Publications by authors named "Hartmut H Schmidt"

74 Publications

Short- and Long-Term Outcomes of Different Reperfusion Sequences in Liver Transplantation.

Ann Transplant 2021 Feb 19;26:e926847. Epub 2021 Feb 19.

Department of General, Visceral and Transplant Surgery, University Hospital of Münster, Münster, Germany.

BACKGROUND Although most centers perform primary portal vein reperfusion (PV) in orthotopic liver transplantation (OLT) for historical reasons, there is so far no sound evidence as to whether this technique is superior. The present study evaluated the long-term outcome of 3 different reperfusion sequences: PV vs primary arterial (A) vs simultaneous reperfusion (SIM). MATERIAL AND METHODS All patients at our center who underwent OLT (who received a primary, whole-organ liver graft) from 2006 to 2007 were evaluated for analysis. RESULTS A total of 61 patients were found eligible (PV: 25, A: 22, SIM: 14). Twenty-one patients (35%) were still alive after the follow-up period of 12 years. Despite poorer starting conditions such as higher recipient age (59 y (SIM) vs 55 y (A) vs 50 y (PV), P=0.01) and donor age (56 y (SIM) vs 51 y (PV) vs 50 y (A), n.s.), higher MELD scores (22 vs 19 (PV) vs 17 (A), n.s.), as well as a higher number of marginal donor organs (79% (SIM) vs 36% (A/PV), P=0.02), SIM-recipients demonstrated superior outcomes. Overall survival was 8.1 y (SIM), 4.8 y (PV), and 5.9 y (A, n.s.)). None of the SIM-recipients underwent re-transplantation, while the rate was 32% in the PV-group. The 8.1 y graft survival in SIM-recipients was significantly longer than in the other 2 groups, which were 3.3 y (PV) and 5.5 y (A, P=0.013). CONCLUSIONS Although SIM-reperfused recipients were the oldest and received grafts of inferior quality, these recipients showed superior results in terms of overall patient and graft survival. Multicentric randomized controlled trials with larger study populations are required to confirm this finding.
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http://dx.doi.org/10.12659/AOT.926847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901155PMC
February 2021

Bile Acids in Control of the Gut-Liver-Axis.

Z Gastroenterol 2021 Jan 11;59(1):63-68. Epub 2021 Jan 11.

Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany.

The liver and gut share an intimate relationship whose communication relies heavily on metabolites, among which bile acids play a major role. Beyond their function as emulsifiers, bile acids have been recognized for their influence on metabolism of glucose and lipids as well as for their impact on immune responses. Therefore, changes to the composition of the bile acid pool can be consequential to liver and to gut physiology. By metabolizing primary bile acids to secondary bile acids, the bacterial gut microbiome modifies how bile acids exert influence. An altered ratio of secondary to primary bile acids is found to be substantial in many studies. Thus, disease pathogenesis and progression could be changed by gut microbiome modification which influences the bile acid pool.
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http://dx.doi.org/10.1055/a-1330-9644DOI Listing
January 2021

Portal and hepatic vein embolization prior to major hepatectomy.

Z Gastroenterol 2021 Jan 11;59(1):35-42. Epub 2021 Jan 11.

Department for General, Visceral and Transplantation Surgery, University Hospital Muenster, Muenster, Germany.

Purpose:  To analyze safety and effectiveness of simultaneous portal and hepatic vein embolization (PHVE) or sequential hepatic vein embolization (HVE) compared to portal vein embolization (PVE) for future remnant liver (FRL) hypertrophy prior to major hepatic surgery.

Methods:  Patients undergoing PVE, PHVE or HVE at our tertiary care center between 2018 and 2020 were retrospectively included. FRLV, standardized FRLV (sFRLV) and sFRLV growth rate per day were assessed via volumetry, as well as laboratory parameters.

Results:  36 patients (f = 15, m = 21; median 64.5 y) were included, 16 patients received PHVE and 20 patients PVE, of which 4 received sequential HVE. Significant increase of FRLV was achieved with both PVE and PHVE compared to baseline (p < 0.0001). sFRLV growth rate did not significantly differ following PHVE (2.2 ± 1.2 %/d) or PVE (2.2 ± 1.7 %/d, p = 0.94). Left portal vein thrombosis (LPVT) was observed after PHVE in 6 patients and in 1 patient after PVE. Sequential HVE showed a considerably high growth rate of 1.42 ± 0.45 %/d after PVE.

Conclusion:  PHVE effectively induces FRL hypertrophy but yields comparable sFRLV to PVE. Sequential HVE further induces hypertrophy after insufficient growth due to PVE. Considering a potentially higher rate of LPVT after PHVE, PVE might be preferred in patients with moderate baseline sFRLV, with optional sequential HVE in non-sufficient responders.
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http://dx.doi.org/10.1055/a-1330-9450DOI Listing
January 2021

Evaluation of impact of elective invasive examinations in patients with transjugular intrahepatic portosystemic shunt in the long-term follow up.

Z Gastroenterol 2021 Jan 11;59(1):24-34. Epub 2021 Jan 11.

