Publications by authors named "Tom Luedde"

242 Publications

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression.

Cells 2021 Sep 23;10(10). Epub 2021 Sep 23.

Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty at Heinrich-Heine-University, University Hospital Duesseldorf, 40225 Dusseldorf, Germany.

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of 'rest-and-jump genes' that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30-48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
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http://dx.doi.org/10.3390/cells10102516DOI Listing
September 2021

Diabetes mellitus is associated with an increased incidence of aortic valve stenosis.

Diab Vasc Dis Res 2021 Sep-Oct;18(5):14791641211033819

Christian-Albrechts-University of Kiel, Germany.

Background: The prognosis of patients with diabetes mellitus (DM) is particularly determined by vascular comorbidities. A recent theory implies that DM could also promote aortic valve stenosis (AS). The present study investigates this association in a large collective of outpatients.

Methods: This retrospective cohort study compared the incidence of AS in patients with an initial diagnosis of type 2 DM and a matched non-DM cohort in 809 general and diabetologist practices in Germany between January 2005 and December 2018. Cox regression models were performed to study the association between type 2 DM and AS incidence.

Results: A total of 78,805 patients with type 2 DM and 78,805 patients without diabetes were analysed. Diabetes patients were more frequently diagnosed with obesity (52% vs 21%). Four percent of patients with and three percent of without diabetes were diagnosed with AS ( < 0.001). Diabetes was significantly associated with an increased incidence of AS (HR: 1.36, < 0.001). This association was higher in men (HR: 1.41) versus women (HR: 1.30). The strongest association was observed in young patients (18-50 years, HR: 2.35, < 0.001).

Conclusion: In our study, diabetes patients had a higher incidence of aortic stenosis during their disease course.
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http://dx.doi.org/10.1177/14791641211033819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532229PMC
October 2021

Sarcopenia and Myosteatosis as Prognostic Markers in Patients with Advanced Cholangiocarcinoma Undergoing Palliative Treatment.

J Clin Med 2021 Sep 23;10(19). Epub 2021 Sep 23.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Background: Cholangiocarcinoma (CCA) represents the second most common primary liver cancer and is characterized by a very poor outcome, but reliable prognostic markers are largely missing. Sarcopenia, the progressive loss of muscle mass and strength, as well as myosteatosis have been associated with an unfavorable outcome in several clinical conditions, including cancer. Here, we evaluated the prognostic relevance of sarcopenia and myosteatosis using routine abdominal CT (computed tomography) scans in advanced stage CCA patients undergoing palliative treatment.

Methods: Routine abdominal CT scans were used to assess the skeletal muscle and the psoas muscle index (L3SMI/L3PMI) at the level of the third lumbar vertebra as radiological indices for sarcopenia as well as the mean skeletal muscle attenuation (MMA) as a surrogate for myosteatosis. Results were correlated with clinical data and outcomes.

Results: Using a calculated optimal cut-off value of 71.95 mm/cm, CCA patients with an L3SMI value below this cut-off showed a significantly reduced median overall survival (OS) of only 250 days compared to 450 days in patients with a higher L3SMI. Moreover, the median OS of CCA patients with an L3PMI above 6345 mm/cm was 552 days compared to 252 days in patients with a lower L3PMI. Finally, CCA patients with an MMA above 30.51 Hounsfield Units survived significantly longer (median OS: 430 days) compared to patients with an MMA value below this ideal cut-off (median OS: 215 days). The prognostic relevance of L3SMI, L3PMI, and MMA was confirmed in uni- and multivariate Cox regression analyses.

Conclusion: Routine abdominal CT scans represent a unique opportunity to evaluate sarcopenia as well as myosteatosis in advanced CCA patients. We identified the L3SMI/L3PMI as well as the MMA as negative prognostic factors in CCA patients undergoing palliative therapy, arguing that the "opportunistic" evaluation of these parameters might yield important clinical information in daily routine.
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http://dx.doi.org/10.3390/jcm10194340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509694PMC
September 2021

Characterization of HIV-1 drug resistance among patients with failure of second-line combined antiretroviral therapy in central Ethiopia.

