Estimated Dermal Penetration of Tetrachlorvinphos (TCVP) in Humans Based on In Silico Modeling and In Vitro and In Vivo Data.

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient in some collars for dogs and cats. The objective of this study was to provide a refined estimate of dermal penetration of TCVP in humans using in silico predictions as well as in vitro and in vivo data. The in vivo dermal absorption of TCVP was previously studied in the rat and shown to be saturable, ranging from 21.7% (10 µg/cm2) down to 3% (1000 µg/cm2) Subsequent in silico predictions were conducted for rats and humans to provide initial evaluations of species and dose-dependent differences in dermal absorption. A definitive comparison of TCVP systemic exposure in rat and human following dermal application was then conducted via a standard in vitro assay. TCVP dose levels of 10, 100, or 1000 µg/cm2 were applied to excised rat and human skin mounted in flow-through diffusion cells. The vehicle was 1% hydroxypropylmethylcellulose (HPMC) in water. An additional 5 µg/cm2 dose was applied to excised human skin only. The in vitro dermal absorption of TCVP was also assessed from artificial sebum at dose levels of 5, 10, or 100 µg/cm2 applied to human skin only. Utilizing the so-called triple pack approach with in vitro and in vivo rat data and in vitro human data, dermal absorption for TCVP was calculated for humans. In silico modeling indicated absorption of TCVP through human skin might be 3- to 4- fold lower than rat skin at all application levels, with a maximum dermal absorption of 9.6% at the lowest exposure of 10 µg/cm2, down to 0.1% at 1000 µg/cm2. Similar species differences were also found in the definitive in vitro absorption assays. Modeling overestimated TCVP human dermal absorption (9.6%) as compared to excised human skin results (1.7%) for the HPMC vehicle at the lowest exposure (10 µg/cm2), with better agreement at the higher exposures. Conversely, modeling accurately predicted rat dermal absorption (27.9%) as compared to in vivo rat results (21.7%) at the lowest exposure in HPMC, with diminished agreement at the higher exposures. As a first approximation, in silico estimates of dermal absorption are useful; however, these tend to be more variable than in vitro or in vivo measurements. TCVP dermal penetration measured in vitro was lower in 1% HPMC vehicle as compared to artificial sebum. For the 1% HPMC vehicle, in vitro rat dermal absorption was similar to data obtained for in vivo rats, giving confidence in the triple pack approach. In consideration of the triple pack approach, estimated human dermal absorption from 1% HPMC was ≤2%. Based upon excised human skin determinations directly, estimated human dermal absorption of TCVP from artificial sebum was ≤7%.

[Endoscopic Ultrasound Drainage of the Gallbladder in Acute Cholecystitis in Patients at High Surgical Risk]. / Endosonografische Drainage der Gallenblase wegen akuter Cholezystitis bei Patienten mit hohem Operationsrisiko.

BACKGROUND: The standard treatment for acute cholecystitis is laparoscopic cholecystectomy. Alternative procedures are used for patients at high surgical risk. Percutaneous drainage is widely available. The alternative of transpapillary drainage of the gallbladder via the ductus cysticus has only limited prospects of success. With the widespread use of interventional endoscopic ultrasound and the development of new stent systems, endoscopic ultrasound gallbladder drainage has proven to be a safe and reliable procedure. MATERIAL AND METHOD: We retrospectively report on our experiences in 11 consecutive patients with endoscopic ultrasound gallbladder drainage in acute cholecystitis between December 2018 and January 2021. RESULTS: 11 patients with acute cholecystitis with a mean age of 84.5 years (70-95 years) are reported. All patients had severe general comorbidities or advanced abdominal tumours or a combination of these conditions. After interdisciplinary debate, the indication for interventional therapy was made. This was carried out in 9 cases by means of endosonographic drainage alone and in 2 cases by means of percutaneous and two-stage endosonographic drainage. Technical success was achieved in 10 cases (91%), clinical success in 9 cases (82%). In 2 cases there were procedural complications that led to the operation. CONCLUSION: In the case of high surgical risks, endosonographic drainage of the gall bladder is a safe and definitive therapy. This can be performed alone or in combination with percutaneous drainage. Endoscopic ultrasound drainage is superior to percutaneous drainage alone, due to its lower complication rates and lower rates of necessary follow-up interventions. Therefore, in cases of relatively high surgical risk, endoscopic ultrasound drainage of the gall bladder should be preferred to percutaneous drainage, especially when definitive therapy is required.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.