Medical Clinic B, Department of Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology, University Hospital Muenster, Muenster, Germany.

Introduction:  In the management of patients with decompensated liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) insertion is well-established but common recommendations in the follow up management are inconsistent. Doppler sonography is commonly used for detection for TIPS dysfunction whilst data on the impact of elective invasive examinations are scarce.

Aim:  The aim of this retrospective analysis is to evaluate potential benefits of elective invasive examinations in the follow up management of patients after TIPS insertion METHODS:  Data of all patients receiving TIPS at the university hospitals of Muenster and Bonn between 2013 and 2018 (n = 534) were collected. The impact of performance of elective invasive examinations at 12 months after TIPS insertion on the occurrence of liver related events (LREs) and frequency of TIPS revisions within 24 months after TIPS insertion was analyzed.

Results:  No significant differences were found concerning occurrence of liver related events after 24 months depending on whether an elective invasive examination was performed. Occurrence of hepatic encephalopathy, relapse of initial indication for TIPS, as well as death or liver transplantation all did not differ. These findings were verified by a subgroup analysis including only patients who did not experience a LRE or TIPS revision within the first 12 months after TIPS procedure.

Conclusion:  The analyzed data suggest no evidence for a beneficial impact due to implementation of an elective invasive examination program after TIPS insertion. Invasive examinations should remain reserved to patients with suspected TIPS dysfunction.
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http://dx.doi.org/10.1055/a-1330-9867DOI Listing
January 2021

Standard versus Endocuff versus cap-assisted colonoscopy for adenoma detection: A randomised controlled clinical trial.

United European Gastroenterol J 2021 Feb 16. Epub 2021 Feb 16.

Department of Medicine 1, Klinikum Ibbenbueren, Teaching Hospital University of Muenster, Münster, Germany.

Background And Aims: Adenoma detection rate (ADR) in colon cancer screening is most important for cancer prophylaxis. This work is the first three-armed randomised controlled clinical trial aimed at comparing a head-to-head setting standard colonoscopy (SC) with Endocuff-assisted colonoscopy (EC) and cap-assisted colonoscopy (CAC) for improvement of ADR.

Methods: Patients from Poland and Germany with independent indication for colonoscopy were randomised into three arms of this trial: EC, CAC and SC. Exclusion criteria were age <18 years, active Crohn's disease or ulcerative colitis, known stenosis and post-colonic resection status.

Results: A total of 585 patients (195 SC, 189 EC and 186 CAC) were enrolled in this study. Indications were not different between the groups (colorectal cancer screening 51%, diagnostic colonoscopy in 31% and post-polypectomy follow-up in 18%; p = 0.94). Withdrawal time was a mean of 7 min in all groups (p = 0.658), and bowel preparation did not differ between the groups. The time to reach the caecum was significantly reduced when using the cap (a mean of 6 min for CAC vs. 7 min for SC; p = 0.0001). There was no significant difference in the primary outcome of the ADR between the groups (EC 32%, CAC 30%, SC 30%; p = 0.815). EC proved to be superior (EC vs. SC) in the sigmoid colon and transverse colon for polyp detection.

Conclusion: The use of EC increased the total number of polyps seen during colonoscopy. In contrast to recent studies, no significant improvement of the ADR was detected.
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http://dx.doi.org/10.1177/2050640620982952DOI Listing
February 2021

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

Lancet Neurol 2021 01 16;20(1):49-59. Epub 2020 Nov 16.

Centro Hospitalar Universitário do Porto, Porto, Portugal.

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261.

Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups.

Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Funding: Alnylam Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30368-9DOI Listing
January 2021

Impaired IFN-γ-dependent STAT3 Activation Is Associated With Dysregulation of Regulatory and Inflammatory Signaling in Monocytes of Ulcerative Colitis Patients.

Inflamm Bowel Dis 2020 Nov 9. Epub 2020 Nov 9.

Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany.

Background: The Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor tofacitinib has been recently approved for the treatment of ulcerative colitis (UC) but not Crohn's disease (CD). Systematic analysis of the JAK/STAT pathway in inflammatory bowel disease is still missing. The aim of this study was to investigate JAK/STAT activation and adjacent signaling in monocytes of patients with inflammatory bowel diseases, which are key players in inflammatory responses.

Methods: Blood samples of active UC (n = 28) and CD patients (n = 28) and healthy controls (n = 22) were collected for primary monocyte investigation. STAT phosphorylation (pSTAT), cytokine secretion, and surface marker expression ± prior tofacitinib blockade in addition to Th-17 and regulatory T cell induction in cocultures were analyzed upon interferon (IFN)-γ timulation.

Results: Baseline frequencies of pSTAT1+ and pSTAT3+ monocytes were significantly higher in UC, whereas IFN-γ-associated crosstalk induction of pSTAT3+ monocytes was missing in UC-derived monocytes compared with controls and CD. This coincided with decreased interleukin (IL)-10 and cluster of differentiation (CD)39 levels, diminished regulatory T cell (Treg) induction, and increased IL-12 and IL-23 secretion compared with controls, which was not observed in CD monocytes. Tofacitinib induced stronger inhibition of inflammatory cytokine release (IL-6, TNFα, IL-12, IL-23) in UC compared with CD monocytes.