HIV Med 2021 Oct 7. Epub 2021 Oct 7.

Hirsch Institute of Tropical Medicine, Asella, Ethiopia.

Background: As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia.

Methods: HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application.

Results: Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/µL and median (IQR) HIV-1 viral load was 30 220 (7963-82 598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected.

Conclusions: We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.
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http://dx.doi.org/10.1111/hiv.13176DOI Listing
October 2021

The prognostic role of in-hospital transfusion of fresh frozen plasma in patients with cholangiocarcinoma undergoing curative-intent liver surgery.

Eur J Surg Oncol 2021 Sep 20. Epub 2021 Sep 20.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, Netherlands. Electronic address:

Introduction: Major hepatectomy for perihilar and intrahepatic cholangiocarcinoma (CCA) is often associated with a significant intraoperative blood loss and the requirement for perioperative transfusion of blood products. The aim of this study was to investigate the oncological impact of fresh frozen plasma (FFP) transfusion during hospitalization in patients undergoing hepatectomy for CCA as adverse effects have been described in other malignancies.

Material And Methods: Patients undergoing hepatectomy for CCA from 2010 to 2019 at a single institution were eligible for this study. Survival analysis was carried out according to Kaplan-Meier and the associations of cancer-specific (CSS) and recurrence-free survival (RFS) with in-hospital application of FFP and other clinico-pathological characteristics were assessed using Cox regression models. Perioperatively deceased patients were excluded from the analysis.

Results: A total of 219 CCA patients were included in this survival analysis of which 53.0% (116/219) received FFP during hospitalization. Patients receiving in-hospital FFP showed a median CCS of 33 months (3-year-CSS = 46%, 5-year-CSS = 29%) compared to 83 months (3-year-CSS = 55%, 5-year-CSS = 53%) in patients who did not receive in-hospital FFP (p = 0.006 log rank). Further, in-hospital FFP was identified as an independent predictor of oncological outcome in multivariable analysis (CSS: HR = 1.71, p = 0.016; RFS: HR = 1.89, p = 0.003).

Conclusion: In a large European cohort of patients, in-hospital transfusion of FFP was identified as a novel independent prognostic marker in CCA patients undergoing curative-intent liver surgery. A restrictive transfusion policy is therefore recommended to improve long-term outcome in these patients.
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http://dx.doi.org/10.1016/j.ejso.2021.09.011DOI Listing
September 2021

miR-23a contributes to T cellular redox metabolism in juvenile idiopathic oligoarthritis.

Rheumatology (Oxford) 2021 Sep 24. Epub 2021 Sep 24.

Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany.

Objective: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of unknown origin. The regulation of inflammatory processes involves multiple cellular steps including mRNA transcription and translation. Different miRNAs tightly control these processes. We aimed to determine the roles of specific miRNAs within JIA pathogenesis.

Methods: We performed a global miRNA expression analysis in parallel in cells from the arthritic joint and peripheral blood of oligoarticular JIA patients and healthy controls. QRT-PCR analysis was used to verify expression of miRNA in T cells. Ex vivo experiments and flow cytometric analyses were used to analyze proliferation and redox metabolism.

Results: Global miRNA expression analysis demonstrated a different composition of miRNA expression at the site of inflammation compared with peripheral blood. Bioinformatic analysis of predicted miRNA target genes suggest a huge overrepresentation of genes involved in metabolic and oxidative stress pathways in the inflamed joint. Despite enhanced ROS levels within the local inflammatory milieu, JIA T cells are hyperproliferative and reveal an overexpression of miR-23a, which is an inhibitor of PPIF, the regulator of mitochondrial ROS escape. Mitochondrial ROS escape is diminished in JIA T cells resulting in their prolonged survival.

Conclusion: Our data suggest that miRNA dependent mitochondrial ROS shuttling might be a mechanism that contributes to T cell regulation in JIA at the site of inflammation.
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http://dx.doi.org/10.1093/rheumatology/keab709DOI Listing
September 2021

Intensity of mycophenolate mofetil treatment is associated with an impaired immune response to SARS-CoV-2 vaccination in kidney transplant recipients.

