (MGS) at F0 (p<0.001) and showed a stronger decrease of DNA damage under NS (p=0.002). Laboratory data were stable, with tendential reduction in oxidative stress, without progression of subclinical inflammation. The number of γ-H2AX foci did not differ among patients divided by sex, age, nicotine or alcohol intake or the presence of distant metastases.

Conclusion: Increased baseline DNA damage in patients with newly diagnosed tumors and malnutrition decreased under pretherapeutic NS, independent of other known genotoxic factors. This contributes towards understanding the positive effects of early NS in cancer management.
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http://dx.doi.org/10.15403/jgld-2589DOI Listing
October 2020

Distant Metastases in Patients with Intrahepatic Cholangiocarcinoma: Does Location Matter? A Retrospective Analysis of 370 Patients.

J Oncol 2020 10;2020:7195373. Epub 2020 Oct 10.

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

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor entity, and distant metastases are common. However, studies investigating patterns and clinical relevance of distant metastases are rare. Therefore, we aimed to analyze occurrence, location, and prognostic impact of distant metastases on overall survival (OS).

Methods: Between 1997 and 2018, 417 patients with ICC were treated at our tertiary care center. Distant metastases and intrahepatic tumor burden were retrospectively evaluated in a longitudinal approach using volumetric assessment of cross-sectional imaging studies and all available medical/histopathological reports.

Results: Finally, 370 patients with histopathologically confirmed ICC were included. Of these, 186 showed distant metastases, either initially ( = 59) or during follow-up ( = 127). The most common metastatic sites were the lung ( = 105), peritoneum ( = 81), and bone ( = 50). After detection of lung metastases, the residual median OS was 5.3 months; followed by peritoneal metastases, 4.5 months, and bone metastases, 4.4 months (=0.17). At the time of first metastatic occurrence, residual OS according to intrahepatic tumor burden of <25%, 25-50%, and >50% was 6.5 months, 4.9 months, and 1.2 months, respectively ( < 0.001). In multivariate hazard regression, hepatic tumor burden, liver function, and subsequent treatment were significant predictors of survival.

Conclusions: During the disease course, every second patient developed extrahepatic metastases. While the presence of distant metastases was associated with poor patient outcomes, there was no significant difference between metastatic sites. However, hepatic tumor burden was the life-limiting risk factor in a majority of patients at the time of distant metastatic disease.
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http://dx.doi.org/10.1155/2020/7195373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569461PMC
October 2020

Incident Dementia in Elderly Patients with Nonalcoholic Fatty Liver Disease in Germany.

Dig Dis Sci 2020 Oct 10. Epub 2020 Oct 10.

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

Dementia and NAFLD are two frequent conditions that share underlying risk factors mainly in the realm of metabolic disease. Additionally, an association between NAFLD and brain aging has been proposed. Therefore, we investigated the hypothesis if NAFLD is an independent risk factor for emerging dementia. In this population-based cohort study, elderly patients (≥ 65 years) with NAFLD diagnosed between 2000 and 2015 were matched 1:1 to a cohort without NAFLD based on ICD-10 coding in the Disease Analyzer database. Matching criteria were age, sex, physician, index year, and co-diagnoses associated with dementia. The primary outcomes of this study were all-cause dementia diagnoses, the incidence of vascular dementia, and antidementive drug prescription. A total of 22,317 patients with NAFLD were matched to 22,317 patients without NAFLD. Within 10 years of the index date, 16.0% of patients with NAFLD and 15.6% of the patients without NAFLD were diagnosed with dementia. On Cox regression analysis, there is no association between NAFLD and the incidence of all-cause dementia (HR 0.97, 95% CI 0.92-1.04), vascular dementia (HR 0.89, 95% CI 0.78-1.02), or the new prescription of antidementive therapy (HR 0.87, 95% CI 0.76-1.01). In sensitivity analyses, there was no association between NAFLD and dementia in different age-groups as well as men or women. In conclusion, in this database study of elderly patients coded with NAFLD no independent association with incident dementia was detected. Risk assessment regarding dementia in patients with NAFLD should be carried out in the same way as for metabolic burdened patients.
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http://dx.doi.org/10.1007/s10620-020-06644-1DOI Listing
October 2020

Molecular endoscopic imaging for the detection of Barrett's metaplasia using biodegradable inorganic nanoparticles: An ex-vivo pilot study on human tissue.

PLoS One 2020 1;15(10):e0239814. Epub 2020 Oct 1.

Inner Medicine, University Medical Centre, Mainz, Germany.

Background And Study Aims: Despite major technical advancements, endoscopic surveillance for detecting premalignant lesions in Barrett's esophagus is challenging because of their flat appearance with only subtle morphological changes. Molecular endoscopic imaging (MEI) using nanoparticles (NPs), coupled with fluorescently labeled antibody permits visualization of disease-specific molecular alterations. The aim of this ex vivo study was to assess the diagnostic applicability of MEI with NPs to detect Barrett's metaplasia.

