M.A. van den Broek

Feasibility of randomized controlled trials in liver surgery using surgery-related mortality or morbidity as endpoint

There is a shortage of randomized controlled trials (RCTs) on which to base guidelines in liver surgery. The feasibility of conducting an adequately powered RCT in liver surgery using the dichotomous endpoints surgery‐related mortality or morbidity was examined.

Development of a composite endpoint for randomized controlled trials in liver surgery

The feasibility of randomized controlled trials (RCTs) in liver surgery using a single‐component clinical endpoint is low as such endpoints require large sample sizes owing to their low incidence. A liver surgery‐specific composite endpoint (CEP) could solve this problem. The aim of this study was to develop a liver surgery‐specific CEP with well‐defined components.

Positive End-Expiratory Pressure Induces Liver Congestion in Living Donor Liver Transplant Patients : Myth or Fact

Living-donated liver transplant (LDLT) patients may develop lung edema during reperfusion, requiring higher positive end-expiratory pressure (PEEP) levels, which may impair liver outflow. The aim of the study was to assess the effect of increased PEEP levels on venous liver outflow and systemic hemodynamics in patients after LDLT. Thirty-nine LDLT recipients were enrolled in this study. All patients were postoperatively pressure-controlled ventilated and three different PEEP levels (0, 5 and 10 mbar) were randomly set. Systemic hemodynamic parameters and flow velocities of the hepatic artery, portal vein, and right hepatic vein were recorded at each PEEP level. PEEP of 10 mbar increased significantly central venous and pulmonary capillary pressure. Flow velocities in the right hepatic vein, the portal vein, the hepatic artery, mean arterial pressure, pulmonary arterial pressure, and cardiac index were not influenced by PEEP. Our study demonstrated that PEEP up to 10 mbar did not impair liver outflow in LDLT recipients.

Glutathione S -transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer

Background:Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin.Methods:In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR.Results:Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate–severe) SOS (P=0.026).Conclusion:The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.

Sinusoidal obstruction syndrome (SOS): A light and electron microscopy study in human liver

AIMS Oxaliplatin is an important chemotherapeutic agent, used in the treatment of hepatic colorectal metastases, and known to induce the sinusoidal obstruction syndrome (SOS). Pathophysiological knowledge concerning SOS is based on a rat model. Therefore, the aim was to perform a comprehensive study of the features of human SOS, using both light microscopy (LM) and electron microscopy (EM). METHODS AND RESULTS Included were all patients of whom wedge liver biopsies were collected during a partial hepatectomy for colorectal liver metastases, in a 4-year period. The wedge biopsy were perfusion fixated and processed for LM and EM. The SOS lesions were selected by LM and details were studied using EM. Material was available of 30 patients, of whom 28 patients received neo-adjuvant oxaliplatin. Eighteen (64%) of the 28 patients showed SOS lesions, based on microscopy. The lesions consisted of sinusoidal endothelial cell detachment from the space of Disse on EM. In the enlarged space of Disse a variable amount of erythrocytes were located. CONCLUSION Sinusoidal endothelial cell detachment was present in human SOS, accompanied by enlargement of the space of Disse and erythrocytes in this area. These findings, originally described in a rat model, were now for the first time confirmed in human livers under clinically relevant settings.

Urinary ammonia excretion increases acutely during living donor liver transplantation.

Introduction: Arterial ammonia concentrations increase acutely during the anhepatic phase of a liver transplantation (LTx) and return to baseline within 1 h after reperfusion of a functioning liver graft. So far, this return to baseline has solely been attributed to hepatic ammonia clearance. No data exist on the potential contribution of altered renal ammonia handling to peritransplantation ammonia homoeostasis.

