Publications by authors named "Christian P Strassburg"

223 Publications

Renal replacement therapy as bridging-to-recovery in refractory hepatorenal syndrome.

Z Gastroenterol 2021 Feb 25. Epub 2021 Feb 25.

Department of Internal Medicine I, University Hospital Bonn, Venusberg Campus 1, Bonn, Germany.

A 50-year-old female patient with cirrhosis due to alcoholic steatohepatitis was referred to our department because of recurrent hepatorenal syndrome (HRS) and hepatic hydrothorax. Clinically, severe anasarca was the leading problem. In contrast to previous episodes, HRS did not respond to standard treatment including terlipressin.Given the severe, refractory hyperhydration, we finally initiated renal replacement therapy (RRT). Subsequently, RRT was performed without severe side effects for more than 100 days. In the meantime, liver function remarkably improved, most probably due to the prolonged abstinence from alcohol. Finally, RRT could be stopped. Since then, our patient has remained in good clinical condition for more than 6 months, with well-compensated Child-Pugh stage A cirrhosis and only mild chronic kidney disease stage III.In conclusion, this case highlights that RRT may be considered in individual cases as bridging therapy in refractory HRS until the liver regenerates due to the absence of damaging mechanisms.
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http://dx.doi.org/10.1055/a-1369-9859DOI Listing
February 2021

Improving quality of life in pancreatic cancer patients following high-intensity focused ultrasound (HIFU) in two European centers.

Eur Radiol 2021 Jan 23. Epub 2021 Jan 23.

Clinic for Diagnostic and Interventional Radiology, University Hospital Bonn, Venusberg-Campus 1, D-53127, Bonn, Germany.

Objectives: Pancreatic cancer patients often have a high symptom burden, significantly impairing patients' quality of life (QOL). Nevertheless, there are hardly any reports on the impact of high-intensity focused ultrasound (HIFU) on the QOL of treated patients. For the first time, this study evaluated the effect of HIFU on QOL and compared these results in two European centers.

Methods: Eighty patients with advanced pancreatic cancer underwent HIFU (50 in Germany, 30 in Bulgaria). Clinical assessment included evaluation of QOL and symptoms using the EORTC QLQ-C30 questionnaire at baseline and 1, 3, and 6 months after HIFU. Pain intensity was additionally evaluated with the numerical rating score (NRS).

Results: Compared to baseline, global health significantly improved 3 and 6 months after HIFU treatment (p = 0.02). Functional subscales including physical, emotional, and social functioning were considerably improved at 6 months (p = 0.02, p = 0.01, and p = 0.01, respectively) as were leading symptom pain (p = 0.04 at 6 months), fatigue (p = 0.03 at 3 and p = 0.01 at 6 months), and appetite loss (p = 0.01 at 6 months). Moreover, pain intensity measured by NRS revealed effective and strong pain relief at all time points (p < 0.001). Reported effects were independent of tumor stage, metastatic status, and country of treatment.

Conclusions: This study showed that HIFU represents an effective treatment option of advanced pancreatic cancer improving QOL by increasing global health and mitigation of physical complaints with a low rate of side effects, independent of the examiner. Therefore, HIFU is a worthwhile additional treatment besides systemic palliative chemotherapy or best supportive care in management of this aggressive disease.

Key Points: • In a prospective two-center study, it was shown that HIFU represents an effective treatment option of advanced pancreatic cancer improving QOL. • HIFU in pancreatic cancer patients is associated with a low rate of side effects, independent of the performer. • HIFU is a worthwhile additional treatment besides systemic palliative chemotherapy or best supportive care in management of this aggressive disease.
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http://dx.doi.org/10.1007/s00330-020-07682-zDOI Listing
January 2021

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

Gut 2021 Jan 21. Epub 2021 Jan 21.

Internal Medicine I, University of Bonn, Bonn, Germany.

Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.

Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.

Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.

Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
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http://dx.doi.org/10.1136/gutjnl-2020-323419DOI Listing
January 2021

Regulation of uridine diphosphate-glucuronosyltransferase 1A expression by miRNA-214-5p and miRNA-486-3p.

Epigenomics 2021 Feb 12;13(4):271-283. Epub 2021 Jan 12.

Department of Internal Medicine I, University Hospital Bonn, Bonn 53127, Germany.

