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Presents letters to the editor of the 2001 issue of the 'British Journal of Surgery.' Effect of colectomy on gastric emptying in idiopathic slow-transit constipation; Causes of polytetrafluoroethylene patch saphenoplasty re-recurrence; Factors influencing the outcome after surgery for fecal incontinence.

This review of the influence of host systemic inflammatory response(SIR) on the outcome of pancreatic ductal adenocarcinoma (PDAC)was the kernel of the 2014 George E Palade Memorial Prize Lecture at the Combined IAP-EPC Meeting held June 25-8 in Southampton,UK. The ability of the modified Glasgow Prognostic Score(mGPS) to stratify cancer outcomes has been demonstrated in >50 studies including >25000 patients from many countries. Other markers of SIR such as Prognostic Index and neutrophil/lymphocyte ratio(NLR) may also be used emphasising the non homogeneity of the PDAC patients. The mGPS score 0 is associated with better outcome,while scores of 1 & 2 are linked to poor performance status, greater weight loss, comorbidity and earlier death. Two papers show in resectable PDAC that longer life (27-37 months) occurs with mGPS 0, and < 18 months for mGPS 1 and 2, such that alternative therapy employing RFA may well be better than resection in those patients. In the greater number of PDAC patients unsuitable for resection the JAK-STAT inhibitor, ruxolitinib, has been found only to favourably modify PDAC in those with mGPS 1 or 2. Likewise the possible benefits of older anti inflammatory agents may be confined to these patients. An urgent reappraisal of the prognostic and therapeutic implications is now required in PDAC. Local inflammatory responses(LIR) are beneficial in PDAC and other cancers. Four grade stratification systems using Klintrup histology, T cell subtype analysis and Galon immune scores are accurate prognosticators., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer., Methods: An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature on extended pancreatectomies and worked together to establish a consensus on the definition and the role of extended pancreatectomy in pancreatic cancer., Results: Macroscopic (R1) and microscopic (R0) complete tumor resection can be achieved in patients with locally advanced disease by extended pancreatectomy. Operative time, blood loss, need for blood transfusions, duration of stay in the intensive care unit, and hospital morbidity, and possibly also perioperative mortality are increased with extended resections. Long-term survival is similar compared with standard resections but appears to be better compared with bypass surgery or nonsurgical palliative chemotherapy or chemoradiotherapy. It was not possible to identify any clear prognostic criteria based on the specific additional organ resected., Conclusion: Despite increased perioperative morbidity, extended pancreatectomy is warranted in locally advanced disease to achieve long-term survival in pancreatic ductal adenocarcinoma if macroscopic clearance can be achieved. Definitions of extended pancreatectomies for locally advanced disease (and not distant metastatic disease) are established that are crucial for comparison of results of future trials across different practices and countries, in particular for those using neoadjuvant therapy., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: The tumor-associated inflammatory cell infiltrate is recognized to have prognostic value in various common solid tumors. However, the prognostic value of the tumor inflammatory cell infiltrate has not been established in pancreatic ductal adenocarcinoma (PDAC) nor has its relationship with the systemic inflammatory response., Methods: Retrospective study was made of 173 patients who underwent surgery between 1997 and 2009. Routine pathology specimens were scored according to density of the tumor inflammatory cell infiltrate, and biochemical data were collected preoperatively., Results: Low-grade tumor inflammatory cell infiltrate was associated with earlier tumor recurrence (P < 0.001) and particularly in the liver (P = 0.027). It was also associated with T3 tumors (P < 0.05), lymph node involvement (P < 0.05), and resection margin involvement (P < 0.05). On univariate survival analysis, age <65 years (P < 0.05), mGPS (P < 0.001), increased tumor stage (P < 0.01), nodal involvement (P < 0.01), size (P < 0.05), grade (P < 0.05), perineural invasion (P < 0.05), venous invasion (P < 0.01), resection margin involvement (P ≤ 0.001), vascular reconstruction (P < 0.05), and no adjuvant chemotherapy (P < 0.05) were associated with poor survival. In contrast, high-grade tumor inflammatory cell infiltrate was associated with better survival (P < 0.001). On multivariate survival analysis, mGPS [hazard ratio (HR): 1.77, 95% confidence interval (95% CI): 1.19-2.62, P = 0.005], tumor stage (HR: 2.21, 95% CI: 1.16-4.23, P = 0.016), resection margin involvement (HR: 2.19, 95% CI: 1.41-3.44, P = 0.001), venous invasion (HR: 1.79, 95% CI: 1.22-2.63, P = 0.003), tumor inflammatory cell infiltrate (HR: 0.37, 95% CI: 0.25-0.55, P = 0.0001), and adjuvant chemotherapy (P = 0.04) were independently prognostic., Conclusions: The results of the study show, for the first time, that the presence of a high-grade tumor inflammatory cell infiltrate is an independent predictor of prolonged overall survival following resection for PDAC. Furthermore, measures of the local and the systemic inflammatory response were inversely associated.