Conclusions: In UC monocytes, IFN-γ-associated activation of the JAK/STAT pathway is impaired with an imbalance between STAT1 and STAT3, coinciding with stronger induction of inflammatory monocytes by IFN-γ compared with controls or CD. The fact that tofacitinib had stronger regulatory impact on UC than on CD monocytes further underlines a stronger inflammatory involvement of the JAK/STAT pathway in UC pathogenesis, which might result from missing STAT3 activation to counteract STAT1-induced inflammation.
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http://dx.doi.org/10.1093/ibd/izaa280DOI Listing
November 2020

Analysis of failed therapy evaluations in radioembolization of primary and secondary liver cancers.

J Cancer Res Clin Oncol 2021 May 6;147(5):1537-1545. Epub 2020 Nov 6.

Institute of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Munster, Germany.

Purpose: To analyze patients' characteristics and reasons for not performing planned transarterial radioembolization (TARE) in liver cancer after Tc-labeled macroaggregated albumin (Tc-MAA) evaluation.

Methods: In this retrospective single-center cohort, all patients undergoing Tc-MAA evaluation prior to planned TARE for primary or secondary liver cancer between 2009 and 2018 were analyzed. Patients were assigned to either "TARE" or "no TARE" group. Patients' characteristics, arising reasons for not performing the planned TARE treatment as well as predictive factors for occurrence of these causes were analyzed.

Results: 436 patients [male = 248, female = 188, median age 62 (23-88) years] with Tc-MAA evaluation prior to planned TARE of primary or secondary liver cancer were included in this study. 148 patients (33.9%) did not receive planned TARE. Patients with a hepatic tumor burden > 50%, no liver cirrhosis, no previous therapies and a higher bilirubin were significantly more frequent in "no TARE" compared to "TARE" group. Main reasons for not performing TARE were extrahepatic tracer accumulation (n = 70, 40.5%), non-target accumulation of Tc-MAA (n = 27, 15.6%) or a hepatopulmonary shunt fraction of more than 20% (n = 23, 13.3%). Independent preprocedural parameters for not performing planned TARE were elevated bilirubin (p = 0.021) and creatinine (p = 0.018) and lower MELD score (p = 0.031).

Conclusion: A substantial number of patients are precluded from TARE following Tc-MAA evaluation, which is, therefore, implicitly needed to determine contraindications to TARE and should not be refrained from in pretreatment process. However, a preceding careful patient selection is needed especially in patients with high hepatic tumor burden and alteration in lab parameters.
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http://dx.doi.org/10.1007/s00432-020-03443-zDOI Listing
May 2021

Repeated radioembolization in advanced liver cancer.

Ann Transl Med 2020 Sep;8(17):1055

Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany.

Background: To evaluate safety and clinical outcome of repeated transarterial Y (yttrium) radioembolization (TARE) in primary and metastatic liver cancer.

Methods: Between 2009 and 2018, n=288 patients underwent TARE for treatment of malignant liver disease in a tertiary care hospital. This retrospective single center study analyzed the safety and outcome of patients (n=11/288) undergoing repeated resin microsphere TARE. Included patients suffered from hepatocellular carcinoma (n=3), colorectal cancer (n=2), breast cancer (n=2), intrahepatic cholangiocarcinoma (n=3), and neuroendocrine carcinoma (n=1). All patients had shown either partial response (n=9) or stable disease (n=2) after first TARE. Lab parameters, response assessed by the Response Evaluation Criteria in Solid Tumors (mRECIST/RECIST) at 3 months and overall survival was analyzed. Additionally, patients with repeated TARE were compared to a matched control group (n=56) with single TARE therapy. Kaplan Meier analysis was performed to analyze survival.

Results: Patients after repeated TARE showed similar increase in lab parameters as compared to their first TARE. No case of radioembolization induced liver disease was observed. While n=5/11 patients showed a partial response and n=4/11 patients a stable disease after repeated TARE, only n=2/11 patients suffered from progressive disease. Median overall survival was 20.9±11.9 months for the repeated TARE group while it was 5.9±16.2 months for the control group.

Conclusions: Repeated Y TARE is safe and can be of benefit for patients yielding a comparable degree of local disease control compared to patients with singular TARE.
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http://dx.doi.org/10.21037/atm-20-2658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575953PMC
September 2020

Patient-reported outcomes on familial amyloid polyneuropathy (FAP).

Orphanet J Rare Dis 2020 10 14;15(1):287. Epub 2020 Oct 14.

Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A14, 48149, Münster, Germany.

Background: Transthyretin familial amyloid polyneuropathy (ATTR-FAP) is a rare autosomal dominant inherited disease affecting multiple organ systems. ATTR-FAP patients' experiences have rarely been documented. The aim of this study was to collect patient reported outcomes across different countries to assess unmet needs and challenges. An anonymous survey was conducted at the 2nd European meeting on ATTR amyloidosis in Berlin in September 2019. Survey questions captured information on demographics, clinical characteristics, diagnostic experience, quality of life, disability and ATTR-FAP management.

