Publications by authors named "Felix Braun"

67 Publications

Early everolimus-facilitated reduced tacrolimus in liver transplantation: Results from the randomized HEPHAISTOS trial.

Liver Transpl 2021 Sep 15. Epub 2021 Sep 15.

Novartis Pharma GmbH, Nürnberg, Germany.

Background: Everolimus-facilitated reduced tacrolimus exposure (EVR+rTAC) at 30 days post-liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR+rTAC in de novo liver transplant recipients (LTR).

Methods: In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month (M), multicenter, controlled study, LTR were randomized at 7-21 days post-LT to receive EVR+rTAC or standard tacrolimus (sTAC), with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR+rTAC versus sTAC at M12 in full analysis set (FAS). Other assessments at M12 included evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death or treated biopsy proven acute rejection [tBPAR] and individual components) in FAS, and safety.

Results: In total, 333 patients (EVR+rTAC: 169, sTAC: 164) were included in the FAS. A high proportion of patients was non-adherent in maintaining tacrolimus trough levels (EVR+rTAC: 36.1%, sTAC: 34.7%). At M12, the adjusted LS mean eGFR was numerically higher with EVR+rTAC versus sTAC (76.2 vs 72.1 mL/min/1.73 m , difference: 4.1 mL/min/1.73 m , P=0.097). A significant difference of 8.3 mL/min/1.73 m (P=0.03) favoring EVR+rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% vs 7.9%) and tBPAR (7.1% vs 5.5%) at M12, as well as incidence of treatment emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR+rTAC than sTAC treatment (27.2% vs 34.1%).

Conclusion: Early use of EVR in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at M12. Of note, renal function was significantly enhanced in compliance set.
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http://dx.doi.org/10.1002/lt.26298DOI Listing
September 2021

Mobile app requirements for patients with rare liver diseases: A single center survey for the ERN RARE-LIVER‬‬‬.

Clin Res Hepatol Gastroenterol 2021 Jul 27;45(6):101760. Epub 2021 Jul 27.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: More patient data are needed to improve research on rare liver diseases. Mobile health apps enable an exhaustive data collection. Therefore, the European Reference Network on Hepatological diseases (ERN RARE-LIVER) intends to implement an app for patients with rare liver diseases communicating with a patient registry, but little is known about which features patients and their healthcare providers regard as being useful.

Aims: This study aimed to investigate how an app for rare liver diseases would be accepted, and to find out which features are considered useful.

Methods: An anonymous survey was conducted on adult patients with rare liver diseases at a single academic, tertiary care outpatient-service. Additionally, medical experts of the ERN working group on autoimmune hepatitis were invited to participate in an online survey.

Results: In total, the responses from 100 patients with autoimmune (n = 90) or other rare (n = 10) liver diseases and 32 experts were analyzed. Patients were convinced to use a disease specific app (80%) and expected some benefit to their health (78%) but responses differed significantly between younger and older patients (93% vs. 62%, p < 0.001; 88% vs. 64%, p < 0.01). Comparing patients' and experts' feedback, patients more often expected a simplified healthcare pathway (e.g. 89% vs. 59% (p < 0.001) wanted access to one's own medical records), while healthcare providers saw the benefit mainly in improving compliance and treatment outcome (e.g. 93% vs. 31% (p < 0.001) and 70% vs. 21% (p < 0.001) expected the app to reduce mistakes in taking medication and improve quality of life, respectively).

Conclusion: Our results underline the great desire for disease-specific apps but also the need to involve patients and healthcare providers in the development of such apps in order to achieve long-term use and, thereby, improvements of patient care and research. The results of this study will help tremendously to implement the first cross-country app that communicates with an ERN patient registry.
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http://dx.doi.org/10.1016/j.clinre.2021.101760DOI Listing
July 2021

The evolution of surgery for colorectal liver metastases: A persistent challenge to improve survival.

Surgery 2021 Jul 22. Epub 2021 Jul 22.