The chlorophenoxy herbicide MCPA: a mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs.

Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50%-67% dose in rat, ∼40% in human and 2%-27% in dog. No dog specific metabolite is apparent.In rat and human, MCPA and metabolites are rapidly eliminated in urine (65%-70% within 24 h) but in dog, excretion is via urine and faeces (20%-30% within 24 h), with renal excretion saturating between 5 and 100 mg/kg bw.The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15-17 h) but higher in dog (47 h). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing.The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.

In silico predictions of absorption of MDI substances after dermal or inhalation exposures to support a category based read-across assessment.

Methylenediphenyl diisocyanate (MDI) substances used polyurethane production can range from their simplest monomeric forms (e.g., 4,4'-MDI) to mixtures of the monomers with various homologues, homopolymer, and prepolymer derivatives. The relative dermal or inhalation absorption of 39 constituents of these substances in human were predicted using the GastroPlus® program. Predicted dermal uptake and absorption of the three MDI monomers from an acetone vehicle was 84-86% and 1.4-1.5%, respectively, with lower uptake and absorption predicted for the higher MW analogs. Lower absorption was predicted from exposures in a more lipophilic vehicle (1-octanol). Modeled inhalation exposures afforded the highest pulmonary absorption for the MDI monomers (38-54%), with 3-27% for the MW range of 381-751, and <0.1% for the remaining, higher MW derivatives. Predicted oral absorption, representing mucociliary transport, ranged from 5 to 10% for the MDI monomers, 10-25% for constituents of MW 381-751, and ≤3% for constituents with MW > 900. These in silico evaluations should be useful in category-based, worst-case, Read-Across assessments for MDI monomers and modified MDI substances for potential systemic effects. Predictions of appreciable mucociliary transport may also be useful to address data gaps in oral toxicity testing for this category of compounds.

Weight of evidence analysis of the tumorigenic potential of 1,3-dichloropropene supports a threshold-based risk assessment.

1,3-Dichloropropene (1,3-D; CAS #542-75-6) is a fumigant used for preplant treatment of soil to control parasitic nematodes and manage soil borne diseases for numerous fruit, vegetable, field and tree and vine crops across diverse global agricultural areas. In the USA, 1,3-D has historically been classified by the U.S. EPA as likely to be carcinogenic to humans via both oral and inhalation routes. This classification for the oral route was primarily based upon increases in multiple tumor types observed in National Toxicology Program (NTP) cancer bioassays in rats and mice, while the classification for the inhalation route was based upon increased benign bronchioloalveolar adenomas in a mouse study conducted by The Dow Chemical Company. Based on U.S. EPA standard risk assessment methodologies, a low-dose linear extrapolation approach has been used to estimate risks to humans. Furthermore, genotoxicity associated with 1,3-D was historically considered a potential mode of action (MOA) for its tumorigenicity. New information is available and additional studies have been conducted that reveal a different picture of the tumorigenic potential of 1,3-D. These data and information include: (1) initial cancer studies by the NTP were conducted on an antiquated form of 1,3-D which contained a known mutagen/carcinogen, epichlorohydrin, as a stabilizer while current 1,3-D fumigants use epoxidized soybean oil (ESO) as the stabilizer; (2) results from two additional oral rodent cancer bioassays conducted on the modern form of 1,3-D became available and these two studies reveal a lack of carcinogenicity; (3) a newly conducted Big Blue study in F344 rats via the oral route further confirms that 1,3-D is not an in vivo genotoxicant; and (4) a newly conducted repeat dose inhalation toxicokinetic (TK) study shows that linear dose proportionality is observed below 30 ppm, which demonstrates the non-relevance of 60 ppm 1,3-D-induced benign lung tumors in mice for human health assessment. This weight of evidence review is organized as follows: (a) the TK of 1,3-D are presented because of relevant considerations when evaluating test doses/concentrations and reported findings of tumorigenicity; (b) the genotoxicity profile of 1,3-D is presented, including a contemporary study in order to put a possible genotoxicity MOA into perspective; (c) the six available bioassays are reviewed followed by (d) scientifically supported points of departure (PODs) and evaluation of human exposure for use in risk assessment. Through this assessment, all available data support the conclusion that 1,3-D is not a tumorigen at doses below 12.5 mg/kg bw/day via the oral route or at doses below 30 ppm via the inhalation route. These findings and clearly identified PODs show that a linear low dose extrapolation approach is not appropriate and a threshold-based risk assessment for 1,3-D is human health protective. Finally, in 2019, the Cancer Assessment Review Committee (CARC) reevaluated the carcinogenic potential of 1,3-D. In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment, the CARC classified 1,3-D (Telone) as "Suggestive Evidence of Carcinogenic Potential based on the presence of liver tumors by the oral route in male rats only." Given this finding, EPA stated that "quantification of human cancer risk is not required. The CARC recommends using a non-linear approach (i.e. reference dose (RfD)) that will adequately account for all chronic toxicity including carcinogenicity, that could result from exposure to 1,3-dichloropropene."