Results: A total of 38 ATTR-FAP patients from 15 different countries participated in the survey. ATTR-FAP had a substantial impact on patients' day-to-day life, including difficulties in standing, walking, and participation in community activities. It also had negative effects on the mental health of patients. The survey highlighted several unmet needs and challenges from a patients' perspective, including (i) a need for increased awareness and a standardized diagnostic pathway, (ii) a need for better treatment access and supportive care and (iii) a need for better information about research and clinical trials.

Conclusions: This global patient survey provides valuable findings to address ATTR-FAP patients' needs and challenges in order to further the goal of patient-centered care.
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http://dx.doi.org/10.1186/s13023-020-01575-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556910PMC
October 2020

CRISPR/Cas9-mediated correction of mutated copper transporter ATP7B.

PLoS One 2020 30;15(9):e0239411. Epub 2020 Sep 30.

Medizinische Klinik B, Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie, Universitätsklinikum Münster, Münster, Germany.

Wilson's disease (WD) is a monogenetic liver disease that is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion in the liver. The excess Cu accumulates in various organs such as the liver and brain. WD patients show clinical heterogeneity, which can range from acute or chronic liver failure to neurological symptoms. The course of the disease can be improved by a life-long treatment with zinc or chelators such as D-penicillamine in a majority of patients, but serious side effects have been observed in a significant portion of patients, e.g. neurological deterioration and nephrotoxicity, so that a liver transplant would be inevitable. An alternative therapy option would be the genetic correction of the ATP7B gene. The novel gene therapy method CRISPR/Cas9, which has recently been used in the clinic, may represent a suitable therapeutic opportunity. In this study, we first initiated an artificial ATP7B point mutation in a human cell line using CRISPR/Cas9 gene editing, and corrected this mutation by the additional use of single-stranded oligo DNA nucleotides (ssODNs), simulating a gene correction of a WD point mutation in vitro. By the addition of 0.5 mM of Cu three days after lipofection, a high yield of CRISPR/Cas9-mediated ATP7B repaired cell clones was achieved (60%). Moreover, the repair efficiency was enhanced using ssODNs that incorporated three blocking mutations. The repaired cell clones showed a high resistance to Cu after exposure to increasing Cu concentrations. Our findings indicate that CRISPR/Cas9-mediated correction of ATP7B point mutations is feasible and may have the potential to be transferred to the clinic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239411PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526882PMC
November 2020

A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

Orphanet J Rare Dis 2020 07 8;15(1):179. Epub 2020 Jul 8.

Umeå University, Universitetstorget 16, 901 87, Umeå, Sweden.

Background: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.

Results: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.

Conclusions: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.

Trial Registration: The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.
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http://dx.doi.org/10.1186/s13023-020-01399-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341568PMC
July 2020

Persisting SARS-CoV-2 viraemia after rituximab therapy: two cases with fatal outcome and a review of the literature.

Br J Haematol 2020 07 22;190(2):185-188. Epub 2020 Jun 22.

Department of Gastroenterology and Hepatology, Section for Infectious Diseases, University Hospital Muenster, Muenster, Germany.

SARS-CoV-2 infection can cause severe pneumonia (COVID-19). There is evidence that patients with comorbidities are at higher risk of a severe disease course. The role of immunosuppression in the disease course is not clear. In the present report, we first describe two cases of persisting SARS-CoV-2 viraemia with fatal outcome in patients after rituximab therapy.
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http://dx.doi.org/10.1111/bjh.16896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300950PMC
July 2020

Conversion from Standard-Release Tacrolimus to MeltDose Tacrolimus (LCPT) Improves Renal Function after Liver Transplantation.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, 48149 Münster, Germany.

Renal impairment is a typical side effect of tacrolimus (Tac) treatment in liver transplant (LT) recipients. One strategy to avoid renal dysfunction is to increase the concentration/dose (C/D) ratio by improving drug bioavailability. LT recipients converted from standard-release Tac to MeltDose Tac (LCPT), a novel technological formulation, were able to reduce the required Tac dose due to higher bioavailability. Hence, we hypothesize that such a conversion increases the C/D ratio, resulting in a preservation of renal function. In the intervention group, patients were switched from standard-release Tac to LCPT. Clinical data were collected for 12 months after conversion. Patients maintained on standard-release Tac were enrolled as a control group. Twelve months after conversion to LCPT, median C/D ratio had increased significantly by 50% ( < 0.001), with the first significant increase seen 3 months after conversion ( = 0.008). In contrast, C/D ratio in the control group was unchanged after 12 months (1.75 vs. 1.76; = 0.847). Estimated glomerular filtration rate (eGFR) had already significantly deteriorated in the control group at 9 months (65.6 vs. 70.6 mL/min/1.73 m at study onset; = 0.006). Notably, patients converted to LCPT already had significant recovery of mean eGFR 6 months after conversion (67.5 vs. 65.3 mL/min/1.73 m at study onset; = 0.029). In summary, conversion of LT recipients to LCPT increased C/D ratio associated with renal function improvement.
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http://dx.doi.org/10.3390/jcm9061654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356524PMC
June 2020

MicroRNA-320a Monitors Intestinal Disease Activity in Patients With Inflammatory Bowel Disease.