Am J Transplant 2021 Sep 22. Epub 2021 Sep 22.

Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Kidney transplant recipients (KTRs) are extremely vulnerable to SARS-CoV-2 infection and show an impaired immune response to SARS-CoV-2 vaccination. We analyzed factors related to vaccination efficiency in KTRs. In a multicenter prospective observational study (NCT04743947), IgG antibodies levels against SARS-CoV-2 spike S1 subunit and their neutralization capacity after SARS-CoV-2 vaccination were analyzed in 225 KTRs and compared to 176 controls. After the vaccination, 56 (24.9%) KTRs became seropositive of whom 68% had neutralizing antibodies. This immune response was significantly lower compared to controls [239 (78-519) BAU/ml versus 1826 (560-3180) BAU/ml for KTRs and controls, p<0.0001]. The strongest predictor for an impaired response was mycophenolate mofetil (MMF) treatment. Multivariate regression analysis revealed that MMF-free regimen was highly associated with seroconversion (OR 13.25, 95% CI 3.22-54.6; p<0.001). In contrast, other immunosuppressive drugs had no significant influence. 187 out of 225 KTRs were treated with MMF of whom 26 (13.9%) developed antibodies. 23 of these seropositive KTRs had a daily MMF dose ≤1g. Furthermore, higher trough MMF concentrations correlated with lower antibody titers (R -0.354, p<0.001) supporting a dose-dependent unfavorable effect of MMF. Our data indicate that MMF dose modification could lead to an improved immune response.
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http://dx.doi.org/10.1111/ajt.16851DOI Listing
September 2021

An elevated FIB-4 score predicts liver cancer development: a longitudinal analysis from 29,999 NAFLD patients: Reply to: "EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis- 2021 update".

J Hepatol 2021 Sep 11. Epub 2021 Sep 11.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.08.030DOI Listing
September 2021

Reply to: "Multiple investigations for a very common disorder: Finding the right balance in NAFLD".

J Hepatol 2021 Sep 11. Epub 2021 Sep 11.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.08.032DOI Listing
September 2021

Perioperative rifaximin is not associated with enhanced functional and volumetric recovery after major liver resection.

Sci Rep 2021 09 9;11(1):17936. Epub 2021 Sep 9.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.

The objective of this randomized controlled trial (RCT) was to assess the impact of rifaximin on the course of liver function, liver regeneration and volumetric recovery in patients undergoing major hepatectomy. The ARROW trial was an investigator initiated, single-center, open-label, phase 3 RCT with two parallel treatment groups, conducted at our hepatobiliary center from 03/2016 to 07/2020. Patients undergoing major hepatectomy were eligible and randomly assigned 1:1 to receive oral rifaximin (550 mg twice daily for 7-10 or 14-21 days in case of portal vein embolization preoperatively and 7 days postoperatively) versus no intervention. Primary endpoint was the relative increase in postoperative liver function measured by LiMAx from postoperative day (POD) 4 to 7. Secondary endpoint were the course of liver function and liver volume during the study period as well as postoperative morbidity and mortality. Between 2016 and 2020, 45 patients were randomized and 35 patients (16 individuals in the rifaximin and 19 individuals in the control group) were eligible for per-protocol analysis. The study was prematurely terminated following interim analysis, due to the unlikelihood of reaching a significant primary endpoint. The median relative increase in liver function from POD 4 to POD 7 was 27% in the rifaximin group and 41% in the control group (p = 0.399). Further, no significant difference was found in terms of any other endpoints of functional liver- and volume regeneration or perioperative surgical complications following the application of rifaximin versus no intervention. Perioperative application of rifaximin has no effect on functional or volumetric regeneration after major hepatectomy (NCT02555293; EudraCT 2013-004644-28).
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http://dx.doi.org/10.1038/s41598-021-97442-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429542PMC
September 2021

Pre-Operative MDCT Staging Predicts Mesopancreatic Fat Infiltration-A Novel Marker for Neoadjuvant Treatment?

Cancers (Basel) 2021 Aug 28;13(17). Epub 2021 Aug 28.

