Untersuchung chirurgischer Techniken zur Behandlung fortgeschrittener Lebererkrankungen und assoziierter Risikofaktoren

In den folgenden Publikationen wurden folgende Fragestellungen systematisch untersucht: 1. Der Stellenwert der präoperativen Bildgebung für die chirurgische Strategie bei der portosystemischen Shunt-Chirurgie. 2. Die Machbarkeit der Lebertransplantation ohne Kältekonservierung 3. Die Assoziation zwischen der Rekurrenz des hepatozellulären Karzinoms nach Lebertransplantation mit Episoden akuter Abstoßung 4. Der Einfluss der Teil-Leber-Lebendspende auf die Lebensqualität des Spenders und Untersuchung postoperativer Ergebnisse 5. Der Stellenwert eines biologischen Netzes beim Bauchwandverschlusses in mehreren Etappen nach pädiatrischer Lebertransplantation bei Kleinkinder

Safety of transanal ileal pouch-anal anastomosis for ulcerative colitis: a retrospective observational cohort study

Background: Colectomy with transanal ileal pouch-anal anastomosis (taIPAA) is a surgical technique that can be used to treat benign colorectal disease. Ulcerative colitis is the most frequent inflammatory bowel disease (IBD) and although pharmacological therapy has improved, colectomy rates reach up to 15%. The objective of this study was to determine anastomotic leakage rates and treatment after taIPAA as well as short- and long-term pouch function. Methods: We conducted a retrospective analysis of a prospective database of all patients undergoing taIPAA at an academic tertiary referral center in Germany, between 01/03/2015 and 31/08/2019. Patients with indications other than ulcerative colitis or with adjuvant chemotherapy following colectomy for colorectal carcinoma were excluded for short- and long-term follow up due to diverging postoperative care yet considered for evaluation of anastomotic leakage. Results: A total of 22 patients undergoing taIPAA during the study time-window were included in analysis. Median age at the time of surgery was 32 +/- 12.5 (14-54) years. Two patients developed an anastomotic leakage at 11 days (early anastomotic leakage) and 9 months (late anastomotic leakage) after surgery, respectively. In both patients, pouches could be preserved with a multimodal approach. Twenty patients out of 22 met the inclusion criteria for short and long term follow-up. Data on short-term pouch function could be obtained in 14 patients and showed satisfactory pouch function with only four patients reporting intermittent incontinence at a median stool frequency of 9-10 times per day. In the long-term we observed an inflammation or "pouchitis" in 11 patients and a pouch failure in one patient. Conclusion: Postoperative complication rates in patients with benign colorectal disease remain an area of concern for surgical patient safety. In this pilot study on 22 selected patients, taIPAA was associated with two patients developing anastomotic leakage. Future large-scale validation studies are required to determine the safety and feasibility of taIPAA in patients with ulcerative colitis

Recurrence of Hepatocellular Carcinoma After Liver Transplantation is Associated with Episodes of Acute Rejections.

Purpose The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival. Patients and Methods Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox's regression analysis was conducted revealing risk factors for HCC recurrence. Results HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30-6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28-2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019). Conclusion Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation

Outcome after pediatric liver transplantation for staged abdominal wall closure with use of biological mesh—Study with long‐term follow‐up

Abdominal wall closure after pediatric liver transplantation (pLT) in infants may be hampered by graft-to-recipient size discrepancy. Herein, we describe the use of a porcine dermal collagen acellular graft (PDCG) as a biological mesh (BM) for abdominal wall closure in pLT recipients. Patients <2 years of age, who underwent pLT from 2011 to 2014, were analyzed, divided into definite abdominal wall closure with and without implantation of a BM. Primary end-point was the occurrence of postoperative abdominal wall infection. Secondary end-points included 1- and 5-year patient and graft survival and the development of abdominal wall hernia. In five out of 21 pLT recipients (23.8%), direct abdominal wall closure was achieved, whereas 16 recipients (76.2%) received a BM. BM removal was necessary in one patient (6.3%) due to abdominal wall infection, whereas no abdominal wall infection occurred in the no-BM group. No significant differences between the two groups were observed for 1- and 5-year patient and graft survival. Two late abdominal wall hernias were observed in the BM group vs none in the no-BM group. Definite abdominal wall closure with a BM after pLT is feasible and safe when direct closure cannot be achieved with comparable postoperative patient and graft survival rates

