Ajith K. Siriwardena

Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation.

Objective:To develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. Background:The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric description of occurrences that are merely associated with severity. Methods:A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. Result:The new international classification is based on the actual local and systemic determinants of severity, rather than description of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity—mild, moderate, severe, and critical. Conclusions:This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America, Europe, Asia, Oceania, and Africa. It provides a set of concise up-to-date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world.

Systematic review of outcome of synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer.

Tumour clearance during pancreatectomy may be facilitated by resection of the portal–superior mesenteric vein, but this is associated with increased perioperative risk. There is no consensus about which patients benefit from portal–superior mesenteric vein resection.

Radiofrequency ablation of liver tumours: systematic review

Thermal ablation by use of radiofrequency energy can be used to achieve necrosis of liver tumours, and increased availability of this technique is leading to more widespread use. Much of the impetus for the use of radiofrequency ablation has come from cohort series that have provided an evidence base for this technique. Here, we give an overview of the current status of radiofrequency ablation for liver tumours, including its physical properties, to assess the characteristics that make this technique applicable in clinical practice. We review the technical development of probe design and summarise current indications and outcomes of reported clinical use. We also provide a profile of side-effects and information on the integration of this technique into the general management of patients with liver tumours. Current evidence suggests that radiofrequency ablation can be done with few side effects; however, although this technique seems to ablate tumours effectively, it should form part of multidisciplinary care for liver cancer. Crucially, the role of radiofrequency ablation in lengthening the survival of patients with liver tumours remains to be assessed.

Randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis

Background: Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis. Methods: We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty-three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE-II score and hospital site, and delivered groups that were similar at baseline. Results: Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p = 0.33) or any secondary end point of organ dysfunction or patient outcome. Conclusions: This study provides no evidence to justify continued use of n-acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study.

Role of tumor necrosis factor-alpha in acute pancreatitis: from biological basis to clinical evidence.

Tumor necrosis factor (TNF)-&agr; is a pleiotropic cytokine that exerts host-damaging effects in different autoimmune and inflammatory diseases. It is a key regulator of other proinflammatory cytokines and of leukocyte adhesion molecules, and it is a priming activator of immune cells. In recent years, several research lines-mostly derived from animal models and in vitro studies-suggested that TNF-&agr; plays a pivotal role in the pathogenesis of acute pancreatitis. In particular, it contributes to the systemic progression of the inflammatory response and to the end-organ dysfunction often observed in severe disease. Current clinical applications of TNF-&agr; in acute pancreatitis include the assessment of blood concentrations to predict disease severity and to identify individuals prone to develop complications such as multiple organ failure and septic shock. However, TNF-&agr; is rapidly cleared from the bloodstream, and sensitivity and overall accuracy of its measurement seem strictly time dependent, thereby being of potential prognostic value only in the first days after the onset of the disease. In parallel, TNF-&agr; has been evaluated as a novel pharmacologic target for treating pancreatitis. Although promising results have been observed in the laboratory, transition to clinical practice seems problematic, in particular, in the light of divergent results obtained in sepsis trials. Therefore, in future clinical trials pertaining to TNF-&agr; neutralization in acute pancreatitis, timing of intervention should be related to changes in TNF-&agr; serum levels, and inclusion and exclusion criteria should be accurately selected to better define the population most likely to benefit.

Systematic appraisal of the role of metallic endobiliary stents in the treatment of benign bile duct stricture

Objective:To carry out a systematic appraisal of the current status of the use of metallic endobiliary stents in the treatment of benign biliary strictures. Methods:A computerized search of the MEDLINE and EMBASE databases identified 37 studies providing detailed clinical course data on outcome of metallic endobiliary stent placement in 400 patients. Pooled data were examined for etiology of stricture, indications for stent placement, procedure-related complications, and outcome with reference to stent patency. Results:The median (range) number of patients per report was 8 (2–54) with a median recruitment period of 44 (9–126) months. The most frequent indications were postoperative biliary strictures in 123 (31%), stenosed biliary-enteric anastomoses in 79 (20%), and biliary strictures following liver transplantation in 88 (22%). During a median follow up of 31 (1–111) months, 139 (35%) stents occluded, and there are little patency data beyond 2 years after deployment, with 99 (25%) known to be patent at 3 years from stent placement. Conclusions:These pooled data on 400 patients constitute the largest collective report to date on the use of metallic endobiliary stents for benign biliary strictures. The results show a critical lack of data on long-term patency such that at the present time, metallic endobiliary stents should not be used for benign stricture in those patients with a predicted life expectancy greater than 2 years.