Department of General, Visceral, Thoracic and Pediatric Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany.

The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival ( = 0.023). A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM- resections, MPS should be considered in the decision for neoadjuvant therapy.
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http://dx.doi.org/10.3390/cancers13174361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430607PMC
August 2021

Circulating Osteopontin Levels and Outcomes in Patients Hospitalized for COVID-19.

J Clin Med 2021 Aug 30;10(17). Epub 2021 Aug 30.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.

Background: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown.

Methods: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers.

Results: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44-8.27) increase in the odds of death, and 4.9 × (95%CI 2.48-9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint.

Conclusion: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable.
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http://dx.doi.org/10.3390/jcm10173907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432103PMC
August 2021

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.

Front Oncol 2021 19;11:729207. Epub 2021 Aug 19.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.

Methods: Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.

Results: ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.

Conclusion: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.
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http://dx.doi.org/10.3389/fonc.2021.729207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417059PMC
August 2021

The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors.

Int J Mol Sci 2021 Aug 9;22(16). Epub 2021 Aug 9.

Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
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http://dx.doi.org/10.3390/ijms22168569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395312PMC
August 2021

Decreased Bone Mineral Density Is a Predictor of Poor Survival in Critically Ill Patients.

J Clin Med 2021 Aug 23;10(16). Epub 2021 Aug 23.

Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Alterations in bone mineral density (BMD) have been suggested as independent predictors of survival for several diseases. However, little is known about the role of BMD in the context of critical illness and intensive care medicine. We therefore evaluated the prognostic role of BMD in critically ill patients upon admission to an intensive care unit (ICU). Routine computed tomography (CT) scans of 153 patients were used to assess BMD in the first lumbar vertebra. Results were correlated with clinical data and outcomes. While median BMD was comparable between patients with and without sepsis, BMD was lower in patients with pre-existing arterial hypertension or chronic obstructive pulmonary disease. A low BMD upon ICU admission was significantly associated with impaired short-term ICU survival. Moreover, patients with baseline BMD < 122 HU had significantly impaired overall survival. The prognostic relevance of low BMD was confirmed in uni- and multivariate Cox-regression analyses including several clinicopathological parameters. In the present study, we describe a previously unrecognised association of individual BMD with short- and long-term outcomes in critically ill patients. Due to its easy accessibility in routine CT, BMD provides a novel prognostic tool to guide decision making in critically ill patients.
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http://dx.doi.org/10.3390/jcm10163741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397072PMC
August 2021

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction.

Eur J Med Res 2021 Aug 25;26(1):98. Epub 2021 Aug 25.

Department of Radiation Oncology, University Hospital Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Düsseldorf, Germany.

Background: The coronavirus disease 2019 (COVID-19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain-like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear.

Patients And Methods: 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database.

Results: Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals.

Conclusion: Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.
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http://dx.doi.org/10.1186/s40001-021-00557-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386154PMC
August 2021

Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study.

Lancet Digit Health 2021 10 17;3(10):e654-e664. Epub 2021 Aug 17.

Department of Medicine II, Mannheim Institute for Innate Immunoscience and Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides.

Methods: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5.

Findings: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522-0·737) to 0·836 (0·795-0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752-0·841) to 0·897 (0·513-0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676-0·794) to 0·863 (0·747-0·969) for detection of microsatellite instability and from 0·672 (0·403-0·989) to 0·859 (0·823-0·919) for detection of EBV status.

Interpretation: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer.

Funding: German Cancer Aid and German Federal Ministry of Health.
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http://dx.doi.org/10.1016/S2589-7500(21)00133-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460994PMC
October 2021

Enlarged extracellular vesicles are a negative prognostic factor in patients undergoing TACE for primary or secondary liver cancer-a case series.

PLoS One 2021 18;16(8):e0255983. Epub 2021 Aug 18.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Transarterial chemoembolization (TACE) has evolved as a standard treatment option in patients with intermediate stage, unresectable HCC [Barcelona Clinic Liver Cancer (BCLC) stage B] as well as in patients with liver metastases, when surgery or systemic therapy is considered not appropriate. Concentration and sizes of extracellular vesicles (EVs) recently emerged as novel diagnostic and prognostic biomarkers in patients with liver cancer, but no data on its prognostic relevance in the context of TACE exists. Here, we evaluate pre-interventional EVs as a potential biomarker in patients undergoing TACE for primary and secondary hepatic malignancies.