Department of Surgery and Transplantation, University Medical Center Schleswig-Holstein, Campus Kiel, Germany. Electronic address:

Only a few decades ago, the opinion that colorectal liver metastases were a palliative diagnosis changed. In fact, previously, the prevailing view was strongly resistant against resecting colorectal liver metastases. Constant technical improvement of liver surgery and, much later, effective chemotherapy allowed for a successful wider application of surgery. The clinical use of portal vein embolization was the starting signal of regenerative liver surgery, where insufficient liver volume can be expanded to an extent where safe resection is possible. Today, a number of these techniques including portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy, and bi-embolization (portal and hepatic vein) can be successfully used to address an insufficient future liver remnant in staged resections. It turned out that the road to success is embedding surgery in a well-orchestrated oncological concept of controlling systemic disease. This concept was the prerequisite that meant liver transplantation could enter the treatment strategy for colorectal liver metastases, ending up with a 5-year overall survival of 80% in highly selected cases. In particular, techniques combining principles of 2-stage hepatectomy and liver transplantation, such as "resection and partial liver segment 2-3 transplantation with delayed total hepatectomy" (RAPID) are on the rise. These techniques enable the use of partial liver grafts with primarily insufficient liver volume. All this progress also prompted a number of innovative local therapies to address recurrences ultimately transferring colorectal liver metastases from instantly deadly into a chronic disease in some cases.
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http://dx.doi.org/10.1016/j.surg.2021.06.033DOI Listing
July 2021

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

HPB (Oxford) 2021 Jul 7. Epub 2021 Jul 7.

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, and Christian-Albrecht University (CAU), Kiel, Germany.

Background: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review.

Methods: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed.

Results: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found.

Conclusion: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.
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http://dx.doi.org/10.1016/j.hpb.2021.06.423DOI Listing
July 2021

A surprising foreign body abscess.

IDCases 2021 31;24:e01108. Epub 2021 Mar 31.

Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Arnold-Heller-Str. 3, 24105 Kiel, Schleswig-Holstein, Germany.

An abscess is a common complication after surgical interventions. Furthermore, abscesses of different genesis often occur under immunosuppression. In the case of a kidney transplant patient described here, however, the cause of an abscess-like mass in the abdomen was an unusual one, the etiology of which we could only clarify after surgical removal.
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http://dx.doi.org/10.1016/j.idcr.2021.e01108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050007PMC
March 2021

[Organ Donation in Germany: "Wind of Change"?]

Zentralbl Chir 2021 Aug 21;146(4):407-412. Epub 2021 Apr 21.

Transplantationsmedizin, Bundesärztekammer, Berlin, Deutschland.

Donor organ shortage has been a problem in Germany for many decades. In 2017, the organ donor rate reached a historic low number. The analysis showed multifactorial reasons and starting-points. The latter resulted in two amendments of the German transplant act. The first amendment focused on strengthening the position of transplant coordinators in donor hospitals. The second amendment includes the implementation of organ donor registers. Both amendments are accompanied by an action plan to transfer the statutory provisions into daily practice. The long-term objective of the adopted measures is an increase in the organ donation rate in Germany, a rational instead of an emotional debate of the topic and finally the socially accepted establishment of organ donation culture.
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http://dx.doi.org/10.1055/a-1447-1770DOI Listing
August 2021

Indication of Liver Transplantation for Hepatocellular Carcinoma Should Be Reconsidered in Case of Microvascular Invasion and Multilocular Tumor Occurrence.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Campus Kiel, University Medical Center Schleswig-Holstein (UKSH), Arnold-Heller-Strasse 3, 24105 Kiel, Germany.