This study aimed to identify novel miRNAs (miRs) as regulators of gene expression and to evaluate them as potential risk factors for the development of liver fibrosis/cirrhosis. miRNA target sites in UDP-glucuronosyltransferase 1A (UGT1A) 3'-UTR were predicted and confirmed by luciferase assays, quantitative real-time PCR and western blot using HEK293, HepG2 and Huh7 cells. and miRNA expression were analyzed in cirrhotic patients and a mouse model of alcoholic liver fibrosis. miR-214-5p and miR-486-3p overexpression reduced UGT1A mRNA, protein levels and enzyme activity in HepG2 and Huh7 cells. miR-486-3p was upregulated in cirrhotic patients and fibrotic mice livers, whereas UGT1A mRNA levels were reduced. In conclusion, we identified two novel miRNAs capable to repress UGT1A expression and . Furthermore, miR-486-3p may represent a potential risk factor for the development or progression of liver fibrosis/cirrhosis by means of a reduced UGT1A-mediated detoxification activity.
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http://dx.doi.org/10.2217/epi-2020-0244DOI Listing
February 2021

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic or germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic variants (PV) in 60 patients (28 families) and one PV in two patients from one family. Sixty-eight percent ( = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% ( = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
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http://dx.doi.org/10.3390/cancers12123726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763201PMC
December 2020

Alteration of contrast enhanced ultrasound (CEUS) of hepatocellular carcinoma in patients with cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS).

Sci Rep 2020 11 26;10(1):20682. Epub 2020 Nov 26.

Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Transjugular intrahepatic portosystemic shunt (TIPS) can treat portal hypertensive complications and modifies hepatic hemodynamics. Modification of liver perfusion can alter contrast enhancement dynamics of liver nodules. This study investigated the diagnostic performance of contrast-enhanced ultrasound (CEUS) to diagnose hepatocellular carcinoma (HCC) in cirrhosis with TIPS. In this prospective monocentric observational study, CEUS was used to characterize focal liver lesions in patients at risk for HCC with and without TIPS. Times of arterial phase hyperenhancement (APHE) und washout were quantified. Perfusion-index (PI) and resistance-index (RI) of hepatic artery and portal venous flow parameters were measured via doppler ultrasonography. Diagnostic gold standard was MRI/CT or histology. This study included 49 liver lesions [23 TIPS (11 HCC), 26 no TIPS (15 HCC)]. 26 were diagnosed as HCC by gold standard. Sensitivity and specificity of CEUS to diagnose HCC with and without TIPS were 93.3% and 100% vs. 90.9% and 93.3%, respectively. APHE appeared significantly earlier in patients with TIPS compared to patients without TIPS. TIPS significantly accentuates APHE of HCC in CEUS. CEUS has good diagnostic performance for diagnosis of HCC in patients with TIPS.
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http://dx.doi.org/10.1038/s41598-020-77801-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692482PMC
November 2020

Pseudoaneurysm associated haemosuccus pancreaticus - a rare and dangerous disease.

CVIR Endovasc 2020 Nov 19;3(1):82. Epub 2020 Nov 19.

Department of Radiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: In patients with upper gastrointestinal bleeding and hemorrhage originating from the major duodenal papilla pseudoaneurysm associated haemosuccus pancreaticus (HP) is a rare differential diagnosis which should be considered. Diagnosis may be challenging, as clinical presentation is often unspecific with only intermittent hemorrhage. Treatment of the causal pseudoaneurysm is mandatory and endovascular coil embolization is the suitable first-line management strategy. Until now there are only a very few studies about this clinical picture and its therapeutic options, especially data regarding whether additional fluid embolization is beneficial/necessary in HP is currently lacking.

Case Presentation: We report a case of a 59-year-old male patient with chronic pancreatitis and haemosuccus pancreaticus caused by a pancreatico-arterial fistula with an associated inflammatory pseudoaneurysm of the splenic artery. Initially we sought to embolize the pseudoaneurysm with microcoils. As only one coil could be safely deployed in the pseudoaneurysm we additionally employed tissue adhesive embolization in order to achieve complete occlusion of the pseudoaneurysm as well as the pancretico-arterial fistula. In the presented case inflammatory levels decreased following embolization, possibly linked to a decline in pathologic excretion of elastase and autodigestion. As not only the pseudoaneurysm but also the underlying fistula were occluded, the risk of recurrence may conceivably be reduced.

