Publications by authors named "Dominik Bettinger"

68 Publications

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice.

Eur J Cancer 2021 Sep 8;157:140-152. Epub 2021 Sep 8.

Dept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC).

Patients And Methods: We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association.

Results: In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25-0.75) and PFS (HR 0.48; 95% CI: 0.31-0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46-0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32-0.95) in the multi-institutional dataset.

Conclusion: Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.
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http://dx.doi.org/10.1016/j.ejca.2021.08.020DOI Listing
September 2021

Over-the-scope clip versus transcatheter arterial embolization for refractory peptic ulcer bleeding-A propensity score matched analysis.

United European Gastroenterol J 2021 Aug 25. Epub 2021 Aug 25.

Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Transcatheter arterial embolization (TAE) or surgery are standard treatment of peptic ulcer bleeding (PUB) refractory to endoscopic hemostasis. Over-the-scope clips (OTSC) have shown superiority to standard endoscopic treatment.

Objective: To compare OTSC treatment to TAE in refractory peptic ulcer bleeding.

Patients And Methods: In this retrospective, multicenter study, 128 patients treated with OTSC (n = 66) or TAE (n = 62) for refractory PUB between 2009 and 2019 in four academic centers were analyzed. Primary endpoint was clinical success (hemostasis + no rebleeding within 7 days). Secondary endpoints were adverse events, length of ICU stay, and mortality. Propensity score matching was performed to adjust for differences in baseline characteristics.

Results: Patients characteristics were similar in both groups but ulcers in the TAE group were larger, more often located in the duodenal bulb (85.5% vs. 65.2%; p = 0.014), and that the proportion of Forrest Ia bleedings was higher (38.7% vs. 19.7%; p = 0.018). Clinical success was comparable in both groups (74.2% vs. 59.7%; p = 0.092). Stay on the intensive care unit (ICU) was significantly longer in the TAE group (mean 8.0 vs. 4.7 days; p = 0.002). Serious adverse events after re-therapy (12.9% vs. 1.5%; p = 0.042) and in-hospital mortality were significantly higher in the TAE group (9.1 vs. 22.6%, OR 2.92 [95% CI 1.04-8.16]; p = 0.05). After propensity score matching, the differences found regarding ICU stay (4.9± 5.9 and 9.2 ± 11.2; p = 0.009) and in-hospital mortality (5% vs. 22.5%; OR 5.52 [95% CI: 1.11-27.43]; p = 0.048) stayed significant.

Conclusions: OTSC treatment for refractory PUB was superior to TAE in terms of ICU stay and in-hospital mortality.
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http://dx.doi.org/10.1002/ueg2.12135DOI Listing
August 2021

Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort.

Liver Cancer 2021 Jul 1;10(4):360-369. Epub 2021 Jun 1.

Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany.

Background And Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib.

Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients' characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020.

Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%).

Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease - in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL).
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http://dx.doi.org/10.1159/000515490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339523PMC
July 2021

Reply to: "TIPS and liver transplantation should always be discussed together".

J Hepatol 2021 Oct 6;75(4):1002. Epub 2021 Jul 6.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.

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http://dx.doi.org/10.1016/j.jhep.2021.07.001DOI Listing
October 2021

Adaptive Subsets Limit the Anti-Tumoral NK-Cell Activity in Hepatocellular Carcinoma.

Cells 2021 Jun 2;10(6). Epub 2021 Jun 2.

Department of Medicine II, Faculty of Medicine, University Hospital Freiburg, University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany.

Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.
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http://dx.doi.org/10.3390/cells10061369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227986PMC
June 2021

Reply to: Correspondence on "Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival".

J Hepatol 2021 Sep 19;75(3):749-750. Epub 2021 Jun 19.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.

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http://dx.doi.org/10.1016/j.jhep.2021.06.001DOI Listing
September 2021

Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma.

Ther Adv Med Oncol 2021 28;13:17588359211010937. Epub 2021 Apr 28.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1079, New York, NY 10029, USA.

Background: Antibiotic exposure has been associated with worse outcomes with immune checkpoint inhibitors (ICIs) in cancer patients, likely due to disruption of the gut microbiome. Other commonly prescribed medications, such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), are also known to disrupt the microbiome, but data on their association with ICI outcomes are conflicting.