Treatment of Anti-HLA Donor-Specific Antibodies Results in Increased Infectious Complications and Impairs Survival after Liver Transplantation

Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 December 2015 were examined. Recipients < 18 years, living donor-, combined, high-urgency-, and re-transplantations were excluded. Out of 510 LTs, 113 DSA-positive cases were propensity score-matched with DSA-negative cases based on the components of the Balance of Risk score. One-, three-, and five-year survival after LT were 74.3% in DSA-positive vs. 84.8% (p = 0.053) in DSA-negative recipients, 71.8% vs. 71.5% (p = 0.821), and 69.3% vs. 64.9% (p = 0.818), respectively. Rejection therapy was more often applied to DSA-positive recipients (n = 77 (68.1%) vs. 37 (32.7%) in the control group, p < 0.001). At one year after LT, 9.7% of DSA-positive patients died due to sepsis compared to 1.8% in the DSA-negative group (p = 0.046). The remaining causes of death were comparable in both groups (cardiovascular 6.2% vs. 8.0%; p = 0.692; hepatic 3.5% vs. 2.7%, p = 0.788; malignancy 3.5% vs. 2.7%, p = 0.788). DSA seem to have an indirect effect on the outcome of adult LTs, impacting decision-making in post-transplant immunosuppression and rejection therapies and ultimately increasing mortality due to infectious complications

Hepatic artery reconstruction using an operating microscope in pediatric liver transplantation—Is it worth the effort?

Introduction: In pediatric liver transplantation (pLT), hepatic artery thrombosis (HAT) is associated with inferior transplant outcome. Hepatic artery reconstruction (HAR) using an operating microscope (OM) is considered to reduce the incidence of HAT. Methods: HAR using an OM was compared to a historic cohort using surgical loupes (SL) in pLT performed between 2009 and 2020. Primary endpoint was the occurrence of HAT. Secondary endpoints were 1-year patient and graft survival determined by Kaplan-Meier analysis and complications. Multivariate analysis was used to identify independent risk factors for HAT and adverse events. Results: A total of 79 pLTs were performed [30 (38.0%) living donations; 49 (62.0%) postmortem donations] divided into 23 (29.1%) segment 2/3, 32 (40.5%) left lobe, 4 (5.1%) extended right lobe, and 20 (25.3%) full-size grafts. One-year patient and graft survival were both 95.2% in the OM group versus 86.2% and 77.8% in the SL group (p = .276 and p = .077). HAT rate was 0% in the OM group versus 24.1% in the SL group (p = .013). One-year patient and graft survival were 64.3% and 35.7% in patient with HAT, compared to 93.9% and 92.8% in patients with no HAT (both p < .001). Multivariate analysis revealed HAR with SL (p = .022) and deceased donor liver transplantation (DDLT) (p = .014) as independent risk factors for HAT. The occurrence of HAT was independently associated with the need for retransplantation (p < .001) and biliary leakage (p = .045). Conclusion: In pLT, the use of an OM is significantly associated to reduce HAT rate, biliary complications, and graft loss and outweighs the disadvantages of delayed arterial perfusion and prolonged warm ischemia time (WIT)

