Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin.

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.

Aqueous extraction from dachengqi formula granules reduces the severity of mouse acute pancreatitis via inhibition of pancreatic pro-inflammatory signalling pathways.

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.

The heparin-binding proteome in normal pancreas and murine experimental acute pancreatitis.

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.

Earlier surgery improves outcomes from painful chronic pancreatitis.

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 < .001), but less frequently abdominal pain alone (73.5% vs 85.9%, P = .009), ductal dilatation alone (31% vs 71%, P < .001), parenchymal calcification (91.8% vs 100%, P < .001) or exocrine insufficiency (60% vs 72%, P = .034); there were no other significant differences. The early group had longer hospital stay (14.4 vs 12.2 days, P = .009), but no difference in complications. Significantly greater pain relief followed early surgery (complete 69% vs 47%, partial 22% vs 37%, none 8% vs 16%, P = .01) with lower rates of exocrine (60% vs 80%, P = .005) and endocrine insufficiency (36% vs 53%, P = .033).Our data indicate that early surgery results in higher rates of pain relief and pancreatic sufficiency than late surgery for chronic pancreatitis patients. Frey and Berne procedures showed better results than other surgical procedures.

Author Correction: Laparoscopic Versus Open Liver Resection for Colorectal Liver Metastases: A Comprehensive Systematic Review and Meta-analysis.

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.

Antibiotics versus no antibiotics in the treatment of acute uncomplicated diverticulitis - a systematic review and meta-analysis.

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.

Laparoscopic Versus Open Liver Resection for Colorectal Liver Metastases: A Comprehensive Systematic Review and Meta-analysis.

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 < 0.00001) in the LLR group, without significant differences in disease recurrence, 3- or 5-year overall survival(OS) and disease free survival(DFS) between the two approaches. LLR was associated with less intraoperative blood loss (WMD: -147.46 [-195.78 to -99.15] mL, P < 0.00001) and fewer blood transfusions (OR: 0.41 [0.30-0.58], P < 0.00001), but with longer operation time (WMD:14.44 [1.01 to 27.88] min, P < 0.00001) compared to OLR. Less overall morbidity (OR: 0.64 [0.55 to 0.75], p < 0.00001) and shorter postoperative hospital stay (WMD: -2.36 [-3.06 to -1.66] d, p < 0.00001) were observed for patients undergoing LLR, while there was no statistical difference in mortality. LLR appears to be a safe and feasible alternative to OLR in the treatment of CCLM in selected patients.

Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

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<0.00001; I2=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I2=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.

Enhanced Recovery After Surgery Program in Patients Undergoing Pancreaticoduodenectomy: A PRISMA-Compliant Systematic Review and Meta-Analysis.

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 < 0.001). There were no statistically significant differences in other postoperative outcomes. Age, gender, and ERAS component implementation did not significantly contribute to heterogeneity for PLOS as shown by meta-regression analysis.Our study suggested that ERAS was as safe as CPC and improved recovery of patients undergoing PD, thus reducing in-hospital costs. General adoption of ERAS protocols during PD should be recommended.

Fibroblast growth factors as tissue repair and regeneration therapeutics.

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.

In silico analyses of heparin binding proteins expression in human periodontal tissues.

BACKGROUND: Periodontitis is described as a group of inflammatory diseases of the gingiva and supporting structures of the periodontium. The accumulation of plaque bacteria, which include putative periodontal pathogens, is known to initiate the disease but the host immune response is the major contributing factor for destruction of periodontal tissues. Proteins that bind to heparin heparin-binding protein (HBPs) play important roles in health and disease and interact with each other via networks known as 'heparin interactomes'. This study aimed at evaluating published datasets of HBPs and its role in periodontitis. METHODS: To elucidate the role of HBPs in periodontitis, bioinformatics analyses of published data was used. In silico analyses of published datasets were used to construct a putative HBPs interactome using an online database resource, 'STRING' (Search Tool for the Retrieval of Interacting Genes). RESULTS: PubMed searches identified 249 genes that were up regulated and 146 genes that were down regulated in periodontal disease, compared with periodontal disease-free gingival samples. In silico analyses using published datasets revealed 25 up-regulated and 23 down-regulated HBPs in periodontitis. Of these HBPs; chemokines, such as CXCL12 was up regulated where as some of the matrixmetalloproteinases (MMPs; MMP-2 and MMP9) were up-regulated while MMP-14 was down regulated. CONCLUSIONS: The results indicate that HBP analyses will provide multiple targets for the biological mechanisms underlying periodontal disease (such as MMPs, cytokines and chemokines) that will have important clinical implications in the future drug design and management of periodontal disease.

