Publications by authors named "Hartmut Schmidt"

255 Publications

Less severe course of COVID-19 is associated with elevated levels of antibodies against seasonal human coronaviruses OC43 and HKU1 (HCoV OC43, HCoV HKU1).

Int J Infect Dis 2021 Feb 23. Epub 2021 Feb 23.

Institute of Virology, Department of Clinical Virology, University Hospital Münster, Germany.

The clinical course of COVID-19 is very heterogeneous: Most infected individuals can be managed in an outpatient setting, but a substantial proportion of patients requires intensive care, resulting in a high rate of fatalities. We performed a biomarker study to assess the impact of prior infections with seasonal coronaviruses on COVID-19 severity. 60 patients with confirmed COVID-19 infections were included (age 30 - 82 years; 52 males, 8 females): 19 inpatients with critical disease, 16 inpatients with severe or moderate disease and 25 outpatients. Patients with critical disease had significantly lower levels of anti-HCoV OC43-NP (p = 0.016) and HCoV HKU1-NP (p = 0.023) antibodies at the first encounter compared to other COVID-19 patients. Our results indicate that prior infections with seasonal coronaviruses might protect against a severe course of disease.
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http://dx.doi.org/10.1016/j.ijid.2021.02.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901274PMC
February 2021

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
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

A Dual Nanosensor Approach to Determine the Cytosolic Concentration of ATP in Astrocytes.

Front Cell Neurosci 2020 18;14:565921. Epub 2020 Sep 18.

Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University Leipzig, Leipzig, Germany.

Adenosine triphosphate (ATP) is the central energy carrier of all cells and knowledge on the dynamics of the concentration of ATP ([ATP]) provides important insights into the energetic state of a cell. Several genetically encoded fluorescent nanosensors for ATP were developed, which allow following the cytosolic [ATP] at high spatial and temporal resolution using fluorescence microscopy. However, to calibrate the fluorescent signal to [ATP] has remained challenging. To estimate basal cytosolic [ATP] ([ATP]) in astrocytes, we here took advantage of two ATP nanosensors of the ATeam-family (ATeam1.03; ATeam1.03YEMK) with different affinities for ATP. Altering [ATP] by external stimuli resulted in characteristic pairs of signal changes of both nanosensors, which depend on [ATP]. Using this dual nanosensor strategy and epifluorescence microscopy, [ATP] was estimated to be around 1.5 mM in primary cultures of cortical astrocytes from mice. Furthermore, in astrocytes in acutely isolated cortical slices from mice expressing both nanosensors after stereotactic injection of AAV-vectors, 2-photon microscopy revealed [ATP] of 0.7 mM to 1.3 mM. Finally, the change in [ATP] induced in the cytosol of cultured cortical astrocytes by application of azide, glutamate, and an increased extracellular concentration of K were calculated as -0.50 mM, -0.16 mM, and 0.07 mM, respectively. In summary, the dual nanosensor approach adds another option for determining the concentration of [ATP] to the increasing toolbox of fluorescent nanosensors for metabolites. This approach can also be applied to other metabolites when two sensors with different binding properties are available.
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http://dx.doi.org/10.3389/fncel.2020.565921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530325PMC
September 2020

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 2020 Nov 6. 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
November 2020

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

EFFICACY OF 90Y-RADIOEMBOLIZATION IN METASTATIC COLORECTAL CANCER DEPENDING ON THE PRIMARY TUMOR SIDE.

Dig Dis 2020 Nov 3. Epub 2020 Nov 3.