Background: Outcome prediction after resection with curative intent for pancreatic ductal adenocarcinoma remains a challenge. There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients undergoing resection for a variety of common solid tumors. Our aim was to prospectively evaluate the prognostic value of tumor- and patient-related factors including the systemic inflammatory response in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma of the head of pancreas., Methods: The prognostic impact of tumor factors such as stage and host factors, including the systemic inflammatory response (modified Glasgow Prognostic Score [mGPS]), were evaluated in a prospective study of 135 patients who underwent elective pancreaticoduodenectomy for pancreatic ductal adenocarcinoma from January 2002 to April 2009., Results: In addition to the established tumor-related pathological factors (in particular margin involvement; hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.65-4.84, P < 0.001), an elevated mGPS (HR 2.26, 95% CI 1.43-3.57, P < 0.001) was independently associated with lower overall survival after pancreaticoduodenectomy. Additionally, in an adjuvant therapy subgroup of 74 patients, both margin involvement and an elevated mGPS remained independently associated with reduced overall survival., Conclusions: We have prospectively validated the influence of tumor-related and patient-related factors. Margin involvement and the preoperative mGPS were the most important determinants of overall survival in patients undergoing potentially curative pancreaticoduodenectomy. Furthermore, both had independent prognostic value in those patients receiving adjuvant chemotherapy. In the future, this may be considered a stratification factor for entry onto therapeutic trials.

Background: Following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC), identification of peripancreatic fat tumor invasion promotes a tumor to stage T3. We sought to understand better the impact of histological peripancreatic fat invasion on prognosis and site of recurrence in a cohort of patients with PDAC., Methods: We analyzed the patient demographics, outcome, and recurrence data that had been prospectively collected in 189 consecutive PDAC undergoing potentially curative pancreaticoduodenectomy between 1996 and 2009. Pathological features were reassessed for all patients. Survival outcome was compared using Kaplan-Meier/Cox proportional hazards analysis. The primary site of recurrence was defined as either locoregional or distant metastases., Results: The median survival of this PDAC cohort was 18.9 months (95% confidence interval (CI) 15.7-22.2). Histological peripancreatic fat invasion was evident in 51 (27%) patients and was associated with lymph node metastases (p = 0.004) and larger tumor size (p = 0.015). The presence of peripancreatic fat invasion was associated with reduced overall survival following resection (12.4 months [95% CI 9.9-15.0]) when compared to those patients with no evidence of fat invasion (22.6 months [95% CI 18.5-26.7]; p < 0.0001). By multivariate survival analysis, independent predictors of overall survival included tumor grade (p = 0.002), lymph node involvement (p = 0.025), resection margin status (p = 0.003), venous invasion (p = 0.045), and peripancreatic fat invasion (p = 0.007). Invasion into the pancreatic fat was significantly associated with the primary site of recurrence being locoregional failure (p = 0.002)., Conclusions: Peripancreatic fat invasion was identified as being an independent predictor of poor outcome following pancreaticoduodenectomy for PDAC. Additionally, the presence of peripancreatic fat invasion was associated with locoregional disease as the primary site of recurrence. This may have implications for the staging of PDAC and potentially require incorporation into future staging systems to improve outcome stratification.

