James J. Powell

Activation of nuclear factor kappa B in Crohn's disease

Abstract.Objectives and Design: The location and degree of activation of nuclear factor kappa (NFκB), a primary transcription factor that plays a regulating role in immune and inflammatory responses, was determined in Crohns disease using full thickness specimens of bowel collected at surgery.¶Materials and Methods: Resected specimens of inflamed and non-inflamed bowel were collected from thirteen patients with Crohns disease and non-inflamed bowel from eleven control subjects. Prepared frozen sections were immunostained using a monoclonal antibody to the activated form of the p65 subunit of NFκB and the number of positive staining cells counted using a Lennox graticule.¶Results: The number of cells positive for activated NFκB was significantly increased (p = 0.001) in all layers of inflamed Crohns disease bowel, compared to non-inflamed bowel from controls. There was also a significant increase (p = 0.009) in the number of positive cells, when compared to non-inflamed bowel from control subjects, in the submucosa of non-inflamed areas of Crohns disease bowel. Cells positive for activated NFκB were provisionally identified by morphological criteria as mostly macrophages with some lymphocytes. There was no activation in endothelia.¶Conclusion: NFκB is activated within large mononuclear cells in all layers of inflamed areas of the bowel in Crohns disease and may represent key events in the inflammatory process. Increased activation in the submucosa of non-inflamed Crohns disease bowel provides further evidence of early immunological activation in macroscopically and microscopically uninvolved areas and an underlying abnormal immune system in Crohns disease.

Endothelial-derived selectins in the development of organ dysfunction in acute pancreatitis

ObjectiveThe development of organ dysfunction is the principal determinant of outcome in acute pancreatitis and is mediated through a systemic inflammatory response characterized by leukocyte and endothelial cell activation. Up-regulation of the endothelial cell adhesion molecules, E-selectin and P-selectin, is important for endothelial/leukocyte interactions. Levels of serum-soluble E-selectin and P-selectin have been suggested as markers of endothelial activation. This study examines the kinetics of serum-soluble selectins in patients with acute pancreatitis complicated by organ dysfunction. DesignProspective observational study. SettingUniversity teaching hospital with a specialist hepato-pancreatico-biliary service. PatientsEighteen patients with acute pancreatitis were studied, nine of whom had organ dysfunction. Measurements and Main Results Serial venous blood samples were collected on the first 3 days after admission for measurement of soluble E-selectin and P-selectin by enzyme-linked immunosorbent assay. In all patients, soluble P-selectin concentrations decreased significantly during the study period. Nonsurvivors had significantly higher levels of soluble P-selectin than survivors. In contrast, soluble E-selectin increased significantly during the study period in patients with organ dysfunction, whereas it remained constant in patients without evidence of organ dysfunction. ConclusionsThese results suggest a role for endothelial-derived selectins in the development of organ dysfunction in patients with acute pancreatitis. The observed temporal differences in serum selectin concentrations is in keeping with in vitro observations of endothelial selectin expression.

Long‐term outcome following liver transplantation for paracetamol overdose

Paracetamol overdose (POD) is a major cause of acute liver failure (ALF) requiring liver transplantation in the United Kingdom. To characterize the early and late outcome after orthotopic liver transplantation (OLT) for POD in the Scottish Liver Transplant Unit over a 14‐year period (1992–2006). Data were obtained from a prospective database combined with case‐note review. Of 127 liver transplants performed for ALF, 44 were for POD. The median age was 30 (range 18–51). In 18 patients (63.7%), POD was associated with alcohol/other drugs, nine (20.5%) had a staggered overdose and four patients (9.1%) accidentally overdosed. Nineteen patients (43.2%) had a history of previous overdose/psychiatric illness. Post‐transplant mortality during the index admission was 30% (13 patients), whilst five patients died during follow‐up. The actuarial 5‐year patient survival was 54.5%, whilst graft survival was 49.5%. Some 23% of the patients were re‐transplanted: primary nonfunction (1), hepatic artery thrombosis (3) and chronic rejection (2). Three patients had a subsequent transplant; three patients had two further transplants. Nine patients (35%) continue to have social/psychiatric issues. OLT for POD is associated with significant early and late morbidity and mortality. A multidisciplinary approach is required to identify the suitable candidates, in whom transplantation should be pursued promptly.

ALPPS: Adverse Outcomes Demand Clear Justification in an Era of Improving Survival for Colorectal Liver Metastases.