Clin Transl Gastroenterol 2020 03;11(3):e00134

Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.

Objectives: In patients with inflammatory bowel disease (IBD), a treat-to-target treatment strategy requires tight monitoring of disease activity. Noninvasive biomarkers may help to monitor the intestinal disease activity. We demonstrated recently that peripheral microRNA (miR)-320a expression in mice follows the course of experimental colitis. The aim of this study was to evaluate the potential of miR-320a to monitor the disease activity in patients with IBD, to predict the course of disease, and to distinguish IBD from infectious colitis.

Methods: The miR-320a levels were prospectively assessed by quantitative real-time polymerase chain reaction analysis of peripheral blood samples from 40 patients with Crohn's disease (CD) and 37 patients with ulcerative colitis (UC) as well as from 19 healthy control individuals and 7 patients with infectious colitis. Disease activity was quantified by appropriate clinical disease indices and endoscopic scoring systems.

Results: When compared with healthy controls, miR-320a blood levels were significantly increased in patients with active CD and UC (16.1 ± 2.6 vs 2,573 ± 941; vs 434 ± 96; both P < 0.001) and patients with IBD in remission (316 ± 251 [CD] and 91 ± 29 [UC]; both P < 0.001). In patients with CD, miR-320a levels showed a strong correlation with the endoscopic disease activity (r = 0.76; P < 0.001). Similarly, in patients with UC, we detected a significantly enhanced miR-320a expression, which was highest in patients with severe endoscopic disease activity (eMayo = 0-1: 66 ± 16 vs eMayo = 2: 352 ± 102; vs eMayo = 3: 577 ± 206; both P < 0.001). Finally, miR-320a blood expression in patients with active CD and UC significantly increased compared with patients with infectious colitis (63 ± 13, P < 0.001).

Discussion: MiR-320a expression in peripheral blood from patients with IBD follows the clinical and endoscopic disease activities and may help to distinguish IBD from infectious colitis.
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http://dx.doi.org/10.14309/ctg.0000000000000134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145033PMC
March 2020

ATP7B knockout disturbs copper and lipid metabolism in Caco-2 cells.

PLoS One 2020 10;15(3):e0230025. Epub 2020 Mar 10.

Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.

Intestinal cells control delivery of lipids to the body by adsorption, storage and secretion. Copper (Cu) is an important trace element and has been shown to modulate lipid metabolism. Mutation of the liver Cu exporter ATP7B is the cause of Wilson disease and is associated with Cu accumulation in different tissues. To determine the relationship of Cu and lipid homeostasis in intestinal cells, a CRISPR/Cas9 knockout of ATP7B (KO) was introduced in Caco-2 cells. KO cells showed increased sensitivity to Cu, elevated intracellular Cu storage, and induction of genes regulating oxidative stress. Chylomicron structural protein ApoB48 was significantly downregulated in KO cells by Cu. Apolipoproteins ApoA1, ApoC3 and ApoE were constitutively induced by loss of ATP7B. Formation of small sized lipid droplets (LDs) was enhanced by Cu, whereas large sized LDs were reduced. Cu reduced triglyceride (TG) storage and secretion. Exposure of KO cells to oleic acid (OA) resulted in enhanced TG storage. The findings suggest that Cu represses intestinal TG lipogenesis, while loss of ATP7B results in OA-induced TG storage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230025PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064347PMC
June 2020

TIPS Modification in the Management of Shunt-Induced Hepatic Encephalopathy: Analysis of Predictive Factors and Outcome with Shunt Modification.

J Clin Med 2020 Feb 19;9(2). Epub 2020 Feb 19.

Institute of Clinical Radiology, University Hospital Muenster, D-48149 Muenster, Germany.

Purpose: To evaluate predictive parameters for the development of Hepatic Encephalopathy (HE) after Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement and for success of shunt modification in the management of shunt-induced HE.

Methods: A retrospective analysis of all patients with TIPS ( = 344) has been performed since 2011 in our university liver center. = 45 patients with HE after TIPS were compared to = 48 patients without HE after TIPS (case-control-matching). Of = 45 patients with TIPS-induced HE, = 20 patients received a reduction stent ( = 18) or TIPS occlusion ( = 2) and were differentiated into responders (improvement by at least one HE grade according to the West Haven classification) and non-responders (no improvement).

Results: Older patient age, increased serum creatinine and elevated International Normalized Ratio (INR) immediately after TIPS placement were independent predictors for the development of HE. In 11/20 patients (responders, 55%) undergoing shunt modification, the HE grade was improved compared with nine non-responders (45%), with no relevant recurrence of refractory ascites or variceal bleeding. A high HE grade after TIPS insertion was the only positive predictor of treatment response ( = 0.019). A total of 10/11 responders (91%) survived the 6 months follow-up after modification but only 6/9 non-responders (67%) survived.