Meta-analysis of subtotal stomach-preserving pancreaticoduodenectomy vs pylorus preserving pancreaticoduodenectomy.

AIM: To investigate the differences in outcome following pylorus preserving pancreaticoduodenectomy (PPPD) and subtotal stomach-preserving pancreaticoduodenectomy (SSPPD). METHODS: Major databases including PubMed (Medline), EMBASE and Science Citation Index Expanded and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were searched for comparative studies between patients with PPPD and SSPPD published between January 1978 and July 2014. Studies were selected based on specific inclusion and exclusion criteria. The primary outcome was delayed gastric emptying (DGE). Secondary outcomes included operation time, intraoperative blood loss, pancreatic fistula, postoperative hemorrhage, intraabdominal abscess, wound infection, time to starting liquid diet, time to starting solid diet, period of nasogastric intubation, reinsertion of nasogastric tube, mortality and hospital stay. The pooled odds ratios (OR) or weighted mean difference (WMD) with 95% confidence intervals (95%CI) were calculated using either a fixed-effects or random-effects model. RESULTS: Eight comparative studies recruiting 650 patients were analyzed, which include two RCTs, one non-randomized prospective and 5 retrospective trial designs. Patients undergoing SSPPD experienced significantly lower rates of DGE (OR = 2.75; 95%CI: 1.75-4.30, P < 0.00001) and a shorter period of nasogastric intubation (OR = 2.68; 95%CI: 0.77-4.58, P < 0.00001), with a tendency towards shorter time to liquid (WMD = 2.97, 95%CI: -0.46-7.83; P = 0.09) and solid diets (WMD = 3.69, 95%CI: -0.46-7.83; P = 0.08) as well as shorter inpatient stay (WMD = 3.92, 95%CI: -0.37-8.22; P = 0.07), although these latter three did not reach statistical significance. PPPD, however, was associated with less intraoperative blood loss than SSPPD [WMD = -217.70, 95%CI: -429.77-(-5.63); P = 0.04]. There were no differences in other parameters between the two approaches, including operative time (WMD = -5.30, 95%CI: -43.44-32.84; P = 0.79), pancreatic fistula (OR = 0.91; 95%CI: 0.56-1.49; P = 0.70), postoperative hemorrhage (OR = 0.51; 95%CI: 0.15-1.74; P = 0.29), intraabdominal abscess (OR = 1.05; 95%CI: 0.54-2.05; P = 0.89), wound infection (OR = 0.88; 95%CI: 0.39-1.97; P = 0.75), reinsertion of nasogastric tube (OR = 1.90; 95%CI: 0.91-3.97; P = 0.09) and mortality (OR = 0.31; 95%CI: 0.05-2.01; P = 0.22). CONCLUSION: SSPPD may improve intraoperative and short-term postoperative outcomes compared to PPPD, especially DGE. However, these findings need to be further ascertained by well-designed randomized controlled trials.

Prophylactic intra-peritoneal drain placement following pancreaticoduodenectomy: a systematic review and meta-analysis.

AIM: To conduct a meta-analysis comparing outcomes after pancreaticoduodenectomy (PD) with or without prophylactic drainage. METHODS: Relevant comparative randomized and non-randomized studies were systemically searched based on specific inclusion and exclusion criteria. Postoperative outcomes were compared between patients with and those without routine drainage. Pooled odds ratios (OR) with 95%CI were calculated using either fixed effects or random effects models. RESULTS: One randomized controlled trial and four non-randomized comparative studies recruiting 1728 patients were analyzed. Patients without prophylactic drainage after PD had significantly higher mortality (OR=2.32, 95%CI: 1.11-4.85; P=0.02), despite the fact that they were associated with fewer overall complications (OR=0.62, 95%CI: 0.48-0.82; P=0.00), major complications (OR=0.75, 95%CI: 0.60-0.93; P=0.01) and readmissions (OR=0.77, 95%CI: 0.60-0.98; P=0.04). There were no significant differences in the rates of pancreatic fistula, intra-abdominal abscesses, postpancreatectomy hemorrhage, biliary fistula, delayed gastric emptying, reoperation or radiologic-guided drains between the two groups. CONCLUSION: Indiscriminate abandonment of intra-abdominal drainage following PD is associated with greater mortality, but lower complication rates. Future randomized trials should compare routine vs selective drainage.