Liver transplantation (LT) is routinely performed for hepatocellular carcinoma (HCC) in cirrhosis without major vascular invasion. Although the adverse influence of microvascular invasion is recognized, its occurrence does not contraindicate LT. We retrospectively analyzed in our LT cohort the significance of microvascular invasion on survival and demonstrate bridging procedures. At our hospital, 346 patients were diagnosed with HCC, 171 patients were evaluated for LT, and 153 were listed at Eurotransplant during a period of 11 years. Among these, 112 patients received LT and were included in this study. Overall survival after 1, 3 and 5 years was 86.3%, 73.9%, and 67.9%, respectively. Microvascular invasion led to significantly reduced overall ( = 0.030) and disease-free survival ( = 0.002). Five-year disease-free survival with microvascular invasion was 10.5%. Multilocular tumor occurrence with simultaneous microvascular invasion revealed the worst prognosis. In our LT cohort, predominant bridging treatment was transarterial chemoembolization (TACE) and the number of TACE significantly correlated with poorer overall survival after LT ( = 0.028), which was confirmed in multiple Cox regression analysis for overall and disease-free survival ( = 0.015 and = 0.011). Microvascular tumor invasion is significantly associated with reduced prognosis after LT, which is aggravated by simultaneous occurrence of multiple lesions. Therefore, indication strategies for LT should be reconsidered.
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http://dx.doi.org/10.3390/jcm10061155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998779PMC
March 2021

[Education of Abdominal Organ Procurement Surgeons in Germany - Challenges and Possible Solutions].

Zentralbl Chir 2021 Aug 29;146(4):392-399. Epub 2021 Mar 29.

Region Baden-Württemberg, Deutsche Stiftung Organtransplantation, Frankfurt, Deutschland.

The procurement of abdominal organs is a highly specialised operation, which marks the first important step for a successful transplantation. The article gives an overview of the organisation and the current state of the education of procurement surgeons in Germany. We comment on current challenges and discuss these in an international context.
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http://dx.doi.org/10.1055/a-1346-0346DOI Listing
August 2021

Usability of Indocyanine Green in Robot-Assisted Hepatic Surgery.

J Clin Med 2021 Jan 25;10(3). Epub 2021 Jan 25.

Deptpartment Of General, Abdominal, Thoracic, Transplantation and Pediatric Surgery, Campus Kiel, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany.

Recent developments in robotic surgery have led to an increasing number of robot-assisted hepatobiliary procedures. However, a limitation of robotic surgery is the missing haptic feedback. The fluorescent dye indocyanine green (ICG) may help in this context, which accumulates in hepatocellular cancers and around hepatic metastasis. ICG accumulation may be visualized by a near-infrared camera integrated into some robotic systems, helping to perform surgery more accurately. We aimed to test the feasibility of preoperative ICG application and its intraoperative use in patients suffering from hepatocellular carcinoma and metastasis of colorectal cancer, but also of other origins. In a single-arm, single-center feasibility study, we tested preoperative ICG application and its intraoperative use in patients undergoing robot-assisted hepatic resections. Twenty patients were included in the final analysis. ICG staining helped in most cases by detecting a clear lesion or additional metastases or when performing an R0 resection. However, it has limitations if applied too late before surgery and in patients suffering from severe liver cirrhosis. ICG staining may serve as a beneficial intraoperative aid in patients undergoing robot-assisted hepatic surgery. Dose and time of application and standardized fluorescence intensity need to be further determined.
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http://dx.doi.org/10.3390/jcm10030456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865567PMC
January 2021

Liver Transplantation for Acute Intermittent Porphyria.

Liver Transpl 2021 04 29;27(4):491-501. Epub 2021 Jan 29.

Hepatology Division, Department of Upper GI Diseases, Porphyria Centre Sweden, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
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http://dx.doi.org/10.1002/lt.25959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248103PMC
April 2021

Current Challenges in the Post-Transplant Care of Liver Transplant Recipients in Germany.

J Clin Med 2020 Nov 5;9(11). Epub 2020 Nov 5.

Department of Hepatology & Gastroenterology, Campus Charité Mitte/Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany.

Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.
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http://dx.doi.org/10.3390/jcm9113570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694452PMC
November 2020

Trivalent Actinide Ions Showing Tenfold Coordination in Solution.

Inorg Chem 2020 Sep 14;59(17):12410-12421. Epub 2020 Aug 14.

Karlsruhe Institute of Technology (KIT), Institute for Nuclear Waste Disposal (INE), P.O. Box 3640, 76021 Karlsruhe, Germany.

Trivalent actinides generally exhibit ninefold coordination in solution. 2,6-Bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine (nPr-BTP), a tridentate nitrogen donor ligand, is known to form ninefold coordinated 1:3 complexes, [An(nPr-BTP)] (An = U, Pu, Am, Cm) in solution. We report a Cm(III) complex with tenfold coordination in solution, [Cm(nPr-BTP)(NO)]. This species was identified using time-resolved laser fluorescence spectroscopy (TRLFS), vibronic side band spectroscopy (VSBS), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT). Adding nitrate to a solution of the [Cm(nPr-BTP)] complex in 2-propanol shifts the Cm(III) emission band from 613.1 to 617.3 nm. This bathochromic shift is due to a higher coordination number of the Cm(III) ion in solution, in agreement with the formation of the [Cm(nPr-BTP)(NO)] complex. The formation of this complex exhibits slow kinetics in the range of 5 to 12 days, depending on the water content of the solvent. Formation of a complex [Cm(nPr-BTP)(X)] was not observed for anions other than nitrate (X = NO, CN, or OTf). The formation of the [Cm(nPr-BTP)(NO)] complex was studied as a function of NO and nPr-BTP concentrations, and slope analyses confirmed the addition of one nitrate anion to the [Cm(nPr-BTP)] complex. Experiments with varied nPr-BTP concentration show that [Cm(nPr-BTP)(NO)] only forms at nPr-BTP concentrations below 10 mol/L whereas for concentrations greater than 10 mol/L the formation of the tenfold species is suppressed and [Cm(nPr-BTP)] is the only species present. The presence of the tenfold coordinated complex is supported by VSBS, XPS, and DFT calculations. The vibronic side band of the [Cm(nPr-BTP)(NO)] complex exhibits a nitrate stretching mode not observed in the [Cm(nPr-BTP)] complex. Moreover, XPS on [M(nPr-BTP)(NO)](NO) (M = Eu, Am) yields signals from both non-coordinated and coordinated nitrate. Finally, DFT calculations reveal that the energetically most favored structure is obtained if the nitrate is positioned on the axis of the D symmetrical [Cm(nPr-BTP)] complex with a bond distance of 413 pm. Combining results from TRLFS, VSBS, XPS, and DFT provides sound evidence for a unique tenfold coordinated Cm(III) complex in solution-a novelty in An(III) solution chemistry.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01526DOI Listing
September 2020

Inferior Vena Cava Constriction After Liver Transplantation Is a Severe Complication Requiring Individually Adapted Treatment: Report of a Single-Center Experience.

Ann Transplant 2020 Aug 4;25:e925194. Epub 2020 Aug 4.

Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany.

BACKGROUND Reports on vena cava occlusion after liver transplantation (LT) are rare, but this finding represents a severe complication in the early postoperative period. In the context of the complex presentation of a patient after LT, symptoms are often misinterpreted and can be subtle. MATERIAL AND METHODS In our cohort of 138 LTs performed between 2014 and 2017 at our University's Transplantation Department, 117 transplantations were valid for further analysis after exclusion of pediatric transplantations and transplants with primary non-function grafts. In 101 cases (73%), patients received a deceased-donor full-size organ. Living-donor LT was performed in 8 patients (6.4%) and 8 patients (6.4%) received a split graft. We report on 6 patients who had inferior vena cava (IVC) occlusion and summarize the treatment choices. RESULTS In our series, patients with positive findings (age 38-70 years) received an orthotopic full-size deceased-donor graft with end-to-end IVC anastomosis. In the subsequent period, imaging revealing IVC occlusion was done on a follow-up basis (n=2), due to dyspnea (n=1), and for progressive ascites (n=2). In 3 cases, a thrombus was found. We give detailed information on our treatment options from interventional treatment to transcardial thrombus removal and anastomosis augmentation. CONCLUSIONS IVC constriction and subsequent thrombosis are severe complications after LT that require individually adapted treatment in specialized centers. Since patients often present with subclinical symptoms, vascular diagnosis should be performed early to detect caval anastomosis pathologies. Despite regular ultrasonography, we favor CT and cavography for subsequent quantification. We also review the literature on IVC occlusion after LT.
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http://dx.doi.org/10.12659/AOT.925194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427346PMC
August 2020

Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers.

J Clin Med 2020 Jul 23;9(8). Epub 2020 Jul 23.

Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany.

Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
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http://dx.doi.org/10.3390/jcm9082352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465768PMC
July 2020

Forces during cellular uptake of viruses and nanoparticles at the ventral side.

Nat Commun 2020 01 2;11(1):32. Epub 2020 Jan 2.

Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.

Many intracellular pathogens, such as mammalian reovirus, mimic extracellular matrix motifs to specifically interact with the host membrane. Whether and how cell-matrix interactions influence virus particle uptake is unknown, as it is usually studied from the dorsal side. Here we show that the forces exerted at the ventral side of adherent cells during reovirus uptake exceed the binding strength of biotin-neutravidin anchoring viruses to a biofunctionalized substrate. Analysis of virus dissociation kinetics using the Bell model revealed mean forces higher than 30 pN per virus, preferentially applied in the cell periphery where close matrix contacts form. Utilizing 100 nm-sized nanoparticles decorated with integrin adhesion motifs, we demonstrate that the uptake forces scale with the adhesion energy, while actin/myosin inhibitions strongly reduce the uptake frequency, but not uptake kinetics. We hypothesize that particle adhesion and the push by the substrate provide the main driving forces for uptake.
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http://dx.doi.org/10.1038/s41467-019-13877-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940367PMC
January 2020

Lethal thrombosis of the iliac artery caused by Aspergillus fumigatus after liver transplantation: case report and review of the literature.

BMC Surg 2019 Dec 27;19(1):200. Epub 2019 Dec 27.

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, and Christian-Albrecht University (CAU), Arnold-Heller-Str. 3, 24105, Kiel, Germany.

Background: Aspergillus fumigatus infections frequently occur after solid organ transplantation. Yet, a fungal thrombosis after liver transplantation is an exceptional finding.

Case Presentation: We report on a 44-year-old female with an aspergillosis after liver transplantation for autoimmune hepatitis. On postoperative day (pod) 7, seizures occurred and imaging diagnostics revealed an intracranial lesion. Anidulafungin was initiated in suspicion of mycosis and switched to voriconazole on suspicion of an Aspergillus spp. infection. Progression of the cerebral lesion prompted craniotomy (pod 48) and the aspergillosis was verified. The patient was discharged with oral voriconazole therapy. Re-admission was necessary with acute-on-chronic renal failure after a tacrolimus overdose on pod 130. The patient received a pelvic angiography due to a temperature difference in the legs. It showed a complete iliac artery thrombosis which was subsecutively surgically removed. The histopathological examination revealed an Aspergillus fumigatus conglomerate. The patient died on pod 210 due to systemic aspergillosis.

Conclusion: The acute development of focal neurologic deficits is common in patients with an aspergillosis of the brain. Nevertheless, arterial thrombosis after Aspergillus fumigatus is less frequent and, to the best of our knowledge, its occurrence after liver transplantation has not yet been reported so far. Due to its rarity, we added a review of the literature to this manuscript.
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http://dx.doi.org/10.1186/s12893-019-0668-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935117PMC
December 2019

Molecular diagnosis of kidney transplant failure based on urine.

