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Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher’s exact, p MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.

Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006–2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33–80). The median follow-up was 21.7 months (range 0.3–92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P 0.05). Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Clinical decision-making around the management of liver-limited stage IV colorectal cancer involves careful assessment of the potential risks and benefits of surgery. This balance can often be optimised through appropriate patient selection to ensure long-term benefit of any operation, with fastidious perioperative care to minimize risk. We reviewed selected relevant articles from the existing literature. Multi-platform imaging is routinely used to determine distribution of disease and whether lesions are technically resectable, but what remains less clear is how to identify patients in whom resection is likely to deliver long-term benefits. A number of prognostic markers have been identified, with growing interest in direct assessment of tumour biology; genotyping of RAS status is routine in specific situations. Following a multidisciplinary team decision to proceed to surgery, patients undergo perioperative assessment and optimisation. Cardiopulmonary exercise testing helps to stratify perioperative risk: patients with low uptake of oxygen at the anaerobic threshold are known to have worse perioperative outcomes, and prehabilitation may offer the chance to reduce this risk. Intraoperative anaesthetic management is on a patient-by-patient basis but sub-normal hydration, epidural anaesthesia and steroids play a key role. Enhanced recovery after surgery programmes have improved perioperative outcomes while providing a potential economic benefit. Despite very good perioperative results, surgical management is not curative for the majority of patients, highlighting the need to further refine patient selection and definition of treatment aim on a patient-by-patient basis.

Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds., Drug-induced liver injury: mathematical model quantifies impact of liver-damaging drugs Drug-induced liver injury (DILI) is one of the most important obstacles during drug development. More than 1000 drugs have been identified to damage the liver, but the current test systems are poor in predicting DILI. A team of cell biologists, theoretical physicists, and clinical pharmacologists combined experimental data generated in cultured liver cells with mathematical modeling to quantify the impact of the anti-inflammatory drug diclofenac. The analysis demonstrated that diclofenac induces multiple changes in the signal transduction network activated by the tumor necrosis factor alpha (TNFα), one of the known factors to amplify liver toxicity. Data of other liver injury-causing compounds were integrated into the mathematical model and their impact was quantified, thereby demonstrating the potential use of the mathematical model for the further analysis of other compounds in order to improve DILI test systems.

The role of physical interventions (surgical resection and surgical/radiological ablation) for liver metastases of colorectal cancer has changed dramatically over the last 10–15 years. Whereas in the 1990s, when only those patients with up to three unilobar metastases were considered for any form of such intervention, our present approach to these physical interventions is determined by how much viable disease-free liver can be preserved (most authorities accepting 25–30% disease-free future remnant liver volume) and the possibility of further such interventions if the disease recurs in the liver. There is increasing evidence that for smaller tumours (

The aim of this study was to analyze and model the effect of knitting parameters on the air permeability of Cotton/ Polyester double layer interlock knitted fabrics. Fabric samples of areal densities ranging from 315-488 g/m were knitted using yarns of three different cotton/polyester blends, each of two different linear densities by systematically varying knitting loop lengths for achieving different cover factors. It was found that by changing the polyester content in the inner and outer fabric layer from 52 to 65 % in the double layer knitted fabric did not have statistically significant effect on the fabric air permeability. Air permeability sharply increased with increase in knitting loop length owing to decrease in fabric areal density. Decrease in yarn linear density (tex) resulted in increase in air permeability due to decrease in areal density as well as the fabric thickness. It was concluded that response surface regression modeling could adequately model the effect of knitting parameters on the double layer knitted fabric air permeability. The model was validated by unseen data set and it was found that the actual and predicted values were in good agreement with each other with less than 10 % absolute error. Sensitivity analysis was also performed to find out the relative contribution of each input parameter on the air permeability of the double layer interlock knitted fabrics.

