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Importance: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival., Objective: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI., Design, Setting, and Participants: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017., Interventions: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86)., Main Outcomes and Measures: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined., Results: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, -23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group., Conclusions and Relevance: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02182440.

Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NH 4 Cl, administered 12 hs after birth. The maze tests showed that MMA and NH 4 Cl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NH 4 Cl increased the levels of 2',7'-dichlorofluorescein-diacetate (DCF), TNF-α, IL-1β in the cortex, hippocampus and striatum of mice. MMA and NH 4 Cl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to examine the cognitive function and depressive traits most frequently associated with the clinical assessment of patients with epilepsy and if these clinical parameters are linked to glycolipid levels and inflammatory and apoptotic markers., Methods: Patients with epilepsy (n = 32) and healthy subjects (n = 41) were recruited to participate in this study. Neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. Additionally, the metabolic markers total cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and glucose (GLU) levels were analyzed., Results: Statistical analyses showed that patients with epilepsy presented decreased scores in memory, attention, language, and executive function tests compared with the control group. Analysis revealed that there was negative correlation in epilepsy for seizure duration vs. oral language (R = -0.4484, p < 0.05) and seizure duration vs. problem solving (executive functions) (R = -0.3995, p < 0.05). This was also observed when comparing depression with temporal-spatial orientation (TSO) (R = -0.39, p < 0.05). Furthermore, we observed a higher depression score in patients with epilepsy than in the healthy ones. Statistical analyses showed higher acetylcholinesterase (AChE) (p < 0.05), interleukin 1β (IL-1β, p < 0.001), and tumor necrosis factor-alpha (TNF-α) (p < 0.001) levels compared with those in the control group. Moreover, patients with epilepsy had significantly higher serum levels of caspase 3 (CASP 3) (p < 0.001) and Picogreen (p < 0.001) compared with the control subjects. Regarding the metabolic markers, higher glycolipid levels were observed in the patients with epilepsy (CHO < 0.05*, LDL < 0.0001*, TG < 0.05*, GLU p < 0.05). High-density lipoprotein levels were not significant. The patients with epilepsy had significant correlation when comparing total language with TNF-α (R = -0.4, p < 0.05), praxes with CASP 3 (R = -0.52, p < 0.01), total CHO with total language (R = -0.48, p < 0.05), TG with semantic memory (R = -0.54, p < 0.05), TG with prospective memory (R = -0.2165, p < 0.02), TG with total memory (R = -0.53, p < 0.02), and GLU with total attention (R = -0.62, p < 0.002)., Conclusion: This study supports the evidence of a distinct neuropsychological profile between patients with epilepsy and healthy subjects. Furthermore, our findings suggest that inflammatory pathway, glycolipid profile, and depressive factors may be associated with cognitive dysfunction in patients with epilepsy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Staple line leak after laparoscopic sleeve gastrectomy (LSG) still represents the most feared complication. The purpose of this study was to investigate whether there are factors that increase the risk for a leakage. Furthermore, we aimed to analyze the impact of a leak on weight change and resolution of comorbidities., Methods: Since 2005, data from obese patients that undergo bariatric procedures in Germany are prospectively registered. For the current analysis, all adult subjects that had undergone primary LSG from 2005 to 2014 were considered., Results: Overall, 241/15,756 (1.53%) patients experienced a leak. The occurrence of a leakage resulted in a significant increase of the mortality rate (3.7 vs. 0.2%; p < 0.01). Percent excess weight loss did not differ between leak and non-leak patients, both, at 12 (64.2 vs. 60.9%; p = 1.0) and 24 months (68.5 vs. 64.0%, p = 0.86). Similarly, no significant difference was observed for resolution rate of all comorbid conditions. Matched pair analysis confirmed these findings. Multivariable analysis identified operation time, conversion, intraoperative complications, and hypertension and degenerative joint disease as risk factors for a leak. Oversewing the staple line was associated with the lowest risk., Conclusion: The postoperative staple line leak after primary LSG significantly increases postoperative morbidity and mortality. We found that there are patient-related factors and operative variables that predispose to leakage after LSG. However, the occurrence of a leakage does not adversely impact the weight loss and resolution of comorbidities in the mid-term.

