Search

The dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. Significance: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.

Introduction Heller myotomy (HM) remains the gold standard procedure for achalasia. The addition of different types of fundoplication to HM has been debated in several studies. Given the contradictory reports, this meta-analysis was undertaken to compare different outcomes after HM and HM with fundoplication (HMF). Methods An electronic search was performed among five major databases (PubMed, Ovid, Scopus, Cochrane Library, Google Scholar) from inception to October 2019, identifying all randomised and non-randomised studies comparing HM with HMF. Two authors searched electronic databases using the keywords ‘achalasia’ AND ‘dysphagia’ AND ‘gastroesophageal reflux’ and all data were pooled for random-effects meta-analysis. The primary and secondary outcomes were gastroesophageal reflux and dysphagia, respectively. Results A total of six studies were included and involved 576 patients comparing HM and HMF. There was no statistically significant difference between gastroesophageal reflux in the HM vs HMF group (21.3% vs 22.9%, RR 1.32, 95% CI 0.60–2.88, p = 0.49). There was a slightly higher incidence of dysphagia observed in HM vs HMF (14.8% vs 10.8%, RR 1.54, 95% CI 0.98–2.41, p = 0.06). Conclusions There was no statistically significant difference in long-term outcomes between a group of patients undergoing HM and a group who underwent HM with fundoplication.

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

IntroductionCOVID-19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anti-coagulant actions of nebulised heparin limit fibrin deposition and progression of lung injury. Serendipitously, unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit both fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. For these reasons we have initiated a multi-centre international trial of nebulised heparin in patients with COVID-19.Methods and interventionMechanically ventilated patients with confirmed or strongly suspected SARS-CoV-2 infection, hypoxaemia and an acute pulmonary opacity in at least one lung quadrant on chest X-ray, will be randomised to nebulised heparin 25,000 Units every 6 hours or standard care for up to 10 days while mechanically ventilated. The primary outcome is the time to separation from invasive ventilation to day 28, where non-survivors to day 28 are treated as though not separated from invasive ventilation.Ethics and disseminationThe study protocol has been submitted to the human research and ethics committee of St Vincent’s Hospital, Melbourne, Australia. Submission is pending in other jurisdictions. Results of this study will be published in scientific journals and presented at scientific meetings.Trial RegistrationACTRN: 12620000517976

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysaccharide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses when added exogenously, including S-associated coronavirus strain HSR1 and inhibits cellular invasion by SARS-CoV-2. We have previously demonstrated that unfractionated heparin binds to the Spike (S1) protein receptor binding domain, induces a conformational change and have reported the structural features of heparin on which this interaction depends. Furthermore, we have demonstrated that enoxaparin, a low molecular weight clinical anticoagulant, also binds the S1 RBD protein and induces conformational change. Here we expand upon these studies, to a wide range of low molecular weight heparins and demonstrate that they induce a variety of conformational changes in the SARS-CoV-2 RBD. These findings may have further implications for the rapid development of a first-line therapeutic by repurposing low molecular weight heparins, as well as for next-generation, tailor-made, GAG-based antiviral agents, against SARS-CoV-2 and other members of the Coronaviridae.

The glycosaminoglycan (GAG) class of polysaccharides are utilised by a plethora of microbial pathogens as receptors for adherence and invasion. The GAG heparin prevents infection by a range of viruses when added exogenously, including the S-associated coronavirus strain HSR1 and more recently we have demonstrated that heparin can block cellular invasion by SARS-CoV-2. Heparin has found widespread clinical use as anticoagulant drug and this molecule is routinely used as a proxy for the GAG, heparan sulphate (HS), a structural analogue located on the cell surface, which is a known receptor for viral invasion. Previous work has demonstrated that unfractionated heparin and low molecular weight heparins binds to the Spike (S1) protein receptor binding domain, inducing distinct conformational change and we have further explored the structural features of heparin with regard to these interactions. In this article, previous research is expanded to now include a broader range of GAG family members, including heparan sulphate. This research demonstrates that GAGs, other than those of heparin (or its derivatives), can also interact with the SARS-CoV-2 Spike S1 receptor binding domain and induce distinct conformational changes within this region. These findings pave the way for future research into next-generation, tailor-made, GAG-based antiviral agents, against SARS-CoV-2 and other members of the Coronaviridae.

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysaccharide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses if added exogenously, including S-associated coronavirus strain HSR1. Heparin prevents infection by a range of viruses if added exogenously, including S-associated coronavirus strain HSR1. Here, we show that the addition of heparin to Vero cells between 6.25 - 200 μg.ml−1, which spans the concentration of heparin in therapeutic use, and inhibits invasion by SARS-CoV-2 at between 44 and 80%. We also demonstrate that heparin binds to the Spike (S1) protein receptor binding domain and induces a conformational change, illustrated by surface plasmon resonance and circular dichroism spectroscopy studies. The structural features of heparin on which this interaction depends were investigated using a library of heparin derivatives and size-defined fragments. Binding is more strongly dependent on the presence of 2-O or 6-O sulphation, and the consequent conformational consequences in the heparin structure, than on N-sulphation. A hexasaccharide is required for conformational changes to be induced in the secondary structure that are comparable to those that arise from heparin binding. Enoxaparin, a low molecular weight clinical anticoagulant, also binds the S1 RBD protein and induces conformational change. These findings have implications for the rapid development of a first-line therapeutic by repurposing heparin as well as for next-generation, tailor-made, GAG-based antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

