Systematic review and meta-analysis of fibrin sealants for patients undergoing pancreatic resection

AbstractIntroductionPost-operative pancreatic fistula (POPF) is a common complication after partial pancreatic resection, and is associated with increased rates of sepsis, mortality and costs. The role of fibrin sealants in decreasing the risk of POPF remains debatable. The aim of this study was to evaluate the literature regarding the effectiveness of fibrin sealants in pancreatic surgery.MethodsA comprehensive database search was conducted. Only randomized controlled trials comparing fibrin sealants with standard care were included. A meta-analysis regarding POPF, intra-abdominal collections, post-operative haemorrhage, pancreatitis and wound infections was performed according to the recommendations of the Cochrane collaboration.ResultsSeven studies were included, accounting for 897 patients. Compared with controls, patients receiving fibrin sealants had a pooled odds ratio (OR) of developing a POPF of 0.83 [95% confidence interval (CI): 0.6–1.14], P = 0.245. There was a trend towards a reduction in post-operative haemorrhage (OR = 0.43 (95%CI: 0.18–1.0), P = 0.05) and intra-abdominal collections (OR = 0.52 (95%CI: 0.25–1.06), P = 0.073) in those patients receiving fibrin sealants. No difference was observed in terms of mortality, wound infections, re-interventions or hospital stay.ConclusionOn the basis of these results, fibrin sealants cannot be recommended for routine clinical use in the setting of pancreatic resection

Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) may be a risk factor for hepatocellular carcinoma (HCC), but the extent of this association still needs to be addressed. Pooled incidence rates of HCC across the disease spectrum of NAFLD have never been estimated by meta-analysis. Methods In this systematic review, we searched Web of Science, Embase, PubMed, and the Cochrane Library from January 1, 1950 through July 30, 2020. We included studies reporting on HCC incidence in patients with NAFLD. The main outcomes were pooled HCC incidences in patients with NAFLD at distinct severity stages. Summary estimates were calculated with random-effects models. Sensitivity analyses and meta-regression analyses were carried out to address heterogeneity. Results We included 18 studies involving 470,404 patients. In patients with NAFLD at a stage earlier than cirrhosis, the incidence rate of HCC was 0.03 per 100 person-years (95% confidence interval [CI], 0.01–0.07; I2 = 98%). In patients with cirrhosis, the incidence rate was 3.78 per 100 person-years (95% CI, 2.47–5.78; I2 = 93%). Patients with cirrhosis undergoing regular screening for HCC had an incidence rate of 4.62 per 100 person-years (95% CI, 2.77–7.72; I2 = 77%). Conclusions Patients with NAFLD-related cirrhosis have a risk of developing HCC similar to that reported for patients with cirrhosis from other etiologies. Evidence documenting the risk in patients with nonalcoholic steatohepatitis or simple steatosis is limited, but the incidence of HCC in these populations may lie below thresholds used to recommend a screening. Well-designed prospective studies in these subpopulations are needed. The protocol for this systematic review is registered in the Prospero database (registration number CRD42018092861)

Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation

Background & Aims Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation – ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Methods HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10min or 30min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. Results I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10min and 30min ISC recipients ( p =0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs ( p =0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1 , Hif1a and Serpine1 . Conclusions This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval

Alloimmunity-associated cytotoxicity is mediated through the NKG2D receptor.

<p>(A) Liver expression of <i>nkg2d</i> on day ten after liver transplantation. (B) Representative NKG2D expression levels in blood NK cells (left) and monocytes (right) of allogeneic (black) and syngeneic (grey) recipients. Isotype was used as control (dashed lines). (C) Sorted blood NK cell cytotoxicity inhibition with anti-NKG2D antibody or with anti-NKp30 antibody. (D) Levels of NKG2D ligand (<i>rae1l, rrlt</i> and <i>irp94</i>) expression in the liver on day ten after transplantation. (E) Levels of NKG2D ligand (<i>rae1l</i>, <i>rrlt</i> and <i>irp94</i>) expression in rat HCC cell lines. (F) Representative level of recombinant NKG2D-Fc binding to rat HCC cells lines. *p<0.05, **<0.01.</p

Alloimmunity-associated liver mononuclear cells cytotoxicity on ten days after transplantation.

<p>(A) Representative images of sections of allogeneic (left) and syngeneic (right) liver graft labeled with anti-NKRP1 antibodies (red). Nuclei were stained with Hoechst (blue). Number of labeled-NK cells per image counted on multiple liver sections. (B) Representative images of sections of allogeneic (left) and syngeneic (right) liver graft labeled with anti-Iba1 antibodies (red). Number of labeled macrophages per image counted on multiple liver sections. (C) <i>Ex vivo</i> liver NK cell anti-cancer cytotoxicity on day ten after allogeneic and syngeneic transplantation. Two effector/target ratio (E/T) were tested. (D) Activation level of liver monocyte/macrophages (NKRP1 expression level (MFI) among CD172a+ cells). *p<0.05, **<0.01.</p

Alloimmunity-associated peripheral cytotoxicity.

<p>(A) <i>Ex vivo</i> PBMC anti-cancer cytotoxicity on day ten after allogeneic and syngeneic transplantations and in naïve control rats at various effector/target ratio (E/T). (B) Frequency of NKRP1^high cells (NK cells) among PBMCs on day 7 (D7) and 10 (D10) after transplantation. Flow cytometry dot-plot assessed the gating strategy. (C) Flow cytometry dot-plot and histogram assessing the gating strategy for monocytes/macrophages (CD172+) and NKRP1 expression level on CD172+ cells. (D) Frequency of monocyte/macrophage (CD172+ cells) among PBMCs. (E) Activation level of monocyte/macrophages (NKRP1 expression level (mean fluorescence intensity (MFI)) among CD172a+ cells). *p<0.05, **<0.01.</p

Alloimmunity-associated spleen cytotoxicity on ten days after transplantation.

<p>(A) IFNγ secretion after splenocyte mixed lymphocyte reaction on day ten post-transplantation with donor and third part stimulation. (B) <i>Ex vivo</i> spleen NK cell anti-cancer cytotoxicity on day ten after allogeneic and syngeneic transplantation.</p

Assessment of alloimmunity and rejection.

<p>(A) Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels after allogeneic Dark Agouti-to-Lewis (black) and syngeneic Lewis-to-Lewis (white) rat liver transplantations. (B) Bilirubine levels after allogeneic (black) and syngeneic (white) transplantation. (C) Representative hematoxilin-eosin stained biopsies on day 10 after allogeneic (right) and syngeneic (left) rat liver transplantation. (D) Post-transplant blood CD4/CD8 ratios on day 7 (D7) and 11 (D11). (E) IFNγ secretion after peripheral blood mononuclear cells (PBMC) mixed lymphocyte reaction on day ten post-transplantation with donor (DA) and third part stimulation. *p<0.05, **<0.01.</p