[Morbidity and Mortality of Single Incision Cholecystectomy: Results of a 3-Year Register Analysis]. / Morbidität und Letalität der Single-Incision-Cholezystektomie: eine 3-Jahres-Registeranalyse.

INTRODUCTION: Two decades ago, single-incision surgery was established as a new concept in minimally invasive surgery. Single incision cholecystectomy is the most frequently performed procedure in clinical routine. Most of the results have been based on randomised trials. Large prospective multicentre observational datasets from clinical routine do not exist. This analysis of clinical health service research is based on the SILAP study (single-incision multiport/single port laparoscopic abdominal surgery study). PATIENTS AND METHODS: The data of the register were collected in 47 hospitals in the period of 2012 to 2014. Overall morbidity and mortality were the primary outcome. Multiple linear and logistic regression analyses were performed. Statistical significance was set at p < 0.05. RESULTS: Data from 975 patients in clinical routine with single incision cholecystectomy were collected. Intraoperative complications were recorded in 3.2% of cases. Bile duct injuries were registered in 0.1% of cases. Postoperative complications were detected in 3.7% of cases. The mortality rate was 0.2%.The median operating time dropped from 60.0 to 51.5 min (p < 0.001) during the study. The use of an extra trocar was necessary in 10.3% of cases. Conversion to open surgery was performed in 0.7% of cases. Body mass index (p = 0.024), male gender (p = 0.012) and operating time (p < 0.001) had a significant effect on intraoperative complications in multivariate analysis. Classification of ASA III (p = 0.001) and modification or conversion of single incision technique (p = 0.001) were significantly associated with postoperative complications. CONCLUSION: The register analysis of the prospective multicentre data shows that single incision cholecystectomy is feasible in clinical routine even outside the selective criteria of randomised studies. The only limitation is a BMI > 30 kg/m2 which has a significant influence on the intraoperative rate of complications in mild adverse events.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

How to establish and maintain a multimodal animal research dataset using DataLad.

Sharing of data, processing tools, and workflows require open data hosting services and management tools. Despite FAIR guidelines and the increasing demand from funding agencies and publishers, only a few animal studies share all experimental data and processing tools. We present a step-by-step protocol to perform version control and remote collaboration for large multimodal datasets. A data management plan was introduced to ensure data security in addition to a homogeneous file and folder structure. Changes to the data were automatically tracked using DataLad and all data was shared on the research data platform GIN. This simple and cost-effective workflow facilitates the adoption of FAIR data logistics and processing workflows by making the raw and processed data available and providing the technical infrastructure to independently reproduce the data processing steps. It enables the community to collect heterogeneously acquired and stored datasets not limited to a specific category of data and serves as a technical infrastructure blueprint with rich potential to improve data handling at other sites and extend to other research areas.

Applicability of the surgical risk calculator by the American College of Surgeons in the setting of German patients undergoing complete pancreatectomy: multicentre study using data from the StuDoQ|Pancreas registry.

INTRODUCTION: Surgical risk calculators can estimate risk probabilities for postoperative outcomes utilizing patient-specific risk factors. They provide meaningful information for obtaining informed consent. The aim of the present paper was to evaluate the predictive value of the surgical risk calculators by the American College of Surgeons in German patients undergoing total pancreatectomy. METHODS: Data for patients who underwent total pancreatectomy between 2014 and 2018 were acquired from the Study, Documentation, and Quality Center of the German Society for General and Visceral Surgery. Risk factors were entered manually into the surgical risk calculators and calculated risks were compared with actual outcomes. RESULTS: Of the 408 patients analysed, predicted risk was higher in patients with complications except for the prediction of re-admission (P = 0.127), delayed gastric emptying (P = 0.243), and thrombosis (P = 0.256). In contrast, classification of patients into below, above, or average risk by the surgical risk calculators only produced meaningful results for discharge to nursing facility (P < 0.001), renal failure (P = 0.003), pneumonia (P = 0.001), serious complications, and overall morbidity (both P < 0.001). Assessment of discrimination and calibration showed poor results (scaled Brier scores 8.46 per cent or less). CONCLUSION: Overall surgical risk calculator performance was poor. This finding promotes the development of a specific surgical risk calculator applicable to the German healthcare system.

Neutrophil phenotype and function in partial hepatectomy in man.