Background Neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP) and Glasgow Prognostic Score (GPS) have demonstrated good prognostic value in several cancers but their role in gallbladder cancer (GBC) remains unclear. The aim of this study is to systematically review the current literature to determine their role in predicting survival outcomes in GBC. Methods Using a pre-specified inclusive search strategy MEDLINE, EMBASE and CINAHL databases were used to identify studies describing survival in patients after GBC resection with high or low pre-operative CRP, GPS or NLR. A proforma was used to extract study author and date, number of patients, age, gender, tumour stage, use of adjuvant therapy and primary outcome data. Results In all, 46 studies were identified after initial screening with four studies reporting survival outcomes. All studies described a reduction in survival in patients with an elevated NLR, GPS or CRP. Three studies showed NLR to be an independent prognostic marker and one study additionally demonstrated that elevated CRP and GPS were associated with poorer survival. Conclusions Elevated pre-operative inflammatory markers are inversely related to survival outcomes. They are relatively inexpensive, easy measurable parameters that could aid in the decision making process involved in the management of GBC. Sub-stratification of groups utilizing inflammatory markers may help guide surgical strategy. However, these studies are retrospective and of low to moderate quality. High quality, prospective studies with well-defined inclusion criteria and outcomes are needed to guide the role of inflammatory markers in the management of GBC.

// Min Yang 1, * , Neng-Wen Ke 2, * , Yi Zhang 2, * , Chun-Lu Tan 2 , Bo-Le Tian 2 , Xu-Bao Liu 2 , Wei Huang 3, 4 , Quentin Nunes 4 and Robert Sutton 4 1 Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China 2 Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China 3 Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, China 4 National Institute for Health Research (NIHR) Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK * These authors have contributed equally to this work and shared the co-first authorship Correspondence to: Xu-Bao Liu, email: hx2014bsym@163.com Keywords: pancreatic neuroendocrine tumours, functional status, TNM, ENETS, AJCC Received: December 19, 2016 Accepted: June 12, 2017 Published: August 07, 2017 ABSTRACT Background: There are currently 2 Tumour-Node-Metastasis (TNM) staging systems for pancreatic neuroendocrine tumours (p-NETs) - European Neuroendocrine Tumour Society (ENETS) and American Joint Committee on Cancer (AJCC). P-NETs being heterogeneous, we investigated the prognostic value of the 2 systems in p-NETs, as a whole, and more interestingly in functional and non-functional sub-groups separately, with a view to ascertaining any potential clinical benefits of using one system over the other. Methods: Data from patients with surgically resected p-NETs were retrospectively reviewed. Kaplan-Meier method and Cox Regression proportional hazards model were used to analyse overall survival (OS) and prognostic predictors respectively. Results: In the whole group of 165 patients, both TNM systems successfully discriminated OS differences when comparing stages I and II with stages III and IV ( P

Ethnopharmacological relevance Dachengqi decoction (DCQD) belongs to a family of purgative herbal formulas widely used in China for the treatment of acute pancreatitis (AP). AP is a prevalent digestive disease currently without an effective pharmacological intervention. Formula granules have become the preferred method for delivery of herbal formulation in China given its benefit of potency retention, dosing precision and ease of use. The efficacy of DCQD formula granules (DFGs) in experimental AP models has not been investigated. Aim of the study To analyse and compare the differences in chemical composition of DFGs, with their aqueous extraction (AE) and chloroform extraction (CE) derivatives. To assess their efficacy on severity and targeted pancreatic pro-inflammatory signalling pathways in freshly isolated acinar cells and two models of experimental AP. Material and methods UPLC-Q-TOF-MS was used to analyse chemical components of DFGs and their extractions. Freshly isolated mouse pancreatic acinar cells were treated with taurolithocholic acid 3-sulphate disodium salt (TLCS, 500 μM) with or without DFGs, AE and CE. Apoptotic and necrotic cell death pathway activation was measured by caspase 3/7 (10 μl/mL) and propidium iodide (PI, 1 μM), respectively, using a fluorescent plate reader. Necrotic acinar cells were also counted by epifluorescence microscopy. Mice received either 7 intraperitoneal injections of caerulein (50 μg/kg) at hourly intervals or retrograde infusion of TLCS (3 mM, 50 μl) to induce AP (CER-AP and TLCS-AP, respectively). In CER-AP, mice received oral gavage of DFGs (2.1, 4.2 and 5.2 g/kg), AE (0.6, 1.2, and 2.4 g/kg) and CE (4, 9 and 17 mg/kg), or matched DFGs (1.8 g/kg) and AE (1 g/kg) for 3 times at 2-hourly intervals, or a single intraperitoneal injection of DCQD-related monomers rhein (20 mg/kg), narigeinine (25 mg/kg), and honokiol (5 mg/kg) begun at the 3rd injection of caerulein. In TLCS-AP, DFGs (4.2 g/kg) were given orally at 1, 3 and 5 h post-surgery. Disease severity and pancreatic pro-inflammatory markers were determined. Results The main effective anthraquinones and their glycosides, flavonoids and their glycosides, polyphenols and lignans were found in the DFGs. A higher proportion of polar components including glycosides attached to anthraquinones, phenols and flavonoids was found in AE. Conversely, lower polar components containing methoxy substituted flavonoids and anthraquinones were more abundant in CE. DFGs were given at 4.2 g/kg, a consistent reduction in the pancreatic histopathology score and severity indices was observed in both CER-AP and TLCS-AP. In vitro, AE significantly reduced both apoptotic and necrotic cell death pathway activation, while CE increased TLCS-induced acinar cell necrosis. In vivo, AE at dose of 1.2 g/kg consistently reduced pancreatic histopathological scores and myeloperoxidase in the CER-AP that were associated with suppressed expression of pro-inflammatory meditator mRNAs and proteins. CE increased lung myeloperoxidase and failed to protect against CER-AP in all dosages. AE was demonstrated to be more effective than DFGs in reducing pancreatic histopathological scores and myeloperoxidase. Conclusions AE from DFGs alleviated the severity of mouse AP models via an inhibition of pancreatic pro-inflammatory signalling pathways. Efficacy of AE on experimental AP was more potent than its original DFGs and DCQD monomers.