Methods: We conducted a retrospective, multicenter, international cohort study including 314 hepatocellular carcinoma (HCC) patients treated with ICIs from 2017 to 2019 to assess the association between PPI or H2RA exposure (up to 30 days before ICI) and overall survival. Secondary outcomes included overall response rate (ORR) and development of any treatment-related adverse events (AEs).

Results: Baseline PPI/H2RA exposure was not associated with overall survival in univariable (HR 1.01, 95% CI 0.75-1.35) or multivariable analysis (HR 0.98, 95% CI 0.71-1.36). Baseline PPI/H2RA exposure was not associated with either ORR (OR 1.32, 95% CI 0.66-2.65) or AEs (OR 1.07, 95% CI 0.54-2.12) in multivariable analysis.

Conclusions: Our results suggest that exposure to PPI/H2RA prior to ICIs does not adversely affect outcomes in HCC patients.
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http://dx.doi.org/10.1177/17588359211010937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107671PMC
April 2021

Reply to: "Freiburg index of post-TIPS survival (FIPS) a valid prognostic score in patients with cirrhosis but also an advisor against TIPS?"

J Hepatol 2021 Aug 26;75(2):489-490. Epub 2021 Apr 26.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.

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http://dx.doi.org/10.1016/j.jhep.2021.04.028DOI Listing
August 2021

Prognostic Value of the CLIF-C AD Score in Patients With Implantation of Transjugular Intrahepatic Portosystemic Shunt.

Hepatol Commun 2021 04 5;5(4):650-660. Epub 2021 Jan 5.

Department of Medicine II Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany.

Prognostic assessment of patients with liver cirrhosis allocated for implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a challenging task in clinical practice. The aim of our study was to assess the prognostic value of the CLIF-C AD (Acute Decompensation) score in patients with TIPS implantation. Transplant-free survival (TFS) and 3-month mortality were reviewed in 880 patients who received TIPS implantation for the treatment of cirrhotic portal hypertension. The prognostic value of the CLIF-C AD score was compared with the Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, and albumin-bilirubin (ALBI) score using Harrell's C concordance index. The median TFS after TIPS implantation was 40.0 (34.6-45.4) months. The CLIF-C AD score (c = 0.635 [0.609-0.661]) was superior in the prediction of TFS in comparison to MELD score (c = 0.597 [0.570-0.623],  = 0.006), Child-Pugh score (c = 0.579 [0.552-0.606],  < 0.001), and ALBI score (c = 0.573 [0.545-0.600],  < 0.001). However, the CLIF-C AD score did not perform significantly better than the MELD-Na score (c = 0.626 [0.599-0.653],  = 0.442). There were no profound differences in the scores' ranking with respect to indication for TIPS implantation, stent type, or underlying liver disease. Subgroup analyses revealed that a CLIF-C AD score >45 was a predictor of 3-month mortality in the supposed low-risk group of patients with a MELD score ≤12 (14.7% vs. 5.1%,  < 0.001). The CLIF-C AD score is suitable for prognostic assessment of patients with cirrhotic portal hypertension receiving TIPS implantation. In the prediction of TFS, the CLIF-C AD score is superior to MELD score, Child-Pugh score, and ALBI score but not the MELD-Na score.
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http://dx.doi.org/10.1002/hep4.1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034565PMC
April 2021

Efficacy of Stereotactic Body Radiotherapy in Patients With Hepatocellular Carcinoma Not Suitable for Transarterial Chemoembolization (HERACLES: HEpatocellular Carcinoma Stereotactic RAdiotherapy CLinical Efficacy Study).

Front Oncol 2021 19;11:653141. Epub 2021 Mar 19.

Department of Radiation Oncology, Medical Center - University of Freiburg, Freiburg, Germany.