Discussion: Older patient age as well as an increased serum creatinine and INR after TIPS are potential predictors for the development of HE. TIPS reduction for the treatment of TIPS-induced HE is safe, with particular benefit for patients with pronounced HE.
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http://dx.doi.org/10.3390/jcm9020567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073830PMC
February 2020

Prognostic Factors for Overall Survival in Advanced Intrahepatic Cholangiocarcinoma Treated with Yttrium-90 Radioembolization.

J Clin Med 2019 Dec 25;9(1). Epub 2019 Dec 25.

Department of Clinical Radiology, Universitätsklinikum Münster, D-48149 Münster, Germany.

Purpose: To evaluate factors associated with survival following transarterial Y (yttrium) radioembolization (TARE) in patients with advanced intrahepatic cholangiocarcinoma (ICC).

Methods: This retrospective multicenter study analyzed the outcome of three tertiary care cancer centers in patients with advanced ICC following resin microsphere TARE. Patients were included either after failed previous anticancer therapy, including relapse after surgical resection, or for having a minimum of 25% of total liver volume affected by ICC. Patients were stratified and response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria at 3 months. Kaplan-Meier analysis was performed to analyze survival followed by cox regression to determine independent prognostic factors for survival.

Results: 46 patients were included (19 male, 27 female), median age 62.5 years (range 29-88 years). A total of 65% of patients had undergone previous therapy, while 63% had a tumor volume > 25% of the entire liver volume. Median survival was 9.5 months (95% CI: 6.1-12.9 months). Due to loss in follow-up, = 37 patients were included in the survival analysis. Cox regression revealed the extent of liver disease to one or both liver lobes being associated with survival, irrespective of tumor volume ( = 0.041). Patients with previous surgical resection of ICC had significantly decreased survival (3.9 vs. 12.8 months, = 0.002). No case of radiation-induced liver disease was observed.

Discussion: Survival after Y TARE in patients with advanced ICC primarily depends on disease extent. Only limited prognostic factors are associated with a general poor overall survival.
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http://dx.doi.org/10.3390/jcm9010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020033PMC
December 2019

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis.

J Neurol 2020 Apr 18;267(4):1070-1079. Epub 2019 Dec 18.

Boston University School of Medicine, Boston, MA, USA.

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo.

Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2 Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66.

Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm.

Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.
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http://dx.doi.org/10.1007/s00415-019-09671-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109169PMC
April 2020

Inflammation, etiologies and Model for End-stage Liver Disease score: What makes liver disease patients susceptible to developing colorectal neoplasia?

Hepatol Res 2020 Mar 17;50(3):342-352. Epub 2020 Jan 17.

Department of Gastroenterology and Hepatology, University Hospital Münster, Albert-Schweitzer-Campus 1, Münster, Germany.

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http://dx.doi.org/10.1111/hepr.13463DOI Listing
March 2020

Radiotherapy of extranodal low-grade follicular and marginal zone lymphomas: long-term follow-up of 159 patients.

Strahlenther Onkol 2020 Feb 15;196(2):117-125. Epub 2019 Nov 15.

Radiation Oncology Department, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.

Objective: To evaluate clinical, histopathologic, and radiation (RT) dose parameters in patients with extranodal low-grade (ENLG) non-Hodgkin lymphoma (NHL) and their possible impact on local control (LC) and survival.

Materials And Methods: The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively.

Results: The predominant histological subtype (73%) was marginal zone lymphoma (MZL). Common lesion sites were the gastrointestinal tract (GIT; 33%), skin (26%), and orbit (21%). The majority of patients (88%) presented with stage I/II disease. Thirty-three (20%) lesions were treated with reduced-dose RT (≤30.6 Gy) and 148 lesions (80%) with conventional-dose RT (>30.6 Gy), with an overall median dose of 39.6 Gy (range 4-63). The median follow-up period was 72 months. The 10-year local control (LC), Progression-free survival (PFS), and overall survival (OS) rates were 96, 65, and 82%, respectively. Higher overall response rate (ORR; 98% vs. 94%, p = 0.001) and complete response rate (CRR; 95% vs. 73%, p = 0.001) were observed in patients treated with conventional-dose regimens than in those treated with reduced-dose regimens. Ten-year PFS (p = 0.90) and OS (p = 0.40) was similar between the two dose groups. RT was well tolerated in both dose groups, with no grade 4/5 toxicities. In the multivariate analysis, RT dose and timing (upfront or salvage) were related to LC, whereas age, histology, and complete response (CR) to RT were associated with PFS. Patient age and radiation field size impacted OS.

Conclusion: RT is an effective and curative local treatment for early-stage FL and MZL at conventional and reduced radiation doses. Conventional-doses seems to be associated with local response improvement, without significant differences in PFS rates. Age, histology, and response to RT may influence the PFS.
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http://dx.doi.org/10.1007/s00066-019-01538-2DOI Listing
February 2020

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

J Neurol 2020 Mar 14;267(3):703-712. Epub 2019 Nov 14.