an intravital microscopic study on mice

Die Wandschubspannung ist ein zentraler Faktor der mikrovaskulären Hämodynamik. Ihre tangentiale Wirkung auf die Endothelzellen gewährleistet und etabliert die Aufrechterhaltung eines physiologischen Gleichgewichtes der Perfusion in vielen Geweben, so auch im Skelettmuskel. Wie die mikrovaskuläre Hämodynamik in dem jeweiligen Gewebe sich in einer Feedback-Reaktion adaptiert, ist jedoch weitgehend unbekannt. Allerdings scheint das Signalmolekül (NO), hergestellt durch NO-Synthasen (NOS) dabei eine wichtige Rolle einzunehmen. Im Skelettmuskel wird NO sowohl durch die im Endothelium verankerte eNOS als auch durch die sarkolemmal lokalisierte nNOS bereitgestellt. Das Ziel in der vorliegenden Arbeit war es in vivo den Einfluss der eNOS und nNOS auf die Etablierung der Wandschubspannung in Kapillaren zu analysieren. Die Umsetzung dieser Fragestellung konnte nach Ausarbeitung und Etablierung eines intravitalmikroskopischen Verfahrens erfolgen. Auf diese Art konnte das mikrovaskuläre Kapillarsystem im Musculus extensor digitorum longus (EDL) der Maus durch kontinuierliches Videomonitoring dargestellt und offline analysiert werden. Im Rahmen der Auswertung erfolgte durch Bestimmung der Geschwindigkeit der Erythrozytenströmung und des Kapillardurchmessers eine Berechnung der apparenten Wandschubspannung in den Kapillaren. Diese Untersuchungen wurden an drei Mausstämmen (C57/B16-, nNOS- und eNOS-Knockout-Mäuse) sowohl im unbehandelten (basal) als auch nach Behandlung mit Prazosin (über 36 Stunden als Zusatz im Trinkwasser) durchgeführt. Alle Versuchstiere der Kontrollgruppe ohne Prazosinbehandlung wiesen während der intravitalmikroskopischen Untersuchung einen nahezu konstanten mittleren arteriellen Blutdruck von 90 – 110 mmHg auf. Der Vergleich zu den Versuchsgruppen nach Prazosinbehandlung präsentierte dagegen eine deutliche Erniedrigung des mittleren arteriellen Blutdruckes auf 80 – 100 mmHg. In beiden Gruppen mit und ohne Prazosinbehandlung lag der durchschnittliche Kapillardurchmesser zwischen 6,0 +/- 0,5 μm. Es zeigen sich keine signifikanten Unterschiede im Vergleich der einzelnen Gruppen. Auffallend war die Veränderung der Erythrozytenflussgeschwindigkeiten in den einzelnen Versuchsgruppen. So hatten die nNOS-defizienten Mäuse mit 90 μm/sec im Vergleich zu den eNOS-defizienten Mäusen mit 80 μm/sec und den C57/Bl6-Mäuse mit 70 μm/sec die höchsten Werte. Eine signifikante Änderung im Sinne einer Geschwindigkeitssteigerung um das 2- bis 3-fache in den Kapillaren war nach der Behandlung mit Prazosin nachweisbar. Es ließen sich Messwerte zwischen 200 - 300 μm/sec bei den eNOS- und nNOS-defizienten sowie den C57/B16-Mäusen ableiten. Die hieraus berechnete Wandschubspannung zeigte analog in allen drei Mausgruppen nach Prazosinbehandlung eine signifikante Erhöhung der Wandschubspannung. Die Werte für die Wandschubspannung lagen ohne Behandlung zwischen 2 – 4 dyne/cm². Nach Prazosinbehandlung (high flow) steigerte sich die Wandschubspannung auf Werte zwischen 11 – 14 dyne/cm². Weder unter Basalbedingungen noch unter high flow Bedingungen nach Prazosinbehandlung führte die genetische Ablation von nNOS und eNOS zu einer veränderten Wandschubspannung. Diese Daten lassen vermuten, dass NO nicht bei der Erhöhung der Wandschubspannung nach arterieller Vasodilatation beteiligt ist.The wall shear stress is a central factor in microvascular hemodynamics. Its tangential effect on the endothelial cells allows perfusion in many tissues, including the skeletal muscles, to be kept physiologically balanced. The way in which the microvascular hemodynamics is adapted to the respective tissues in a feedback reaction is largely unknown. However, the signal molecule (NO), made by NO synthases (NOS) appears to play an important role. NO is present in the skeletal muscles both as eNOS embedded in the endothelium and as nNOS found in the sarcolemma. The aim of this study was to analyse the effect of eNOS and nNOS on the establishment of the wall shear stress in capillaries in vivo. The research question was investigated by developing and using an intravital microscopic process. In this way, the microvascular capillary system in the extensor digitorum longus (EDL) muscle of the mouse could be shown with continuous video monitoring and analysed offline. In terms of evaluation, a calculation of the apparent wall shear stress in the capillaries was made by determining the speed of the erythrocyte flow and the capillary diameter. These investigations were carried out on three strains of mouse (C57/B16, nNOS and eNOS knockout mice), both untreated (control) and after treatment with Prazosin (added to the drinking water over a period of 36 hours). All test animals in the control group not being treated with Prazosin showed a virtually constant central arterial blood pressure of 90 – 110 mmHg during the intravital microscopic tests. In comparison, the test group following treatment with Prazosin showed a significant decrease in the central arterial blood pressure to 80 – 100 mmHg. In both groups with and without treatment with Prazosin, the average capillary diameter was 6.0 +/- 0.5 µm. There were no significant differences within the individual groups. The change in the erythrocyte speeds within the individual test groups was notable. The nNOS-48 deficient mice showed highest speeds of 90 µm/sec as compared with the eNOS-deficient mice with speeds of 80 µm/sec and the C57/B16 mice with speeds of 70 µm/sec. A significant increase in speed of 2 to 3 times could be seen in the capillaries after treatment with Prazosin. Measurement values between 200 - 300 µm/sec could be identified for the eNOS, nNOS-deficient and the C57/B16 mice. The wall shear stress calculated from this showed a significant increase in wall shear stress after treatment with Prazosin for all three groups of mice. The values for the wall shear stress were between 2 – 4 dyne/cm2 for mice which had not been treated with Prazosin. After treatment with Prazosin (high flow) the wall shear stress increased to between 11 – 14 dyne/cm2. Genetic ablation of nNOS and eNOS did not lead to a change in the wall shear stress in either the control group or under high flow conditions after treatment with Prazosin. The assumption can therefore be made that NO is not involved in the increase in wall shear stress following arterial vasodilation