Methods: Vesicle size distribution and concentration were measured by nanoparticle tracking analysis (NTA) in patient sera before and after TACE in 38 patients.

Results: Extracellular vesicle size distribution measured before TACE is of prognostic significance with respect to overall survival in patients after TACE. Overall survival is significantly reduced when initial vesicle size (X50) is in the upper quartile (>145.65nm). Median overall survival in patients in the upper quartile was only 314 days, compared to 799 days in patients with vesicle size in the first to third quartile (<145.65nm; p = 0.007). Vesicle size was also shown to be a significant prognostic marker for overall survival in Cox regression analysis [HR 1.089, 95% CI: 1.021-1.162, p = 0.010]. In addition, a significant correlation was observed between initial EVs concentration/BMI (rS = 0.358, p = 0.029), X50/IL-8-concentration (rS = 0.409, p = 0.011) and X50/CRP-concentration (rS = 0.404, p = 0.016). In contrast, with regard to immediate tumor response after TACE, EVs concentration and size did not differ.

Summary: Sizes (but not concentrations) of EVs represent a novel prognostic marker in patients receiving TACE for primary and secondary hepatic malignancies since patients with enlarged EVs display a significantly impaired prognosis after TACE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255983PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372935PMC
August 2021

Prognostic Discrimination of Alternative Lymph Node Classification Systems for Patients with Radically Resected Non-Metastatic Colorectal Cancer: A Cohort Study from a Single Tertiary Referral Center.

Cancers (Basel) 2021 Aug 2;13(15). Epub 2021 Aug 2.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Background: Lymph node ratio (LNR) and the Log odds of positive lymph nodes (LODDS) have been proposed as a new prognostic indicator in surgical oncology. Various studies have shown a superior discriminating power of LODDS over LNR and lymph node category (N) in diverse cancer entities, when examined as a continuous variable. However, for each of the classification systems various cut-off values have been defined, with the question of the most appropriate for patients with CRC still remaining open. The present study aimed to compare the predictive impact of different lymph node classification systems and to define the best cut-off values regarding accurate evaluation of overall survival in patients with resectable, non-metastatic colorectal cancer (CRC).

Methods: CRC patients who underwent surgical resection from 1996 to 2018 were extracted from our medical data base. Cox proportional hazards regression models and C-statistics were performed to assess the discriminative power of 25 LNR and 26 LODDS classifications. Regression models were adjusted for age, sex, extent of the tumor, differentiation, tumor size and localization.

Results: Our study group consisted of 654 consecutive patients with non-metastatic CRC. C-statistic revealed 2 LNR and 5 LODDS classifications that demonstrated superior prognostic performance in patients with UICC III CRC, compared to the N category. No clear advantage of one classification over another could be demonstrated in any other patient subgroup.

Conclusions: Distinct LNR and LODDS classifications demonstrate a prognostic superiority over the N category only in patients with Stage III radically resected CRC.
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http://dx.doi.org/10.3390/cancers13153898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345552PMC
August 2021

Gallbladder Wall Thickening associated with Dengue Shock Syndrome in a German traveller - no indication for surgical therapy - a case report.

Trop Dis Travel Med Vaccines 2021 Aug 3;7(1):23. Epub 2021 Aug 3.

Department of Gastroenterology, Hepatology and Infectious Diseases, Duesseldorf University Hospital, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany.

Background: With the increasing number of dengue virus infections imported into Germany, knowledge about the different phases of the disease and possible complications is essential for the treatment of patients. The virus is endemic in the tropics and subtropics and up to 2.5 billion people are at risk of infection.