Acute pancreatitis is a common inflammatory condition affecting the pancreas, predominantly caused by gallstones, alcohol excess, and hypertriglyceridaemia, with severe disease carrying up to 50% mortality. Despite significant research and preclinical promise, no targeted drug treatments exist for the disease and precision medicine approaches are lacking significantly, when compared to other health conditions. Advances in omics applications will facilitate improved preclinical models and target identification as well as biomarker discovery for refined trial design, focusing on risk stratification, subject selection, and outcome determination. Randomised treatment of Acute Pancreatitis with Infliximab: Double-blind, placebo-controlled, multi-centre trial (RAPID-I) is a pioneering trial, currently under way in acute pancreatitis, which may serve as an innovative model for the implementation of precision medicine strategies for acute pancreatitis in the future.

Background Laparoscopic incisional and ventral hernia repair (LIVHR) is being used increasingly, with reported outcomes equivalent to those of open hernia repair. Closure of the fascial defect (CFD) is a technique that may reduce seroma formation and bulging after LIVHR. Non-closure of the fascial defect makes the repair of larger defects easier and reduces postoperative pain. The aim of this systematic review was to determine whether CFD affects the rate of adverse outcomes, such as recurrence, pseudo-recurrence, mesh eventration or bulging, and the rate of seroma formation. Methods A systematic search was performed of PubMed, Ovid, the Cochrane Library, Google Scholar and Scopus to identify RCTs that analysed CFD with regard to rates of adverse outcomes. A meta-analysis was done using fixed-effect methods. The primary outcome of interest was adverse events. Secondary outcomes were seroma, postoperative pain, mean hospital stay, mean duration of operation and surgical techniques employed. Results A total of 16 studies were identified involving 3638 patients, 2963 in the CFD group and 675 in the non-closure of facial defect group. Significantly fewer adverse events were noted following CFD than non-closure (4·9 per cent (79 of 1613) versus 22·3 per cent (114 of 511)), with a combined risk ratio (RR) of 0·25 (95 per cent c.i. 0·18 to 0·33; P < 0·001). CFD resulted in a significantly lower rate of seroma (2·5 per cent (39 of 1546) versus 12·2 per cent (47 of 385)), with a combined RR of 0·37 (0·23 to 0·57; P < 0·001), and shorter duration of hospital stay. No significant difference was noted in postoperative pain. Conclusion CFD during LIVHR reduces the rate of seroma formation and adverse hernia-site events.

Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in cell communication. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional processes such as acute phase response signalling, complement activation and mitochondrial dysfunction. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. These need further investigation for potential applications in the management of AP.

The timing of surgery for painful chronic pancreatitis (CP) may affect outcomes. Clinical course, Izbicki pain scores, and pancreatic function were retrospectively compared and analyzed between patients undergoing either early or late surgery (< 3 or ≥ 3 years from diagnosis) for painful CP in a single center from 2007 to 2012. The early surgery group (n = 98) more frequently than the late group (n = 199) had abdominal pain with jaundice (22.4% vs 9.5%, P = .002) and pancreatic mass +/− ductal dilatation (47% vs 27%, P