Tissue-based miRNA mapping in alcoholic liver cirrhosis: different profiles in cirrhosis with or without hepatocellular carcinoma.

Context: Alcoholic liver cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). The importance of tumour-associated cirrhosis in the development or progression of HCC is not understood. MiRNAs are important regulators for HCC development, but their role in HCC due to alcoholic liver cirrhosis is unclear.Objective: The aim of this study is the detection of miRNA expression in alcoholic liver cirrhosis, tumour-associated cirrhosis, and HCC.Materials and methods: We analysed the differences in the miRNA profiles of HCC, tumour-associated cirrhosis, and cirrhosis without HCC samples from 30 patients who underwent liver transplantation because of alcoholic liver disease.Results: Microarray analyses revealed 40 significantly differentially expressed miRNAs between HCC tissue and tumour-associated cirrhosis tissue. Furthermore, the microarray analysis discovered 56 differentially expressed miRNAs in tumour-associated cirrhosis and cirrhosis without HCC.Discussion: The differences of miRNA profile in alcoholic liver cirrhosis with and without HCC could improve understanding of HCC development, as well as lead to a new diagnostic tool in HCC screening.Conclusion: We were able to show for the first time, the differences of miRNA profile as promising biomarker in HCC, tumour-associated cirrhosis, and cirrhosis without HCC in context of alcoholic liver disease.

Review of the pharmacokinetics and metabolism of triclopyr herbicide in mammals: Impact on safety assessments.

A review of pharmacokinetic and metabolism studies show that triclopyr is well absorbed from the oral route in numerous species (≥80%), primarily as parent compound. Absorption is quite rapid in rats, dogs and human volunteers. Plasma or blood clearance is also rapid (t1/2 3-9 h), except for dog (12-96 h). Systemic exposure is not dose-proportional: in the rat above 20 mg/kg (dietary) or between 3 and 60 mg/kg (gavage), or in dogs above 5 mg/kg, with systemic exposure in human more comparable to rat than dog. Triclopyr is highly bound to protein in rat, dog and human plasma (≥97% at or below 7 µg/mL), indicating that species differences in systemic exposure are not due to differences in the free fraction of this test material in plasma. An in vitro flux study in renal proximal tubule cells showed that net renal transport of triclopyr is in the direction of secretion in rat and human donors, while reabsorption predominated in the dog, possibly via organic anion transporters such as OAT1/3. These results fit well into the framework of utilizing metabolism and toxicokinetics across species and exposure levels to allow for toxicity testing in the most relevant species as well as at proper dose levels.

Milan criteria in the MELD era-is it justifiable to extend the limits for orthotopic liver transplantation?