The aim of this prospective observational trial was to evaluate the efficacy, toxicity and quality of life after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to assess the results of this treatment in comparison to trans-arterial chemoembolization (TACE). Patients with HCC, treated with TACE or SBRT, over a period of 12 months, enrolled in the study. The primary endpoint was feasibility; secondary endpoints were toxicity, quality of life (QOL), local progression (LP) and overall survival (OS). Between 06/2016 and 06/2017, 19 patients received TACE and 20 SBRT, 2 of whom were excluded due to progression. The median follow-up was 31 months. The QOL remained stable before and after treatment and was comparable in both treatment groups. Five patients developed grade ≥ 3 toxicities in the TACE group and 3 in the SBRT group. The cumulative incidence of LP after 1-, 2- and 3-years was 6, 6, 6% in the SBRT group and 28, 39, and 65% in the TACE group ( = 0.02). The 1- and 2- years OS rates were 84% and 47% in the TACE group and 44% and 39% in the SBRT group ( = 0.20). In conclusion, SBRT is a well-tolerated local treatment with a high local control rates and can be safely delivered, while preserving the QOL of HCC patients.
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http://dx.doi.org/10.3389/fonc.2021.653141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017336PMC
March 2021

Reply to: "IgG, a novel predictor for acute-on-chronic liver failure and survival in patients with decompensated cirrhosis?"

J Hepatol 2021 Jul 23;75(1):231-232. Epub 2021 Mar 23.

Department of Medicine II, Medical Center - University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.03.015DOI Listing
July 2021

International multicenter experience of transjugular intrahepatic portosystemic shunt implantation in patients with common variable immunodeficiency.

J Allergy Clin Immunol Pract 2021 07 13;9(7):2931-2935.e1. Epub 2021 Mar 13.

Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277733PMC
July 2021

Blood reelin in the progression of chronic liver disease.

Adv Med Sci 2021 Mar 6;66(1):148-154. Epub 2021 Feb 6.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Purpose: Reelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases.

Patients And Methods: We analyzed blood samples of patients with chronic liver disease without liver fibrosis (n ​= ​25), with liver fibrosis (n ​= ​36), with liver cirrhosis (n ​= ​74), with HCC (n ​= ​26) as well as of healthy controls (n ​= ​15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay.

Results: Blood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2-21.1) ng/ml vs. 11.2 (8.8-16.8) ng/ml, p ​= ​0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3-35.9) ng/ml vs. 16.6 (11.0-22.7) ng/ml, p ​< ​0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease.

Conclusions: Our results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.
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http://dx.doi.org/10.1016/j.advms.2021.01.006DOI Listing
March 2021

Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival.

J Hepatol 2021 Jun 26;74(6):1362-1372. Epub 2021 Jan 26.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; PraxisZentrum für Gastroenterologie und Endokrinologie, Freiburg, Germany.

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective and safe treatment for complications of portal hypertension. Survival prediction is important in these patients as they constitute a high-risk population. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation.

Methods: A total of 1,871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided into a training set (80% of study patients; n = 1,496) and a validation set (20% of study patients; n = 375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n = 290). Medical data and overall survival (OS) were assessed. A Cox regression model was used to create an alternative prediction model, which includes significant prognostic factors.

Results: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced median survival of 5.0 (3.1-6.9) months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9-5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh, MELD, MELD-Na score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation.

Conclusions: The FIPS score is superior to established scoring systems for the identification of high-risk patients with a worse prognosis following elective TIPS implantation.

Lay Summary: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective treatment for patients with cirrhosis and clinically significant portal hypertension. However, risk stratification is a major challenge in these patients as currently available scoring systems have major drawbacks. Age, bilirubin, albumin and creatinine were included in a new risk score which was named the Freiburg index of post-TIPS survival (FIPS). The FIPS score can identify patients at high risk and may guide clinical decision making.
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http://dx.doi.org/10.1016/j.jhep.2021.01.023DOI Listing
June 2021

Proton pump inhibitor therapy is associated with reduced survival following first-time transarterial chemoembolization in patients with hepatocellular carcinoma.

Eur J Gastroenterol Hepatol 2020 Dec 14. Epub 2020 Dec 14.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg.

Background And Aims: Several studies have reported associations of proton pump inhibitor (PPI) treatment with the incidence of complications and even increased mortality in patients with liver cirrhosis. Up to now, there are no studies on the impact of PPI treatment in patients with hepatocellular carcinoma (HCC). Therefore, the aim of our study was to investigate the prognostic effects of PPI treatment in a cohort of patients with HCC treated by transarterial chemoembolization (TACE) METHODS: Three hundred fifty-eight patients with HCC that received first-time TACE were included in a retrospective analysis. We explored effects of PPI treatment using uni- and multivariable regression models.

