British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress.

BACKGROUND & AIMS: PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen. METHODS: Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non-disruptive tag in native PIEZO1 or endothelial-specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively. RESULTS: PIEZO1 activation leads to nitric oxide synthase- and endothelium-dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium-dependent but independent of nitric oxide synthase. The TRPV4-mediated contraction is suppressed by inhibitors of phospholipase A2 and cyclooxygenases and mimicked by prostaglandin E2 , suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo-osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses. CONCLUSIONS: The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.

Primary liver resection for patients with cirrhosis and hepatocellular carcinoma: the role of surgery in BCLC early (A) and intermediate stages (B).

AIM: This study aims to report the outcomes following primary liver resection (PLR) in patients with cirrhosis including stratification according to the Barcelona Clinic Liver Cancer (BCLC) classification. METHODS: Patients with cirrhosis and hepatocellular carcinoma (HCC) who had PLR between 2000 and 2013 were examined. Overall survival (OS), disease-free survival (DFS) and recurrence rate (RR) were analysed. Management after recurrence was reviewed as well as comparison to a series of 116 patients listed directly for liver transplant. RESULTS: Seventy-one patients underwent PLR. Median follow-up was 40 months. The 1-, 3- and 5-year OS and DFS for the series were 77, 69 and 61 % and 69, 39 and 28 % respectively. Overall recurrence was 59 % (44/71) and only 36 % (15/44) of those patients had a further potentially curative procedure. The 1-3-5-year OS and DFS in the BCLC-A (44 patients) were 86, 78 and 68 % and 78, 48 and 44 % respectively. The RR in BCLC-A was 45 % (20 patients) with half (11 patients) suitable for further treatment with curative intent. The 1-3-5-year OS and DFS in the BCLC-B (17 patients) were 81, 74 and 60 % and 58, 29 and 7 % respectively. The overall RR in BCLC-B was 76 % (13 patients). CONCLUSION: Recurrence following PLR for HCC in patients with cirrhosis is high with only a third of patients suitable for further potentially curative procedures. For patients with BCLC-A (or within Milan criteria), PLR provided a 68 % 5-year OS with 44 % of them free of disease. Surgery can offer satisfactory OS in carefully selected patients in the BCLC-B stage.

Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) acts, in part, by triggering calcium ion (Ca(2+)) entry. Here, we sought understanding of a Synta66-resistant Ca(2+) entry pathway activated by VEGF. APPROACH AND RESULTS: Measurement of intracellular Ca(2+) in human umbilical vein endothelial cells detected a Synta66-resistant component of VEGF-activated Ca(2+) entry that occurred within 2 minutes after VEGF exposure. Knockdown of the channel-forming protein Orai3 suppressed this Ca(2+) entry. Similar effects occurred in 3 further types of human endothelial cell. Orai3 knockdown was inhibitory for VEGF-dependent endothelial tube formation in Matrigel in vitro and in vivo in the mouse. Unexpectedly, immunofluorescence and biotinylation experiments showed that Orai3 was not at the surface membrane unless VEGF was applied, after which it accumulated in the membrane within 2 minutes. The signaling pathway coupling VEGF to the effect on Orai3 involved activation of phospholipase Cγ1, Ca(2+) release, cytosolic group IV phospholipase A2α, arachidonic acid production, and, in part, microsomal glutathione S-transferase 2, an enzyme which catalyses the formation of leukotriene C4 from arachidonic acid. Shear stress reduced microsomal glutathione S-transferase 2 expression while inducing expression of leukotriene C4 synthase, suggesting reciprocal regulation of leukotriene C4-synthesizing enzymes and greater role of microsomal glutathione S-transferase 2 in low shear stress. CONCLUSIONS: VEGF signaling via arachidonic acid and arachidonic acid metabolism causes Orai3 to accumulate at the cell surface to mediate Ca(2+) entry and downstream endothelial cell remodeling.