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Background Acute uncomplicated diverticulitis (AUD) is common and antibiotics are the cornerstone of traditional conservative management. This approach lacks clear evidence base and studies have recently suggested that avoidance of antibiotics is a safe and efficacious way to manage AUD. The aim of this systematic review is to determine the safety and efficacy of treating AUD without antibiotics. Methods A systematic search of Embase, Cochrane library, MEDLINE, Science Citation Index Expanded, and ClinicalTrials. gov was performed. Studies comparing antibiotics versus no antibiotics in the treatment of AUD were included. Meta-analysis was performed using the random effects model with the primary outcome measure being diverticulitis-associated complications. Secondary outcomes were readmission rate, diverticulitis recurrence, mean hospital stay, requirement for surgery and requirement for percutaneous drainage. Results Eight studies were included involving 2469 patients; 1626 in the non-antibiotic group (NAb) and 843 in the antibiotic group (Ab). There was a higher complication rate in the Ab group however this was not significant (1.9% versus 2.6%) with a combined risk ratio (RR) of 0.63 (95% CI, 0.25 to 1.57, p=0.32). There was a shorter mean length of hospital stay in the Nab group (standard mean difference of -1.18 (95% CI, -2.34 to -0.03 p= 0.04). There was no significant difference in readmission, recurrence and surgical intervention rate or requirement for percutaneous drainage. Conclusion Treatment of AUD without antibiotics may be feasible with outcomes that are comparable to antibiotic treatment and with potential benefits for patients and the NHS. Large scale randomised multicentre studies are needed. This article is protected by copyright. All rights reserved.

Rectal cancer is a common entity and often presents with synchronous liver metastases. There are discrepancies in management guidelines throughout the world regarding the treatment of advanced rectal cancer, which are further compounded when it presents with synchronous liver metastases. The following article examines the evidence regarding treatment options for patients with synchronous rectal liver metastases and suggests potential treatment algorithms.

Historically, hilar bile duct resection (HBDR) has been regarded as the choice of treatment for Bismuth types I and II hilar cholangiocarcinoma (HCCA). The present study aimed to evaluate the advantages of major liver resection (MLR) in the treatment of patients with Bismuth types I and II HCCA when compared with HBDR.Between January 2005 and September 2012, in total, 52 patients with Bismuth types I and II HCCA who underwent HBDR alone or MLR were included for retrospective analysis. The intraoperative outcomes, postoperative complications, and oncological outcomes including recurrence and overall or disease-free survival rate were compared.The MLR group had significantly higher curative resection rates compared with the HBDR group (95% versus 62.5%, P = 0.021) and lower tumor recurrence (28% versus 63%, P = 0.049), albeit with longer operating time (395.5 ± 112.7 versus 270.9 ± 98.8, P0.001), and higher blood transfusion requirements (70% versus 16%, P0.001). MLR resulted in significantly higher overall postoperative morbidity (70% versus 34.4%, P = 0.012), compared with HBDR alone. When restricted to R0 resections for all the procedures, MLR significantly increased the overall postoperative survival rate compared with the HBDR group (P = 0.016); the overall survival rate at 1, 3 y was 68.4% and 60.8% for MLR group and 59.6% and 21.9% for HBDR group, respectively. Also, the disease-free survival rate was significantly higher in patients who underwent MLR, as compared with those who underwent HBDR (53.2% versus 0% at 3 y, P = 0.005).Our study has shown that MLR results in higher curative resections, fewer recurrences, and increased postoperative survival rate for Bismuth types I and II HCCA as compared with HBDR alone. However, there is a need for well-designed, multicenter studies to be undertaken to better inform a decision on the standard treatment for Bismuth types I and II HCCA.

Introduction The incidence of gastro-oesophageal reflux disease and obesity has increased significantly in recent years. The number of antireflux procedures being carried out on people with a higher body mass index (BMI) has been rising. Evidence is conflicting for outcomes of antireflux surgery in obese patients in terms of its safety and efficacy. Given the contradictory reports, this meta-analysis was undertaken to establish the outcomes of antireflux surgery (ARS) in obese patients and its associated safety. Methods A systematic electronic search was conducted using the PubMed, MEDLINE®, Ovid®, Cochrane Library and Google Scholar™ databases to identify studies that analysed the effect of BMI on the outcomes of ARS. A meta-analysis was performed using the random effects model. The intraoperative and postoperative outcomes that were examined included operative time, conversion to an open procedure, mean length of hospital stay, recurrence of acid reflux requiring reoperation and wrap migration. Results A total of 3,772 patients were included in 13 studies. There was no significant difference in procedure conversion rate, recurrence of reflux requiring reoperation or wrap migration between obese and non-obese patients. However, both the mean operative time and mean length of stay were longer for obese patients. Conclusions ARS in obese patients with gastro-oesophageal reflux disease is safe and outcomes are comparable with those in patients with a BMI in the normal range. A high BMI should therefore not be a deterrent to considering ARS for appropriate patients.