Results: One hundred sixty-seven of the 358 patients (46.6%) received PPI treatment. Median transplant-free survival after TACE was significantly lower in patients treated with PPIs compared to patients without PPI treatment [16.0 (10.7-21.3) months vs. 26 (22.2-29.8) months, P = 0.006]. Importantly, PPI treatment remained a significant prognostic factor for reduced survival after adjustment for patient demographics, tumor stadium and liver function [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.09-1.78, P = 0.005]. We observed a dose-dependent association of PPI treatment with survival: A higher daily PPI dose was an independent prognostic factor for reduced survival (HR 1.32, 95% CI 1.14-1.54, P < 0.001). Notably, 58.1% of patients receiving PPIs had no clear indication therefor.

Conclusion: PPI treatment is associated with reduced survival in patients with HCC in a dose-dependent manner. Thus, indication for PPI treatment should be evaluated attentively in these patients. Further, prospective studies are needed to validate the findings of this study.
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http://dx.doi.org/10.1097/MEG.0000000000002018DOI Listing
December 2020

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis.

J Hepatol 2021 03 24;74(3):649-660. Epub 2020 Oct 24.

Department of Medicine II, Medical Center - University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany; Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Germany. Electronic address:

Background & Aims: Patients with decompensated cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity, we hypothesized that Tfh cell responses may be altered in advanced liver disease and we aimed to identify the mechanisms underlying any such alterations.

Methods: Tfh, regulatory T (Treg) cells, B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n = 37) and decompensated cirrhosis (n = 82) and in non-cirrhotic controls (n = 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated in vitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells.

Results: Tfh cell frequencies were reduced in patients with decompensated cirrhosis, with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure in vitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival.

Conclusions: Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. The presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome.

Lay Summary: Patients with advanced cirrhosis often fail to generate protective immunity after prophylactic vaccinations and suffer from recurring infections that are associated with high mortality. Follicular T helper (Tfh) cells are specialized CD4 T cells that enable the emergence of antibody responses against microbial pathogens. This report demonstrates that Tfh cells are impaired in patients with advanced cirrhosis due to interleukin-2 signaling, a cytokine that is known to impair the generation of Tfh cells.
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http://dx.doi.org/10.1016/j.jhep.2020.10.012DOI Listing
March 2021

Characterization of pre-existing and induced SARS-CoV-2-specific CD8 T cells.

Nat Med 2021 01 12;27(1):78-85. Epub 2020 Nov 12.

Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Emerging data indicate that SARS-CoV-2-specific CD8 T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8 T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8 T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8 T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8 T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8 T cells exhibited functional characteristics comparable to influenza-specific CD8 T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8 T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41591-020-01143-2DOI Listing
January 2021

A large cervical osteophyte causing dysphagia in an elderly patient.

Ann Gastroenterol 2020 Nov-Dec;33(6):687. Epub 2020 Jun 30.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine.

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http://dx.doi.org/10.20524/aog.2020.0509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599349PMC
June 2020

Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study.

Br J Cancer 2021 01 19;124(2):407-413. Epub 2020 Oct 19.

Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.

Background: There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly.

Methods: In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models.

Results: Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib.

Conclusions: Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
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http://dx.doi.org/10.1038/s41416-020-01116-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852559PMC
January 2021

Impact of corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy.

J Immunother Cancer 2020 10;8(2)

Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital School of Medicine, New York, New York, USA.

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received 10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p<0.001) and was associated with refractoriness to ICI (75% vs 33%, p=0.05) compared with cancer-unrelated indications. This is the first study to demonstrate that neither bCT nor cCT influence response and OS following ICI in HCC. Worse outcomes in CT recipients for cancer-related indications appear driven by the poor prognosis associated with symptomatic HCC.
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http://dx.doi.org/10.1136/jitc-2020-000726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542664PMC
October 2020

[30 Years of Transjugular Intrahepatic Portosystemic Shunt (TIPS): casting a retrospective glance and future perspectives].

Z Gastroenterol 2020 Sep 18;58(9):877-889. Epub 2020 Sep 18.

Department Innere Medizin, Klinik für Innere Medizin II, Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg.