Outcome of Necrosectomy in Acute Pancreatitis: the Case for Continued Vigilance

Background: Surgery for pancreatic necrosis complicating acute severe pancreatitis carries a high risk of mortality and may be influenced by a range of variables including patterns of referral, case selection and quality of care. Methods: An observational study of a consecutive series of 54 patients undergoing pancreatic necrosectomy in a specialist Hepatobiliary unit over an 8-year study period. Principal outcomes were organ dysfunction and physiological derangement in relation to surgery, microbial colonization of necrosis and relation to outcome, re-operation rates, requirement for peri-operative nutritional support, trends in mortality and survival analysis. Results: Necrosectomy was associated with statistically significant deterioration in immediate postoperative organ dysfunction scores (ANOVA P < 0.01). Infected necrosis was present in 36 (68%). Fungal colonization of necrosis was present in 5 (9%). Mortality in this subgroup was 80% (4 deaths). There was no association between bacterial colonization of necrosis and death in this study ( P = 0.77; Fisher exact test; relative risk 0.9, 95% confidence interval 0.54-1.54). Twenty patients (37%) required further surgical intervention with an average of 1.5 surgical procedures per patient. Twenty-three patients (43%) died. Patient survival to discharge was best predicted by admission APACHE-II score with relative risk of death increasing 14% for each unit increase in APACHE-II score at admission. Conclusions: The results of the present study illustrate that there is no place for complacency in the surgical management of patients with severe acute pancreatitis. A clinical governance approach would promote pre-defined protocols between admitting hospitals and tertiary referral centres. Future research should target new interventions in patients with high admission APACHE-II scores in whom prognosis is particularly poor and explore the role of infection of necrotic tissue.

Antioxidant Therapy Does Not Reduce Pain in Patients With Chronic Pancreatitis: The ANTICIPATE Study

BACKGROUND & AIMS We investigated whether antioxidant therapy reduces pain and improves quality of life in patients with chronic pancreatitis. METHODS We performed a double-blind, randomized, controlled trial that compared the effects of antioxidant therapy with placebo in 70 patients with chronic pancreatitis. Patients provided 1 month of baseline data and were followed for 6 months while receiving either antioxidant therapy (Antox version 1.2, Pharma Nord, Morpeth, UK) or matched placebo (2 tablets, 3 times/day). The primary analysis was baseline-adjusted change in pain score at 6 months, assessed by an 11-point numeric rating scale. Secondary analyses included alternative assessments of clinical and diary pain scores, scores on quality-of-life tests (the European Organization for Research and Treatment of Cancer [EORTC-QLQ-C30], Quality of Life Questionnaire-Pancreatic modification [QLQ-PAN28], European Quality of Life questionnaire [EuroQOL EQ-5D], and European Quality of Life questionnaire - Visual Analog Score [EQ-VAS]), levels of antioxidants, use of opiates, and adverse events. Analyses, reported by intention to treat, were prospectively defined by protocol. RESULTS After 6 months, pain scores reported to the clinic were reduced by 1.97 from baseline in the placebo group and by 2.33 in the antioxidant group but were similar between groups (-0.36; 95% confidence interval [CI], -1.44 to 0.72; P = .509). Average daily pain scores from diaries were also similar (3.05 for the placebo group and 2.93 for the antioxidant group, a difference of 0.11; 95% CI, 1.05-0.82; P = .808). Measures of quality of life were similar between groups, as was opiate use and number of hospital admissions and outpatient visits. Blood levels of vitamin C and E, β-carotene, and selenium were increased significantly in the antioxidant group. CONCLUSIONS Administration of antioxidants to patients with painful chronic pancreatitis of predominantly alcoholic origin does not reduce pain or improve quality of life, despite causing a sustained increase in blood levels of antioxidants.

Experimental and clinical evidence for modification of hepatic ischaemia–reperfusion injury by N-acetylcysteine during major liver surgery

BACKGROUND Hepatic ischaemia-reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation. METHODS A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group. RESULTS Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival. CONCLUSION N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery.

The liver-first approach to the management of colorectal cancer with synchronous hepatic metastases - a systematic review.

IMPORTANCE To our knowledge, this is the first systematic review of the liver-first approach to the management of patients with colorectal cancer with synchronous liver metastases. OBJECTIVE To review current evidence for the liver-first approach to the management of patients with colorectal cancer with synchronous liver metastases. EVIDENCE REVIEW PubMed, EMBASE, the Science Citation Index, the Social Sciences Citation Index, Conference Proceedings Citation Index, and the Derwent Innovations Index were searched for the period from January 2000 to May 2012 using terms describing colorectal cancer, liver metastases, and surgery. A predefined protocol for data extraction was used to retrieve data on the design of each study including demographic profile, distribution of primary and hepatic metastatic disease, management of chemotherapy, surgery, the sequence of intervention, disease progression, the numbers completing treatment algorithm, and outcome and survival. FINDINGS The literature search identified 417 articles, of which 4 cohort study reports described the liver-first approach and reported survival data. There was good agreement between studies on the sequence of treatment using the liver-first approach. The preferred algorithm was systemic chemotherapy, followed by liver resection, then chemoradiotherapy for those patients with rectal lesions, and colorectal resection as the last operative step. Two protocols provided further adjuvant chemotherapy after colorectal resection. Of 121 patients starting treatment, 90 (74%) completed the specified treatment protocol. Disease progression during the protocol period occurred in 23 patients (19%). There was wide variation in survival despite apparently similar protocols. CONCLUSIONS AND RELEVANCE The liver-first approach for patients with colorectal cancer with synchronous liver metastases is possible but is associated with a wide range of survival outcomes, despite protocol similarities between studies. There is a need for a well-designed clinical trial comparing this liver-first approach with the classic (bowel-first) approach.