The effects of laparoscopic liver resection (LLR) and open liver resection (OLR) on oncological outcomes for colorectal cancer liver metastases (CCLM) remain inconclusive. Major databases were searched from January 1992 to October 2016. Effects of LLR vs OLR were determined. The primary endpoints were oncological outcomes. In total, 32 eligible non-randomized studies with 4697 patients (LLR: 1809, OLR: 2888) were analyzed. There were higher rates of clear surgical margins (OR: 1.64, 95%CI: 1.32 to 2.05, p P P , P p p

Background Surgical reconstruction following pancreaticoduodenectomy (PD) is associated with significant morbidity and mortality. Because of great variability in definitions of specific complications, it remains unclear whether there is a difference in complication rates following the two commonest types of reconstruction, pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ). Published consensus definitions for postoperative pancreatic fistula (POPF) have led to a series of randomized clinical trials (RCTs) uniquely placed to address this question. Methods A literature search was carried out to identify all RCTs comparing postoperative complications of PG versus PJ reconstruction following PD published between January 1995 and December 2013. Pooled odds ratios (ORs) with 95 percent confidence intervals (c.i.) were calculated using fixed-effect or random-effects models. Results In total, seven RCTs with 1121 patients were included. Four of these trials applied definitions as published by the International Study Group on Pancreatic Fistula (ISGPF). Using ISGPF definitions, the incidence of POPF was lower in patients undergoing PG than in those having PJ (OR 0·50, 95 per cent c.i. 0·34 to 0·73; P < 0·001). Using definitions applied by each individual study, PG was associated with significantly lower rates of POPF (OR 0·51, 0·36 to 0·71; P < 0·001), intra-abdominal fluid collection (OR 0·50, 0·34 to 0·74; P < 0·001) and biliary fistula (OR 0·42, 0·18 to 0·93; P = 0·03) than PJ. Conclusion Meta-analysis of four RCTs based on ISGPF criteria, and seven RCTs using non-standard criteria, revealed that PG reduced the incidence of POPF after PD compared with PJ.

Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP.

Background The cellular microenvironment plays an important role in the regulation of homoeostasis and is a source of potential biomarkers and drug targets. In a genome-wide analysis the extracellular proteins that bind to heparin (HBPs) have been shown to form highly modular and interconnected extracellular protein regulatory networks. Using a systems biology approach, we have investigated the role of HBP networks in the normal pancreas and pancreatic digestive diseases. Methods Lists of mRNAs encoding for HBPs associated with the normal pancreas (NP), acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were obtained using public databases and publications. Networks of the putative protein interactomes derived from mRNA expression data of HBPs were built and analysed using cluster analysis, gene ontology term enrichment and canonical pathways analysis. Results The extracellular heparin-binding putative protein interactomes in the pancreas were better connected than their non heparin-binding counterparts, having higher clustering coefficients in the normal pancreas (0.273), acute pancreatitis (0.457), chronic pancreatitis (0.329) and pancreatic ductal adenocarcinoma (0.269). ‘Hepatic Fibrosis/Hepatic Stellate Cell Activation’ appears to be a significant canonical pathway in pancreatic homoeostasis in health and disease with a large number of important HBPs. Conclusions Our analyses clearly demonstrate that HBPs form disease-specific and highly connected networks that can be explored for potential biomarkers and as collective drug targets via the modification of heparin binding properties.

BACKGROUND Gastric cancer has a high incidence in the elderly in the UK, with a significant number of patients aged 75 years or more. While surgery forms the mainstay of treatment, evidence pertaining to the management of gastric cancer in the Western population in this age group is scarce. METHODS We retrospectively reviewed the outcomes of laparoscopy-assisted total and distal gastrectomies at our centre from 2005 to 2015. Patients aged 70 years or above were included in the elderly group. RESULTS A total of 60 patients underwent laparoscopy-assisted gastrectomy over a 10-year period, with a predominance of male patients. There was no significant difference in the rate of overall surgical and non-surgical complications, in-hospital mortality, operation time and length of hospital stay, between the elderly and non-elderly groups. Univariate analysis, performed for risk factors relating to anastomotic leak and surgical complications, showed that age over 70 years and higher American Association of Anesthesiologists grades are associated with a higher, though not statistically significant, number of anastomotic leaks (P = 1.000 and P = 0.442, respectively) and surgical complications (P = 0.469 and P = 0.162, respectively). The recurrence rate within the first 3 years of surgery was significantly higher in the non-elderly group compared with the elderly group (Log Rank test, P = 0.002). There was no significant difference in survival between the two groups (Log Rank test, P = 0.619). CONCLUSIONS Laparoscopy-assisted gastrectomy is safe and feasible in an elderly population. There is a need for well-designed, prospective, randomised studies with quality of life data to inform our practice in future.

INTRODUCTION Laparoscopic incisional and ventral hernia repair (LIVHR) is widely accepted and safe but the type of mesh used is still debated. We retrospectively compared postoperative outcomes with two different meshes commonly used in LIVHR. METHODS This is a retrospective study of patients who underwent incisional hernia repair between January 2008 and December 2010. Two meshes were used: Parietex™ Composite (Covidien, New Haven, CT, USA) and the DynaMesh®-IPOM (FEG Textiltechnik mbH, Aachen, Germany). The two groups were compared with respect to recurrence rates, incidence of seroma and intestinal obstruction. RESULTS Among the 88 patients who underwent LIVHR, 75 patients (85.2%) presented with primary incisional hernia, 10 (11.4%) presented with a first recurrence and 3 (3.4%) presented with a second recurrence. Median follow-up was 53.6 months (range 40–61 months). 12.9% of patients had recurrence in the Parietex™ Composite mesh group (n=62) in comparison to 3.8% in the DynaMesh®-IPOM mesh group (n=26; P=0.20). DynaMesh®-IPOM was associated with a significantly higher incidence of intestinal obstruction secondary to adhesions (11.5% vs. 0%, P=0.006) and lower incidence of seroma and haematoma formation compared to Parietex™ composite mesh group (0% vs. 6.4% of patients; P=0.185). CONCLUSIONS LIVHR is a safe and feasible technique. Dynamesh®-IPOM is associated with a significantly higher incidence of adhesion related bowel obstruction, albeit with a lower incidence of recurrence, seroma and haematoma formation compared with Parietex™ Composite mesh. However, there is a need for further well-designed, multicentre randomised controlled studies to investigate the use of these meshes.