Patients And Methods: Seven patients undergoing endoscopic surveillance of known Barrett's esophagus were recruited. Freshly resected biopsy specimens were incubated with NPs coupled with FITC labeled Muc-2 antibodies and examined with MEI. Fluorescence intensity from Barrett's mucosa and control specimens were compared, followed by histological confirmation.

Results: Fluorescence signals, indicating the presence of goblet cells, were noted for traditional MEI using Muc-2 antibodies in Barrett's intestinal metaplasia. Significantly stronger fluorescence signals were achieved with NPs coupled with FITC-conjugated Muc-2 antibodies. The results of MEI with NPs for the prediction of Barrett's metaplasia correlated with the final histopathological examination in all the cases.

Conclusions: Highly-specific NPs detected Barrett's metaplasia more efficiently than conventional MEI in this first feasibility study. MEI was as effective as standard histopathology for identifying Muc-2 containing goblet cells for diagnosis of Barrett's metaplasia. (DRKS-ID: DRKS00017747).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239814PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529275PMC
November 2020

Possible misclassification of cardiovascular risk by SCORE in antisynthetase syndrome: results of the pilot multicenter study RI.CAR.D.A.

Rheumatology (Oxford) 2021 Mar;60(3):1300-1312

Department of Rheumatology, ACURA Rheumatology Center, Bad Kreuznach, Germany.

Objectives: To test the ability of an established traditional cardiovascular (CV) risk prediction score [Systematic COronary Risk Evaluation (SCORE)] and its EULAR modified version (mSCORE) to identify antisynthetase syndrome (ASyS) patients at high CV risk and to examine for the first time associations of CV and cerebrovascular surrogate markers with clinical and immunological ASyS parameters.

Methods: SCORE/mSCORE and the gold standard marker of aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)] were examined in ASyS patients and healthy controls. Moreover, sonography of the common- (CCA) and internal- (ICA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media thickness (cIMT), plaques and Doppler sonographic cerebrovascular surrogates [resistance (RI) and pulsatility (PI) indices].

Results: We recruited 66 ASyS patients and 88 controls. According to mSCORE, 10% of the patients had high CV risk. However, cfPWV and carotid sonography revealed an increased CV risk in 21.2% and subclinical carotid atherosclerosis (SCA) in 85.7% of the patients, respectively. cfPWV and cIMT were higher in patients compared with controls (Padj=0.021 and Padj=0.003, respectively). In the ASyS group, cfPWV and cIMT correlated significantly with age (r = 0.679; P<0.001 and r = 0.664; P<0.001, respectively). Moreover, cfPWV correlated with BMI (Padj=0.001) and diabetes (Padj=0.043). CCA-RI and CCA-PI showed significant associations with creatine phosphokinase (r = 0.629; P=0.012 and r = 0.574; P=0.032, respectively) and ICA-RI and ICA-PI were higher in patients with lung involvement (both; P=0.039).

Conclusion: ASyS patients had higher aortic stiffness and SCA compared with controls, even after adjustment for confounders. SCORE/mSCORE performed poorly in identifying high-risk patients compared with cfPWV and carotid sonography. Thus, cfPWV and carotid sonography may improve CV and cerebrovascular screening in ASyS.
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http://dx.doi.org/10.1093/rheumatology/keaa525DOI Listing
March 2021

Nonalcoholic Fatty Liver Disease Increases the Risk of Anxiety and Depression.

Hepatol Commun 2020 Sep 22;4(9):1293-1301. Epub 2020 Jun 22.

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

Nonalcoholic fatty liver disease (NAFLD), depression, and anxiety disorders are frequent diseases, and data on mutual influence are inconsistent. The aim of this study was to explore the incidence of depression and anxiety in a large primary care cohort in Germany and to study the impact of NAFLD over a 10-year time frame. Patients with NAFLD diagnosed between 2010 and 2015 were matched to a cohort without NAFLD controlling for age, sex, physician, index year, and Charlson comorbidity index. The primary outcome of the study was the incidence of depression, anxiety, and first prescription of antidepressant drugs. We compared 19,871 patients with NAFLD to 19,871 matched controls. Within 10 years of the index date, 21.2% of patients with NAFLD and 18.2% of controls were diagnosed with depression ( < 0.001). On regression analysis, the hazard ratio (HR) for incidence of depression was 1.21 ( < 0.001). This association was similar for the endpoint of the first prescription of antidepressant drugs (HR, 1.21;  < 0.001). Anxiety disorders were diagnosed in 7.9% of patients with NAFLD and 6.5% of controls during the observation time ( = 0.003). The HR for incidence of anxiety was 1.23 ( < 0.001). This association remained significant in women ( < 0.001), while there was only a trend in men (HR, 1.15; 95% confidence interval, 0.99-1.34;  < 0.067). The risk of developing anxiety disorders was higher in younger patients. NAFLD constitutes an independent risk factor for emerging depression and anxiety even after controlling for confounding comorbidities.
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http://dx.doi.org/10.1002/hep4.1541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471420PMC
September 2020

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

Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials.