PURPOSE: Hepatic resections are still associated with considerable morbidity mainly because of postoperative infection. Adequate function of neutrophils is a crucial element in host defense. The aim of the study was to characterize neutrophils during partial hepatectomy. METHODS: Fourteen patients undergoing partial liver resection were enrolled. Twenty-four hours pre-, intra- (after induction of anesthesia, after preparation of the liver, and 15 min after release of the Pringle maneuver), as well as postoperatively (3 h after Pringle; 24, 48, and 120 h after surgery), blood samples were obtained. In addition, healthy volunteers (n = 5) were investigated. Adhesion molecules (CD 62, CD 18), Fcy receptors (CD 16, CD 32), and phagocytosis by neutrophils were characterized by fluorescence-activated cell sorter analysis. Spontaneous and stimulated (formyl-methionyl-leucyl-phenylalanine) oxygen radical generation was measured by lucigenin-enhanced chemiluminescence. RESULTS: Numeric upregulation of CD 62 and CD 18 on neutrophils was seen before the use of Pringle maneuver and persisted thereafter (p < 0.05). Spontaneous numeric expression of Fcy receptors (CD16 and CD 32) was unchanged during liver dissection but downregulated after Pringle maneuver was opened (p < 0.05). Although numeric Fcy receptors were downregulated, phagocytosis of heterologous opsonized Escherichia coli bacteria by neutrophils was unaffected. Spontaneous oxygen radical production peaked sharply 15 min after release of the Pringle maneuver (p < 0.05), contrary to stimulated oxygen radical production, which was depressed 3 h after the release of the Pringle maneuver (ns). CONCLUSIONS: Uneventful partial hepatectomy in man resulted already in a significant change in the phenotype but in less significant changes in the functions of neutrophils.

[Introduction of an interdisciplinary tumor board leads to improvement of treatment outcome of cholangiocarcinoma (bile duct cancer)]. / Einführung eines interdisziplinären Tumorboards führt zur Verbesserung der Behandlungsergebnisse von Cholangio- und Gallenblasenkarzinomen.

BACKGROUND: Cholangiocarcinoma (CCA, bile duct cancer) is a rare malignant disease with a poor prognosis. For several years interdisciplinary tumor boards (TuB) with the participation of experts from various disciplines have been organized to optimize medical treatment for patients suffering from oncological diseases. OBJECTIVE: This study addressed the question whether the introduction of TuB leads to a better life expectancy and quality of life for patients with CCA. MATERIAL AND METHODS: In this retrospective study 161 patients treated for CCA were investigated. The patient collective was divided in two groups (TuB+ vs. TuB-) and a propensity score matching was carried out. RESULTS: The patient group TuB+ included 109 patients (67.7%) and the control group (TuB-) included 52 patients (32.3%). Using propensity score matching 84 patients in the TuB+ and 50 in the TuB group were identified and matched. The survival rates of the matched patients demonstrated an advantage for patients in the TuB+ group (1-year survival rate 61.9%, 5­year survival rate 23.6%, 10-year survival rate 18.0%) over patients in the TuB-group (1-year survival rate 32.0%, 5­year survival rate 8.0%, 10-year survival rate 0%) with p < 0.001. The results of the univariate (hazard ratio, HR 0.513, 95% confidence interval, CI 0.350-0.751, p = 0.001) and the multivariate Cox proportional hazard models (HR 0.459, 95% CI 0.303-0.694, p < 0.001) showed a significant benefit in survival for patients in the TuB+ group. CONCLUSION: This article shows that the introduction of a TuB meeting can provide a measurable benefit for patients with CCA. Hence it is recommended that all cases of patients with CCA should be discussed in a TuB.

The Effect of Donor Age and Recipient Characteristics on Renal Outcomes in Patients Receiving Prolonged-Release Tacrolimus After Liver Transplantation: Post-Hoc Analyses of the DIAMOND Study.

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.

Delayed bottom-up and amended simple method of dosing with once-daily tacrolimus application to achieve stable trough levels in liver transplantation.

BACKGROUND: Tacrolimus once-daily formulation (TacOD) was introduced as an alternative to twice-daily formulations de novo. Dosing recommendations range between 0.1 to 0.2 mg/kg BW/d. MATERIAL AND METHODS: Amended dosing with a simple bottom-up de novo algorithm is presented. Primary outcome measure was feasibility of establishing adequate target trough levels and avoidance of over-immunosuppression, with adequate safety and efficacy after liver transplantation (LT). RESULTS: TacOD was given to 101 patients. Standard steroid-free immunosuppression consisted of MMF 2 g/d, basiliximab 20 mg on day 0 and 4, and delayed bottom-up IS with TacOD starting with 1 mg/d and doubling the dosage every day until target trough levels of 5 to 8 ng/ml were reached. By day 7 after LT, all except 3 patients had received TacOD. The earliest time point of introduction was day 2. A median of 9 mg/d (range: 0 to 25 mg/d) of TacOD were necessary to establish the trough levels by day 10, which was then 5.4 ng/ml (range: 1.5 to 20 ng/ml). Incidence of adverse events (AE), in particular neurological AEs (n=3), were low. Efficacy failure (acute rejection) was low (4.9%). Renal function was stable and did not deteriorate under CNI treatment. CONCLUSIONS: This is the first report of bottom-up, amended, and simple dosing of TacOD in LT. The algorithm is feasible, safe, and efficient, avoiding trough level peaks and top-down strategies.