AP-HP, Université Paris Saclay, CHU Bicêtre, Université Paris-Sud, INSERM 1195, Paris, France.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.
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http://dx.doi.org/10.1007/s00415-019-09602-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035216PMC
March 2020

Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype.

Inflamm Bowel Dis 2020 02;26(3):391-406

Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany.

Background: The inhibition of Janus kinases (JAKs) and subsequent signal transducers and activators of transcription (STATs) by tofacitinib represents a new therapeutic strategy in inflammatory bowel diseases (IBD) as clinical trials have led to approval of tofacitinib for ulcerative colitis (UC) and hint at a possible efficacy for Crohn`s disease (CD). However, the impact of tofacitinib on cellular response of monocytes, which are key players in inflammatory responses, has not been investigated so far. We aimed to analyze JAK/STAT-inhibition by tofacitinib in monocytes of IBD patients and healthy controls.

Methods: Primary monocytes of IBD patients with active disease and healthy controls (n = 18) were analyzed for cytokine expression and phenotype after granulocyte macrophage colony-stimulating factor (GM-CSF)/interferon (IFN)γ-stimulation and tofacitinib pretreatment (1-1000 nM) and capacity to induce Foxp3+-regulatory T cells (Tregs) in cocultures. In total, 20 UC patients and 21 CD patients were included. Additionally, dose-dependent inhibition of JAK/STAT-phosphorylation was analyzed in controls.

Results: Pro-inflammatory costimulation with GM-CSF/IFNγ resulted in significant tumor necrosis factor (TNFα) and interleukin (IL)-6 increase, whereas IL-10 expression decreased in monocytes. Tofacitinib modulated the responses of activated monocytes toward a regulatory phenotype through reduced TNFα and IL-6 secretion and enhanced Treg induction in cocultures. However, in monocytes from active IBD patients, higher tofacitinib dosages were needed for blockade of pro-inflammatory cytokines. Tofacitinib induced stronger regulatory phenotypes in monocytes of UC patients, including more effective inhibition of pro-inflammatory pathways and better restoration of anti-inflammatory mechanisms as compared with CD-derived monocytes.

Conclusion: Tofacitinib dose-dependently reprograms monocytes toward a more regulatory cell type. This beneficial effect possibly results from selective JAK/STAT-blockade by adequate tofacitinib dosage with inhibition of pro-inflammatory responses and permission of a balance-shift toward regulatory pathways.
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http://dx.doi.org/10.1093/ibd/izz213DOI Listing
February 2020

Compound-specific adaptation of hepatoma cell lines to toxic iron.

Metallomics 2019 11 25;11(11):1836-1846. Epub 2019 Sep 25.

Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A14, 48149 Münster, Germany.

Cellular adaptation to excess iron (Fe) is a major determinant to protect tissues from toxicity. The adaptation of hepatoma cell lines following exposure to toxic levels of Fe compounds was studied. A dose- and time-dependent induction of toxicity was observed that was strictly compound-specific. Similar ranging orders of toxicity, i.e. iron chloride >iron sulfate >iron citrate, were observed in four human hepatoma cell lines. Long-term cultivation of HepG2 cells in 10 mM iron citrate resulted in a resistant cell line that displayed high proliferation rates for several months. Resistant cells showed increased viability at iron citrate concentrations ranging from 5-15 mM, while exposition to iron chloride or iron sulfate induced high rates of toxicity similar to parental cells. Resistance was not due to decreased Fe uptake/storage since high intracellular Fe levels were observed. A broad range of modulated gene expression was associated with short- and long-term iron citrate exposition; however, after weaning of resistant cells, re-exposition to Fe induced a similar level of toxicity as observed in parental cells suggesting that a transient adaptation of gene expression was mounted. The results indicate that, depending on the nature of the Fe compound, a specific level of toxicity is induced in hepatic cells which however can be overcome by establishment of resistance.
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http://dx.doi.org/10.1039/c9mt00202bDOI Listing
November 2019

Chronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment.

Pathogens 2019 Aug 22;8(3). Epub 2019 Aug 22.

Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.

Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib , we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle . First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect.
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http://dx.doi.org/10.3390/pathogens8030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789582PMC
August 2019

Chronic liver disease promotes lesions of the colorectal adenoma-carcinoma sequence, independent of liver cirrhosis.

United European Gastroenterol J 2019 06 21;7(5):662-672. Epub 2019 Jan 21.

Department of Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.

Background: Research increasingly focuses on identifying individuals at greater risk of colorectal cancer (CRC) to enhance colonoscopy screening efficacy.

Objective: The objective of this article is to determine associations between chronic liver disease and lesions along the colorectal adenoma-carcinoma sequence.

Methods: This retrospective study encompasses consecutive liver disease patients (LDPs) of all etiologies evaluated for liver transplantation at a single institution and a control group of liver-healthy patients (LHPs) undergoing colonoscopy as part of the German CRC screening program.Rates of polyps, adenomas, high-risk situations (HRS) and CRC were analyzed in univariable and multivariable settings adjusting for age, gender, body mass index and number of colonoscopies. Differences between LHPs and LDPs and between cirrhotic and noncirrhotic hepatopathy were assessed.