Despite national and local governing board recommendations in the United States of America to perform an HCV screening test in baby boomers, screening rates remain low. Our goal was to study the impact of an HCV screening and link-to-care programme with patient navigation in two New York City primary care practices. This was a 2-year prospective study of patients born between 1945-1965 ("baby boomers") with encounters at two primary care practices at the Mount Sinai Hospital between November 1, 2013 and November 30, 2015. Baseline HCV screening rates were collected for four months. A multifaceted intervention was sequentially implemented involving electronic alerts, housestaff education, data feedback and patient navigation. HCV screening rates and link to care, defined as attending an appointment with a viral hepatitis specialist, were compared before and after these interventions. There were 14 642 primary care baby boomer patients of which 4419 (30.2%) were newly screened during the study. There was a significant increase in HCV screening rates from 55% to 75% (P<.01) with an HCV seropositive rate of 3.3%. Factors associated with being HCV seropositive included older age (P<.01), male sex (P<.01), African American race (P<.01) and receiving care in the housestaff practice (P<.01). With patient navigation, 78 of 84 (93%) newly diagnosed HCV-infected persons were referred to a specialist and 60 (77%) attended their first appointment. A structured, multifaceted HCV screening programme using well-studied principles identifies a large number of undiagnosed baby boomers within hospital-based primary care and improves access to specialty providers in a timely manner., (© 2017 John Wiley & Sons Ltd.)

Background and Objective: Previous clinical trials have suggested that bovine intestinal alkaline phosphatase has renal protective effects in patients with sepsis-associated acute kidney injury. We conducted a first-in-human study to investigate the pharmacokinetics, safety and tolerability of a novel human recombinant alkaline phosphatase (recAP), and we developed a population pharmacokinetic model to support dose selection for future patient studies., Methods: In a randomized, double-blind, placebo-controlled, phase I trial, healthy volunteers received a single dose of recAP (200, 500, 1000 or 2000 U/kg; n = 33; 3:1 ratio) or multiple doses of recAP (500 or 1000 U/kg; n = 18; 2:1 ratio) via a 1-h intravenous infusion on three consecutive days. Serum recAP concentrations, alkaline phosphatase (AP) activity levels and anti-drug antibodies were measured, and safety parameters were monitored. A population pharmacokinetic model was developed, and simulations were performed to guide dose selection for a phase IIa/b trial., Results: Peak concentrations of recAP and peak AP activity were reached at the end of the 1-h infusion and showed a rapid decline, with about 10 % of the maximum concentration remaining at 4 h and less than 5 % remaining 24 h post-start. RecAP treatment was generally well tolerated, and anti-drug antibodies could not be detected in the serum up to 2 weeks post-injection after a single dose, or up to 3 weeks post-injection after multiple doses. A four-compartment model best described the pharmacokinetics of recAP administration, with moderate inter-individual variability on the central volume of distribution and elimination rate constant. Simulations showed that 1-h intravenous infusions of 250, 500 and 1000 U/kg recAP once every 24 h for three consecutive days constituted the dosing regimen that best met the criteria for dose selection in patient studies., Conclusion: RecAP did not raise any safety concerns when administered to healthy volunteers. A population pharmacokinetic model was developed to support dose selection for patient studies., Trial Registration: 2013-002694-21 (EudraCT)., Competing Interests: Compliance with Ethical StandardsAll protocols were approved by the local ethics committee, and the study, including amendments, was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the International Conference on Harmonisation E6 Guideline for Good Clinical Practice (CPMP/ICH/135/95) and the European Union Clinical Trial Directive (2001/20/EC). All healthy volunteers who participated in the study provided written informed consent before the start of any study-related procedures.FundingThis study was fully funded by AM-Pharma.Conflict of interestPeter Pickkers received consultancy fees from AM-Pharma for the design of the phase IIa/b trial of recAP. Andrea van Elsas is an inventor on patent applications relating to recAP and received advisory fees and stock options from AM-Pharma. Jacques Arend is an employee of AM-Pharma. Renger Tiessen is an employee of the contract research organization (CRO) sponsored to conduct this research. The remaining authors declare that they have no relevant financial interests. Jacques Arend has full control of all primary data from the study and agrees to allow the journal to review the data if requested.