For 30 years the transjugular intrahepatic portosystemic shunt (TIPS) is successfully used for the treatment of portal hypertension. Indication for TIPS in relation to variceal bleeding and refractory ascites is scientifically documented and defined by national and international guidelines. For rare indications such as hepatorenal syndrome, portal vein thrombosis or the neodjuvant TIPS larger evidence-based studies are missing. An important contraindication and the leading clinical complication after TIPS is the development of hepatic encephalopathy (HE). Reduction of post-TIPS HE is therefore aimed through development of further technical enhancements of the TIPS-stents.
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http://dx.doi.org/10.1055/a-1217-7866DOI Listing
September 2020

Editorial: acute non-cirrhotic and non-malignant portal vein thrombosis--who should be candidates for interventional treatment? Authors' reply.

Aliment Pharmacol Ther 2020 08;52(4):729-730

Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/apt.15930DOI Listing
August 2020

Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study.

J Immunother Cancer 2020 08;8(2)

Department of Surgery and Cancer, Imperial College London, London, UK

Background: Nivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking.

Patients And Methods: We performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia.

Results: Patients received nivolumab for Barcelona Clinic Liver Cancer stage C (n191, 92.0%) and Child-Pugh (CP) A (n158, 67.8%) or B (n75, 32.2%) HCC as first (n85, 36.5%) or second to fourth systemic therapy line (n148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p<0.001) and in post-first line use (10.4 months vs 16.3 months, p0.05). Achievement of an objective response predicted for improved OS (25.4 months vs 13.2 months, p<0.001).

Conclusions: This study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than the patients with CP-A.
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http://dx.doi.org/10.1136/jitc-2020-001033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462152PMC
August 2020

The Transjugular Intrahepatic Portosystemic Shunt Improves Survival in Patients with Acute Variceal Bleeding: Evidence beyond Randomized Controlled Trials.

J Vasc Interv Radiol 2020 09;31(9):1392-1393

Department of Gastroenterology, University Hospital Freiburg, Praxiszentrum, Bertoldstrasse 48, 79098, Freiburg, Germany.

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http://dx.doi.org/10.1016/j.jvir.2020.07.001DOI Listing
September 2020

Immunotherapy in Hepatocellular Cancer Patients with Mild to Severe Liver Dysfunction: Adjunctive Role of the ALBI Grade.

Cancers (Basel) 2020 Jul 10;12(7). Epub 2020 Jul 10.

Department of Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217, Taiwan.

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors ( = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades ( < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57-0.74) versus 0.63 (95% CI 0.54-0.72). ALBI grade at ICI cessation independently predicted for PIOS ( < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events ( > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.
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http://dx.doi.org/10.3390/cancers12071862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408648PMC
July 2020

A prospective, multicentre study in acute non-cirrhotic, non-malignant portal vein thrombosis: comparison of medical and interventional treatment.

Aliment Pharmacol Ther 2020 07 7;52(2):329-339. Epub 2020 Jun 7.

Freiburg, Germany.

Background: To evaluate medical versus interventional treatment (transjugular thrombus fragmentation, local thrombolysis with or without stent implantation) in patients with acute non-cirrhotic, non-malignant portal vein thrombosis (PVT).

Methods: This prospective, observational study enrolled 65 patients with acute (<28 days since begin of symptoms, no cavernoma) PVT in nine centres. Thirty patients received medical treatment and 35 patients received interventional treatment. PVT was graded into grade 1: short thrombosis and incomplete occlusion of the vessel lumen and grade 2: extended thrombosis or complete occlusion. Treatment response was classified as partial or complete, if thrombosis was reduced by one grade or to <25% of the vessel diameter respectively.

Results: Partial and complete response rates were 7% and 30% in the medical compared to 17% and 54% (P < 0.001) in the interventional treatment group. In the multivariate analysis, interventional treatment showed a strong positive (OR 4.32, P < 0.016) and a myeloproliferative aetiology a negative (OR 0.09, P = 0.006) prediction of complete response. Complications were rare in the medical group and consisted of septicaemia and upper gastrointestinal bleeding of unknown origin in one patient each. Interventional treatment was accompanied by mild and self-limiting bleeding complications in nine patients, moderate intra-abdominal bleeding requiring transfusions (2 units) in one patient and peritoneal bleeding requiring surgical rescue in one patient. Four patients in each group developed intestinal gangrene requiring surgery. One patient died 52 days after unsuccessful interventional treatment.