BACKGROUND: The Milan criteria (MC) are widely used for the indication of liver transplantation (LTx) in hepatocellular carcinoma (HCC). Good long-term results have also been reported following LTx for patients exceeding the MC. In this article, we compare the overall and recurrence-free survival of our patients fulfilling and exceeding the MC according to the post-transplant histopathological results. PATIENTS AND METHODS: Data from 120 patients with HCC (22 females and 98 males) were analyzed. The median patient age was 61 years (Q1, Q3 54.7, 65.4), and the median MELD score was 11 (Q1, Q3 8, 15). The median follow-up period was 53 months (Q1, Q3 16.6, 78). Patients were categorized into established criteria (MC, up-to-seven (UTS), Asan criteria, AFP score), and the outcome of the individual groups was compared. RESULTS: Seventy-four of 120 patients fulfilled the MC, 86 patients met the UTS criteria, 85 patients fulfilled the Asan criteria, and 79 patients had an AFP score less than or equal to 2. The 1- and 5-year survival rates of all patients were 76.7% and 55.6%, respectively. In total, 14.2% of all patients (5.4% of patients who met the MC, 7% of patients who met the UTS criteria, 5.9% of patients who met the Asan criteria, and 6.3% of patients who had an AFP score less than 2) experienced recurrence. CONCLUSIONS: The outcomes of the patients were comparable to those reported in the current literature. In our population, similar recurrence and survival rates of the patients were noted for patients fulfilling the UTS criteria irrespective of fulfilling or exceeding the MC. Consequently, we consider using UTS criteria as the extended criterion for LTx indication.

Successful surgical management of hepatic alveolar echinococcosis by inductive therapy with albendazole - a case report.

We report the case of a 65-year-old female patient with hepatic alveolar echinococcosis (AE) caused by Echinococcus multilocularis. This infrequent zoonosis has a considerable morbidity and mortality. The malignant appearing hepatic mass was initially misdiagnosed as cholangiocarcinoma of the right hepatic lobe (segments VII, VIII, and IVa, sized 10.9 cm × 7.6 cm) involving the right and middle hepatic vein and extending close to the left hepatic vein. During exploratory laparotomy, the frozen-section biopsy was indicative of AE (World Health Organization [WHO] classification: stage P3N0M0). Due to the high operative risk, it was decided to pretreat the patient with albendazole as inductive therapy in order to remove the AE secondarily in accordance with the patient's request. After year-long treatment with albendazole (under strict control of the maximum blood levels), a right hemihepatectomy was successfully performed. Postoperative treatment with albendazole had to be stopped prematurely after 11 months due to considerable subjective intolerance and a more-than-tenfold elevation of transaminases despite normal therapeutic albendazole blood levels. A 18F-FDG-PET/CT scan revealed no evidence of AE residues. Conducting follow-up examinations by 18F-FDG-PET/CT scans every 2 years is planned in order to recognize possible recurrence at an early stage.

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.

BACKGROUND & AIMS: Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. METHODS: We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. RESULTS: Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61-65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. CONCLUSIONS: The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. LAY SUMMARY: The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.

Power of computed-tomography-defined sarcopenia for prediction of morbidity after pancreaticoduodenectomy.

BACKGROUND: The goal of our study was to evaluate the current approach in prediction of postoperative major complications after pancreaticoduodenectomy (PD), especially symptomatic pancreatic fistula (POPF), using parameters derived from computed tomography (CT). METHODS: Patients after PD were prospectively collected in a database of the local department of surgery and all patients with CT scans available were assessed in this study. CT parameters were measured at the level of the intervertebral disc L3/L4 and consisted of the areas of the visceral adipose tissue (AVAT), the diameters of the pancreatic parenchyma (DPP) and the pancreatic duct (DPD), the areas of ventral abdominal wall muscle (AMVEN), psoas muscle (AMPSO), paraspinal muscle (AMSPI), total muscle (AMTOT), as well as the mean muscle attenuation (MA) and skeletal muscle index (SMI). Mann-Whitney-U Test for two independent samples and binary logistic regression were used for statistical analysis. RESULTS: One hundred thirty-nine patients (55 females, 84 males) were included. DPD was 2.9 mm (Range 0.7-10.7) on median and more narrow in patients with complications equal to or greater stadium IIIb (p < 0.04) and severe POPF (p < 0.01). DPP median value was 17 (6.9-37.9) mm and there was no significant difference regarding major complications or POPF. AVAT showed a median value of 127.5 (14.5-473.0) cm2 and was significantly larger in patients with POPF (p < 0.01), but not in cases of major complications (p < 0.06). AMPSO, AMSPI, AMVEN and AMTOT showed no significant differences between major complications and POPF. MA was both lower in groups with major complications (p < 0.01) and POPF (p < 0.01). SMI failed to differentiate between patients with or without major complications or POPF. CONCLUSION: Besides the known factors visceral obesity and narrowness of the pancreatic duct, the mean muscle attenuation can easily be examined on routine preoperative CT scans and seems to be promising parameter to predict postoperative complications and POPF.