Introduction: Acute kidney injury (AKI) occurs in 55-60% of critically ill patients, and sepsis is the most common underlying cause. No pharmacological treatment options are licensed to treat sepsis-associated AKI (SA-AKI); only supportive renal replacement therapy (RRT) is available. One of the limited number of candidate compounds in clinical development to treat SA-AKI is alkaline phosphatase (AP). The renal protective effect of purified bovine intestinal AP has been demonstrated in critically ill sepsis patients. To build on these observations, a human recombinant AP (recAP) was developed, of which safety and efficacy in patients with SA-AKI will be investigated in this trial., Methods: This is a randomised, double-blind, placebo-controlled, 4-arm, proof-of-concept, dose-finding adaptive phase IIa/IIb study, conducted in critically ill patients with SA-AKI. A minimum of 290 patients will be enrolled at ∼50 sites in the European Union and North America. The study involves 2 parts. Patients enrolled during Part 1 will be randomly assigned to receive either placebo (n=30) or 1 of 3 different doses of recAP (n=30 per group) once daily for 3 days (0.4, 0.8 or 1.6 mg/kg). In Part 2, patients will be randomly assigned to receive the most efficacious dose of recAP (n=85), selected during an interim analysis, or placebo (n=85). Treatment must be administered within 24 hours after SA-AKI is first diagnosed and within 96 hours from first diagnosis of sepsis. The primary end point is the area under the time-corrected endogenous creatinine clearance curve from days 1 to 7. The key secondary end point is RRT incidence during days 1-28., Ethics and Dissemination: This study is approved by the relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will reveal the efficacy of recAP for the improvement of renal function in critically ill patients with SA-AKI and will be published in a peer-reviewed scientific journal., Trial Registration Number: NCT02182440; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge., Methods: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phyt-cancer.uni-mainz.de). As a starting point, we have chosen the topic "biopiracy", since we feel this is of pragmatic significance for scientists working with medicinal plants., Results: It was argued that the patenting of herbs or natural products by pharmaceutical corporations disregarded the ownership of the knowledge possessed by the indigenous communities on how these substances worked. Despite numerous court decisions in U.S.A. and Europe, several international treaties, (e.g. from United Nations, World Health Organization, World Trade Organization, the African Unity and others), sharing of a rational set of benefits amongst producers (mainly pharmaceutical companies) and indigenous communities is yet a distant reality. In this paper, we present an overview of the legal frameworks, discuss some exemplary cases of biopiracy and bioprospecting as excellent forms of utilization of natural resources., Conclusions: We suggest certain perspectives, by which we as scientists, may contribute towards prevention of biopiracy and also to foster the fair utilization of natural resources. We discuss ways, in which the interests of indigenous people especially from developing countries can be secured., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Unlabelled: This prospective study compared a 1-d SPECT/CT protocol with the commonly used 3-d protocol for somatostatin receptor scintigraphy in patients with gastroenteropancreatic neuroendocrine neoplasms. Additionally, the influence of SPECT/CT on patient management was evaluated., Methods: From October 2011 to October 2012, all gastroenteropancreatic neuroendocrine neoplasm patients undergoing restaging with somatostatin receptor scintigraphy on a modern SPECT/CT device were enrolled in this study. The protocol consisted of planar imaging at 4, 24, and 48 h; low-dose SPECT/CT at 24 and 48 h; diagnostic CT at 24 h using a triple-phase delay after administration of contrast; and diagnostic SPECT/CT at 24 h. All components of the imaging data were reassessed by 3 masked interpreters. The results were compared with a reference standard based on all clinical, imaging, and histopathology follow-up data available (follow-up range, 24-36 mo; mean, 29.9 mo). The reference standard was defined by a study-specific interdisciplinary tumor board that also reassessed treatment decisions., Results: Thirty-one patients were eligible for analysis (18 men and 13 women; mean age, 60.4 y). Ten had no imaging signs of disease and remained disease-free during follow-up. Twenty-one had persistent or recurrent disease (82 lesions: 24 in the liver, 21 in the lymph nodes, 16 in bone, 12 in the pancreas, and 9 in other locations). The respective lesion detection rates for interpreters 1, 2, and 3 were 51.9%, 49.4%, and 71.6% for low-dose SPECT/CT at 24 h; 51.9%, 55.6%, and 67.9% for low-dose SPECT/CT at 48 h; 63.0%, 70.4%, and 85.2% for diagnostic CT; and 77.8%, 84.0%, and 88.9% for diagnostic SPECT/CT. Interobserver agreement was moderate for diagnostic SPECT/CT (κ = 0.44), diagnostic CT (κ = 0.43), low-dose SPECT/CT at 48 h (κ = 0.61), and low-dose SPECT/CT at 24 h (κ = 0.55). For planar imaging, interobserver agreement was fair after 48 h (κ = 0.36) and 24 h (κ = 0.38) and moderate after 4 h (κ = 0.42). Every lesion detectable on planar imaging or low-dose SPECT/CT was also detectable on diagnostic SPECT/CT. The CT and SPECT components of diagnostic SPECT/CT strongly complemented each other, as 34 of 82 lesions (41.4%) were detected on only the CT component or only the SPECT component. Therapeutic management was influenced by the diagnostic SPECT/CT interpretation in 8 of 31 patients (25.8%)., Conclusion: The highest detection rates were achieved by diagnostic SPECT/CT. Thus, a more patient-friendly 1-d protocol is feasible. Furthermore, multiphase SPECT/CT affected management in about a quarter of patients., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background & Aims: Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce., Methods: Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients., Results: The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor., Conclusions: A significant proportion of patients with HCC is malnourished or at risk for malnutrition. Screening questionnaires and BIA measurement are superior to pure anthropometric measurements to identify the condition that negatively influences survival. The phase angle derived from body impedance analysis is an independent prognostic factor in patients with HCC., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Graft rinse prior reperfusion in liver transplantation (LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant (ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in LT. The most commonly used rinse solution was albumin. Nineteen centers stated interest in participating in a multicenter RCT in the field. The published literature does not provide concluding appraisal of the benefit of graft rinse in LT. Graft rinse protocols are not standardized and are based on personal experience. Appropriately designed clinical trials addressing the topic are demanded. The online survey appears to be a helpful tool for the evaluation of clinical practice and future research topics in the transplant community., (© 2015 Steunstichting ESOT.)