Metastatic colorectal cancer (mCRC) is associated with different molecular biology, clinical characteristics and outcome depending on the primary tumor localization. We aimed to evaluate the effectiveness of 90Y-radioembolization (RE) for therapy of colorectal liver metastases depending on the primary tumor side. We performed a retrospective analysis of n=73 patients with mCRC and RE in our university liver center between 2009 and 2018. Patients were stratified according to the primary tumor side (left vs. right hemicolon), treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) at follow-up after 3 months. Kaplan-Meier analysis was performed to analyze survival followed by Cox regression to determine independent prognostic factors for survival. Prior to RE all patients had received systemic therapy, with either stable or progressive disease, but no partial or complete response. In n=22/73 (30.1%) patients the primary tumor side was in the right colon, in n=51/73 (69.9%) patients in the left colon. Hepatic tumor burden was ≤25% in n=36/73 (49.3%) patients and >25% in n=37/73 (50.7%) patients. At 3 months, n=21 (33.8%) patients showed treatment response [n=2 (3.2%) complete response, n=19 (30.6%) partial response], n=13 (21.0%) stable disease, and n=28 (45.2%) progressive disease after RE. The median survival in case of primary tumor side in the left colon was significantly higher than for primary tumors in the right colon (8.7 vs. 6.0 months, p=0.033). The median survival for a hepatic tumor burden ≤25% was significantly higher compared with >25% (13.9 vs. 4.3 months, p<0.001). The median overall survival was 6.1 months. The median survival after RE in hepatic-metastatic CRC depends on the primary tumor side and the pre-procedural hepatic tumor burden.
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http://dx.doi.org/10.1159/000512744DOI Listing
November 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

Association of contact to small children with a mild course of COVID-19.

Int J Infect Dis 2020 Nov 5;100:314-315. Epub 2020 Sep 5.

Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), University Hospital Münster, Germany.

It is known that severe COVID-19 cases in small children are rare. If a childhood-related infection were protective against a severe course of COVID-19, it would be expected that adults with intensive and regular contact with small children also may have a mild course of COVID-19 more frequently. To test this hypothesis, a survey among 4010 recovered COVID-19 patients was conducted in Germany. 1186 complete answers were collected. 6.9% of these patients reported frequent and regular job-related contact with children below ten years of age, and 23.2% had their own small children, which was higher than expected. In the relatively small subgroup with intensive care treatment (n = 19), patients without contact with small children were overrepresented. These findings are not well explained by age, gender, or BMI distribution of those patients and should be validated in other settings.
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http://dx.doi.org/10.1016/j.ijid.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832519PMC
November 2020

SERPINA1 modulates expression of amyloidogenic transthyretin.

Exp Cell Res 2020 10 5;395(2):112217. Epub 2020 Aug 5.

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

Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression. Oncostatin M (OSM) induced SERPINA1 in hepatoma cells and mice, while concomitantly TTR expression was significantly reduced. SERPINA1 knockdown resulted in specific elevated TTR expression in hepatoma cells; however other genes belonging to the group of acute phase proteins were unaffected. In mice, serum TTR was elevated after mSERPINA1 knockdown throughout antisense treatment. Following SERPINA1 knockdown, TTR deposition in several tissues, including dorsal root ganglia and intestine, was found to be increased, however numbers did not exceed significance levels. The data suggest that SERPINA1 is a co-factor of TTR expression. Our findings provide novel insight in the regulation of TTR and reveal a role of SERPINA1 in the pathogenesis of ATTR amyloidosis.
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http://dx.doi.org/10.1016/j.yexcr.2020.112217DOI Listing
October 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

Immune-Mediated Hepatitis Induced by Therapy With Alemtuzumab in a Patient With Multiple Sclerosis.

Hepatology 2021 Jan 14;73(1):460-463. Epub 2020 Dec 14.

Department of Internal Medicine B, University Hospital Münster, Münster, Germany.

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http://dx.doi.org/10.1002/hep.31435DOI Listing
January 2021

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

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction.

Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts.

Results: MTD was 3 mg/m tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t of 8 to 9 h without accumulation in daily administrations.

Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
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http://dx.doi.org/10.3390/cancers12061488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352358PMC
June 2020

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

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

Freiburg, Germany.

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

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

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

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

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

Serum levels of ferritin and transferrin serve as prognostic factors for mortality and survival in patients with end-stage liver disease: A propensity score-matched cohort study.

United European Gastroenterol J 2020 04 26;8(3):332-339. Epub 2019 Nov 26.

Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, Albert-Schweitzer-Campus 1 A1, Muenster, Germany.

Background: Patients with end-stage liver disease are known to suffer from a significantly high risk of mortality, but accurate prediction of the course of disease is challenging.