Background:   Over 11000 UK patients each year develop pancreatic exocrine insufficiency--the major causes are not rare: cystic fibrosis (>300 new cases/year), pancreatic cancer (>7000 new cases/year) and chronic pancreatitis (>4000 new cases/year). Affected patients present in diverse ways, and for chronic pancreatitis, diagnosis is frequently made rather late in the course of the disease., Aim: To raise awareness of key clinical issues specific to patients with pancreatic exocrine insufficiency through experience from UK clinicians, and to offer advice regarding appropriate treatment with pancreatic enzymes., Methods: Three case studies describe clinical issues relating to pancreatic enzyme supplementation that may lead to underuse in patients with cystic fibrosis, pancreatic and periampullary cancer or chronic pancreatitis., Results: The efficacy of the treatment of exocrine pancreatic insufficiency is dependent on adequate meal-time enzyme replacement therapy. Improvements in patients' weight and nutritional status are what is aimed for - an important reason for all doctors, nurses and dieticians to give this therapy close attention., Conclusions: Pancreatic exocrine insufficiency may result in malnutrition, but enzyme supplementation can greatly improve quality of life in these patients., (© 2010 Blackwell Publishing Ltd.)

Objective: To determine the prognostic influence of residual tumor at or within 1 mm of the mobilization margins (R1Mobilization) compared with transection margins (R1Transection) following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC)., Background: The prognostic strength of R1 status increases with frequency of margin positivity and is enhanced by protocol driven pathology reporting. Currently, margins are treated uniformly with tumor at or close to any margin considered of equal prognostic significance. The resection involves a mobilization phase freeing the posterior margin and anterior surface then a transection phase requiring lympho-vascular division forming the medial resection and pancreatic transection margin. The comparative assessment of the relative importance of tumor involvement of these different margins has not previously been investigated., Methods: Retrospective analysis of 148 consecutive resections for PDAC from 1996-2007 was performed. The individual (pancreatic transection, medial, posterior, and anterior surface) margins were separately identified and analyzed by a senior pathologist. An R1 resection was defined as microscopic evidence of tumor < or = 1 mm from a resection margin. R1Mobilization tumor extension included both R1Anterior and R1Posterior cases; while R1Transection included pancreatic neck/body transection, R1Medial and adjacent transection margins., Results: R1 status was confirmed in 109 patients (74%). The medial (46%) and posterior (44%) margins were most commonly involved. R1 status was found to an independent predictor of poor outcome (P < 0.001). R1Mobilization involvement only (n = 48) was associated with a significantly longer median survival of 18.9 months (95% CI, 13.7-24.8) versus 11.1 months (95% CI, 7.1-15.0) for those with R1Transection tumor involvement (n = 61) (P < 0.001). There was no significant difference in the survival of the R1Mobilization compared with R0 group (P = 0.52)., Conclusions: Following pancreaticoduodenectomy for PDAC, involvement of the transection margins in contrast to mobilization margins defines a group whose outcome is significantly worse. This may impact upon the allocation of adjuvant therapy within the setting of randomized controlled trials.

Unlabelled: In inoperable malignancy, pain relief with opioids is often inadequate. Nerve block procedures may improve symptom control. Our aim was to assess celiac plexus block (CPB) and thoracoscopic splanchnicectomy (TS) in patients receiving appropriate medical management (MM)., Methods: Patients with confirmed irresectable malignancy of the pancreas or upper abdominal viscera who required opioid analgesia were randomized to MM alone, MM+CPB, or MM+TS. Randomization was stratified by treatment centre, tumour type and previous opioid medication. The primary endpoint was pain relief at 2 months., Results: 65 patients (58 pancreas cancer) were randomized, 18 withdrew or died within 2 months. Effective pain relief was achieved in only one third of subjects at 2 weeks, and just under half at 2 months (MM: 6/19 and 5/12 evaluable patients; CPB: 5/14 and 5/9; TS 4/14 and 4/11). There were no significant differences between the groups in pain scores or opioid consumption, and there was no correlation between continued use of opioids and effective pain relief., Discussion: Previous randomized studies have shown small differences in pain scores, but no difference in opioid consumption and quality of life. The absence of any benefit from interventions in the present study questions their value., (Copyright 2010 S. Karger AG, Basel.)