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

Background and Objectives: Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive inherited disease divided into five types (PFIC 1-5). Characteristic for all types is early disease onset, which may result clinically in portal hypertension, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Liver transplantation (LT) is the only successful treatment approach. Our aim is to present the good long-term outcomes after liver transplantation for PFIC1, focusing on liver function as well as the occurrence of extrahepatic manifestation after liver transplantation. Materials and Methods: A total of seven pediatric patients with PFIC1 underwent liver transplantation between January 1999 and September 2019 at the Department of Surgery, Charite Campus Virchow Klinikum and Charite Campus Mitte of Charite-Universitatsmedizin Berlin. Long-term follow-up data were collected on all patients, specifically considering liver function and extrahepatic manifestations. Results: Seven (3.2%) recipients were found from a cohort of 219 pediatric patients. Two of the seven patients had multilocular HCC in cirrhosis. Disease recurrence or graft loss did not occur in any patient. Two patients (male, siblings) had persistently elevated liver parameters but showed excellent liver function. Patient and graft survival during long-term follow-up was 100%, and no severe extrahepatic manifestations requiring hospitalization or surgery occurred. We noted a low complication rate during long-term follow-up and excellent patient outcome. Conclusions: PFIC1 long-term follow-up after LT shows promising results for this rare disease. In particular, the clinical relevance of extrahepatic manifestations seems acceptable, and graft function seems to be barely affected. Further multicenter studies are needed to analyze the clinically inhomogeneous presentation and to better understand the courses after LT

Portosystemic shunt surgery in the era of TIPS: imaging-based planning of the surgical approach

Purpose: With the spread of transjugular intrahepatic portosystemic shunts (TIPS), portosystemic shunt surgery (PSSS) has decreased and leaves more complex patients with great demands for accurate preoperative planning. The aim was to evaluate the role of imaging for predicting the most suitable PSSS approach. Material and methods: Forty-four patients who underwent PSSS (2002 to 2013) were examined by contrast-enhanced CT (n = 33) and/or MRI (n = 15) prior to surgery. Imaging was analyzed independently by two observers (O1 and O2) with different levels of experience (O1 > O2). They recommended two shunting techniques (vessels and anastomotic variant) for each patient and ranked them according to their appropriateness and complexity. Findings were compared with the actually performed shunt procedure and its outcome. Results: The first two choices taken together covered the performed PSSS regarding vessels in 88%/100% (CT/MRI, O1) and 76%/73% (O2); and vessels + anastomosis in 79%/73% (O1) and 67%/60% (O2). The prediction of complex surgical procedures (resection of interposing structures, additional thrombectomy, use of a collateral vessel, and use of a graft interposition) was confirmed in 87%, resulting in 80% sensitivity and 96% specificity. Larger shunt vessel distances were associated with therapy failure (p = 0.030) and a vessel distance of ≥ 20 mm was identified as optimal cutoff, in which a graft interposition was used. There was no significant difference between MRI and CT in predicting the intraoperative decisions (p = 0.294 to 1.000). Conclusion: Preoperative imaging and an experienced radiologist can guide surgeons in PSSS. CT and MRI provide the information necessary to identify technically feasible variants and complicating factors