Major hepatectomy in Bismuth types I and II hilar cholangiocarcinoma.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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, P < 0.001), and higher blood transfusion requirements (70% versus 16%, P < 0.001). 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). CONCLUSIONS: 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.

Prognostic significance of pre-operative C-reactive protein and the neutrophil-lymphocyte ratio in resectable pancreatic cancer: a systematic review.

BACKGROUND: Better pre-operative risk stratification may improve patient selection for pancreatic resection in pancreatic cancer. C-reactive protein (CRP) and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic value in some cancers. The role of CRP and NLR in predicting outcome in pancreatic cancer after curative resection is not well established. METHODS: An electronic search of MEDLINE, EMBASE and CINAHL was performed to identify studies assessing survival in patients after pancreatic cancer resection with high or low pre-operative CRP or NLR. Systematic review was undertaken using the PRISMA protocol. RESULTS: In total, 327 studies were identified with 10 reporting on survival outcomes after a pancreatic resection in patients with high or low CRP, NLR or both. All but one paper showed a trend of lower inflammatory markers in patients with longer survival. Three studies from six showed low CRP to be independently associated with increased survival and two studies of eight showed the same for NLR. All studies were retrospective cohort studies of low to moderate quality. DISCUSSION: Inflammatory markers might prove useful guides to the management of resectable pancreatic cancer but, given the poor quality of evidence, further longitudinal studies are required before incorporating pre-operative inflammatory markers into clinical decision making.

Carcinoma showing thymus-like elements of the thyroid gland: report of three cases including one case with breast cancer history.

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.

Network based meta-analysis prediction of microenvironmental relays involved in stemness of human embryonic stem cells.

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.

Laparoscopic vs open total gastrectomy for gastric cancer: a meta-analysis.

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.

Comparison of short-term clinical outcomes between robotic and laparoscopic gastrectomy for gastric cancer: a meta-analysis of 2495 patients.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Roux-en-Y versus Billroth†I†reconstruction after distal gastrectomy for gastric cancer: a meta-analysis.

AIM: To conduct a meta-analysis to compare Roux-en-Y (R-Y) gastrojejunostomy with gastroduodenal Billroth I (B-I) anastomosis after distal gastrectomy (DG) for gastric cancer. METHODS: A literature search was performed to identify studies comparing R-Y with B-I after DG for gastric cancer from January 1990 to November 2012 in Medline, Embase, Science Citation Index Expanded and the Cochrane Central Register of Controlled Trials in The Cochrane Library. Pooled odds ratios (OR) or weighted mean differences (WMD) with 95%CI were calculated using either fixed or random effects model. Operative outcomes such as operation time, intraoperative blood loss and postoperative outcomes such as anastomotic leakage and stricture, bile reflux, remnant gastritis, reflux esophagitis, dumping symptoms, delayed gastric emptying and hospital stay were the main outcomes assessed. Meta-analyses were performed using RevMan 5.0 software (Cochrane library). RESULTS: Four randomized controlled trials (RCTs) and 9 non-randomized observational clinical studies (OCS) involving 478 and 1402 patients respectively were included. Meta-analysis of RCTs revealed that R-Y reconstruction was associated with a reduced bile reflux (OR 0.04, 95%CI: 0.01, 0.14; P < 0.00 001) and remnant gastritis (OR 0.43, 95%CI: 0.28, 0.66; P = 0.0001), however needing a longer operation time (WMD 40.02, 95%CI: 13.93, 66.11; P = 0.003). Meta-analysis of OCS also revealed R-Y reconstruction had a lower incidence of bile reflux (OR 0.21, 95%CI: 0.08, 0.54; P = 0.001), remnant gastritis (OR 0.18, 95%CI: 0.11, 0.29; P < 0.00 001) and reflux esophagitis (OR 0.48, 95%CI: 0.26, 0.89; P = 0.02). However, this reconstruction method was found to be associated with a longer operation time (WMD 31.30, 95%CI: 12.99, 49.60; P = 0.0008). CONCLUSION: This systematic review point towards some clinical advantages that are rendered by R-Y compared to B-I reconstruction post DG. However there is a need for further adequately powered, well-designed RCTs comparing the same.