Background & Aims: In patients with severe, necrotizing pancreatitis, it is common to administer early, broad-spectrum antibiotics, often a carbapenem, in the hope of reducing the incidence of pancreatic and peripancreatic infections, although the benefits of doing so have not been proved., Methods: A multicenter, prospective, double-blind, placebo-controlled randomized study set in 32 centers within North America and Europe., Participants: One hundred patients with clinically severe, confirmed necrotizing pancreatitis: 50 received meropenem and 50 received placebo., Interventions: Meropenem (1 g intravenously every 8 hours) or placebo within 5 days of the onset of symptoms for 7 to 21 days., Main Outcome Measures: Primary endpoint: development of pancreatic or peripancreatic infection within 42 days following randomization. Other endpoints: time between onset of pancreatitis and the development of pancreatic or peripancreatic infection; all-cause mortality; requirement for surgical intervention; development of nonpancreatic infections within 42 days following randomization., Results: Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group (P = 0.401). Overall mortality rate was 20% (10 of 50) in the meropenem group and 18% (9 of 50) in the placebo group (P = 0.799). Surgical intervention was required in 26% (13 of 50) and 20% (10 of 50) of the meropenem and placebo groups, respectively (P = 0.476)., Conclusions: This study demonstrated no statistically significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention, and did not support early prophylactic antimicrobial use in patients with severe acute necrotizing pancreatitis.

Diffuse renal cortical necrosis from any cause is rare in the Western World. Over the last 5 decades, there have been isolated case reports of acute cortical necrosis as a consequence of acute pancreatitis, but the long-term outcome of these patients has not previously been reported. Here, we report 3 young men, aged 16-21 years, who have presented over the past 19 years with severe acute pancreatitis associated with oliguric acute renal failure. They were all found to have diffuse renal cortical necrosis and consequently made no renal recovery. Despite the appreciable mortality associated with acute pancreatitis complicated by acute renal failure, they all survived the initial illness and all have successfully undergone renal transplantation. We present a detailed account of each patient including diagnostic strategies and discuss the possible factors contributing to a favorable outcome in these patients.

Background: Vasoactive intestinal peptide-secreting tumours (VIPomas) are rare islet cell tumours of the pancreas that can result in life-threatening biochemical abnormalities. The optimal intervention for metastatic VIPoma remains undecided. This case history documents the clinical role of radiofrequency (RF) ablation in the treatment of metastatic VIPoma., Case History: A primary pancreatic VIPoma was diagnosed in a 61-year-old female in 1998 and a distal pancreatectomy and splenectomy were performed. She remained disease-free for 44 months when she presented as an emergency with watery diarrhoea, hypokalaemia, renal failure and an elevated serum VIP level. CT scanning showed a liver metastasis and open RF ablation was performed with complete resolution of symptoms and biochemistry within 48 h. Post-ablation imaging confirmed complete ablation of the metastasis. She remained disease-free until 22 months later when watery diarrhoea resumed and a new hepatic metastasis was seen on CT. Percutaneous RF ablation was performed and follow-up CT scan showed complete ablation of the metastasis. The patient remains disease- and symptom-free 10 months after the second RF ablation., Conclusion: This case illustrates that the pronounced clinical and biochemical upset caused by metastatic VIPoma can be resolved safely, quickly and repeatedly by RF ablation., (2006 S. Karger AG, Basel and IAP)

For most patients with pregnancy-associated pancreatitis there is little maternal survival threat and only occasionally are there foetal deaths. We describe 4 young women with pregnancy-associated severe acute pancreatitis who each had gallstones. Their ages were 17, 18, 20 and 24 years. Each was a tertiary referral to our unit in Glasgow and each pursued a life-threatening course with hospital stays ranging from 37 to 90 days. One patient required pancreatic necrosectomy for infected necrosis, another had percutaneous management of a pancreatic abscess and 2 had cystogastrostomy as treatment for pancreatic pseudocyst. All underwent early endoscopic sphincterotomy and later cholecystectomy. It is important to be aware that pregnancy-associated acute pancreatitis may be severe, posing a survival threat even in the youngest patients. Gallstones, as we reported almost 20 years ago, are the most common aetiological factor in such patients., (Copyright (c) 2006 S. Karger AG, Basel and IAP.)

Background/aims: Patients with pancreatic cancer have one of the poorest survival rates and selection of patients for active treatment remains problematical. The present study assesses the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with inoperable pancreatic cancer., Methods: The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg/l) and hypoalbuminaemia (<35 g/l) were allocated a score of 2. Patients in whom only 1 or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively., Results: One hundred and eighty-seven patients were studied and 49 (26%) underwent an operative palliative bypass procedure. At the end of follow-up, 181 (97%) patients died, 17% of patients were alive at 12 months. On univariate analysis, age (p < 0.01), TNM stage (p < 0.001) and the GPS (p < 0.001) were significant predictors of survival. On multivariate survival analysis, stratified for bypass procedure, age (hazard ratio 1.53, 95%CI 1.12-2.10, p = 0.008), TNM stage (hazard ratio 1.70, 95%CI 1.33-2.18, p < 0.001) and the GPS (hazard ratio 1.72, 95%CI 1.40-2.11, p < 0.001) remained independent significant predictors of survival., Conclusion: At diagnosis, the presence of a systemic inflammatory response (as measured by the GPS) appears to be a useful indicator of poor outcome, independent of TNM stage, in patients with inoperable pancreatic cancer., (Copyright (c) 2006 S. Karger AG, Basel and IAP.)