Conclusions: Diagnosis of HP is difficult and treatment of the causal pseudoaneurysm is mandatory. Endovascular embolization is the suitable first-line management strategy, complete occlusion of the fistula should be considered when possible.
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http://dx.doi.org/10.1186/s42155-020-00178-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674537PMC
November 2020

Induction of cytotoxic effector cells towards cholangiocellular, pancreatic, and colorectal tumor cells by activation of the immune checkpoint CD40/CD40L on dendritic cells.

Cancer Immunol Immunother 2020 Nov 12. Epub 2020 Nov 12.

Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53105, Bonn, Germany.

Introduction: Gastrointestinal (GI) malignancies, such as cholangiocarcinoma, pancreatic carcinoma, and metastatic colorectal carcinoma, have a poor prognosis and effective therapeutic approaches are still challenging. Checkpoint inhibition with PD-1 or PDL-1 antibodies revealed promising results in different tumor entities; however, only few patients with GI tumors can potentially benefit from PD1/PDL1 inhibiting immunotherapy. Further immunotherapeutic strategies for GI malignancies are urgently needed. The aim of this study was to demonstrate that in vitro activation of the immune checkpoint CD40/CD40L can improve DC action towards bile duct, pancreas, and colorectal carcinoma.

Methods: Human DC were isolated from buffy coats from healthy donors, pulsed with tumor lysates and then transduced with adenoviruses encoding human CD40L (Ad-hCD40L). Using transwell assays, the effects of (m)CD40L on DC immunoactivation compared to (s)CD40L were analyzed. Surface marker and cytokine/chemokine expression were measured by flow cytometry, ELISA and cytokine arrays. Capacity of Ad-hCD40L-transduced DC to induce tumor-specific effector cells was tested using MTT proliferation assay and cytotoxicity assays. Apoptosis induction on tumor cells after culturing with supernatants of Ad-hCD40L-transduced DC was analyzed by flow cytometry.

Results: Ad-hCD40L transduction induced a high expression of (s)CD40L and (m)CD40L on DC and seemed to induce a strong cellular CD40/CD40L interaction among DC, leading to the formation of cell aggregates. Due to the CD40/CD40L interaction, a significant upregulation of DC maturation markers and a Th1-shift on cytokines/chemokines in the supernatant of DC were achieved. Interestingly, a pure Th1-shift was only achieved, when a cellular CD40/CD40L interaction among DC took place. (s)CD40L induced almost no upregulation of maturation markers and rather resulted in a Th2-cytokine expression, such as IL-10. Correspondingly, (m)CD40L-expressing DC led to significant proliferation and stimulation of tumor-specific effector cells with increased cytotoxicity towards pancreatic, bile duct and colorectal tumor cells. Supernatants of Ad-hCD40L-transduced DC could also induce apoptosis in the different tumor cells in vitro.

Conclusion: Stimulation of the immune checkpoint CD40L/CD40 by endogenous expression of (m)CD40L provokes a cellular interaction, which increases the immunomodulatory capacity of DC. A Th1 cytokine/chemokine expression is induced, leading to a significant proliferation and enabling cytotoxicity of effector cells towards human bile duct, pancreatic and colorectal tumor cells. The present data point to the promising approach for DC-based immunotherapy of gastrointestinal malignances by activating the CD40/CD40L immune checkpoint.
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http://dx.doi.org/10.1007/s00262-020-02746-xDOI Listing
November 2020

EVs as Potential New Therapeutic Tool/Target in Gastrointestinal Cancer and HCC.

Cancers (Basel) 2020 Oct 17;12(10). Epub 2020 Oct 17.

Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany.

For more than a decade, extracellular vesicles (EVs) have been in focus of science. Once thought to be an efficient way to eliminate undesirable cell content, EVs are now well-accepted as being an important alternative to cytokines and chemokines in cell-to-cell communication route. With their cargos, mainly consisting of functional proteins, lipids and nucleic acids, they can activate signalling cascades and thus change the phenotype of recipient cells at local and systemic levels. Their substantial role as modulators of various physiological and pathological processes is acknowledged. Importantly, more and more evidence arises that EVs play a pivotal role in many stages of carcinogenesis. Via EV-mediated communication, tumour cells can manipulate cells from host immune system or from the tumour microenvironment, and, ultimately, they promote tumour progression and modulate host immunity towards tumour's favour. Additionally, the role of EVs in modulating resistance to pharmacological and radiological therapy of many cancer types has become evident lately. Our understanding of EV biology and their role in cancer promotion and drug resistance has evolved considerably in recent years. In this review, we specifically discuss the current knowledge on the association between EVs and gastrointestinal (GI) and liver cancers, including their potential for diagnosis and treatment.
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http://dx.doi.org/10.3390/cancers12103019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603109PMC
October 2020

Variceal bleeding has increased mortality compared to nonvariceal bleeding only in males.