Objective The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. Design Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. Results A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p 2 =89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I 2 =86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. Conclusions PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.

Supplemental Digital Content is available in the text, Enhanced recovery after surgery (ERAS) pathways are multimodal, evidence-based approaches to optimize patient outcome after surgery. However, the use of ERAS protocols to improve morbidity and recovery time without compromising safety following pancreaticoduodenectomy (PD) remains to be elucidated. We conducted a systemic review and meta-analysis to assess the safety and efficacy of ERAS protocols compared with conventional perioperative care (CPC) in patients following PD. PubMed, Medline, Embase, and Science Citation Index Expanded and Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were searched between January 2000 and June 2015. The patients who underwent PD with ERAS protocols or CPC were eligible. The studies that compared postoperative length of hospital stay (PLOS), postoperative complications, or in-hospital costs in the 2 groups were included. A meta-analysis, meta-regression, sensitivity analysis, and subgroup analysis were performed to estimate the postoperative outcomes between the 2 groups and identified the potential confounders. We used the methodological index for nonrandomized studies checklist to assess methodological qualities. Weighted mean differences (WMD) or odds ratios (OR) were calculated with their corresponding 95% confidence intervals (CI). The publication bias tests were also performed through the funnel plots. In total, 14 nonrandomized comparative studies with 1409 ERAS cases and 1310 controls were analyzed. Implementation of an ERAS protocol significantly reduced PLOS (WMD: −4.17 days; 95%CI: −5.72 to −2.61), delayed gastric emptying (OR: 0.56; 95%CI: 0.44–0.71), overall morbidity (OR: 0.63; 95% CI: 0.54–0.74), and in-hospital costs compared to CPC (all P

Aim The relationship between obesity, body-mass index (BMI) and laparoscopic colorectal resection is unclear. Our object was to assess systematically the available evidence to establish the influence of obesity and BMI on the outcome of laparoscopic colorectal resection. Method A search of PubMed/Medline databases was performed in May 2015 to identify all studies investigating the impact of BMI and obesity on elective laparoscopic colorectal resection performed for benign or malignant bowel disease. Clinical end points examined included operation time, conversion rate to open surgery, post-operative complications including anastomotic leakage, length of hospital stay, readmission rate, reoperation rate and mortality. For patients who underwent an operation for cancer, the harvested number of lymph nodes and long-term oncological data were also examined. Results 45 studies were analysed, the majority of which were Level IV with only four level III case-controlled studies. Thirty comparative studies containing 23649 patients including 17895 non-obese and 5754 obese showed no significant differences between the two groups with respect to intraoperative blood loss, overall postoperative morbidity, anastomotic leakage, reoperation rate, mortality and the number of retrieved lymph nodes in patients operated on for malignancy. Most studies, including 15 non-comparative studies, reported a longer operation time in patients who underwent a laparoscopic procedure with the BMI being an independent predictor in multivariate analyses for the operation time. Conclusion Laparoscopic colorectal resection is safe and technically and oncologically feasible in obese patients. These results, however, may be different outside high volume centres of expertise. This article is protected by copyright. All rights reserved.

Introduction Symptomatic gall stones may require laparoscopic cholecystectomy (LC), which is one of the most commonly performed general surgical operations in the western world. Patients with a high body mass index (BMI) are at increased risk of having gall stones, and are often considered at high risk of surgical complications due to their increased BMI. We believe that day case surgery could nevertheless have significant benefits in terms of potential cost savings and patient satisfaction in this population. We therefore compared the outcomes of day case patients undergoing LC stratified by BMI, with a specific focus on the safety and success of the procedure in obese and morbidly obese groups. Methods We reviewed a database of day case procedures performed between January 2004 and December 2012, including all patients with symptomatic gall stone disease who underwent LC. The patients were divided in four BMI groups: less than 25 kg/m2, 25–29 kg/m2, 30–39 kg/m2 and 40 kg/m2 or above. Results The overall success rate for day case surgery was 78%. There were no significant differences in rates of intra-abdominal collection or readmission with increasing BMI. However, increasing BMI was associated with a significant increase in the rate of wound infection. Conclusions LC in patients with a high BMI is safe and can be performed effectively as a day case procedure.

Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It is usually diagnosed late and only about 10–20% of patients with pancreatic cancer are eligible for resection; after resection, the median survival is 11–20 months and the five-year survival is 7–25%. Patients with unresectable locally advanced disease have a median survival of 6–11 months, and those with metastatic disease have a median survival of 2–6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. CT is widely used in the preoperative staging of pancreatic neoplasms. With recent advances in MRI and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy with gemcitabine can improve survival by 10–15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.

Objective. Activated neutrophils have been implicated as effectors of tissue injury and end-organ damage in adult respiratory distress syndrome and multi-organ dysfunction syndrome. Recent research has shown that hypertonic saline may abrogate neutrophil activation and in turn attenuate end-organ damage, while lactated Ringer's solution causes neutrophil activation. There has been little research investigating the effects of iso-osmolar solutions such as 0.9% saline on neutrophil activation. The aim of this study was to determine the effect of an infusion of 0.9% saline on the activation of human neutrophils in healthy volunteers. Material and methods. A 2-l bolus infusion of 0.9% saline was administered to eight healthy volunteers over a 1-h period after an overnight fast. Venous blood samples were taken on three occasions: pre-infusion (time 0), on completion of the infusion (time 1) and 1 h later (time 2). Neutrophil activation was quantified by flow cytometric analysis of CD11b expression. Submaximal ...

The term ‘acute abdomen’ encompasses a spectrum of medical and surgical conditions ranging from the trivial to the life threatening that require hospital admission, investigation and treatment. A careful, methodical approach (including history taking, clinical examination and investigation) is necessary in the management of acute abdomen. The immediate goal is to ascertain if emergency surgery is indicated. Patients must be adequately resuscitated while being investigated if immediate surgery is not required. Initial management includes assessment of the airway, breathing and circulation, and establishing respiratory and cardiovascular stability. Occasionally, resuscitation and surgical intervention may have to be undertaken simultaneously. A detailed clinical history must be obtained because it provides important clues to the differential diagnosis. The initial step in the clinical examination is to document the vital signs (including pulse rate and rhythm, blood pressure, respiratory rate, temperature, Glasgow Coma Score). A thorough general physical examination, abdominal examination and examination of other relevant systems must be performed. The signs must be interpreted in conjunction with history, general condition, age, sex and potential risk factors. Investigations must be aimed at establishing the diagnosis, determining the need for surgical intervention and assessing the fitness of the patient for intervention. The common laboratory and radiological tests used in the diagnosis of the acute abdomen are discussed in this contribution. A laparotomy or a laparoscopy may be the ultimate diagnostic investigation in the difficult patient (in addition to being therapeutic).

Background. Human embryonic stem cells (hESCs) are pluripotent cells derived from the inner cell mass of in vitro fertilised blastocysts, which can either be maintained in an undifferentiated state or committed into lineages under determined culture conditions. These cells offer great potential for regenerative medicine, but at present, little is known about the mechanisms that regulate hESC stemness; in particular, the role of cell-cell and cell-extracellular matrix interactions remain relatively unexplored. Methods and results. In this study we have performed an in silico analysis of cell-microenvironment interactions to identify novel proteins that may be responsible for the maintenance of hESC stemness. A hESC transcriptome of 8,934 mRNAs was assembled using a meta-analysis approach combining the analysis of microarrays and the use of databases for annotation. The STRING database was utilised to construct a protein-protein interaction network focused on extracellular and transcription factor components contained within the assembled transcriptome. This interactome was structurally studied and filtered to identify a short list of 92 candidate proteins, which may regulate hESC stemness. Conclusion. We hypothesise that this list of proteins, either connecting extracellular components with transcriptional networks, or with hub or bottleneck properties, may contain proteins likely to be involved in determining stemness.

Aim With the advent of several different therapeutic strategies to manage the different stages of colorectal cancer, it would be beneficial to allow substratification of patients into groups who are most likely to benefit from costly interventions. The purpose of this review is to analyse the evidence from several retrospective studies examining the prognostic significance of C-reactive protein (CRP). Method A literature search was performed using PubMed, Embase, Cochrane Library, CINAHL and Google Scholar databases to identify studies that analysed CRP and its prognostic significance in all stages of operable colorectal cancer. The primary end-points of interest were overall survival and disease-free survival. Results In all, 205 studies were identified by the search. Twelve involving 1705 patients fulfilled the inclusion criteria and were included. Three of the included studies including 305 patients considered Stage IV colorectal cancer and the impact of CRP on survival. Overall survival and disease-free survival were shorter in the presence of an elevated preoperative CRP in local and advanced colorectal cancer. Conclusion CRP may be useful for prognosis in patients with primary and metastatic colorectal cancer, but currently there is insufficient evidence to justify its routine use. Further well-designed prospective studies are needed to validate its role in substratification of patients for consideration of (neo)adjuvant therapies.

Colorectal Cancer is a common malignancy. Many patients have metastatic disease at presentation and a significant proportion subsequently go onto develop metastatic disease, following surgery for the primary disease. Some groups advocate that synchronous metastatic disease should be resected at the same time as the primary, whereas others believe that outcomes are better following delayed resection for metastatic disease. The following review aims to outline the arguments in favour of both and to suggest some broad guidelines.