Background: After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis (AP), several clinical studies have shown that early nasojejunal (NJ) feeding can be achieved in most patients. A pilot study of early nasogastric (NG) feeding in patients with objectively graded severe AP proved that this approach was also feasible. A randomized study comparing NG versus NJ feeding has been performed., Methods: A total of 50 consecutive patients with objectively graded severe AP were randomized to receive either NG or NJ feeding via a fine bore feeding tube. The end points were markers of the acute phase response APACHE II scores and C-reactive protein (CRP) measurements, and pain patterns by visual analogue score (VAS) and analgesic requirements. Complications were monitored and comparisons made of both total hospital and intensive-care stays., Results: A total of 27 patients were randomized to NG feeding and 23 to NJ. One of those in the NJ group had a false diagnosis, thereby reducing the number to 22. Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score, CRP measurement, VAS, or analgesic requirement. Clinical differences between the two groups were not significant. Overall mortality was 24.5% with five deaths in the NG group and seven in the NJ group., Conclusions: The simpler, cheaper, and more easily used NG feeding is as good as NJ feeding in patients with objectively graded severe AP. This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP.

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n = 65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20-3.68, P = 0.009), vascular invasion (HR 2.58, 95% CI 1.48-4.50, P < 0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14-3.52, P = 0.015) retained independent significance. Those patients with a postoperative C-reactive protein < or = 10 mg l(-1) had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l(-1) (P < 0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome.

We report a case of intraductal papillary mucinous neoplasm confined to the dorsal (Santorini) pancreatic duct. A 51-year-old woman presented with a cystic lesion in the head of her pancreas and pancreas divisum. A biopsy taken during cyst-enteric drainage revealed dysplastic epithelium so the patient was scheduled for resection. At operation, excision of the entire dorsal pancreas was performed with preservation of the unaffected ventral pancreas and the spleen and its vessels. Over 6 years later she remains well with stable weight and a good quality of life. This case illustrates the benefits of anatomical preservation in pancreatic resection, and was performed some years prior to the only other reported similar case.

Background: Trypsinogen activation peptide (TAP) may be an early marker of severe pancreatitis. Previous studies have included all patients with organ failure in the group with severe pancreatitis, although patients with transient organ failure may have a good prognosis. The aim of this study was to determine the value of urinary TAP estimation for prediction of severity of acute pancreatitis, and to validate use of several markers of prediction of severity against a new, stringent definition of severity., Methods: Patients with acute pancreatitis were recruited within 24 h of onset of symptoms. Urine and blood samples were collected for 24 h, and Acute Physiology And Chronic Health Evaluation (APACHE) II (24 h), Ranson (48 h) and Glasgow (48 h) scores were calculated. Severe acute pancreatitis was defined by the presence of a local complication or the presence of organ failure for more than 48 h., Results: Urinary TAP levels were significantly greater in patients with severe pancreatitis than in those with mild disease during the first 36 h of admission. The highest of three estimations of TAP in the first 24 h was as effective as APACHE II at 24 h in predicting severity. At 24 h after admission, urinary TAP was better than C-reactive protein (CRP) in predicting severity. The combination of TAP and CRP at 24 h allowed identification of high- and low-risk groups. The new definition of severity excluded 24 of 190 patients with transient organ failure; none of these patients died., Conclusion: Use of TAP improved early prediction of the severity of acute pancreatitis. Organ failure that resolves within 48 h does not signify a severe attack of acute pancreatitis., (Copyright 2004 British Journal of Surgery Society Ltd.)

Recent research in the use of ultrasound contrast agents has found they are able to increase the diagnostic power of ultrasound, to a level that may exceed other imaging modalities, in the diagnosis of liver lesions. Their application in the assessment of haemorrhage following angiographic embolisation has not previously been described. We report on a case where metal coil embolisation of a bleeding splenic artery aneurysm was completed to angiographic satisfaction, but on injection of ultrasound contrast medium, the aneurysm, distal to the embolisation, showed the presence of ultrasound contrast medium within it. We suggest that contrast enhanced ultrasound may be more sensitive than conventional angiography in the assessment of blood flow through intra-abdominal small vessel aneurysms or solid organs.