The ADME profile of the fungicide tricyclazole in rodent via the oral route: A critical review for human health safety assessment.

Herein, we publish data from regulatory studies investigating the oral ADME (absorption, distribution, metabolism, excretion) of tricyclazole in vivo, in silico and in vitro. The oral route is relevant to human dietary exposure assessment. Tricyclazole is readily absorbed and highly bioavailable in rodents (>86%) with indication of saturation of absorption at high doses. Enterohepatic recirculation is evident. Excretion occurs quickly both via urinary (31-64%) and faecal routes (39-65%), with substantial biliary elimination in the rat (≥58%). The tricyclazole-derived radioactivity is distributed to major organs, including those investigated in in vivo genotoxicity studies (liver, kidney, gastrointestinal tract and bone marrow). There is no evidence of bioaccumulation. Metabolism is extensive (approximately 30 metabolites), with the liver being identified as the primary metabolism organ with Phase I and II enzymes involved. Several metabolites are formed following an initial cleavage of the central thiazole ring, with no loss of free triazole from the remaining phenyl ring. A group of 4 metabolites derive from an initial oxidation step with the formation of the tricyclazole-alcohol, a relevant crop metabolite, and account for up to 13% of the administered dose. In vitro metabolism, investigated with liver microsomes, confirmed that humans do not form unique metabolites.

PBTK model for assessment of operator exposure to haloxyfop using human biomonitoring and toxicokinetic data.

Physiologically-based toxicokinetic (PBTK) models are mathematical representations of chemical absorption, distribution, metabolism and excretion (ADME) in animals. Each parameter in a PBTK model describes a physiological, physicochemical or biochemical process that affects ADME. Distributions can be assigned to the model parameters to describe population variability and uncertainty. In this study to assess potential crop sprayer operator exposure to the herbicide haloxyfop, a permeability-limited PBTK model was constructed with parameter uncertainty and variability, and calibrated using Bayesian analysis via Markov chain Monte Carlo methods. A hierarchical statistical model was developed to reconstruct operator exposure using available measurement data: experimentally determined octanol/water partition coefficient, mouse and human toxicokinetic data as well as human biomonitoring data from seven operators who participated in a field study. A chemical risk assessment was performed by comparing the estimated systemic exposure to the acceptable operator exposure level (AOEL). The analysis suggested that in one of the seven operators, the model estimates systemic exposure to haloxyfop of 49.04 ±â€¯10.19 SD µg/kg bw in relation to an AOEL of 5.0 µg/kg bw/day. This does not represent a safety concern as this predicted exposure is well within the 100-fold uncertainty factor applied to the No Observed Adverse Effect Level (NOAEL) in animals. In addition, given the availability of human toxicokinetic data, the 10x uncertainty factor for interspecies differences in ADME could be reduced (EFSA, 2006). Thus the AOEL could potentially be raised tenfold from 5.0 to 50.0 µg/kg bw/day.

Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease.