Am J Transplant 2020 05 20;20(5):1410-1416. Epub 2020 Jan 20.

Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor's disease of oral-facial-digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next-generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long-term outcome was enabled for 5 recipients.
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http://dx.doi.org/10.1111/ajt.15738DOI Listing
May 2020

Live-Cell Localization Microscopy with a Fluorogenic and Self-Blinking Tetrazine Probe.

Angew Chem Int Ed Engl 2020 01 18;59(2):804-810. Epub 2019 Nov 18.

Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.

Recent developments in fluorescence microscopy call for novel small-molecule-based labels with multiple functionalities to satisfy different experimental requirements. A current limitation in the advancement of live-cell single-molecule localization microscopy is the high excitation power required to induce blinking. This is in marked contrast to the minimal phototoxicity required in live-cell experiments. At the same time, quality of super-resolution imaging depends on high label specificity, making removal of excess dye essential. Approaching both hurdles, we present the design and synthesis of a small-molecule label comprising both fluorogenic and self-blinking features. Bioorthogonal click chemistry ensures fast and highly selective attachment onto a variety of biomolecular targets. Along with spectroscopic characterization, we demonstrate that the probe improves quality and conditions for regular and single-molecule localization microscopy on live-cell samples.
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http://dx.doi.org/10.1002/anie.201906806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972563PMC
January 2020

Accuracy of Pretransplant Imaging Diagnostic for Hepatocellular Carcinoma: A Retrospective German Multicenter Study.

Can J Gastroenterol Hepatol 2019 5;2019:8747438. Epub 2019 Mar 5.

Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. . There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
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http://dx.doi.org/10.1155/2019/8747438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425358PMC
August 2019

Surgical Aspects of Liver Transplantation and Domino Liver Transplantation in Maple Syrup Urine Disease: Analysis of 15 Donor-Recipient Pairs.

Liver Transpl 2019 06 19;25(6):889-900. Epub 2019 Apr 19.

Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Liver transplantation (LT) has been shown to be a feasible treatment in patients with severe forms of maple syrup urine disease (MSUD). Because of a sufficient extrahepatic enzyme activity in non-MSUD individuals, the organ of MSUD patients can be used as a domino graft. We performed a retrospective data collection of all LTs for MSUD carried out at the University Medical Center Hamburg-Eppendorf (2016-2018). Moreover, data from all consecutive domino LTs of the MSUD grafts either transplanted at our institution or allocated to other transplant centers were analyzed. During the study period, 15 LTs in MSUD patients were performed (12 children, 3 adults; median age, 10.9 years; range, 0.3-26.1 years). Biliary complications occurred in 20%, and 13.3% suffered from bleeding complications. No further surgical problems occurred. At present, all MSUD patients are alive with a well-functioning liver graft and on an unrestricted diet. In total, 14 consecutive domino LTs were performed. No surgical complications requiring intervention occurred. One patient died because of HCC relapse, and all other patients are alive with good liver graft function. In conclusion, the use of MSUD livers as domino grafts is safe and allows application of LT in MSUD patients without net extraction of a liver graft from the limited donor pool.
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http://dx.doi.org/10.1002/lt.25423DOI Listing
June 2019

Outcome of Liver Transplant Patients With High Urgent Priority: Are We Doing the Right Thing?

Transplantation 2019 06;103(6):1181-1190

Department of General-, Visceral-, and Transplant Surgery, University of Munich, Munich, Germany.

Background: About 15% of liver transplantations (LTs) in Eurotransplant are currently performed in patients with a high-urgency (HU) status. Patients who have acute liver failure (ALF) or require an acute retransplantation can apply for this status. This study aims to evaluate the efficacy of this prioritization.

Methods: Patients who were listed for LT with HU status from January 1, 2007, up to December 31, 2015, were included. Waiting list and posttransplantation outcomes were evaluated and compared with a reference group of patients with laboratory Model for End-Stage Liver Disease (MELD) score (labMELD) scores ≥40 (MELD 40+).