Case Presentation: Here we present a German traveller with dengue shock syndrome after returning from Thailand. After hospitalization the patient developed acute upper abdominal pain. The ultrasound findings were consistent with an acute acalculous cholecystitis, but were interpreted as dengue associated gallbladder wall thickening (GBWT). Therefore a surgical intervention was not indicated and would have been associated with an higher risk of complications in this situation. Under supportive care spontaneous regression of GBWT could be documented by sonography four days later as well as complete resolution of clinical symptoms.

Conclusion: GBWT in dengue virus infection mimicking acute cholecystitis is a differential diagnosis one should take into consideration in travellers returning from endemic areas and should be managed conservatively because of an high risk of bleeding and increased mortality under surgical therapy.
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http://dx.doi.org/10.1186/s40794-021-00148-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336325PMC
August 2021

Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany.

Lancet Reg Health Eur 2021 Sep 14;8:100164. Epub 2021 Jul 14.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Background: Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants.

Methods: After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration.

Findings: After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution - known to confer immune escape - was detected at the time of viral rebound but not before bamlanivimab treatment.

Interpretation: Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies.

Funding: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
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http://dx.doi.org/10.1016/j.lanepe.2021.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278033PMC
September 2021

Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma.

Int J Mol Sci 2021 Jun 18;22(12). Epub 2021 Jun 18.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients' prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC.

Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls.

Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome.

Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.
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http://dx.doi.org/10.3390/ijms22126569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233871PMC
June 2021

Heart failure is associated with an increased incidence of cancer diagnoses.

ESC Heart Fail 2021 Oct 27;8(5):3628-3633. Epub 2021 Jun 27.

KGP Bremerhaven, Postbrookstr. 105, Bremerhaven, 27574, Germany.

Aims: The prognosis and quality of life of heart failure patients is determined to a significant extent by co-morbidities. New data suggest that heart failure may be associated with an increased incidence of cancer. The present retrospective study investigates this association in a large collective of outpatients with heart failure.

Methods And Results: This retrospective cohort study assessed the incidence of cancer in patients with an initial diagnosis of heart failure and a matched non-heart failure cohort in 1274 general practices in Germany between January 2000 and December 2018. The study is based on the Disease Analyser database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Hazard regression models were used to study the association between heart failure and the incidences of different cancers. A total of 100 124 patients with heart failure and 100 124 patients without heart failure were included in the analysis. Patients were matched individually by sex, age, diabetes, obesity, and yearly consultation frequency. Within the 10 year observation period, 25.7% of patients with heart failure and 16.2% of patients without heart failure had been diagnosed with cancer (log-rank P < 0.001). These proportions were 28.6% vs. 18.8% in female and 23.2% vs. 13.8% in male patients. Heart failure was significantly associated with the incidence of cancer [hazard ratio (HR), 95% confidence interval: 1.76, 1.71-1.81; P < 0.001 in total; HR: 1.85, 1.77-1.92, P < 0.001 in women; HR: 1.69, 1.63-1.76, P < 0.001 in men]. A significant association was found between heart failure and all cancer sites assessed. The strongest association was observed for cancer of lip, oral cavity, and pharynx (HR: 2.10, 95% confidence interval: 1.66-2.17; P < 0.001), followed by respiratory organs (HR: 1.91, 1.74-2.10; P < 0.001) and genital organs of female patients (HR: 1.86, 1.56-2.17; P < 0.001). The association for skin tumours was 1.83 (1.72-1.94; P < 0.001), for cancer of lymphoid and haematopoietic tissue 1.77 (1.63-1.91; P < 0.001), for cancer of the digestive tract 1.75 (1.64-1. 87; P < 0.001), for breast cancer 1.67 (1.52-1.84; P < 0.001), for cancer of the genitourinary tract 1.64 (1.48-1.81; P < 0.001), and for male genital organ cancer 1.52 (1.40-1.66; P < 0.001).

Conclusions: Our study indicates that heart failure patients experience a significantly higher incidence of cancer during the course of the disease.
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http://dx.doi.org/10.1002/ehf2.13421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497216PMC
October 2021

Nonalcoholic fatty liver disease is associated with a higher incidence of coeliac disease.

Eur J Gastroenterol Hepatol 2021 Jun 17. Epub 2021 Jun 17.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf Epidemiology, IQVIA, Frankfurt Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.