We read with interest the multicenter study by Schadde and colleagues in the April issue regarding the novel procedure of Associating Liver Partition and Portal vein Ligation for Staged Liver resection (ALPPS) [1]. Since the initial description 2 years ago [2] ALPPS has gained popularity as a surgical option for treating patients with advanced liver lesions not considered amenable to conventional two-stage or future liver remnant-enhancing procedures propagated by Rene Adam et al. [3] a decade ago. Indeed, the explosion of interest in ALPPS by surgeons and its adoption as a procedure of choice is concerning, given that the procedure appears to come with considerable cost to the patient, as shown in this study. The increased severe morbidity of 27 versus 15 % and the mortality of 15 versus 6 % may not achieve traditional measures of statistical significance in this study, but the effect size is concerning, and the direction of effect is consistent across outcome measures and studies. Is ALPPS in its current form safe enough for the widespread adoption that has occurred given increasingly effective nonsurgical approaches, including ablation, chemotherapy, selective internal radiation therapy [4], and growth factor/receptor inhibition? As the authors rightly point out, the risk of selection bias is significant given the study design. It is unclear whether the logistic regression analysis adequately adjusts for the imbalance in baseline risk in favor of the ALPPS group: why, for instance, was operative risk (ASA grade) not controlled for in the multivariate analysis? One of the potential benefits of a two-stage procedure is that it may disclose biologically unfavorable disease. By its very nature, ALPPS does not lend itself to such selection given the short time interval between the first and second stages. The authors appear to reject this argument, citing a similar overall recurrence rate seen in this study. We were puzzled with this position given that the study highlights an interesting observation: in the PVE/PVL group 11 % of patients had systemic progression prior to the second stage. Presumably this group of patients would not have benefitted from ALPPS. In our practice, patients who may be deemed by others to be ideal candidates for ALPPS are seldom not amenable to either a two-stage liver resection or a single-stage resection with prior volume-enhancing maneuvers. Indeed, it is difficult to understand why an ALPPS approach was used at all in some of the cases presented at recent international conferences. We wonder what proportion and kind of patients with advanced liver lesions would really benefit from the ALPPS approach. The international ALPPS registry will perhaps provide clearer evidence for the role of this challenging approach to liver resection.

Meta-analysis of intermittent Pringle manoeuvre versus no Pringle manoeuvre in elective liver surgery.

Intermittent Pringle manoeuvre (IPM) is frequently used during liver surgery. This meta‐analysis aimed to review the impact on blood loss, operating time and morbidity and mortality with and without use of IPM.

Systematic review of perioperative and survival outcomes of liver resections with and without preoperative portal vein embolization for colorectal metastases

BACKGROUND The aim of this systematic review was to evaluate perioperative and long term outcomes in patients who underwent PVE prior to liver resection for colorectal liver metastases. METHODS A systematic search of PubMed, MEDLINE, Embase and the Cochrane library was performed in accordance with PRISMA guidelines. Studies including patients who underwent liver resection with and without PVE (N-PVE) were included. RESULTS Thirteen studies including 1345 were included of which 539 patients had PVE and 806 had N-PVE. Eight studies reported that from a total of 450 patients who underwent PVE, 136 (30%) did not proceed to liver resection. In 114 (84%) patients this was due to disease progression. The postoperative morbidity was 42% (n = 151) after PVE and 10% (n = 35) developed postoperative liver failure after liver resection. Median overall survival, reported in all studies, was 38.9 months and 45.6 months respectively, following resection with PVE and N-PVE. The median disease free survival, reported in eight studies, was 15.7 (PVE) and 21.4 (N-PVE) months respectively. CONCLUSION Following PVE 70% of patients proceed to liver resection, with a 10% risk of postoperative liver failure. Tumour progression after PVE was the predominant reason for not proceeding to liver resection.

Competition between IL-1, IL-1ra and TGF-β1 modulates the response of the ELA4.NOB-1/CTLL bioassay: Implications for clinical investigations

AbstractObjective:The use of ELISA techniques to measure cytokine levels in clinical samples has chiefly replaced more labour intensive bioassays. ELISA measurements, however, do not reflect the functional activity of a cytokine within a sample; interleukin-1 (IL-1), for example, has two agonist isoforms (IL-1α and IL-1β) and a competitive receptor antagonist (IL-1ra), and can be regulated by transforming growth factor β1 (TGF-β1). The net effect of these cytokines, rather than IL-1 levels, are frequently suggested to regulate tissue inflammation, but confirming this has been difficult. Methods:We used the ELA4.NOB-1/CTLL co-culture IL-1 bioassay to investigate whether IL-1 activity was inhibited by IL-1ra and TGF-β1 in a predictable manner. Results:Thymidine incorporation into CTLL cells, induced by IL-1, was reduced dose dependently by IL-1ra and TGF-β1. With optimal levels of IL-1 CTLL responsiveness was reduced by 90% by 1 ng/ml TGF-β1 and completely abolished by 100 ng/ml IL-1ra. As expected, TGF-β1 and IL-1ra had independent mechanisms of action on the bioassay cell lines, and, in combination, they caused an additive, but not synergistic, effect. Importantly, the effect of these cytokines could be completely abolished in the presence of neutralising antibodies. Conclusions:Bioassay should provide specific functional information on the net IL-1 activity of clinical samples, while the use of specific antibodies could ascertain the contribution of individual cytokines within such samples.