Eur J Gastroenterol Hepatol 2020 Oct 16. Epub 2020 Oct 16.

Department of Medicine I, University of Bonn, Bonn, Germany.

Background: Gastrointestinal bleedings (GIBs) are frequent in cirrhotic patients and lead to high morbidity and mortality. Lately, there have been conflicting reports on the role of and bleeding type [variceal bleeding and nonvariceal bleeding (NVB)]. This study investigated the predictors of mortality in patients with variceal bleeding and NVB with relationship to sex differences.

Materials And Methods: A total of 271 patients with suspected upper GIB who underwent endoscopy were included. Patients were followed up at 1 week, 6 months and 1 year after admission. Univariate and multivariate logistic or Cox regression analyses investigated correlations of predictive factors and clinical outcomes. Propensity score matching was performed to control for severity of disease and compare groups for sex and bleeding type.

Results: A total of 42 patients were excluded (cirrhosis or bleeding not confirmed). The remaining patients were classified by bleeding type into patients with variceal bleeding (n = 115) or NVB (n = 156). Males (n = 155) had higher mortality in variceal bleeding than in NVB, while in females (n = 116) mortality was similar in the two bleeding types. This was confirmed after matching in males (n = 116) and females (n = 82). Further independent predictors of mortality in males were model for end-stage liver disease (MELD) at baseline, blood urea nitrogen, alanine aminotransferase, while in females age, leukocytes, MELD, history of ascites and hepatic encephalopathy.

Conclusion: This study shows that variceal bleeding has higher mortality in males compared to NVB, while in females the type of GIB does not impact the outcome. This highlights that sex-specific clinical management should be based on bleeding type after endoscopy.
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http://dx.doi.org/10.1097/MEG.0000000000001964DOI Listing
October 2020

Non-invasive assessment of liver fibrosis in autoimmune hepatitis: Diagnostic value of liver magnetic resonance parametric mapping including extracellular volume fraction.

Abdom Radiol (NY) 2020 Oct 19. Epub 2020 Oct 19.

Department of Diagnostic and Interventional Radiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Purpose: Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that leads to severe fibrosis and cirrhosis. The aim of this study was to determine the diagnostic value of T1 and T2 mapping as well as extracellular volume fraction (ECV) for non-invasive assessment of liver fibrosis in AIH patients.

Methods: In this prospective study, 27 patients (age range: 19-77 years) with AIH underwent liver MRI. T1 and T2 relaxation times as well as ECV were quantified by mapping techniques. The presence of significant fibrosis (≥ F2) was defined as magnetic resonance elastography (MRE)-based liver stiffness ≥ 3.66 kPa. MRE was used as reference standard, against which the diagnostic performance of MRI-derived mapping parameters was tested. Diagnostic performance was compared by utilizing receiver-operating characteristic (ROC) analysis.

Results: MRE-based liver stiffness correlated with both, hepatic native T1 (r = 0.69; P < 0.001) as well as ECV (r = 0.80; P < 0.001). For the assessment of significant fibrosis, ECV yielded a sensitivity of 85.7% (95% confidence interval (CI): 60.1-96.0%) and a specificity of 84.6% (CI 60.1-96.0%); hepatic native T1 yielded a sensitivity of 85.7% (CI 60.1-96.0%); and a specificity of 76.9% (CI 49.7-91.8%). Diagnostic performance of hepatic ECV (area under the curve (AUC): 0.885), native hepatic T1 (AUC: 0.846) for assessment of significant fibrosis was similar compared to clinical fibrosis scores (APRI (AUC: 0.852), FIB-4 (AUC: 0.758), and AAR (0.654) (P > 0.05 for each comparison)).

Conclusion: Quantitative mapping parameters such as T1 and ECV can identify significant fibrosis in AIH patients. Future studies are needed to explore the value of parametric mapping for the evaluation of different disease stages.
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http://dx.doi.org/10.1007/s00261-020-02822-xDOI Listing
October 2020

Transpapillary tissue sampling of biliary strictures: balloon dilatation prior to forceps biopsy improves sensitivity and accuracy.