Background: Recently the incidence of nonalcoholic fatty liver disease (NAFLD) has risen to become the most frequent liver disease worldwide. NAFLD is not a disease limited to the liver, but rather represents a systemic inflammatory disease involving multiple organ systems. Previous studies have suggested an association between NAFLD and coeliac disease, another disease related to inflammation. As the available clinical data is scarce and at least partially contradictory, we aimed at investigating a potential association between NAFLD and celiac disease in outpatients in Germany.

Methods: Using the Disease Analyzer database featuring data on diagnoses, prescriptions and demographic variables for 7.49 million cases of patients followed in general practices in Germany, we matched a total of 57 336 patients with NAFLD/diagnosed between 2000 and 2015 to a cohort of equal size without NAFLD by age, sex and index year. Incidence of celiac disease was compared between groups within 10 years from the index date.

Results: During the 10-years observation period, we observed a higher incidence of coeliac disease in NAFLD patients compared to patients without NAFLD (11.2 vs. 7.5 cases per 100 000 patients' years). Interestingly, this association was most prominent in men (hazard ratio, 2.02; 95% CI, 1.01-4.04) and patients between 18 and 50 years (hazard ratio, 2.79; 95% CI, 1.12-6.94).

Summary: Our data suggest that NAFLD promotes the development of coeliac disease particularly in young men. This finding argues that coeliac disease should be recognized as another nonliver-related complication of NAFLD and suggests screening of selected NAFLD patients for the presence of coeliac disease.
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http://dx.doi.org/10.1097/MEG.0000000000002234DOI Listing
June 2021

Impact of the COVID-19 Pandemic on Consultations and Diagnoses in Gastroenterology Practices in Germany.

Front Med (Lausanne) 2021 31;8:684032. Epub 2021 May 31.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

The COVID-19 pandemic has been a major burden for healthcare systems worldwide and has caused multiple changes and problems in outpatient care. The aim of this study was to investigate the impact of the COVID-19 pandemic on consultations and diagnoses in gastroenterology practices in Germany. To this end, we retrospectively analyzed data from the Disease Analyzer database (IQVIA) using the International Classification of Diseases, 10th revision (ICD-10). We included all patients aged ≥18 years with at least one visit to one of 48 gastroenterology practices in Germany between April and September 2019 and April and September 2020. A total of 63,914 patients in the 2nd quarter of 2019, 63,701 in the 3rd quarter of 2019, 55,769 in the 2nd quarter of 2020, and 60,446 in the 3rd quarter of 2020 were included. Overall, a clear downward trend in the number of visits to gastroenterologists was observed in the 2nd quarter of 2020 compared to 2019 (-13%, = 0.228). The decrease in consultations was particularly pronounced in patients >70 years of age (-17%, = 0.096). This trend was evident for all gastrointestinal diagnoses except for tumors. Most notably, rates of gastrointestinal infections (-19%) or ulcers (-43%) were significantly lower in this period than in the same quarter of 2019. Reflecting the course of the pandemic, the differences between the 3rd quarter of 2020 and that of 2019 were less pronounced (-5%, = 0.560). Our data show that the pandemic changed patients' behavior with respect to the health care system. Using the example of German gastroenterology practices, we show that the number of consultations as well as the number and range of diagnoses have changed compared to the same period in 2019.
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http://dx.doi.org/10.3389/fmed.2021.684032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200395PMC
May 2021

Correction to: Multicentric Castleman's disease in HIV patients: a single-center cohort diagnosed from 2008 to 2018.

Infection 2021 Oct;49(5):953

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.

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http://dx.doi.org/10.1007/s15010-021-01627-4DOI Listing
October 2021

Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.

Clin Case Rep 2021 May 24;9(5):e04068. Epub 2021 May 24.

Clinic for Gastroenterology, Hepatology and Infectious Diseases Heinrich-Heine-University Düsseldorf Düsseldorf Germany.