Conclusions: Compared to medical treatment alone, interventional treatment doubled response rates at the cost of increased bleeding complications.
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http://dx.doi.org/10.1111/apt.15811DOI Listing
July 2020

Duodenal-Jejunal Bypass Liner (DJBL) Improves Cardiovascular Risk Biomarkers and Predicted 4-Year Risk of Major CV Events in Patients with Type 2 Diabetes and Metabolic Syndrome.

Obes Surg 2020 04;30(4):1200-1210

Department of Medicine II, Medical Center, Division of Endocrinology and Diabetology, Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg im Breisgau, Germany.

Background: The duodenal-jejunal bypass liner (DJBL) represents a novel endoscopic minimally invasive treatment option for obesity-associated type 2 diabetes (T2D), affecting body weight and metabolic control. Until now, the effects of DJBL on cardiovascular risk have never been investigated.

Methods: Between 2012 and 2017, 71 patients with T2D and metabolic syndrome (MS) were recruited for implantation of DJBL for 9-12 months. Within DJBL treatment and a follow-up period of 6 months, patients were analysed for dynamics of cardiovascular biomarkers. Overall cardiovascular risk was estimated by the ADVANCE Risk Engine at time of implantation, explantation and 6 months after explantation of DJBL.

Results: DJBL-induced weight loss and improvements in blood sugar control were accompanied by significant decreases of the cardiovascular biomarkers high-sensitive CRP, lipoprotein-associated phospholipase A2 and small dense lipoprotein fraction LDL-4 (p = 0.001, p < 0.001 and p = 0.04, respectively). Estimated overall cardiovascular risk decreased significantly after DJBL implantation and remained stable within 6 months after explantation.

Conclusions: In addition to beneficial effects of DJBL on weight loss, glycaemic control and lipid parameters in patients with MS, this is the first study that could further reveal significant impact on serological cardiovascular biomarkers and estimated CV risk, suggesting putative protective effects of DJBL on CV outcome.
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http://dx.doi.org/10.1007/s11695-019-04324-2DOI Listing
April 2020

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.

Clin Gastroenterol Hepatol 2020 03 8;18(3):728-735.e4. Epub 2019 Nov 8.

Department of Mathematics and Computer Science, Philipps-University Marburg, Marburg, Germany.

Background & Aims: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH.

Methods: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development.

Results: The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC.

Conclusions: In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.
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http://dx.doi.org/10.1016/j.cgh.2019.11.012DOI Listing
March 2020

Over-the-scope clips are cost-effective in recurrent peptic ulcer bleeding.

United European Gastroenterol J 2019 11 25;7(9):1226-1233. Epub 2019 Sep 25.

Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: A recent prospective randomised controlled trial ('STING') showed superiority of over-the-scope clips compared to standard treatment in recurrent peptic ulcer bleeding. Cost-effectiveness studies on haemostasis with over-the-scope clips have not been reported so far.

Objective: The aim of this study was to investigate whether the higher efficacy of the over-the-scope clips treatment outweighs the higher costs of the device compared to standard clips.

Methods: For the analysis, the study population of the STING trial was used. Costs for the hospital stay in total as well as treatment-related costs were obtained. The average cost-effectiveness ratio, representing the mean costs per designated outcome, and the incremental cost-effectiveness ratio, expressing the additional costs of a new treatment strategy per difference in outcome were calculated. The designated outcome was defined as successful haemostasis without rebleeding within seven days, which was the primary endpoint of the STING trial. Average cost-effectiveness ratio and incremental cost-effectiveness ratio were calculated for total costs of the hospital stay as well as the haemostasis treatment alone. The cost-effectiveness analysis is taken from the perspective of the care provider. Total costs and treatment-related costs per patient were 13,007.07 € in the standard group vs 12,808.56 € in the over-the-scope clip group ( = 0.812) and 2084.98 € vs 1984.71 € respectively ( = 0.663). The difference was not statistically significant. Total costs per successful haemostasis (average cost-effectiveness ratio) were 30,677.05 € vs 15,104.43 € and 4917.41 € vs 2340.46 € for the haemostasis treatment. The additional costs per successful haemostasis with over-the-scope clip treatment (incremental cost-effectiveness ratio) is -468.18 € for the whole treatment and -236.49€ for the haemostasis treatment.

Conclusions: Over-the-scope clip treatment is cost-effective in recurrent peptic ulcer bleeding.
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http://dx.doi.org/10.1177/2050640619871754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826528PMC
November 2019
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