A cost effective analysis of a laparoscopic versus an open left lateral sectionectomy in a liver transplant unit.

INTRODUCTION: This study aimed to assess the cost effectiveness of a laparoscopic left lateral sectionectomy (LLLS) compared with an open (OLLS) procedure and its role as a training operation as well as the learning curve associated with a laparoscopic approach. METHOD: Between 2004 and 2013, a prospectively maintained database was reviewed. LLLS were compared with age- and sex-matched OLLS. In addition, the outcomes of LLLS with a consultant as the primary surgeon were compared with those performed by trainees. RESULTS: Forty-three LLLS were performed during the study period. LLLS was a significantly cheaper operation compared with OLLS (P = 0.001, £3594.14 versus £5593.41). The median hospital stay was shorter in the laparoscopic group (P = 0.002, 3 versus 7 days). No difference was found in outcomes between a LLLS performed by a trainee or consultant (operating time, morbidity or R1 resection rate). The procedure length was significantly shorter during the later half of the study period [120 versus 129 min (P = 0.045)]. CONCLUSION: LLLS is a significantly cost effective operation compared with an open approach with a reduction in hospital stay. In addition, it is suitable to use as a training operation.

Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom.

Obesity levels in the United Kingdom have risen over the years. Studies from the United States and elsewhere have reported variable outcomes for obese liver transplant recipients in terms of post-liver transplant morbidity, mortality, and graft survival. This study was designed to analyze the impact of the body mass index (BMI) on outcomes following adult liver transplantation. Data from 1994 to 2009 were retrieved from a prospectively maintained database. Patients were stratified into 5 World Health Organization BMI categories: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), obese (30.0-34.9 kg/m(2)), and morbidly obese (≥35.0 kg/m(2)). The primary outcome was an evaluation of graft and patient survival, and the secondary outcome was an assessment of postoperative morbidity. Bonferroni correction was applied with statistical significance set at P < 0.012. Kaplan-Meier curves were used to study the effects of BMI on graft and patient survival. A total of 1325 patients were included in the study: underweight (n = 47 or 3.5%), normal-weight (n = 643 or 48.5%), overweight (n = 417 or 31.5%), obese (n = 145 or 10.9%), and morbidly obese patients (n = 73 or 5.5%). The rate of postoperative infective complications was significantly higher in the overweight (60.7%, P < 0.01) and obese recipients (65.5%, P < 0.01) versus the normal-weight recipients (50.4%). The morbidly obese patients had a longer mean intensive care unit (ICU) stay than the normal-weight patients (4.7 versus 3.2 days, P = 0.03). The mean hospital stay was longer for the overweight (22.4 days, P < 0.001), obese (21.3 days, P = 0.04), and morbidly obese recipients (22.4 days, P = 0.047) versus the normal-weight recipients (18.0 days). There was no difference in death-censored graft survival or patient survival between the groups. In conclusion, this is the largest and only reported UK series on BMI and outcomes following liver transplantation. Overweight and obese patients have significantly increased morbidity in terms of infective complications after liver transplantation and, consequently, longer ICU and hospital stays.

An in vitro model of warm hypoxia-reoxygenation injury in human liver endothelial cells.

BACKGROUND: Ischemia-reperfusion or hypoxia-reoxygenation (H-R) injury adversely affects hepatic function following transplantation and major resection; the death of human sinusoidal endothelial cells (SECs) by apoptosis may play a central role in this process. Caspase-3 is an important intracellular protease in the intrinsic and extrinsic pathways of apoptosis. MATERIALS AND METHODS: SECs and EAhy926 cells were exposed to warm hypoxia at 37°C, followed by reoxygenation at 37°C. Activity of caspase-3 was quantified using Western blotting and colorimetric kinase assays. RESULTS: H-R caused a significant increase in caspase-3 activity compared with controls in both cell types. CONCLUSIONS: Warm H-R injury causes apoptotic cell death of SECs and immortalized cells, but with differing patterns of caspase activity.