Results: In total, 1046 patients (52.6% male, median age 59.6 years) were included, of whom 38.9% had liver disease. A total of 41.0% of all patients showed polyps, 23.2% adenomas, 10.0% HRS, and 0.5% CRC. LDPs were more likely to develop polyps, adenomas and HRS than LHPs, both in univariable and multivariable analysis. There were no significant differences between cirrhotic and noncirrhotic patients.

Conclusion: Chronic liver disease of any etiology is associated with colonic lesions of the colorectal adenoma-carcinoma sequence, independent of cirrhosis. LDPs should receive intensified, and earlier, colonoscopy screening.
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http://dx.doi.org/10.1177/2050640619826391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545718PMC
June 2019

Achieving Complete Remission of Hepatocellular Carcinoma: A Significant Predictor for Recurrence-Free Survival after Liver Transplantation.

Can J Gastroenterol Hepatol 2019 8;2019:5796074. Epub 2019 Jan 8.

Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, 48149 Muenster, Germany.

Background: Liver transplantation (LT) is a curative treatment for hepatocellular carcinoma (HCC) and the underlying primary liver disease; however, tumor recurrence is still a major issue. Therefore, the aim of this study was to assess predictors and risk factors for HCC recurrence after LT in patients within and outside the Milan criteria with a special focus on the impact of different bridging strategies.

Methods: All patients who underwent LT for HCC between 07/2002 and 09/2016 at the University Hospital of Muenster were consecutively included in this retrospective study. Database research was performed and a multivariable regression analysis was conducted to explore potential risk factors for HCC recurrence.

Results: A total of 82 patients were eligible for the statistical analysis. Independent of bridging strategy, achieving complete remission (CR) was significantly associated with a lower risk for tumor recurrence (; OR = 0.426, 95% CI 0.198-0.918). A maximal diameter of lesion < 3 cm was also associated with lower recurrence rates (; OR = 0.140, 95% CI 0.022-0.914). Vascular invasion proved to be an independent risk factor for HCC recurrence (; OR = 11.357, 95% CI 2.142-60.199).

Conclusion: Achieving CR prior to LT results in a significant risk reduction of HCC recurrence after LT independent of the treatment modalities applied.
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http://dx.doi.org/10.1155/2019/5796074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341263PMC
June 2019

Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis.

Gastroenterology 2019 03 17;156(4):1173-1189.e5. Epub 2018 Nov 17.

Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy. Electronic address:

Background & Aims: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD.

Methods: We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b and Atp7b (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with WD in Italy and liver tissues from patients without WD (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, apoptosis assays, and electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy.

Results: After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b mice and rats (but not controls) had multiple autophagosomes. In ATP7B-knockout cells, mammalian target of rapamycin (mTOR) had decreased activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB to the nucleus and activation of autophagy-related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated the death of ATP7B-knockout HepG2 cells compared with wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death.

Conclusion: ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.
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http://dx.doi.org/10.1053/j.gastro.2018.11.032DOI Listing
March 2019

Pictorial Representation of Illness and Self Measure (PRISM): A Novel Visual Instrument to Quantify Suffering in Liver Cirrhosis Patients and Liver Transplant Recipients.

Ann Transplant 2018 Sep 28;23:674-680. Epub 2018 Sep 28.

Department of Gastroenterology and Hepatology, Münster University Hospital, Münster, Germany.

BACKGROUND The level of suffering of chronically ill patients does not necessarily correlate with illness severity. In this study, we evaluated the burden of suffering and its impact on health-related quality of life in liver transplant recipients and liver cirrhosis patients. MATERIAL AND METHODS The Pictorial Representation of Illness and Self Measure (PRISM) was used to explore levels of suffering in outpatients of Münster University Hospital, Germany. Self-illness separation scores were analyzed as a measure of disease-specific burden of suffering. Health-related quality of life was measured using the Short Form Health Survey (SF-36). RESULTS Data from 201 subjects were statistically analyzed. Median Self-illness separation scores for liver transplant recipients and patients with liver cirrhosis were 13.5 (minimum/maximum: 0.2/25.6) cm and 6.3 (0.1/25.6) cm (p<0.001), respectively. The median SF-36 Mental Component Summary and Physical Component Summary scores were 46.4 (12.5/66.2) and 40.1 (12.3/61.1), respectively. Higher health-related quality of life was associated with greater self-illness separation. Liver transplant recipients showed normal Mental Component Summary scores compared with the general German population; patients with liver cirrhosis had significantly lower Mental Component Summary scores. Physical Component Summary scores were significantly higher in liver transplant recipients than in patients with liver cirrhosis, but still lower than in the general population. CONCLUSIONS PRISM is a novel, simple tool for measuring the illness burden in liver transplant recipients and patients with liver cirrhosis. This measure may help to identify patients at a higher risk of psychological disorders.
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http://dx.doi.org/10.12659/AOT.910278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248009PMC
September 2018