Background: Surgical resection of tumors of the upper gastrointestinal (GI) tract represent complex procedures and are still associated with a relevant morbidity and mortality. A targeted preoperative risk analysis and patient selection with consideration of the nutritional status and comorbidities are important in order to reduce the perioperative complication rate., Results and Discussion: Anastomotic leaks still remain the most feared surgical complication and in addition to early recognition, immediate initiation of an appropriate therapy are essential. Conservative treatment can be considered for small and adequately drained fistulas as well as in cervical leakages. Indications for surgical reintervention are leaks that occur in the early postoperative course, fulminant defects with diffuse mediastinitis and conduit necrosis. The majority of anastomotic leaks can be successfully managed with minimally invasive endoscopic techniques, e.g. stent placement and endoluminal vacuum therapy. Delayed gastric emptying is frequently observed following esophageal resection and usually shows a satisfactory response to medicinal treatment and endoscopic interventions. The benefits of pyloroplasty in the primary intervention is still a matter of debate. Chylothorax is a rare but serious complication which should initially be managed with conservative measures., Conclusions: For the successful management of postoperative complications following surgical resection of tumors of the upper GI tract both an interdisciplinary approach and the availability of an appropriate infrastructure with defined algorithms are of paramount importance. Therefore, a concentration of these procedures in specialized centers would be highly desirable.

Papillary tumors originate from the various structures of the ampulla of Vater; therefore, these rare tumors represent a heterogeneous group of tumor entities. Intestinal differentiated adenomas are the most common benign lesions, whereas intestinal differentiated papillary carcinomas are the most common malignant tumors. Carcinomas with pancreaticobiliary differentiation have a poorer prognosis. Mesenchymal and neuroendocrine tumors are among the least frequent papillary tumors. Diagnosis is performed by side-view upper endoscopy and biopsy. In cases of suspected malignancy a complete staging with computed tomography (CT) and endoscopic ultrasound scanning is indicated to determine local tumor spread.Adenomas are removed by endoscopic snare papillectomy whereas the therapy of choice for papillary carcinomas is pancreatic head resection with systematic lymphadenectomy. Patients with papillary carcinomas are most likely to benefit from adjuvant therapy, which should be determined in an interdisciplinary consensus conference considering the histological differentiation of the tumor.