Treatment and surveillance of polypoid lesions of the gallbladder in the United Kingdom.

OBJECTIVES: The increase in the routine use of abdominal imaging has led to a parallel surge in the identification of polypoid lesions in the gallbladder. True gallbladder polyps (GBP) have malignant potential and surgery can prevent or treat early gallbladder cancer. In an era of constraint on health care resources, it is important to ensure that surgery is offered only to patients who have appropriate indications. The aim of this study was to assess treatment and surveillance policies for GBP among hepatobiliary and upper gastrointestinal tract surgeons in the UK in the light of published evidence. METHODS: A questionnaire on the management of GBP was devised and sent to consultant surgeon members of the Association of Upper Gastrointestinal Surgeons (AUGIS) of Great Britain and Ireland with the approval of the AUGIS Committee. It included eight questions on indications for laparoscopic cholecystectomy and surveillance based on GBP (size, number, growth rate) and patient (age, comorbidities, ethnicity) characteristics. RESULTS: A total of 79 completed questionnaires were returned. The vast majority of surgeons (>75%) stated that they would perform surgery when a single GBP reached 10 mm in size. However, there was a lack of uniformity in the management of multiple polyps and polyp growth rate, with different surveillance protocols for patients treated conservatively. CONCLUSIONS: Gallbladder polyps are a relatively common finding on abdominal ultrasound scans. The survey showed considerable heterogeneity among surgeons regarding treatment and surveillance protocols. Although no randomized controlled trials exist, national guidelines would facilitate standardization, the formulation of an appropriate algorithm and appropriate use of resources.

Predictors of blood transfusion requirement in elective liver resection.

BACKGROUND: Liver resection remains major surgery frequently requiring intra-operative blood transfusion. Patients are typically over cross-matched, and with blood donor numbers falling, cross-matching and transfusion policies need rationalizing. AIM: To identify predictors of peri-operative blood transfusion. METHODS: A retrospective review of elective hepatic resections over a 4-year period was performed. Twenty-six variables including clinicopathological variables and intra-operative data were collated, together with the number of units of blood cross-matched and transfused in the immediate peri-operative period (48 h). Multivariate regression analysis was performed to identify independent predictors of blood transfusion, and a Risk Score for transfusion constructed. RESULTS: Five hundred and eighty-nine patients were included in the study, and were cross-matched with a median 10 units of blood. Seventeen per cent of patients received a blood transfusion; median transfusion when required was 2 units. Regression analysis identified seven factors predictive of transfusion: haemoglobin <12.5 g/dL, pre-operative biliary drainage, coronary artery disease, largest tumour >3.5 cm, cholangiocarcinoma, redo resection and extended resection (5+ segments). Patients were stratified into high or low risk of transfusion based on Risk Score with a sensitivity of 73% [receiver-operating characteristic (ROC) 0.77]. CONCLUSIONS: Patients undergoing elective liver resection are over-cross-matched. Patients can be classified into high and low risk of transfusion using a Risk Score, and cross-matched accordingly.

Interaction of tumour biology and tumour burden in determining outcome after hepatic resection for colorectal metastases.

AIMS: To determine the outcome of colorectal liver metastasis (CRLM) patients based on tumour burden, represented by tumour number and size, and tumour biology as assessed by an inflammatory response to tumour (IRT) and margin positivity. METHODS: Data were collated from CRLM patients undergoing resection from January 1993 to March 2007. Patients were divided into: low (3-or=8 metastases and/or >5 cm) tumour burden. RESULTS: Seven hundred and five patients underwent resection, of which 154 (21.8%), 262 (37.2%) and 289 (41.0%) patients were in the low, moderate and high tumour burden groups, respectively. The 5-year disease-free (P < 0.001) and overall (P < 0.001) survival were significantly different between the groups. IRT (P < 0.001), extent of resection (P < 0.001) and margin (P < 0.001) also differed between the groups. Sub-group analysis revealed that IRT was the only adverse predictor for disease-free and overall survival in the low group. In the moderate group, IRT predicted poorer disease-free survival on multi-variate analysis. In the high group, R1 resection and transfusion were predictors of poorer disease-free survival and age >or=65 years, R1 resection and IRT were adverse predictors of overall survival. CONCLUSION: Resection margin influenced the outcome of patients with high tumour burden, hence the importance of achieving clear margins. IRT influenced the outcome of patients with less aggressive disease.

Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review.

Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996-2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis.

Laparoscopic left lateral sectionectomy: surgical technique and our results from Leeds.

BACKGROUND: Although laparoscopic left lateral sectionectomy is increasingly becoming the accepted approach for resection of tumors in hepatic segments II and III, the variations in surgical technique exist. METHODS: Our technique relies on mobilization of the left lateral sector followed by extracorporeal control of the portal pedicle allowing intermittent occlusion when needed. The parenchyma is thinned, exposing the inflow and outflow allowing application of endoscopic staplers under direct vision for parenchymal transection. RESULTS: Eleven patients underwent left lateral sectionectomy between 2000 and November 2007 and had a median postoperative stay of 3 days. Two patients had to be converted early on. CONCLUSION: Left lateral sectionectomy using this approach appears to be safe and reproducible, and this technique should be considered for patients with tumors in hepatic segments II and III.

Results following surgical resection for malignant pancreatic neuroendocrine tumours. A single institutional experience.

OBJECTIVE: The aim of the study was to present clinical outcomes of patients with malignant pancreatic neuroendocrine tumours (NET) following surgical resection with curative intent. Clinical and pathological factors that influenced the outcomes were also analysed. DESIGN: Retrospective case note study. PATIENTS: All patients with pancreatic NET that underwent surgery over a 7-year period (1999-2006). RESULTS: Twelve patients were identified with a median age at diagnosis of 54 years (range: 24-79 years). Common presenting symptoms include abdominal pain (n=8) and weight loss (n=3). Overall morbidity was 25% with one post-operative death. The median follow-up period was 41 months (range: 9-156 months). The overall 2- and 5-year actuarial survival rates were 88% and 70%, respectively. The overall survival was better in patients treated with surgery compared to patients managed medically (P<0.001). The disease-free survival rates were 62% at 2 and 5 years, respectively. Recurrent disease occurred in four patients and the median disease-free interval was 6 months (range: 3-14 months). On univariate analysis, angio-invasion (P=0.015) and degree of differentiation (P=0.024) were associated with developing recurrent disease. CONCLUSION: Surgical resection of malignant pancreatic NET results in good long-term survival in selected patients.

Impact of blood transfusion on outcomes following resection for colorectal liver metastases in the modern era.

BACKGROUND: Evidence suggests that perioperative blood loss and blood transfusions are associated with poorer long-term outcomes in patients undergoing other oncological surgery. The aim of this study was to determine the long-term outcomes of patients requiring a blood transfusion post-hepatectomy for colorectal liver metastases (CRLM). METHODS: This is a retrospective review from 2005 to 2012. Overall survival (OS) and recurrence-free survival (RFS) were assessed using Kaplan-Meier curves. Red blood cell transfusion (RBCT) and other clinic-pathological parameters were handled as covariates for Cox regression analysis. RESULTS: Six hundred and ninety patients were included. Median follow-up was 33 months. Sixty-four (9.3%) patients required a perioperative RBCT. RBCT was a predictor for decreased OS (median 41 versus 49 months, P = 0.04). However, on multivariate regression analyses preoperative chemotherapy, post-operative complications and Clinical Risk Score were independently associated with reduced OS, though RBCT was not. There was no association between RBCT and RFS (median 15 versus 17 months, P = 0.28). CONCLUSIONS: RBCT is not independently associated with a poorer OS.

A cost-effective analysis of fibrin sealants versus no sealant following open right hemihepatectomy for colorectal liver metastases.