Laparoscopic gastrectomy (LG) is being increasingly used to treat gastric cancer. However, there are still several technical disadvantages limiting its use. Robotic gastrectomy (RG) is an emerging minimally invasive technique that overcomes some of these limitations. This study compares RG with LG in the treatment of gastric cancer by performing a systematic review and meta-analysis of all published literature.Comparative studies published between January 1991 and April 2013 in the major databases were systematically searched. Evaluated end points were operative, postoperative, and oncological outcomes. Pooled odds ratios and weighted mean differences with 95% confidence intervals were calculated using either the fixed-effects model or random-effects model.Nine nonrandomized comparative studies with 2495 patients were included, of which 736 procedures were robotic and 1759 were laparoscopic. RG was associated with a lower intraoperative blood loss and a shorter time to oral intake compared with LG. However, it was associated with a significantly longer operative time and shorter distal resection margin. In addition, there was no significant difference in the number of retrieved lymph nodes, proximal resection margin, rate of conversion to open surgery, overall morbidity, anastomotic leakage, anastomotic stenosis, intestinal obstruction, time to first flatus, length of hospital stay, and perioperative mortality rates between the two groups.RG is comparable to LG, with respect to safety, technical feasibility, and oncological effectiveness in the treatment of gastric cancer. However, there is a need for well-designed prospective randomized controlled studies comparing the two procedures with long-term follow-up, to inform future practice.

Carcinoma showing thymus-like elements (CASTLE) is a rare malignant tumor of the thyroid or adjacent neck soft tissues, whose histogenesis is still debated. It may resemble other primary or metastatic poorly differentiated tumors histologically and the differential diagnosis is crucial for CASTLE has a better prognosis. However, CASTLE as a second primary tumor has not been reported in the literature. We report three cases of thyroid CASTLE, including a unique tumor following breast-conserving surgery for early-stage breast invasive carcinoma. There were two female and one male. All three tumors were located in the right lobe of the thyroid, and one tumor showed extension into the surrounding soft tissue. Histologically, all tumors showed expansive growth and consisted of cords, nests or sheets of epithelial cells divided into irregularly shaped lobules by fibrous connective tissue with lymphoplasmacytic infiltration. Focal squamous differentiation resembling Hassall's corpuscles were observed. All cases stained positively for CD5, CD117, high molecular weight cytokeratin, cytokeratin, P63, carcinoembryonic antigen and epithelial membrane antigen. Positive staining for Bcl-2 in two cases and chromogranin A in one case was noted. Ki-67 expression ranged from 15 to 25%. Thyroid transcription factor and CD3 were negative. There was no evidence of recurrent or metastatic disease at following surgery. These features demonstrated CASTLE may arise from branchial pouch remnants, the thyroid solid cell nests. CASTLE is a rare entity, awareness of its occurrence as a second primary tumor is important to avoid overtreatment because it is associated with a favorable prognosis.

AIM: To conduct a meta-analysis comparing laparoscopic total gastrectomy (LTG) with open total gastrectomy (OTG) for the treatment of gastric cancer. METHODS: Major databases such as Medline (PubMed), Embase, Academic Search Premier (EBSCO), Science Citation Index Expanded and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were searched for studies comparing LTG and OTG from January 1994 to May 2013. Evaluated endpoints were operative, postoperative and oncological outcomes. Operative outcomes included operative time and intraoperative blood loss. Postoperative recovery included time to first flatus, time to first oral intake, hospital stay and analgesics use. Postoperative complications comprised morbidity, anastomotic leakage, anastomotic stenosis, ileus, bleeding, abdominal abscess, wound problems and mortality. Oncological outcomes included positive resection margins, number of retrieved lymph nodes, and proximal and distal resection margins. The pooled effect was calculated using either a fixed effects or a random effects model. RESULTS: Fifteen non-randomized comparative studies with 2022 patients were included (LTG - 811, OTG - 1211). Both groups had similar short-term oncological outcomes, analgesic use (WMD -0.09; 95%CI: -2.39-2.20; P = 0.94) and mortality (OR = 0.74; 95%CI: 0.24-2.31; P = 0.61). However, LTG was associated with a lower intraoperative blood loss (WMD -201.19 mL; 95%CI: -296.50--105.87 mL; P < 0.0001) and overall complication rate (OR = 0.73; 95%CI: 0.57-0.92; P = 0.009); fewer wound-related complications (OR = 0.39; 95%CI: 0.21-0.72; P = 0.002); a quicker recovery of gastrointestinal motility with shorter time to first flatus (WMD -0.82; 95%CI: -1.18--0.45; P < 0.0001) and oral intake (WMD -1.30; 95%CI: -1.84--0.75; P < 0.00001); and a shorter hospital stay (WMD -3.55; 95%CI: -5.13--1.96; P < 0.0001), albeit with a longer operation time (WMD 48.25 min; 95%CI: 31.15-65.35; P < 0.00001), as compared with OTG. CONCLUSION: LTG is safe and effective, and may offer some advantages over OTG in the treatment of gastric cancer.

Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West.