Preoperative interleukin-22 values add valuable information for outcome prediction following orthotopic liver transplantation: a preliminary study.

BACKGROUND: Recent findings support the idea that interleukin (IL)-22 serum levels are related to disease severity in end-stage liver disease. Existing scoring systems--Model for End-Stage Liver Disease (MELD), Survival Outcomes Following Liver Transplantation (SOFT) and Pre-allocation-SOFT (P-SOFT)--are well-established in appraising survival rates with or without liver transplantation. We tested the hypothesis that IL-22 serum levels at transplantation date correlate with survival and potentially have value as a predictive factor for survival. MATERIAL AND METHODS: MELD, SOFT, and P-SOFT scores were calculated to estimate post-transplantation survival. Serum levels of IL-22, IL-6, IL-10, C-reactive protein (CRP), and procalcitonin (PCT) were collected prior to transplantation in 41 patients. Outcomes were assessed at 3 months, 1 year, and 3 years after transplantation. RESULTS: IL-22 significantly correlated with MELD, P-SOFT, and SOFT scores (Rs 0.35, 0.63, 0.56 respectively, p<0.05) and with the discrimination in post-transplantation survival. IL-6 showed a heterogeneous pattern (Rs 0.40, 0.63, 0.57, respectively, p<0.05); CRP and PCT did not correlate. We therefore added IL-22 serum values to existing scoring systems in a generalized linear model (GLM), resulting in a significantly improved outcome prediction in 58% of the cases for both the P-SOFT (p<0.01) and SOFT scores (p<0.001). CONCLUSIONS: Further studies are needed to address the concept that IL-22 serum values at the time of transplantation provide valuable information about survival rates following orthotopic liver transplantation.

Detection of a fatty liver after binge drinking: correlation of MR-spectroscopy, DECT, biochemistry and histology in a rat model.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the possibility of detecting a fatty liver after binge drinking in an animal model using (1)H magnetic resonance spectroscopy ((1)H-MRS), dual-energy computed tomography (DECT), biochemistry, and the gold standard of histology. MATERIALS AND METHODS: In 20 inbred female Lewis rats, an alcoholic fatty liver was induced; 20 rats served as controls. To simulate binge drinking, each rat was given a dose of 9.3 g/kg body weight 50% ethanol twice, with 24 hours between applications. Forty-eight hours after the first injection, DECT and (1)H-MRS were performed. Fat content as well as triglycerides were also determined histologically and biochemically, respectively. To assess specific liver enzymes, blood was drawn from the orbital venous plexus. RESULTS: In all 20 animals in the experimental group, fatty livers were detected using (1)H-MRS, DECT, and biochemical and histologic analysis. The spectroscopic fat/water ratio and the biochemical determination were highly correlated (r = 0.892, P < .05). A significant correlation was found between (1)H-MRS and histologic analysis (r = 0.941, P < .001). Also, a positive linear correlation was found between the dual-energy computed tomographic density of ΔHU and the biochemical (r = 0.751, P < .05) and histologic (r = 0.786, P < .001) analyses. CONCLUSIONS: Quantification of hepatic fat content on (1)H-MRS showed high correlation with histologic and biochemical steatosis determination. In comparison to DECT, it is more suitable to reflect the severity of acute fatty liver.

Sequential therapy of transarterial chemoembolisation and sorafenib in intermediate stage hepatocellular carcinoma.

INTRODUCTION: Prolongation of median survival can be achieved for intermediate Barcelona Clinic Liver Cancer stage hepatocellular carcinoma (HCC) by transarterial chemoembolisation (TACE). TACE might induce induction of angiogenic factors, especially in patients not responding to TACE, which might result in further tumour progression with development of new satellite lesions. CASE REPORT: Here, we report a patient with intermediate stage HCC, who initially responded to TACE, but developed new satellite lesions. After careful discussion, TACE was stopped, and a sequential treatment with sorafenib, a vascular endothelial growth factor receptor and RAF tyrosinkinase inhibitor, was started, resulting in a progression-free survival of 10 months. DISCUSSION: The presented case demonstrates the feasibility of sequential TACE and sorafenib treatment. Results of ongoing controlled, clinical trials in this regard are awaited.