BACKGROUND & AIMS: Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD including serum sodium (MELD-Na) score. These scores do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied. METHODS: We performed a retrospective observational cohort study of 474 patients with end-stage liver disease (63.5% male; median age, 56.9 years), evaluated for liver transplantation in Germany, with at least 1 year of follow up. Data were collected on blood levels of CRP, IL6, and white blood cell count (WBC). Findings were analyzed in relation to mortality and compared with patients' MELD scores and MELD-Na scores. For survival analysis, the cohort was divided into quartiles of IL6, CRP, and WBC levels, as well as MELD scores. Log-rank test and the Cox proportional hazards regression model were used to compare the groups, and area under the receiver operating characteristic (AUROC) values were calculated. RESULTS: Blood levels of IL6 and MELD scores associated with mortality: none of the patients with levels of IL6 below the first quartile (below 5.3 pg/mL) died within 1 year. In contrast, 67.7% of the patients in the highest quartile of IL6 level (37.0 pg/mL or more) died within 1 year. MELD score also correlated with mortality: among patients with MELD scores below 8.7, 0.9% died within 1 year, whereas in patients with MELD scores of 18.0 or more, 67.4% died within 1 year. The predictive value of level of IL6 (AUROC, 0.940) was higher than level of CRP (AUROC, 0.866) (P = .009) or WBC (AUROC, 0.773) (P < .001) for 90-day mortality. MELD scores associated with 90-day mortality (AUROC, 0.933) (P = .756) as did MELD-Na score (AUROC, 0.946) (P = .771). Level of IL6 associated with 1-year mortality (AUROC, 0.916) to a greater extent than liver synthesis or detoxification markers international normalized ratio (AUROC, 0.839) (P = .007) or bilirubin (AUROC 0.846) (P = .007). Level of IL6 was an independent, significant risk factor for mortality after adjustment for MELD score, MELD-Na score, level of CRP, or WBC. CONCLUSIONS: In a retrospective analysis, we found high blood levels of IL6 to associate with 90-day and 1-year mortality in patients with end-stage liver disease; its predictive value was comparable to that of MELD or MELD-Na score, and was higher than that of level of CRP or WBC. Further studies should be performed to confirm the results in different cohorts.

Surgical therapy of chronic pancreatitis: clinical results and health-related quality of life.

INTRODUCTION: There are several well-established surgical procedures for the treatment of chronic pancreatitis (CP). The present study seeks to evaluate the perioperative and long-term outcome of these procedures. METHODS: All patients who had undergone pancreaticoduodenectomy (PD), duodenum-preserving pancreatic head resection (DPPHR), and distal pancreatectomy (DP) for CP were retrospectively analyzed with regards to the perioperative outcome and long-term survival. Health-related quality of life (HRQoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. RESULTS: There were 145 patients available for analysis. Major complications (grade IIIb-V) occurred in 19 %, in-hospital mortality was 4.2 %, and 90-day mortality was 3 % with no differences between the different resection groups (all p > 0.05). Ten-year survival was 58 % and was highest in the DP group (100 %) but without statistical significance (p = 0.72). The response rate of the HRQoL assessment was 45 % (65 of 145). There was a significant improvement with regards to pain and HRQoL of all resection groups compared to the preoperative group (all p < 0.05). With respect to HRQoL and pain relief, the PD, DPPHR, and DP did not differ significantly. DISCUSSION: Surgical therapy of CP can be performed safely. The 3 different types of resection performed equally with regards to complications and HRQoL.

Pancreaticoduodenectomy for periampullary cancer: does the tumour entity influence perioperative morbidity and long-term outcome?

BACKGROUND: Malignant tumours of the periampullary region include ductal adenocarcinoma of the pancreas (Pan-Ca), distal bile duct cancer (DBDC) and adenocarcinoma of the ampulla (Amp-Ca). The present retrospective clinical study was designed to evaluate the influence of tumour entity on postoperative complications and identify risk factors predicting survival and morbidity. METHODS: We retrospectively analysed data from all patients who underwent pancreatic resection for periampullary cancer with curative intent (R0 or R1). Demographic data, risk factors, perioperative complications and survival rates for the different subtypes were assessed. RESULTS: A total of 225 patients with periampullary cancer were identified: 124 (55.1%) had Pan-Ca, 55 (24.4%) had DBDC and 46 had (20.4%) Amp-Ca. Sixty-nine patients (30.7%) had major complications (grade IIIb-V). Patients with DBDC had significantly more grade C pancreatic fistulas. Univariate analysis revealed male gender, BMI >30, R1-status, and low-grade tumour differentiation as risk factors for major complications. Overall in-hospital-mortality was 6.7%. CONCLUSIONS: Further research will be needed to implement more individualized therapy.

Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality.