Objective: The study aim was to evaluate the independent prognostic and clinical importance of serum levels of ferritin and transferrin for 90-day survival of patients with liver disease.

Methods: Patients with end-stage liver disease treated during a 2-year period were enrolled retrospectively in a single-centre study. Unmatched and propensity score matching (PSM) analyses were applied.

Results: The study cohort comprised 286 patients with end-stage liver disease, of which 22.9% died during the observational period. High serum ferritin levels and low serum transferrin levels were associated significantly with increased 90-day mortality in the unmatched ( < 0.001) and PSM study population ( = 0.017). Serum levels of ferritin and transferrin had high prognostic capability to predict 90-day survival similar to the Model for End-stage Liver Disease. Patients with serum ferritin values >1030.5 µg/l had a 50% risk of dying within 11 days after measurement, which translated up to a 90-day mortality of 83%.

Conclusion: Serum levels of ferritin and transferrin have independent and excellent capabilities to determine prognosis in patients with end-stage liver disease. Ferritin measurements can reliably identify those with high mortality in daily practice.
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http://dx.doi.org/10.1177/2050640619891283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184660PMC
April 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

Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

Amyloid 2020 Sep 4;27(3):153-162. Epub 2020 Mar 4.

Assistance Publique-Hôpitaux de Paris (APHP), French National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire Bicêtre, Universite Paris-Sud, INSERM Unite, Paris, France.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated. Patients received either patisiran 0.3 mg/kg ( = 148) or placebo ( = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL. At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1;  = 1.10 × 10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2;  = 1.4 × 10), EuroQoL-visual analog scale (LS mean difference: 9.5; =.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0;  = 4.07 × 10) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; =.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation. The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.
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http://dx.doi.org/10.1080/13506129.2020.1730790DOI Listing
September 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

Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review.

Adv Ther 2020 04 17;37(4):1279-1301. Epub 2020 Feb 17.

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

Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85 is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.
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http://dx.doi.org/10.1007/s12325-020-01251-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140758PMC
April 2020

Regression of cardiac amyloid load documented by cardiovascular magnetic resonance in a patient with hereditary amyloidosis.

Clin Res Cardiol 2020 07 11;109(7):949-956. Epub 2020 Feb 11.

Department of Cardiology I, Division of Cardiovascular Imaging, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.

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http://dx.doi.org/10.1007/s00392-020-01611-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308258PMC
July 2020

Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper.

Free Radic Biol Med 2020 04 4;150:1-11. Epub 2020 Feb 4.

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address:

Therapies for lung cancer patients initially elicit desirable responses, but the presence of hypoxia and drug resistant cells within tumors ultimately lead to treatment failure. Disulfiram (DSF) is an FDA approved, copper chelating agent that can target oxidative metabolic frailties in cancer vs. normal cells and be repurposed as an adjuvant to cancer therapy. Clonogenic survival assays showed that DSF (50-150 nM) combined with physiological levels of Cu (15 μM CuSO) was selectively toxic to H292 NSCLC cells vs. normal human bronchial epithelial cells (HBEC). Furthermore, cancer cell toxicity was exacerbated at 1% O, relative to 4 or 21% O. This selective toxicity of DSF/Cu was associated with differential Cu ionophore capabilities. DSF/Cu treatment caused a >20-fold increase in cellular Cu in NSCLCs, with nearly two-fold higher Cu present in NSCLCs vs. HBECs and in cancer cells at 1% Ovs. 21% O. DSF toxicity was shown to be dependent on the retention of Cu as well as oxidative stress mechanisms, including the production of superoxide, peroxide, lipid peroxidation, and mitochondrial damage. DSF was also shown to selectively (relative to HBECs) enhance radiation and chemotherapy-induced NSCLC killing and reduce radiation and chemotherapy resistance in hypoxia. Finally, DSF decreased xenograft tumor growth in vivo when combined with radiation and carboplatin. These results support the hypothesis that DSF could be a promising adjuvant to enhance cancer therapy based on its apparent ability to selectively target fundamental differences in cancer cell oxidative metabolism.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299833PMC
April 2020