The aim of this study was to model the air permeability of polyester cotton blended woven fabrics. Fabrics of varying construction parameters i.e. yarn linear densities and thread densities were selected and tested for air permeability, fabric areal density and fabric thickness. A total of 135 different fabric constructions were tested among which 117 were allocated for development of prediction model while the remaining were utilized for its validation. Four variables were selected as input parameters on basis of statistical analysis i.e. warp yarn linear density, weft yarn linear density, ends per 25 mm and picks per 25 mm. Response surface regression was applied on the collected data set in order to develop the prediction model of the selected variables. The model showed satisfactory predictability when applied on unseen data and yielded an absolute average error of 5.1 %. The developed model can be effectively used for prediction of air permeability of the woven fabrics.

There is increasing evidence that systemic inflammatory response has a positive correlation with a poorer outcome in patients undergoing resection for solid tumours. The aim of this study was to analyse the impact of an elevated C-reactive protein (CRP), an outcome following curative resection for colorectal liver metastases. One hundred and seventy patients who underwent curative resection for colorectal liver metastases were included in the study. Laboratory measurements of haemoglobin, white cell, platelets, albumin and CRP were taken on the day before surgery. Elevated CRP (10 mg l(-1)) was present in 54 (31.8%) patients. The median survival of patients with an elevated CRP was 19 months (95% CI 7.5-31.2 months) compared to 42.8 months (95% CI 33.2-52.5 months) for those with a normal CRP, P=0.004. Similarly, when assessing disease-free survival, patients with an elevated CRP had poorer disease-free survival (median of 11.8 months (95% CI 6.4-17.3) compared to median of 15.1 months (95% CI 11.1-19.1)), P=0.043. The result of the study showed that an elevated preoperative CRP is a predictor of poor outcome in patients undergoing curative resection for colorectal liver metastases.

Many colorectal liver metastasis patients are denied surgical resection on the basis of tumour size. The aim of this study was to explore the impact of metastasis size on modern liver resection.Using a prospectively collected database, this was a retrospective analysis of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into two groups: smaller metastases (8 cm) and larger metastases (or = 8 cm). Those with larger metastases were then further stratified into big metastases (8-12 cm) and giant metastases (12 cm). Demographic, pathological, surgical technique and outcome data were compared between the groups.There were 88 (18%) patients with metastases measuring 8 cm or larger. There was an association between higher carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels and larger metastases. The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for smaller metastases (not statistically significant). Patients with giant metastases had poorer overall and disease-free survival (both nonsignificant) compared with those with big metastases: 29% and 28% at 5 years, respectively.Patients with colorectal liver metastasis greater than 8 cm and up to 12 cm in size should not be treated differently from those with smaller lesions.

Twenty-one elderly patients with end-stage renal disease (ESRD) secondary to various etiologies received IPD at our unit. It was done manually by trained staff nurses. Each patient received 20-24 one hour exchanges of 2 liters PD solution twice a week through a permanent Tenckhoff catheter. Mean age of patients was 63 years (range 60–96),12 were male and 9 female. Mean duration of stay on IPD was 23 months (range 18–41). The etiologies of ESRD were: diabetes mellitus (9 patients), unknown etiology (7), hypertension (3), glomerulonephritis and liver cirrhosis (hepatitis C) (2). The peritonitis rate was one episode per 16.3 patient/month. The causative organisms were staphylococcus, coliforms, acinobacter and pseudomonas. Six patients died due to each of the following: 2 septicemia not related to PD; 2 hepatic failure; 2 massive myocardial infarction. Two patients were changed to hemodialysis due to recurrent peritonitis. We observed 7 episodes of catheter exit-site infection; causative organisms were staphylococcus (4), and pseudomonas (3). Staphylococcus cases of exit-site infection responded to local fucidin ointment and oral antibiotic, while in the pseudomonas cases the catheter had to be removed. All patients received erythropoietin and have maintained good hemoglobin levels (10.1 ± 1.2 gm%). They also had adequate control of their serum creatinine and urea level. As the patients improved, they became less dependent on their relatives.

Background In case of colorectal liver metastases invading the retrohepatic vena cava (RHVC) and the hepatocaval confluence major liver resection and venous resection are the treatment of choice. The use of venovenous bypass is still a matter of debate. We describe our technique without the use of venovenous bypass for resection of a tumor invading the RHVC.