The surgical treatment of hepatopancreatobiliary (HPB) diseases requires complex operative procedures. Within the last decades the morbidity (36-50 %) and mortality (<5 %) of these procedures could be reduced; nonetheless, postoperative complications still occur in 41.2 % of cases. Compared with hepatobiliary procedures, pancreatic surgery shows an increased rate of complications. Postoperative bleeding has a major effect on the outcome and the incidence is 6.7 % after pancreatic surgery and 3.2 % after hepatobiliary surgery. The major causes of early postoperative hemorrhage are related to technical difficulties in surgery whereas late onset postoperative hemorrhage is linked to anastomosis insufficiency, formation of fistulae or abscesses due to vascular arrosion or formation of pseudoaneurysms. In many cases, delayed hemorrhage is preceded by a self-limiting sentinel bleeding. The treatment is dependent on the point in time, location and severity of the hemorrhage. The majority of early postoperative hemorrhages require surgical treatment. Late onset hemorrhage in hemodynamically stable patients is preferably treated by radiological interventions. After interventional hemostatic therapy 8.2 % of patients require secondary procedures. In the case of hemodynamic instability or development of sepsis, a relaparotomy is necessary. The treatment concept includes surgical or interventional remediation of the underlying cause of the hemorrhage. Other causes of postoperative morbidity and mortality are arterial and portal venous stenosis and thrombosis. Following liver resection, thrombosis of the portal vein occurs in 8.5-9.1 % and in 11.6 % following pancreatic resection with vascular involvement. Interventional surgical procedures or conservative treatment are suitable therapeutic options depending on the time of diagnosis and clinical symptoms. The risk of morbidity and mortality after HPB surgery can be reduced only in close interdisciplinary cooperation, which is particularly true for vascular complications.

The surgical treatment of primary and secondary liver pathologies is nowadays standard practice. Since the first major resections performed by Langenbruch in 1888 there have been significant developments in the surgical technique. In addition to the surgical technique, the diagnostics and patient selection, perioperative care and anesthetic management as well as knowledge of liver anatomy and physiology have also shown significant developments. The proportion of complex operations, even within the framework of multimodal concepts has also increased. Despite this increasing complexity, the morbidity (< 45 %) and mortality (< 5 %) of liver surgery could be clearly reduced; however, the incidence of postoperative biliary leaks in large published series currently lies between 0 % and 30  % and has only shown a minimal reduction in recent years. The management of bile leakage requires an interdisciplinary management involving endoscopic and radiological, interventional or operative therapy. Most leakages (69-94 %) persist under conservative treatment (drainage and if necessary antibiotic therapy). For high volume fistulas and persistent biliary leakage endoscopic retrograde cholangiography (ERC) with stent placement represents the therapy of choice. Infections with biliary peritonitis and failure of interventional strategies often require revision surgery, possibly consisting of suturing if a leakage is identifiable, replacement of drainages or application of a bile duct drainage (e.g. T-drain or transhepatic external biliary drainage).

Background: HCC predominantly develops in the condition of chronic inflammation that has led to liver cirrhosis. A small proportion of patients with HCC is diagnosed in the non-cirrhotic liver (NCL). Data on patients with HCC in NCL in advanced stages are scarce., Methods: A retrospective analysis was performed comparing 93 patients with HCC in NCL to 571 patients with HCC in liver cirrhosis (LC) with respect to clinical and demographic characteristics. Also factors influencing survival in patients with HCC in NCL were analyzed., Results: Patients with HCC in NCL were diagnosed at older age and in more advanced tumor stages than patients with LC. More than 25% of patients with HCC in NCL presented with extrahepatic metastases. Only a minority of patients with HCC in NCL lacked any sign of hepatic damage. Risk factors for LC and risk factors for NAFLD are present in the majority of patients with HCC in NCL. The BCLC classification corresponded with the survival of patients with HCC in NCL although the therapeutic options differ from those for patients with liver cirrhosis., Conclusions: It will be one of the major challenges in the future to awake awareness of carrying a risk of hepatic malignancies in patients with chronic liver diseases apart from liver cirrhosis, especially in NAFLD. Surveillance programs need to be implemented if these are cost-effective.

Both gastrointestinal stromal tumors (GIST) and liposarcoma originate from mesenchymal tissue. Their coincidence requires a specific expertise in the diagnostic and therapeutic management. An unusual exemplary case is described representing a 47-year old female patient with a gastric GIST and a monstrous retroperitoneal liposarcoma with infiltration of the left kidney. The gastric tumor lesion was removed with a tangential resection of the gastric wall; the retroperitoneal tumor lesion was resected including the left kidney. Both tumors were resected with no macroscopic tumor residual. The technically difficult surgical intervention did not show any postoperative complication, and the postoperative course was also uneventful. The complete tumor resection is the treatment of choice in mesenchymal tumors (aim: R0). Depending on histologic tumor classification, resection status and tumor sensitivity, a subsequent radiation and/or chemotherapy is necessary, which allowed to achieve a postoperative tumor-free survival of 6 years including a good quality of life.