ESMO Open 2020 08;5(4)

Gastroenterology and Hepatology, Kindai University, Osaka, Japan.

Background: Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab.

Patients And Methods: Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted.

Results: In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings.

Conclusions: Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient-clinician discussions about the benefit-risk profile of this therapy.

Trial Registration Number: NCT01140347; NCT02435433, NCT02435433.
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http://dx.doi.org/10.1136/esmoopen-2020-000797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437873PMC
August 2020

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: a systematic review and meta-analysis.

Eur J Gastroenterol Hepatol 2020 Aug 10. Epub 2020 Aug 10.

Department of Internal Medicine I.

Objective: Coronavirus disease-19 (COVID-19) infection is a global health threat. To inform the liver community on the potential relevance of COVID-19, we performed a systematic review and meta-analysis of published data on liver injury in patients with COVID-19 infection.

Methods: We searched PubMed and Google Scholar through 22 March according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled data were analyzed by using random-effects meta-analyses.

Results: A total of 14 studies combining data from 2.871 patients were identified. The prevalence of pre-existing liver disease was reported at 3.1%. The pooled prevalence of elevated aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were 26% [95% confidence interval (CI), 20-32%] and 19% (95% CI, 14-26%), respectively. Only two studies reported the prevalence of elevated liver function tests according to normal ward versus ICU and here the frequency of elevated levels of AST was 50% and 62% versus ALT 40.8% and thus quantitatively higher in ICU-treated patients. Mean levels of absolute AST levels were 33 U/L (95% CI, 30.21-36.09), while mean ALT levels were 31 U/L (95% CI, 27.52-34.57). Cholestatic liver function tests were only incompletely reported in 510 patients. Here, mean levels of alkaline phosphatase were 71 U/L across three studies, and mean levels of gamma-glutamyl transferase were 40.6 U/L across four studies.

Conclusions: Emerging data on LFTs in COVID-19 are heterogeneous indicating mild LFTs involvement in every fourth to fifth patients with numerical more prevalent AST over ALT elevations. Prospective studies are needed to define the clinical relevance of liver injury in COVID-19.
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http://dx.doi.org/10.1097/MEG.0000000000001827DOI Listing
August 2020

Validation of the Clinical Frailty Scale for the Prediction of Mortality in Patients With Liver Cirrhosis.

Clin Transl Gastroenterol 2020 Jul;11(7):e00211

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

Introduction: Frailty is a common but often underestimated complication in patients with liver cirrhosis. The Clinical Frailty Scale (CFS) allows the assessment of frailty within a short period of time but has only been investigated in a Canadian cohort of outpatients. The aim of the current study was to evaluate the ability of the CFS to predict mortality in outpatients and nonelectively hospitalized German patients.

Methods: Two hundred outpatients and 99 nonelectively hospitalized patients with liver cirrhosis were prospectively enrolled. Outpatients/inpatients were followed for a median of 364/28 days regarding the primary outcome of death or liver transplantation. Eighty-seven patients of the outpatient cohort and 64 patients of the inpatient cohort had available computed tomography-scans for the quantification of muscle mass.

Results: Median CFS was 3 in the outpatient and the inpatient cohort. Twenty-one (10.5%) outpatients were at least prefrail (CFS > 3) and 26 (26.3%) inpatients were frail (CFS > 4). For every one-unit increase, there was an independent association between the CFS and mortality in the outpatient cohort (hazard ratio 1.534, P = 0.007). This association remained significant after controlling for muscle mass in the subcohort with available computed tomography scans. In the inpatient cohort, frailty (CFS > 4) was an independent predictor for 28-day mortality after controlling for acute-on-chronic liver failure, albumin, and infections (odds ratio 4.627, P = 0.045). However, this association did not reach significance in a subcohort after controlling for muscle mass.

Discussion: Especially in outpatients, CFS is a useful predictor regarding increased mortality independent of the muscle mass.
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http://dx.doi.org/10.14309/ctg.0000000000000211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386350PMC
July 2020

Proton pump inhibitors increase risk of bone fractures in men with cirrhosis: a population-based study.

Aliment Pharmacol Ther 2020 09 30;52(6):1042-1050. Epub 2020 Jul 30.

Epidemiology, IQVIA, Frankfurt am Main, Germany.

Background: Bone fractures are a frequent complication in patients with cirrhosis. Proton pump inhibitors (PPIs) are among the most frequently prescribed medications and may impair bone quality and quantity.