Hypoxia and reoxygenation of primary human hepatocytes induce proteome changes of glucose metabolism, oxidative protection and peroxisomal function.

Protective hepatocellular responses to a hypoxic challenge are crucial to preserve liver function. The knowledge of affected metabolic functions could help assess and enhance hepatic ischemic tolerance. Here we studied adaptive mechanisms in human hepatocytes after hypoxia and reoxygenation using a proteomic approach. Proteins from primary hepatocytes were extracted after 6 h of hypoxia and 24 h of reoxygenation. The proteome was analyzed by 2D-electrophoresis. Densitometry and mass spectrometry (MALDI-TOF-MS) were used for protein identification. Two hundred and sixty-two spots were differentially analyzed and 33 spots displayed significant differences between hypoxic and normoxic cells. Seventeen proteins were identified by mass spectrometry. After hypoxia and reoxygenation the UTP-glucose-1-phosphate uridyltransferase, phosphoglycerate kinase1, fructose-1,6-bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, fructose-1,6-bisphosphatase, thiosulfat-sulfurtransferase, thioredoxin peroxidase, peroxiredoxin III, and annexin A2 proteins were down-regulated. An increased expression was found for carbamoyl phosphate synthetase I, heat shock 70 kDa protein5, phosphoenolpyruvate carboxy-kinase, catalase isoform2, peroxiredoxin II, glutathione S-transferase, hydroxyacid oxidase1, and F1-ATP synthase, alpha subunit1. Hepatocellular adaptation to hypoxia and reoxygenation involve glucose metabolism, peroxisomal functions, and oxidative stress protection. The identified proteins can serve as possible diagnostic targets to monitor hepatic hypoxic tolerance e.g. in the context of liver surgery and transplantation.

Efficacy of an escalating dose regimen of pegylated interferon alpha-2a plus ribavirin in the early phase of HCV reinfection after liver transplantation.

We evaluated the safety and efficacy of an escalating dose regimen of pegylated interferon alpha-2a (PEG-IFN(alpha-2a)) and ribavirin in the early phase of recurrent hepatitis C after orthotopic liver transplantation (OLT). In this prospective study, 26 patients transplanted for hepatitis C virus cirrhosis with recurrent hepatitis C were treated 3.4 +/- 3.6 months after OLT and compared with an untreated historical control. PEG-IFN(alpha-2a) was initiated as monotherapy, following stepwise dose escalation up to 180 mug/week and the addition of ribavirin up to 1200 mg/day or maximally tolerated doses for 48 weeks. In the intent-to-treat analysis, 38% showed an early virological response (EVR), 35% an end of treatment response (ETR) and 19% a sustained virological response (SVR). SVR was associated with EVR (P = 0.0001) and cumulative PEG-IFN(alpha-2a) dose (P = 0.04). There was no significant histological improvement compared with untreated patients. There were no treatment-related serious adverse events. Adverse events included leucopenia (77%) and thrombocytopenia (46%). Three patients discontinued therapy due to side effects, fourteen were nonresponders and four relapsers. Treatment with PEG-IFN(alpha-2a) and ribavirin in the acute phase of post-transplant recurrent hepatitis C yielded an EVR of 38% and an SVR of 19%. The combination was safe and well tolerated.

Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma.

Criteria to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) are based on tumor size and number of nodules rather than on tumor biology. The present study was undertaken to assess the role of transarterial chemoembolization (TACE) in selecting patients with tumors suitable for LT. Ninety-six consecutive patients with HCC were treated by repeatedly performed TACE, 62 of them exceeding the Milan criteria. Patients meeting the Milan criteria were immediately listed, and patients beyond the listing criteria were listed upon downstaging of the tumor following successful TACE. Fifty patients were finally transplanted. Of these 50 patients, 34 exceeded the Milan criteria. In these 96 patients, overall 5-year survival was 51.9%. However, it was 80.9% for patients undergoing LT and 0% for patients without transplantation (P < 0.0001). Tumor recurrence was primarily influenced by the control of the disease through continued TACE during the waiting time. Freedom from recurrence after 5 years was 94.5% in patients (n = 39) with progress-free TACE during the waiting time. Tumor recurrence was significantly higher in patients (n = 11) who after initial response to TACE progressed again before LT (freedom from recurrence 35.4%; P = 0.0017). Progress-free course of TACE during the waiting time (P = 0.006; risk ratio, 8.95), and a limited number of tumor nodules as assessed in the surgical specimen (P = 0.025; risk ratio, 0.116) proved to be significant predictors for freedom from recurrence in the multivariate analysis. Milan criteria were without impact on recurrence. Our data suggest that sustained response to TACE is a better selection criterion for LT than the initial assessment of tumor size or number.