Aim. In the present study, we investigated the antiangiogenic properties of 59 plants used in traditional Korean medicine. Selected phytochemicals were investigated in more detail for their modes of action. Methods. A modified chicken-chorioallantoic-membrane (CAM) assay using quail eggs was applied to test for antiangiogenic effects of plant extracts. A molecular docking in silico approached the binding of plant constituents to the vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2). Microarray-based mRNA expression profiling was employed to correlate the 50% inhibition concentrations (IC50) of a panel of 60 NCI cell lines to these phytochemicals. Results. Extracts from Acer mono leaves, Reynoutria sachalniensis fruits, Cinnamomum japonicum stems, Eurya japonica leaves, Adenophora racemosa whole plant, Caryopteris incana leaves-stems, and Schisandra chinensis stems inhibited angiogenesis more than 50% in quail eggs. Selected phytochemicals from Korean plants were analyzed in more detail using microarray-based mRNA expression profiles and molecular docking to VEGFR1 and VEGFR2. These results indicate multifactorial modes of action of these natural products. Conclusion. The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.

Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI). Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions. Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP). In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function. The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage. The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation. Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism. Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP. In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI.

Inhibition of angiogenesis represents one major strategy of cancer chemotherapy. In the present investigation, we investigated the synergism of artesunate and captopril to inhibit angiogenesis. Artesunate is an antimalarial derivative of artemisinin from the Chinese medicinal plant, Artemisia annua L., which also reveals profound anticancer activity in vitro and in vivo. Captopril is an angiotensin I-converting (ACE) inhibitor, which is well established in Western academic medicine. Both compounds inhibited migration of human umbilical vein endothelial cells (HUVECs) in vitro. The combination of both drugs resulted in synergistically inhibited migration. Whereas artesunate inhibited HUVEC growth in the XTT assay, captopril did not, indicating independent modes of action. We established a chorioallantoic membrane (CAM) assay of quail embryos (Coturnix coturnix L.) and a computer-based evaluation routine for quantitative studies on vascularization processes in vivo. Artesunate and captopril inhibited blood vessel formation and growth. For the first time, we demonstrated that both drugs revealed synergistic effects when combined. These results may also have clinical impact, since cardiovascular diseases and cancer frequently occur together in older cancer patients. Therefore, comorbid patients may take advantage, if they take captopril to treat cardiovascular symptoms and artesunate to treat cancer.

Introduction: The incidence of hepatocellular cancer (HCC) continues to rise in Europe with a shift of the primary cause towards alcoholic and non-alcoholic fatty liver disease. Metabolic factors like diabetes mellitus and overweight have been identified as significant risk factors for HCC development., Patients and Methods: A retrospective analysis in a large single-center cohort of 650 patients diagnosed with HCC was performed. Demographic characteristics, risk factors, tumor stage at diagnosis and survival were evaluated., Results: Among 650 patients (aged 17-87 years, with a male: female ratio of 4:1), 80.8% had underlying liver cirrhosis. Alcohol abuse was identified as the only risk factor for liver cirrhosis in 52.2% of patients. Viral infection with hepatitis C and hepatitis B was present in 13.7 and 3.6% of patients, respectively. 66.1% of patients with HCC were overweight with a body mass index exceeding 25, 25.5% even exceeding 30; 52% of patients had diabetes mellitus., Conclusion: Strategies aiming at prevention and surveillance of patients at risk to develop HCC in the future need to widen the focus from patients with chronic viral hepatitis and a history of alcohol abuse to patients with metabolic risk factors., (Copyright © 2013 S. Karger AG, Basel.)