Results: In the study period, 2299 HU patients were listed for LT. Ten days after listing, 72% of all HU patients were transplanted and 14% of patients deceased. Patients with HU status for primary ALF showed better patient survival at 3 years (69%) when compared with patients in the MELD 40+ group (57%). HU patients with labMELD ≥45 and patients with HU status for acute retransplantation and labMELD ≥35 have significantly inferior survival at 3-year follow-up of 46% and 42%, respectively.

Conclusions: Current prioritization for patients with ALF is highly effective in preventing mortality on the waiting list. Although patients with HU status for ALF have good outcomes, survival is significantly inferior for patients with a high MELD score or for retransplantations. With the current scarcity of livers in mind, we should discuss whether potential recipients for a second or even third retransplantation should still receive absolute priority, with HU status, over other recipients with an expected, substantially better prognosis after transplantation.
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http://dx.doi.org/10.1097/TP.0000000000002526DOI Listing
June 2019

Development and validation of a prognostic model for kidney function 1 year after combined pancreas and kidney transplantation using pre-transplant donor and recipient variables.

Langenbecks Arch Surg 2018 Nov 18;403(7):837-849. Epub 2018 Oct 18.

Core Facility Quality Management Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.

Purpose: The widening gap between demand and supply of organs for transplantation provides extraordinary challenges for ethical donor organ allocation rules. The transplant community is forced to define favorable recipient/donor combinations for simultaneous kidney-pancreas transplantation. The aim of this study is the development of a prognostic model for the prediction of kidney function 1 year after simultaneous pancreas and kidney transplantation using pre-transplant donor and recipient variables with subsequent internal and external validation.

Methods: Included were patients with end-stage renal failure due to diabetic nephropathy. Multivariable logistic regression modeling was applied for prognostic model design with retrospective data from Hannover Medical School, Germany (01.01.2000-31.12.2011) followed by prospective internal validation (01 Jan. 2012-31 Dec. 2015). Retrospective data from another German transplant center in Kiel was retrieved for external model validation via the initially derived logit link function.

Results: The developed prognostic model is able to predict kidney graft function 1 year after transplantation ≥ KDIGO stage III with high areas under the receiver operating characteristic curve in the development cohort (0.943) as well as the internal (0.807) and external validation cohorts (0.784).

Conclusion: The proposed validated model is a valuable tool to optimize present allocation rules with the goal to prevent transplant futility. It might be used to support donor organ acceptance decisions for individual recipients.
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http://dx.doi.org/10.1007/s00423-018-1712-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244698PMC
November 2018

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma.

Transplantation 2018 10;102(10):e424-e430

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Germany.

Background: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC.

Methods: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping.

Results: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 × 10) and microvascular invasion (P = 1.31 × 10) were significantly associated with survival in a Cox regression analysis.

Conclusions: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.
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http://dx.doi.org/10.1097/TP.0000000000002356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598094PMC
October 2018

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.

Am J Gastroenterol 2018 10 13;113(10):1475-1483. Epub 2018 Mar 13.

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany. Department of Internal Medicine I, University of Bonn, Bonn, Germany. Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany. Hepatology Section, Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. Department of Gastroenterology, University Hospital Halle/Saale, Halle, Germany. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. Department of Medicine II, Saarland University Medical Center, Homburg, Germany. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. Medical Department 1, University of Erlangen, Nuremberg, Bavaria, Germany. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany. Department of Clinical Toxicology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. These authors have contributed equally to the presented work and share premier authorship: Felix Stickel, Stephan Buch. These authors have contributed equally to the presented work and share senior authorship: Pierre Deltenre, Thomas Berg, Marsha Y. Morgan, and Jochen Hampe.

Objectives: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC.

Methods: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression.