Sci Rep 2020 10 15;10(1):17423. Epub 2020 Oct 15.

Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate.
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http://dx.doi.org/10.1038/s41598-020-74451-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566456PMC
October 2020

When polyuria does not stop: a case report on an unusual complication of hantavirus infection.

BMC Infect Dis 2020 Sep 29;20(1):713. Epub 2020 Sep 29.

Department of Internal Medicine, Faculty of Medicine, University Bonn, Bonn, Germany.

Background: The clinical features, course and outcome of hantavirus infection is highly variable. Symptoms of the central nervous system may occur, but often present atypically and diagnostically challenging. Even though the incidence of hantavirus infection is increasing worldwide, this case is the first to describe diabetes insipidus centralis as a complication of hantavirus infection in the Western world.

Case Presentation: A 49-year old male presenting with severe headache, nausea and photophobia to our neurology department was diagnosed with acute haemorrhage in the pituitary gland by magnetic resonance imaging. In the following days, the patient developed severe oliguric acute kidney failure. Diagnostic workup revealed a hantavirus infection, so that the pituitary haemorrhage resulting in hypopituitarism was seen as a consequence of hantavirus-induced hypophysitis. Under hormone replacement and symptomatic therapy, the patient's condition and kidney function improved considerably, but significant polyuria persisted, which was initially attributed to recovery from kidney injury. However, water deprivation test revealed central diabetes insipidus, indicating involvement of the posterior pituitary gland. The amount of urine production normalized with desmopressin substitution.

Conclusion: Our case report highlights that neurological complications of hantavirus infection should be considered in patients with atypical clinical presentation.
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http://dx.doi.org/10.1186/s12879-020-05429-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526136PMC
September 2020

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.

N Engl J Med 2020 09;383(11):1028-1039

From the Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland (C.A.B., J.C.); the Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (E.D., F.G.K., V.H.R.); the Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (P.L.); the Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix (N.J.S.), and Cancer Prevention Pharmaceuticals, Tucson (A. Cohen) - both in Arizona; the Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (F.B., A. Castells); the Department of Internal Medicine I, University of Bonn (R.H., C.P.S.), and the National Center for Hereditary Tumor Syndromes (R.H., C.P.S.), Bonn, Germany; Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne (J.B., A.H.), and Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester (F.L.) - both in the United Kingdom; Mount Sinai Hospital, Toronto (S. Gallinger, R.G.); the Division of Population Sciences, Dana-Farber Cancer Institute, the Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, and Harvard Medical School - all in Boston (R.L., S.S.); the Division of Gastroenterology, University of Michigan, Ann Arbor (E.M.S.); Veterans Affairs San Diego Healthcare System, San Diego, and the Division of Gastroenterology, University of California San Diego, La Jolla (S. Gupta); Huntsman Cancer Center, Salt Lake City (P.K.); the University of Pennsylvania, Philadelphia (G.G.G., A.K.R.); Mayo Clinic, Rochester, MN (F.A.S.); University Hospital Gasthuisberg, Leuven, Belgium (E.V.C.); Emory University School of Medicine, Atlanta (F.F.W.); Washington University School of Medicine, St. Louis (P.E.W.); University of Washington Medical Center, Seattle (W.M.G.); Vanderbilt University Medical Center, Nashville (M.F.); and the University of Wisconsin School of Medicine and Public Health, Madison (J.M.W.).

Background: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown.

Methods: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease.

Results: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups.

Conclusions: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).
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http://dx.doi.org/10.1056/NEJMoa1916063DOI Listing
September 2020

UDP-glucuronosyltransferase polymorphisms affect diethylnitrosamine-induced carcinogenesis in humanized transgenic mice.

Cancer Sci 2020 Nov 5;111(11):4266-4275. Epub 2020 Sep 5.

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

UDP-glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case-control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)-induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15-day-old htgUGT1A-WT and htgUGT1A-SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver-body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN-treated htgUGT1A-SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A-SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case-control studies implicating impaired UGT1A-mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.
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http://dx.doi.org/10.1111/cas.14635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648041PMC
November 2020

Programmed cell death protein 1 (PD-1)-inhibition in hepatocellular carcinoma (HCC): a single center experience.