Background: Adherence to surveillance recommendations for patients at risk of developing hepatocellular carcinoma (HCC) is influenced by several factors, including the etiology of chronic liver disease., Aim: The aim of this study was to analyze whether tumor stage at diagnosis and prognosis differ in patients with alcohol-related HCC compared to those with chronic viral hepatitis-related HCC., Patients and Methods: Medical records of 650 patients diagnosed with HCC between 1994 and 2011 were analyzed retrospectively. Groups were formed from patients having either alcohol abuse or viral hepatitis (chronic hepatitis B or C virus infection) as the only known HCC risk factors. Demographic data (age and gender), tumor stage at diagnosis, survival, liver function [Child-Pugh-Turcotte (CPT) score] in patients with liver cirrhosis, complications of liver cirrhosis, and serologic parameters were compared between the two groups., Results: A total of 393 HCC cases (male 84%, median age 65 years) were identified, with alcohol abuse as the causative factor in 76.8% and chronic viral hepatitis in 23.2%. In patients with alcohol abuse, 278 (92.1%) were diagnosed with liver cirrhosis (CPT A 49.3%, CPT B 31.1%, CPT C 9.6%), while in patients with viral hepatitis, 84 (92.3%) suffered from liver cirrhosis (CPT A 59.3%, CPT B 23.1%, CPT C 8.8%). Tumor stage in patients with alcohol abuse was Barcelona Clinic Liver Cancer (BCLC) C in 43.7%, BCLC B in 30.5%, and BCLC A in 14.6%. Patients with viral hepatitis showed a trend toward diagnosis at an earlier tumor stage (BCLC B 35.2%, BCLC C 34.1%, BCLC A 22.2%). Etiology of liver cirrhosis did not significantly influence survival in intermediate and advanced tumor stages, but BCLC-A patients with alcohol-related disease demonstrated prolonged survival compared to patients with viral hepatitis., Conclusion: Tumor stage at diagnosis of HCC is influenced by the etiology of underlying chronic liver disease and is more progressed in patients having a disease with alcoholic etiology. Majority of HCC patients are not diagnosed at a curable stage, which underlines the need for specialized care for all patients with chronic liver disease, independent of etiology and consequent adherence to current surveillance guidelines.

The US healthcare system is plagued by unsustainable costs and yields suboptimal outcomes, indicating that new models of healthcare delivery are needed. The patient-centered medical home is one model that is increasingly regarded as a promising strategy for improving healthcare quality, decreasing cost, and enhancing the experience of both patients and providers. Conceptually, the patient-centered medical home may be described as combination of the core attributes of primary care-access, continuity, comprehensiveness, and coordination of care-with new approaches to healthcare delivery, including office practice innovations and reimbursement reform. Implementation efforts are gaining momentum across the country, fueled by both private-payer initiatives as well as supportive public policy. High-quality evidence on the effectiveness of the patient-centered medical home is limited, but the data suggest that, under some circumstances, patient-centered medical home interventions may lead to improved outcomes and generate moderate cost savings. Although the patient-centered medical home enjoys broad support by multiple stakeholders, significant challenges to widespread adoption of the model remain., (© 2012 Mount Sinai School of Medicine.)

Buruli ulcer is a neglected disease caused by Mycobacterium ulcerans and represents the world's third most common mycobacterial infection. It produces the polyketide toxins, mycolactones A, B, C and D, which induce apoptosis and necrosis. Clinical symptoms are subcutaneous nodules, papules, plaques and ulcerating oedemae, which can enlarge and destroy nerves and blood vessels and even invade bones by lymphatic or haematogenous spread (osteomyelitis). Patients usually do not suffer from pain or systematic inflammation. Surgery is the treatment of choice, although recurrence is common and wide surgical excisions including healthy tissues result in significant morbidity. Antibiotic therapy with rifamycins, aminoglycosides, macrolides and quinolones also improves cure rates. Still less exploited treatment options are phytochemicals from medicinal plants used in affected countries. Vaccination against Buruli ulcer is still in its infancy., (Copyright © 2010. Published by Elsevier SAS.)

Cancer remains one of the major causes of death worldwide. The switch to pathological angiogenesis is a key process in the promotion of cancer and consequently provides several new and promising targets to anticancer therapy. Thus, antagonizing angiogenesis cuts off the tumor's oxygen and nutrition supply. This review focuses on angiogenesis inhibitors as option for cancer treatment. Modes of action, adverse effects, mechanisms of resistance as well as new developments are highlighted. One approach in angiogenesis inhibition is intermitting the further VEGF (vascular endothelial growth factor) signal pathway with monoclonal antibodies. Bevacizumab is a highly specific recombinant humanized monoclonal IgG antibody targeting VEGF-A. An efficient antitumor therapy demands more specific antibodies that affect other signal molecules besides VEGF-A, which is in the focus of current research. In addition to antagonizing VEGF, there are also small molecules that inhibit receptor tyrosine kinases (RTKs). Many RTK inhibitors have been described, which exhibit different specificity profiles. The question, whether highly specific antagonists are necessary remains open, because other affected RTKs may also represent growth factor receptors that are essential for tumor growth. Therefore their inhibition may also contribute to anticancer activity. Secondary plant metabolites represent templates for the development of new small molecules. The identification of new drugs from plants has a long and successful history. There is convincing evidence for the beneficial effect of phytochemicals on cancer-related pathways, particularly with regard to anti-angiogenesis. Plant phenolics are the most important category of phytochemicals, including flavanoids. Prominent phytochemicals affecting different pathways of angiogenesis are green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein).