Aims: To investigate whether PPI use predisposes patients with cirrhosis to bone fractures.

Methods: We performed a population-based case-control study exploring a sample of patients with cirrhosis derived from the Disease Analyzer database. In total, 1795 cirrhotic patients with fractures were compared to 10 235 cirrhotic patients without fractures. PPI use overall and the cumulative PPI dose 5 years prior to the index date were analysed. To estimate the association between PPI use and fractures, logistic regression analyses were performed taking cofounding factors into consideration.

Results: PPI use was more frequently seen in cirrhotic patients with fractures compared to controls (67.0% vs 53.4%, P < 0.001). In regression analyses, PPI use was associated with bone fractures after adjusting for important confounders (OR 1.34, 95% CI 1.20-1.51, P < 0.001). Importantly, the strongest effect of PPIs on bone fractures was seen in men and patients below 70 years of age. On further sensitivity analyses, we observed a dose-dependent effect for all PPIs with the strongest effect in cirrhotic patients receiving a dose of >50 000 mg during the 5 years prior to index date (OR 1.63, 95% CI 1.32-2.03).

Conclusions: PPI use was associated with bone fractures in a dose-dependent fashion in patients with cirrhosis. PPI use in these patients should be based on a careful risk-benefit assessment.
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http://dx.doi.org/10.1111/apt.16008DOI Listing
September 2020

Non-alcoholic fatty liver disease increases the risk of incident chronic kidney disease.

United European Gastroenterol J 2020 10 23;8(8):942-948. Epub 2020 Jul 23.

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

Background And Aim: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease. Its role in the development of extrahepatic co-morbidities is under investigation. The impact of NAFLD on the development of chronic kidney disease (CKD) is incompletely understood. The aim of this study was to explore the potential contribution of NAFLD on CKD in Germany.

Methods: The Disease Analyzer Database covering 7.49 million cases in Germany was explored for patients diagnosed with NAFLD between 2000 and 2015 and was matched 1:1 to a cohort without NAFLD. Matching criteria included age, sex, physician, index year and co-diagnoses associated with CKD. The primary outcomes of this study were incidences of CKD and end-stage renal disease.

Results: A total of 48,057 patients with NAFLD were matched to 48,057 patients without NAFLD. Within 10 years of the index date, 17.1% of patients with NAFLD and 11.6% of patients without NAFLD were diagnosed with CKD ( < 0.001). On Cox regression analysis, NAFLD was significantly associated with the incidence of CKD (hazard ratio (HR) = 1.58,  < 0.001). This association remained significant across different age groups and subgroups such as patients with diabetes mellitus or arterial hypertension. There was no association between NAFLD and emerging dialysis therapy (HR = 1.25,  = 0.245).

Conclusions: In this large database analysis in Germany, NAFLD constitutes an independent risk factor for CKD. Patients living with NAFLD should be monitored for a change in kidney function, facilitating therapeutic measures for kidney disease at an early stage.
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http://dx.doi.org/10.1177/2050640620944098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707877PMC
October 2020

Risk Stratification in Advanced Biliary Tract Cancer: Validation of the A.L.A.N. Score.

J Oncol 2020 23;2020:6180613. Epub 2020 Jun 23.

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

Background: In addition to the clinical parameters, immune-inflammatory markers have emerged as prognostic factors in patients with advanced biliary tract cancer (ABC). The recently proposed A.L.A.N. score combines both in an easily applicable manner. The aim of this study was to perform the first external evaluation of this score.

Methods: All patients from our clinical registry unit who had unresectable ABC underwent first-line chemotherapy from 2006 to 2018 and met the inclusion criteria of the original study were included ( =  74). The A.L.A.N. score comprises the following parameters: actual neutrophil count, lymphocyte-to-monocyte ratio, albumin, and neutrophil-to-lymphocyte ratio (A.L.A.N.). Univariate and multivariate hazard regression analyses were performed to evaluate the score's parameters regarding overall survival (OS). The concordance index (C-index) and integrated Brier score (IBS) were calculated to evaluate the score's predictive performance.

Results: Low, intermediate, and high A.L.A.N. scores corresponded to median OS of 21.9, 11.4, and 4.3 months, respectively, resulting in a significant risk stratification (log-rank =0.017). In multivariate analysis, a high-risk A.L.A.N. score remained an independent predictor of poor survival (=0.016). Neutrophil-to-lymphocyte ratio was not a significant factor for poor OS in the analyses in the cohort. The score's ability to predict individual patient survival was only moderate with a C-index of 0.63.

Conclusions: The A.L.A.N. score can be used to identify risk groups with a poor prognosis prior to the start of chemotherapy. However, the ability of the score to predict individual patient outcome was only moderate; thus, it may only serve as a minor component in the complex interdisciplinary discussion.
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http://dx.doi.org/10.1155/2020/6180613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330642PMC
June 2020