Scand J Gastroenterol 2020 Sep 21;55(9):1057-1062. Epub 2020 Jul 21.

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

Background: The prognosis for advanced Hepatocellular carcinoma (HCC)is still very poor. Despite initial usefulness of immune checkpoint inhibitor (PD-1), phase 3 trials failed to show significant benefit of PD-1 inhibition with nivolumab or pembrolizumab in the first and second line therapy of HCC. Clinical evidence of PD-1 inhibition in patients with advanced and heavily pretreated HCC outside clinical trials is extremely limited. In this study, we analyzed the clinical experience with PD-1 inhibition in patients with heavily pretreated HCC.

Methods: Between May 2016 and January 2019 14 patients with advanced and heavily pretreated HCC were treated with nivolumab or pembrolizumab at the University Hospital Bonn, Germany. Base line characteristics prior to immunotherapy, immunohistochemistry of different immunological markers, beneficial outcome and safety were recorded and retrospectively analyzed.

Results: Immunotherapy with PD-1 inhibition was well tolerated and resulted in significant clinical benefit as last line therapy. Median overall survival (OS) was 6.6 months (95%CI:3.9-11.8), progression-free survival (PFS) was 5.3 months (95%CI:2.4-11.7) and overall response rate (ORR) was 30.8%. One patient reached a complete remission.

Conclusions: Despite numerous pretreatments, PD-1 inhibition was well tolerated and showed clinical benefit in patients with heavily pretreated HCC.
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http://dx.doi.org/10.1080/00365521.2020.1794539DOI Listing
September 2020

Suppression of CMV Infection with Letermovir in a Kidney Transplant Patient.

Eur J Case Rep Intern Med 2020 20;7(7):001622. Epub 2020 Apr 20.

Department of Internal Medicine I, Faculty of Medicine, University Bonn, Bonn, Germany.

Infection with cytomegalovirus (CMV) with resistance to ganciclovir (GCV) is a therapeutic challenge in kidney transplant patients, because standard treatment options are nephrotoxic. We report the case of a kidney transplant recipient with GCV-resistant CMV disease, in whom letermovir, a novel inhibitor of CMV packaging, was administered off-label and prevented a relapse of disease once the CMV load was decreased by cidofovir. Furthermore, we observed significant drug interactions between letermovir and tacrolimus.

Learning Points: Cytomegalovirus (CMV) disease with resistance to ganciclovir (GCV) is difficult to manage in transplant patients.Letermovir may become a new option for treatment and prophylaxis of GCV-resistant CMV infection, but assessment of treatment response is difficult.Letermovir may lead to drug interactions via CYP3A4.
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http://dx.doi.org/10.12890/2020_001622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350956PMC
April 2020

Synergistic effects of extracellular vesicle phenotyping and AFP in hepatobiliary cancer differentiation.

Liver Int 2020 12 14;40(12):3103-3116. Epub 2020 Jul 14.

Department of Internal Medicine I, University Medical Center Bonn, Bonn, Germany.

Background: Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation.

Methods: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis.

Results: Two directly tumour-related antigen combinations (AnnV CD44v6 and AnnV CD44v6 CD133 ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV CD133 gp38 and AnnV EpCAM CD133 gp38 ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV CD44v6 EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively.

Conclusions: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.
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http://dx.doi.org/10.1111/liv.14585DOI Listing
December 2020

The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

Br J Pharmacol 2020 Sep 16;177(18):4193-4208. Epub 2020 Jul 16.

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

Background And Purpose: Irinotecan, used in colorectal cancer therapy, is metabolized by glucuronidation involving different UDP-glucuronosyltransferase (UGT)1A isoforms leading to facilitated elimination from the body. Individuals homozygous for the genetic variants UGT1A1*28 (Gilbert syndrome) and UGT1A7*3 are more susceptible to irinotecan side effects, severe diarrhoea and leukopenia. The aim of this study was to investigate the protective effects and active constituents of coffee during irinotecan therapy using humanized transgenic (htg)UGT1A-WT and htgUGT1A-SNP (carry UGT1A1*28 and UGT1A7*3 polymorphisms) mice.

Experimental Approach: HtgUGT1A mice were pretreated with coffee or caffeic acid (CA) + caffeic acid phenylethyl ester (CAPE) and injected with irinotecan. The effects of coffee and CA + CAPE were investigated using reporter gene assays, immunoblot, TaqMan-PCR, siRNA analyses and blood counts.