When there is not plenty for everyone: Options for reconstructing a suprahepatic vena cava injured during organ procurement

In a recent letter from the frontline, Waits et al. described a technique for ensuring an adequate length of infracardiac inferior vena cava (IVC) for both liver and cardiac grafts during organ procurement. The authors highlighted that advances in liver and cardiac transplantation techniques require sharing of the IVC between the 2 transplant teams, and they proposed a 1-cm length of the IVC above the hepatic veins for the liver graft. There are times, however, when a lack of coordination between cardiac and abdominal retrieval teams or, simply, operator error can lead to a very short IVC length or indeed injuries to the suprahepatic vena cava. Although significant injuries to the vena cava or the hepatic veins are infrequent (3%), the lack of a suitable length of suprahepatic IVC jeopardizes hepatic venous outflow after standard implantation techniques; therefore, the graft requires some form of vascular reconstruction to enable successful transplantation. The experience from domino liver transplantation has led to various options for surgical reconstruction, which include the use of the IVC–common iliac bifurcation, a vein patch, or the infrahepatic cava for anastomosis. However, these options are not always practical; therefore, alternative reconstructive strategies should be considered. Recently, at our center, we had a series of 3 liver grafts in which the suprahepatic IVC was divided very close to, or at the level of the hepatic vein ostia during organ procurement. Here we describe 3 different surgical options that allowed the safe reconstruction of suprahepatic caval injuries with no or minimal modification of our routine venous implantation technique. We routinely employ the modified piggyback implantation technique described by Belghiti: the suprahepatic and infrahepatic IVC is closed, and a side-to-side cavocavostomy is created. In the first case, the suprahepatic IVC was divided 3 mm above the hepatic veins at the time of retrieval, and this provided an inadequate length for closure without outflow compromise. During bench surgery, a 1.5 cm cuff of the infrahepatic IVC was transected and transposed to extend the suprahepatic IVC. di Francesco et al. described a similar approach but implanted the liver with the standard piggyback technique. In our case, the caval ends were oversewn, and a cavotomy was created and extended close to the suture line (Fig. 1) to allow modified piggyback implantation. In the second case (with a similar injury), the infrahepatic IVC was too short to allow a cuff transposition. A donor common iliac vein was prepared and opened in half. This was sutured as a circumferential collar to the suprahepatic IVC to create an extension tube. The caval ends were oversewn, and a cavotomy was created as described previously. In the third case, the suprahepatic IVC was divided at the level of the middle hepatic vein (MHV) and left hepatic vein (LHV) junction at the time of organ retrieval (Fig. 2). At this level, the suprahepatic caval diameter was wider than the infrahepatic IVC, so a cuff would not have allowed reconstruction as described previously. Because no iliac vein graft was available, a novel approach was used: an infrahepatic

Patterns of recurrence after curative-intent surgery for pancreas cancer reinforce the importance of locoregional control and adjuvant chemotherapy.

Introduction The pattern of recurrence after surgical excision of pancreas cancer may guide alternative pre-operative strategies to either detect occult disease or need for chemotherapy. This study investigated patterns of recurrence after pancreatic surgery. Methods Recurrence patterns were described in a series of resected pancreas cancers over a 2-year period and recurrence risk expressed as odds ratio (OR) with 95% confidence interval (C.I.). Survival was displayed by Kaplan-Meier curves. Results Of 107 pancreas resections, 69 (65%) had pancreatic cancer. R0 resection was achieved in 21 of 69 (30.4%). Analysis was based on 66 patients who survived 30 days after surgery with median follow up 21 months. Recurrence developed in 41 (62.1%) patients with median time to first recurrence of 13.3 months (interquartile range 6.9, 20.8 months). Recurrence site was most frequently locoregional (n=28, 42%), followed by liver (n=23, 35%), lymph nodes (n=21, 32%), and lungs (n=13, 19%). In patients with recurrence, 9 of 41 had single site recurrence; the remaining 32 patients had more than one site of recurrence. Locoregional recurrence was associated with R+ resection (53% vs 25% for R+ vs R0, respectively; OR 3.5, 95% C.I. 1.1-11.2; P=0.034). Venous invasion was associated with overall recurrence risk (OR 3.3, 95% C.I. 1.1-9.4; P=0.025). In multivariable analysis, R-stage and adjuvant chemotherapy predicted longer survival. Discussion The predominant locoregional recurrence pattern, multiple sites of recurrence and a high R+ resection rate reflect the difficulty in achieving initial local disease control.

Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair

Highlights • First case report on the use of a donor with previous bile duct injury for liver transplantation.• Emphasis on careful liver retrieval and backbench preparation, with attention to arterial blood supply.• Previous bile duct injury does not preclude use of the liver in orthotopic liver transplantation.