Background: Obesity is increasing worldwide at an alarming rate. Particularly in Western countries, obesity and related problems have become a serious medical problem and an enormous socio-economic burden., Discussion: Currently, surgery is the only avail-able treatment for patients with severe obesity which leads to sustained weight loss and cure of co-morbidities in the majority of the patients. The increase in the number of bariatric operations and the occasional failure and complications of these surgical procedures have resulted in an increased need for revision surgery. Overall, 10-25 % of patients are expected to need a revision for failure of the primary bariatric procedure. The main indications for revision procedures are inadequate weight loss, surgery-related complications as well as surgical emergencies and long-term complications caused by malnutrition or -vitamin deficiencies. Unfortunately, there are currently no randomised trials to answer the question as to which operation should be performed in which patient and after which procedure. Decisions are often influenced by the expertise and preference of the operating surgeon as well as by patient's preference. Thus, a systematic review of published data to this complex issue appears to be helpful and important for daily surgical practise., Conclusions: Revision bariatric procedures are technically more complex and associated with increased postoperative complications. These operations should basically be performed in centres with profound expertise in this field of surgery, and - whenever possible - laparoscopically. However, every abdominal surgeon should be able to diagnose and treat some acute complications. After failed restrictive procedures, revision is recommended only in cases of complications but with adequate weight loss at the time of failure. Otherwise, conversion to combined procedures should be considered. After the failure of combined procedures, further weight loss or successful treatment of complications can be achieved by adding more restriction and/or malabsorption components. The latter is associated with an increased risk of nutritional sequelae.

Plant glucosyltransferases (GTs) play a crucial role in natural product biosynthesis and metabolization of xenobiotics. We expressed the arbutin synthase (AS) cDNA from Rauvolfia serpentina cell suspension cultures in Escherichia coli with a 6 x His tag and purified the active enzyme to homogeneity. The recombinant enzyme had a temperature optimum of 50 degrees C and showed two different pH optima (4.5 and 6.8 or 7.5, depending on the buffer). Out of 74 natural and synthetic phenols and two cinnamyl alcohols tested as substrates for the AS, 45 were accepted, covering a broad range of structural features. Converting rates comparable to hydroquinone were not achieved. In contrast to this broad acceptor substrate specificity, only pyrimidine nucleotide activated glucose was tolerated as a donor substrate. Nucleotide and amino acid sequence analysis revealed AS to be a new member of the NRD1beta family of glycosyl transferases and placed the enzyme into the group of plant secondary product GTs. Arbutin synthase is therefore the first example of a broad spectrum multifunctional glucosyltransferase.

Plant-derived glucosides have attracted much attention due to their widespread applications. This class of products is difficult to isolate or to synthesize in pure form because of the resulting low yields. Thus, simple approaches for the generation of such glucosides would be highly beneficial. We purified and characterized a novel glucosyltransferase from plant cell suspension cultures of Rauvolfia serpentina, which showed rather low substrate specificity. We obtained its cDNA and expressed the active recombinant protein in bacteria (Escherichia coli) with excellent plant-specific glucosylation efficiencies. Compared with the plant system, the bacteria delivered the new enzyme, which was in the form of a soluble or matrix-bound enzyme, approximately 1800 times more efficiently for the synthesis of a wide range of glucosides. More importantly, the engineered E. coli strain allowed for in vivo glucosylation and release of the product into the culture medium, as shown by the formation of arbutin, which is a potent inhibitor of human melanin biosynthesis with commercial value., (Copyright 2001 John Wiley & Sons, Inc.)

Plant cell suspension cultures of Rauvolfia are able to produce a high amount of arbutin by glucosylation of exogenously added hydroquinone. A four step purification procedure using anion exchange, hydrophobic interaction, hydroxyapatite-chromatography and chromatofocusing delivered in a yield of 0.5%, an approximately 390 fold enrichment of the involved glucosyltransferase. SDS-PAGE showed a M(r) for the enzyme of 52 kDa. Proteolysis of the pure enzyme with endoproteinase LysC revealed six peptide fragments with 9-23 amino acids which were sequenced. Sequence alignment of the six peptides showed high homologies to glycosyltransferases from other higher plants.