Key Results: Only the combination of the two coffee ingredients, CA and CAPE, mediates protective effects of coffee in a model of irinotecan toxicity by activation of UGT1A genes. Coffee and CA + CAPE significantly increased UGT1A expression and activity along with SN-38 glucuronide excretion in irinotecan-injected htgUGT1A mice, resulting in significant improvement of leukopenia, intestinal oxidative stress and inflammation.

Conclusion And Implications: In this study, we identify the compounds responsible for mediating the previously reported coffee-induced activation of UGT1A gene expression. CA and CAPE represent key factors for the protective properties of coffee which are capable of reducing irinotecan toxicity, exerting antioxidant and protective effects. Provided that CA + CAPE do not affect irinotecan efficacy, they might represent a novel strategy for the treatment of irinotecan toxicity.
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http://dx.doi.org/10.1111/bph.15162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443465PMC
September 2020

A Gilbert syndrome-associated haplotype protects against fatty liver disease in humanized transgenic mice.

Sci Rep 2020 05 26;10(1):8689. Epub 2020 May 26.

Department of Internal Medicine I, University Hospital Bonn, 53127, Bonn, Germany.

UDP-glucuronosyltransferases 1 A (UGT1A) enzymes are capable of detoxifying a broad range of endo- and xenobiotic compounds, which contributes to antioxidative effects, modulation of inflammation and cytoprotection. In the presence of low-function genetic UGT1A variants fibrosis development is increased in various diseases. This study aimed to examine the role of common UGT1A polymorphisms in NASH. Therefore, htgUGT1A-WT mice and htgUGT1A-SNP mice (carrying a common human haplotype present in 10% of the white population) were fed a high-fat Paigen diet for 24 weeks. Serum aminotransferase activities, hepatic triglycerides, fibrosis development and UGT1A expression were assessed. Microscopic examination revealed higher hepatic fat deposition and a significant induction of UGT1A gene expression in htgUGT1A-WT mice. In agreement with these observations, lower serum aminotransferase activities and lower expression levels of fibrosis-related genes were measured in htgUGT1A-SNP mice. This was accompanied by reduced PPARα protein levels in htgUGT1A-WT but not in SNP mice. Our data demonstrate a protective effect of a UGT1A SNP haplotype, leading to milder hepatic steatosis and NASH. Higher PPARα protein levels in animals with impaired UGT1A activity are the likely result of reduced glucuronidation of ligands involved in PPARα-mediated fatty acid oxidation and may lead to the observed protection in htgUGT1A-SNP mice.
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http://dx.doi.org/10.1038/s41598-020-65481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250928PMC
May 2020

Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.

BMC Cancer 2020 May 24;20(1):460. Epub 2020 May 24.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.

Methods: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.

Results: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.

Conclusions: The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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http://dx.doi.org/10.1186/s12885-020-06926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245918PMC
May 2020

Genetic variants of UDP-glucuronosyltransferase 1A genes are associated with disease presentation and outcome in primary sclerosing cholangitis.

Liver Int 2020 07 6;40(7):1645-1654. Epub 2020 May 6.

Department of Internal Medicine 1, University of Bonn, Bonn, Germany.

Background And Aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease without a curative medical therapy. The human UDP-glucuronosyltransferases 1A play a major role in the detoxification and elimination of bilirubin, bile acids and xenobiotics. Whether genetic UGT1A variants determine course and outcome of PSC has not yet been described.

Methods: A large cohort of German PSC patients with a long-term-follow-up was genotyped for UGT1A variants including UGT1A1*28, UGT1A3-66 T>C and UGT1A7 p.N129K/p.R131K using TaqMan 5'-nuclease assays. Results were correlated with clinical characteristics and transplant-free survival.

Results: About 331 patients with PSC were included in the study (69.9% male, mean age at diagnosis 32.6 years). Median transplant-free survival was 14.9 years. Patients with wild-type alleles of all three UGT1A genes had a longer transplant-free survival (17.2 vs. 14.4 years, P = .048) than patients carrying a homozygous or heterozygous SNP variant in at least one of the UGT1A1, UGT1A3 or UGT1A7 genes. Additionally, we found that patients carrying wild-type alleles of all three UGT1A genes had lower serum bilirubin (25 vs. 38 µmol/L, P = .02) and serum cholesterol (195 vs. 223 mg/dL), P = .035) at first presentation. Furthermore, inflammatory bowel disease was found to be associated with wild-type UGT1A alleles (82.2% vs. 68.4%, P = .046).