Results: The development of HCC was independently associated with PNPLA3 rs738409 (OR 1.84 [95% CI 1.55-2.18], p = 1.85 × 10) and TM6SF2 rs58542926 (OR 1.66 [1.30-2.13], p = 5.13 × 10), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (OR 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined.

Conclusions: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.
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http://dx.doi.org/10.1038/s41395-018-0041-8DOI Listing
October 2018

On atomic mechanisms governing the oxidation of BiTe.

J Phys Condens Matter 2017 12 9;29(48):485705. Epub 2017 Nov 9.

Materials Chemistry, RWTH Aachen University, Kopernikusstr. 10, D-52074 Aachen, Germany.

Oxidation of BiTe (space group R [Formula: see text] m) has been investigated using experimental and theoretical means. Based on calorimetry, x-ray photoelectron spectroscopy and thermodynamic modelling, BiTe is at equilibrium with BiO and TeO, whereby the most stable compound is BiTe, followed by BiO. The reactivity of Bi towards oxygen is expected to be higher than that of Te. This notion is supported by density functional theory. The strongest bond is formed between Bi and Te, followed by Bi-O. This gives rise to unanticipated atomic processes. Dissociatively adsorbed oxygen diffuses through Bi and Te basal planes of BiTe(0 0 0 1) and preferably interacts with Bi. The Te termination considerably retards this process. These findings may clarify conflicting literature data. Any basal plane off-cut or Bi terminations trigger oxidation, but a perfect basal cleavage, where only Te terminations are exposed to air, may be stable for a longer period of time. These results are of relevance for applications in which surfaces are of key importance, such as nanostructured BiTe thermoelectric devices.
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http://dx.doi.org/10.1088/1361-648X/aa945fDOI Listing
December 2017

Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats.

Respir Physiol Neurobiol 2018 10 27;256:97-108. Epub 2017 Apr 27.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; James B. Skatrud Pulmonary/Sleep Research Laboratory, Medical Service, William S. Middleton Memorial Veterans Administration Hospital, Madison, WI, United States. Electronic address:

Obstructive sleep apnea (OSA) has been linked to increased mortality in pulmonary fibrosis. Its key feature, chronic intermittent hypoxia (CIH), can lead to oxidative stress and inflammation, known to lead to fibrotic pathology in other organs. We tested the effects of CIH in an animal model of bleomycin-induced lung fibrosis. Sprague Dawley rats were instilled intratracheally with bleomycin (Blm) or saline (Sal), and exposed to CIH or normal air (Norm) for 9 or 30 days. Pulmonary function was tested and lungs were harvested for histological and molecular analyses. In Blm-treated animals, 30days of CIH compared to Norm increased total lung collagen content (p=0.008) and reduced Quasi-static lung compliance (p=0.04). CIH upregulated lipid peroxidation and increased NF-κB activation, IL-17 mRNA and Col1α1 mRNA expression. Our results indicate that following Blm-induced lung injury, CIH amplifies collagen deposition via oxidative and inflammatory pathways, culminating in stiffer lungs. Thus, OSA may augment fibrosis in patients with interstitial lung disease.
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http://dx.doi.org/10.1016/j.resp.2017.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659967PMC
October 2018

Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy.

Transplant Direct 2017 Apr 28;3(4):e146. Epub 2017 Mar 28.

Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Medical Centre Schleswig-Holstein (UKSH), Kiel, Germany.

Background: Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed.

Methods: In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient's compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels.

Results: Two hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion.

Conclusions: Patients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved cognitive functioning, but had no impact on HRQoL or compliance.
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http://dx.doi.org/10.1097/TXD.0000000000000658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381739PMC
April 2017

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

Gastroenterology 2017 06 6;152(8):1975-1984.e8. Epub 2017 Mar 6.

Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Spain.

Background & Aims: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC.

Methods: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates.

Results: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002).

Conclusions: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
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http://dx.doi.org/10.1053/j.gastro.2017.02.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546611PMC
June 2017
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