P32 Liver mobilisation during liver resection induces immediate and profound hepatocellular damage and inflammation in humans

Introduction In a recent study we coincidentally showed that mobilisation of the liver was a major cause of liver surgery-induced damage. The magnitude of and mechanisms by which this damage occurs are unknown. Aim (A) To determine the relative contribution of mobilisation during liver surgery to liver damage and (B) To examine whether there is an association between mobilisation-induced liver damage and liver inflammation. Method Consecutive patients undergoing liver surgery requiring full mobilisation of the right hemi-liver were included. Plasma samples and liver biopsies were obtained immediately after induction, prior to and directly after liver mobilisation, and after liver transection. Liver Fatty Acid Binding Protein (L-FABP) and alanine aminotranferase (ALAT) were analysed as markers of hepatocyte injury. Specimens were stained by immunohistochemistry for myeloperoxidase (MPO), human neutrophil peptide (HNP), and caspase-3-mediated cleavage generated neo-epitope of CK18 (M30). Gene expression of interleukin (IL) 1β, 6 and 8, and intercellular adhesion molecule (ICAM) were analysed by q-RT-PCR. Results Nineteen patients were included (11M/8F, median age 64 years [30–79]) who underwent major liver surgery. L-FABP levels increased significantly during liver mobilisation (from 91.7 ng/ml [11.4–2212.5 ng/ml] to 1014.4 ng/ml [141.4–8986.1 ng/ml], p<0.001) and did not increase significantly thereafter (1315.2 ng/ml [67.0–20 099.2 ng/ml], p=0.75). L-FABP levels after ≥60 min mobilisation time were significantly higher when compared to ≥60 min mobilisation (1679.7 ng/ml vs 645.9 ng/ml, p=0.04). ALAT levels increased significantly from 26 IU/l [13–147] before to 130 IU/l [74–813] after liver mobilisation and to 275 IU/l [13–1352] after transection (all p<0.05). Liver mobilisation increased the numbers of positive cells in staining for MPO (p=0.0007), HNP (p=0.03), and M30 (p=0.01), whereas transaction led to no further increase thereafter. Liver mobilisation increased the gene expression of IL1b (p=0.01), IL-6 (p=0.08), IL-8 (p=0.02) and ICAM (p=0.007). Expression increases ranged from 2.8-fold in ICAM to 130-fold in IL-6. After transection, mRNA levels increased even further in IL-6 (p=0.004), IL-8 (p=0.0004) and ICAM (p=0.02), but not IL1b (p=0.32). Conclusion Mobilisation of the liver during surgery induces profound hepatocellular damage and inflammation, which is associated with activation and/or infiltration of immune cells. Given the short half-life of L-FABP (14 min), hepatocyte damage predominantly occurred during mobilisation of the liver and not during transaction. These data produce insight into the mechanisms of mobilisation-induced liver damage, and provide indications for designing interventions aiming at prevention of surgery-induced liver damage in the future.

Authors' reply: Feasibility of randomized controlled trials in liver surgery using surgery-related mortality or morbidity as endpoint (Br J Surg 2009; 96: 1005–1014)

Sir We read this article with interest. Although we agree with the technical merits of the anastomotic technique that Kleespies and colleagues have described, we are concerned about the authors’ failure to consult with Professor Blumgart about this study before its publication. Doing so would seem to be appropriate academically as the authors have formally attached Professor Blumgart’s name to this technique of pancreaticojejunostomy for the first time. In addition, the authors of the published report have incorrectly referenced the procedure to the fourth edition of Surgery of the Liver and Biliary Tract when in fact the procedure is well highlighted in the third edition of this book (Figure 56.18)1. It should be noted that we have analysed and presented our institutional experiences with this novel technique2. In our larger series of 187 patients from the USA, we reported a similarly low postoperative mortality rate of 1·6 per cent and a very low rate (6·4 per cent) of clinically significant (grade B and C) pancreatic fistula2,3. There were no deaths related to pancreatic anastomotic failure in our series. We agree with the authors’ assertion that the anastomosis is favourable as it avoids shear forces that may lead to disruption of the pancreaticojejunal anastomosis, but also believe that the anastomosis is preferred because it permits excellent visualization for creation of a tension-free duct-to-mucosal anastomosis. Furthermore, the mild compression provided between the pancreas and jejunal serosa afforded by this technique may help reduce leaks from accessory pancreatic ducts. These reported experiences favour the widespread application of this unique anastomosis for pancreaticojejunal reconstruction after pancreaticoduodenectomy. S. R. Grobmyer, D. A. Kooby, S. N. Hochwald and L. H. Blumgart University of Florida, Gainesville, Florida, Emory University School of Medicine, Atlanta, Georgia, and Memorial Sloan-Kettering Cancer Center, New York, New York, USA DOI: 10.1002/bjs.6953