BACKGROUND: There is paucity of data regarding the cost-effectiveness of fibrin sealants during liver surgery. This study aimed to assess the cost-effectiveness of fibrin sealants following right hemihepatectomy for colorectal liver metastases. METHOD: A prospectively maintained database between 2004 and 2013 was reviewed to identify patients who underwent a right hemihepatectomy with and without fibrin sealant application. Perioperative and post-operative outcomes were analysed to assess its cost-effectiveness. RESULTS: One hundred and sixty-three right hemihepatectomies were performed, of which 79 were in the fibrin sealant treatment group and 84 were in the no sealant group. No difference was seen between fibrin sealant and no sealant with regard to bile leak (P = 0.366), intra-abdominal collections (P = 0.200) and overall post-operative complications (P = 0.480). Operating costs were significantly cheaper in the no sealant group (P = 0.010). There was no difference seen in median post-operative stay between fibrin sealant versus no treatment (8 versus 9 days, P = 0.327), median total bed cost (£3900 versus £4300, P = 0.400), mean transfusion cost per patient (P = 0.201) and overall cost (£6706.15 versus £6555.80, P = 0.792). CONCLUSION: Fibrin sealant application to cut surface during liver surgery confers no cost benefit and their routine use may not be recommended.

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.

AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 µM to 3.5 µM. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker γH2AX (5.1% vs. 50.7%) for combination therapy compared with 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared with 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.

The Impact of Advancing Age on Recurrence and Survival Following Major Hepatectomy for Colorectal Liver Metastases.

INTRODUCTION: This study analysed the effect of age on survival in patients undergoing major hepatectomy (MH) for colorectal liver metastases (CRLM). The effect of adjuvant chemotherapy (AC) with age was also assessed. METHOD: Patients undergoing MH for CRLM between 1996 and 2011 were reviewed. Patients aged <75 or ≥75 were compared for disease-free (DFS) and overall survival (OS) as well as impact of AC on survival. RESULTS: Seven hundred twenty-seven patients underwent MH of which 105 (14 %) were aged ≥75. Morbidity was greater in the ≥75 group (25 versus 34 %, p = 0.048). No difference was noted in mortality. There was no difference in DFS between the two groups at 5 years (16.8 vs 18.9 months (p = 0.570). OS was longer in the <75 group (38.6 vs 32.0 months (p = 0.001). DFS was better in groups receiving AC than those not (<75 24.2 vs 12.2 months (p = <0.001) and ≥75 24 vs 12.1 months (p = 0.007)). OS in the ≥75 group was improved in the group receiving AC compared to the ≥75 group not (41.1 vs 16.6 months, p = 0.005). Age ≥75 was not an independent risk factor for reduced DFS on multivariate analysis. CONCLUSION: Well-selected patients aged ≥75 should be considered for MH followed by adjuvant chemotherapy.

Relationship between primary colorectal tumour and location of colorectal liver metastases.

BACKGROUND: There is conflicting evidence regarding whether streamlining of blood flow within the portal vein influences the anatomical distribution of colorectal liver metastases (CRLM). This study assesses the relationship between primary tumour location and metastases location. METHODS: Patients were identified using a prospectively maintained database, and those with known site of primary colorectal tumour and hemiliver involvement were included. Site of metastases and segments affected were confirmed via review of the radiology reports. The location of primary colonic tumour was confirmed via review of clinical correspondence letters. RESULTS: A total of 2364 metastases were identified in 891 patients. Of these, 379 metastases were in the right lobe and 156 in the left lobe, with 356 having bilobar disease. There was no significant relationship between the distribution of CRLM and the site of primary disease (left colon versus right colon) (P = 0.819). However, when the segmental location of the metastases was considered, there is a statistically significant difference between the number of right-sided CRLM compared with left-sided CRLM (P < 0.001). CONCLUSIONS: Right-sided CRLM is more likely regardless of the primary location. Portal streaming may have an effect, although the natural anatomical 'angulation', particularly of the left portal vein branch is more likely to play a role.