This case of secondary sclerosing cholangitis (SSC-CIP) emphasizes the need to provide follow-up care for patients that have recovered from COVID-19 in order to understand the complexity of SARS-CoV-2 associated sequela.
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http://dx.doi.org/10.1002/ccr3.4068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142800PMC
May 2021

Pulmonary hypertension is associated with an increased incidence of NAFLD: A retrospective cohort study of 18,910 patients.

J Intern Med 2021 Oct;290(4):886-893

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Pulmonary hypertension (PH) represents a multicausal disease with increasing global incidence that eventually leads to right ventricular failure. In addition to cardiac sequelae, noncardiac comorbidities appear to be of increasing relevance, especially in times of improved therapeutic options that often result in long-term survival. Here, we examined a potential association between PH and nonalcoholic fatty liver disease (NAFLD) as well as liver cirrhosis in an outpatient cohort in Germany.

Methods: A total of 9455 PH patients followed in general and internist practices between 2005 and 2019 were matched by propensity scoring based on age, sex, yearly consultation frequency and relevant comorbidities (obesity, diabetes, heart failure, lipid metabolism disorders) to a cohort of equal size without PH. The association between PH and NAFLD/liver cirrhosis was evaluated using Cox regression models.

Results: Within 10 years from the index date, cumulative incidence rates of NAFLD were significantly higher amongst patients with PH (7.3%) compared to non-PH patients (3.5%, log-rank p < 0.001). In regression analysis, this association was significant for both female (HR: 1.93, p < 0.001) and male (HR 1.51, p = 0.005) patients and was most prominent amongst patients > 80 years (HR: 3.30, p = 0.001). Moreover, PH patients showed a strong trend towards higher incidence rates of liver cirrhosis compared to non-PH patients (1.4 vs. 1.1%, p = 0.066).

Conclusion: Our data suggest that incidence rates of NAFLD are strongly elevated in patients with PH. This finding should trigger awareness of noncardiac comorbidities in these patients and argues for potential liver-directed screening programs in patients with PH.
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http://dx.doi.org/10.1111/joim.13337DOI Listing
October 2021

Variables associated with increased incidence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes.

BMJ Open Diabetes Res Care 2021 05;9(1)

Epidemiology, IQVIA, Durham, North Carolina, USA.

Introduction: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) show a rapidly increasing incidence worldwide. Although both diseases often occur in the same patient population, their mutual influence is not fully understood. We therefore aimed at analyzing the impact of T2D on the incidence of NAFLD in a large cohort of outpatients in Germany.

Research Design And Methods: 32 201 patients with T2D diagnosed between 2012 and 2018 were identified in the IQVIA Disease Analyzer database. Probability of NAFLD was analyzed using Cox regression models.

Results: The cumulative incidence of NAFLD within the 7-year observation period was 4.3%. The probability of NAFLD was significantly higher among patients with T2D with increased body mass index but not hemoglobin A1c. Prescriptions of sodium-glucose cotransporter-2 inhibitors (HR: 0.54, 95% CI 0.45 to 0.64), glucagon-like peptide-1 receptor antagonists (HR: 0.65, 95% CI 0.52 to 0.81), and insulin (HR: 0.72, 95% CI 0.62 to 0.8) were significantly associated with lower incidence of NAFLD.

Conclusion: Our data from a large population-based cohort of patients with T2D identified sociodemographic and therapeutic parameters associated with NAFLD incidence in patients with T2D which should be taken into account for novel therapeutic concepts.
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http://dx.doi.org/10.1136/bmjdrc-2021-002243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166633PMC
May 2021

Case Report: Convalescent Plasma Achieves SARS-CoV-2 Viral Clearance in a Patient With Persistently High Viral Replication Over 8 Weeks Due to Severe Combined Immunodeficiency (SCID) and Graft Failure.

Front Immunol 2021;12:645989. Epub 2021 May 3.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.

We describe the unique disease course and cure of SARS-CoV-2 infection in a patient with SCID and graft failure. In absence of a humoral immune response, viral clearance was only achieved after transfusion of convalescent plasma. This observation underscores the necessity of the humoral immune response for SARS-CoV-2 clearance.
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http://dx.doi.org/10.3389/fimmu.2021.645989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126709PMC
June 2021
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