Conclusions: This large cohort shows an association with single nucleotide polymorphisms of the UGT1A1, UGT1A3 and UGT1A7 genes and outcome in PSC. Thus, UGT1A variants may represent a tool for the prognostic stratification of PSC patients and establish a link between disease progression and the regulation of detoxification by glucuronidation in PSC.
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http://dx.doi.org/10.1111/liv.14487DOI Listing
July 2020

Systemic Therapy of Neuroendocrine Neoplasia: Single Center Experience from a Cohort of 110 Consecutive Cases.

Int J Endocrinol 2020 31;2020:1491475. Epub 2020 Jan 31.

Department of Internal Medicine 3, Center of Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital of Bonn, Bonn, Germany.

Objective: Neuroendocrine neoplasias (NENs) represent a rare and biologically heterogeneous group of malignancies. Treatment of NEN patients remains challenging due to lack of prospective evidence on the choice of ideal therapeutic sequence and therapeutic efficacy in specific individual scenarios.

Methods: Clinical data on 110 consecutive patients suffering from NEN treated at a single German university center were analyzed, therapeutic regimens applied were assessed, and the outcome was evaluated.

Results: Histological grading, Ki67 proliferation index, functional activity, and presence of metastases were identified as prognostic markers. 10-year overall survival rates were 92%, 44%, and 0% for G1, G2, and G3 tumors, and 60%, 39%, 69%, 53%, and 0% for Ki67 <2%, 3-5%, 6-20%, 21-49%, and >50%, respectively. Peptide receptor radionuclide therapy (PRRT) and cytostatic chemotherapy were the second most common options, with PRRT being used more frequently in NET G1 and G2 and chemotherapy in NEC G3. Combination chemotherapy with etoposide plus cisplatin or carboplatin showed disease control rates (DCRs) of overall 74%, with a short median progression-free survival (PFS) of 7 or 5 months, respectively. DCR and PFS for PRRT were 89% and 22 months when administered as monotherapy, versus 100% and 27 months upon combination with somatostatin analog (SSA) therapy. Of note, PRRT also achieved disease control as best response in 5/5 (100%) selected cases of NEC G3.

Conclusion: Further prospective studies are warranted to help stratify available options for therapeutic intervention in NEN patients.
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http://dx.doi.org/10.1155/2020/1491475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013359PMC
January 2020

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis.

J Hepatol 2020 06 15;72(6):1140-1150. Epub 2020 Jan 15.

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Internal Medicine I, University of Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure - EF CLIF, Barcelona, Spain; Institute for Bioengineering of Catalonia, Barcelona, Spain. Electronic address:

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.

Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.

Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02-2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.

Conclusion: This study suggests that TSA >83 mm increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.

Lay Summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
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http://dx.doi.org/10.1016/j.jhep.2019.12.021DOI Listing
June 2020

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome.

Gastroenterology 2020 04 8;158(5):1326-1333. Epub 2020 Jan 8.

Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Background & Aims: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients.

Methods: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1.

Results: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC.

Conclusions: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
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http://dx.doi.org/10.1053/j.gastro.2019.12.032DOI Listing
April 2020

[Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients].

Z Gastroenterol 2019 Nov 18;57(11):1309-1320. Epub 2019 Nov 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn.

Introduction:  Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (, and ). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers.

Methods:  The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany.

Results:  A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years.

Conclusion:  LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.
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http://dx.doi.org/10.1055/a-1008-9827DOI Listing
November 2019

Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma.

Cancer Immunol Immunother 2019 Dec 13;68(12):2055-2066. Epub 2019 Nov 13.

Department I of Internal Medicine, University Hospital of Bonn (UKB), Venusberg-Campus-1, 53127, Bonn, Germany.

Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4CD25Foxp3 Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8 T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells.
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http://dx.doi.org/10.1007/s00262-019-02427-4DOI Listing
December 2019

A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.

BMC Cancer 2019 Oct 30;19(1):1024. Epub 2019 Oct 30.

Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016.

Methods: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment.

Results: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis.

Conclusions: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.
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http://dx.doi.org/10.1186/s12885-019-6241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822384PMC
October 2019