BACKGROUND: Advanced stages of liver cirrhosis lead to a dramatically increased mortality. For valid identification of these patients suitable biomarkers are essential. The most important biomarkers for liver function are bilirubin and prothrombin time expressed as International Normalized Ratio (INR). However, the influence of several anticoagulants on the prothrombin time limits its diagnostic value. Aim of this study was the evaluation of cholesterol esterification (CE) fraction (esterified cholesterol vs. total cholesterol) as an alternative biomarker for liver synthesis and mortality prediction. Under physiological conditions the CE fraction in blood is closely regulated by lecithin-cholesterol acyltransferase (LCAT) which is produced in the liver. METHODS: One hundred forty-two patients with liver disease clinically considered for orthotopic liver transplant for different indications were enrolled in the study. One patient was excluded because of the intake of a direct oral factor Xa inhibitor which has a strong impact on prothrombin time. RESULTS: Results of CE fraction were in good agreement with INR (R2 = 0.73; p < 0.001). In patients who died or survived within three months mean CE fraction was 56% vs. 74% (p < 0.001) and mean INR was 2.0 vs. 1.3 (p < 0.001), respectively. The predictive value of CE fraction for three-month mortality risk was higher compared to INR (p = 0.04). Results for one-year mortality were comparable. CONCLUSIONS: The cholesterol esterification fraction is a valid biomarker for liver synthesis and allows reliable prediction of mortality. In contrast to INR, it is independent of anticoagulation and other analytical limitations of coagulation tests.

Primary liver transplantation and liver retransplantation: comparison of health-related quality of life and mental status - a cross-sectional study.

BACKGROUND: Liver Retransplantation (Re-LT) procedures are associated with an increased risk of morbidity and mortality. Up to date, there is no knowledge on the health-related quality of life and the mental status of these patients. METHODS: Health-Related Quality of Life (HRQoL) was assessed by using the Short Form 36 (SF-36) Health Survey and Mental Status was assessed by using the Hospital Anxiety and Depression Scale (HADS). The patients were examined in different assessments: During regular check-up examinations in the LT outpatient department in 2011 (Survey 1) and in a postal survey in 2013 (Survey 2). Their medical data was collected by using an established database. RESULTS: We received eligible surveys of 383 patients (55.6%) with a history of LT, of which 15 (3.9%) had undergone Re-LT (Re-LT group). These patients were compared to a group of 60 patients who had undergone only one LT. With regard to their HRQoL, the Re-LT group had significantly lower scores on the scales of physical function (PF, p = 0.026), their role-physical (RP, p = 0.008), their vitality (VIT, p = 0.040), and their role-emotional (RE, p = 0.005). The scores for anxiety and depression did not differ significantly between the groups. In a multiple regression analysis, chronic kidney disease was found to be an independent risk factor for decreased scores of PF (p = 0.023). CONCLUSIONS: Patients who have to undergo Re-LT procedures are faceing impairments in physical aspects of a HRQoL. Together with clinical results from other studies, the findings of the present examination underline the need for an optimized organ distribution strategy since not all patients listed for Re-LT appear to benefit from it.

Socio-economic disparities in long-term cancer survival-10 year follow-up with individual patient data.

PURPOSE: Reasons for the social gradient in cancer survival are not fully understood yet. Previous studies were often only able to determine the socio-economic status of the patients from the area they live in, not from their individual socio-economic characteristics. METHODS: In a multi-centre cohort study with 1633 cancer patients and 10-year follow-up, individual socio-economic position was measured using the indicators: education, job grade, job type, and equivalence income. The effect on survival was measured for each indicator individually, adjusting for age, gender, and medical characteristics. The mediating effect of health behaviour (alcohol and tobacco consumption) was analysed in separate models. RESULTS: Patients without vocational training were at increased risk of dying (rate ratio (RR) 1.5, 95% confidence interval (CI) 1.1-2.2) compared to patients with the highest vocational training; patients with blue collar jobs were at increased risk (RR 1.2; 95% CI 1.0-1.5) compared to patients with white collar jobs; income had a gradual effect (RR for the lowest income compared to highest was 2.7, 95% CI 1.9-3.8). Adding health behaviour to the models did not change the effect estimates considerably. There was no evidence for an effect of school education and job grade on cancer survival. CONCLUSIONS: Patients with higher income, better vocational training, and white collar jobs survived longer, regardless of disease stage at baseline and of tobacco and alcohol consumption.