Several approaches have been used in an attempt to predict the severity and prognosis of attacks of acute pancreatitis. The Ranson and Glasgow criteria include a variety of simple laboratory parameters that are measured on admission and again within 48 h. They are the most widely used indices in clinical practice. The Acute Physiological and Chronic Health Evaluation II system is more complicated, but can be applied to a wide variety of conditions, especially in intensive care settings. The usefulness of this system depends on the threshold score for defining severe pancreatitis; a score of eight appears to be the most appropriate. The finding of nonperfused areas in the pancreas at contrast-enhanced computed tomography is indicative of pancreatic necrosis and portends an unfavourable prognosis. Other clinical and laboratory indices have been proposed, but the most important predictive factor of early mortality seems to be the presence and persistence of a Marshall organ failure score of two or more. This is especially true if organ dysfunction persists beyond 36 h. Radiological findings do not always correlate well with the presence of organ dysfunction, and more investigations are required.

In the last 5 years naso-enteric feeding has increasingly been used in clinical practice in patients with severe acute pancreatitis. Randomized clinical studies in both mild and severe forms of the disease have demonstrated not only the feasibility but also the safety of this approach. The majority of patients have been fed by variously placed nasojejunal tubes with varied problems in maintaining both location and patency. Most have been surprised to find that it is possible to feed the patients in this way with the potential of improving gut barrier function and immune response, at reduced cost and greater safety than with parenteral nutrition. The current evidence points to nasojejunal feeding being preferable to parenteral feeding, but evidence has yet to be produced to prove beyond reasonable doubt that such feeding is an improvement on conservative management without feeding. Finally, the most recent development has indicated that fine-bore nasogastric feeding may well be a realistic alternative to nasojejunal feeding even in the more severe forms of this disease. A small percentage of patients may still need parenteral nutrition., (Copyright 2002 Elsevier Science Ltd.)

Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease., Patients and Methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome., Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity., Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Background: All patients with organ dysfunction are currently classified as having severe acute pancreatitis. The aim of this study was to characterize the systemic inflammatory response syndrome (SIRS) and early organ dysfunction in patients with acute pancreatitis and the relationship with overall mortality., Methods: Patients with predicted severe acute pancreatitis of less than 48 h duration had daily organ dysfunction scores and SIRS criteria calculated. These features were then correlated with outcome., Results: Of 121 patients, 68 (56 per cent) did not develop organ dysfunction; only two of these patients died (mortality rate 3 per cent). Fifty-three (44 per cent) had early organ dysfunction, of whom 11 died (21 per cent). Organ dysfunction and persistent SIRS were both associated with an increased mortality rate, but on multivariate analysis only deteriorating organ dysfunction was an independent determinant of survival., Conclusion: Early organ dysfunction in acute pancreatitis usually resolves and in itself has no significant influence on mortality. In contrast, worsening organ dysfunction was associated with death in more than half of the patients (11 of 20); it is this group of patients who should be classified as having severe acute pancreatitis.

Pancreatic cancer has a poor response to conventional chemotherapy and radiotherapy. Inhibition of matrix metalloproteinase activity involved in tumour invasion and metastases is a novel biological approach for cancer treatment. This multicentre phase II clinical trial assessed marimastat, an oral matrix metalloproteinase inhibitor, in patients with advanced pancreatic cancer. A total of 113 patients received marimastat for 28 days at 100 mg b.d. (n = 9), 25 mg o.d. (n = 90) or 10 mg b.d. (n = 14). Patients with a response to treatment could continue marimastat beyond 28 days. Of 113 patients, 90 (80%) completed the 28-day study and 83 (73%) continued treatment. The principal side effect was arthralgia in 14 (12%) patients at 28 days and 33 (29%) patients over the whole study. There were 31 patients (27%) who required dose modification. Of 76 patients with evaluable CA19-9 levels, 23 (30%) showed no increase or fall in CA19-9. Of 83 patients with radiologically assessable disease, 41 (49%) had stable disease. The median survival was 245 days for those with a stable or falling CA19-9 level 128 days in those with rising CA19-9. The overall survival was 3.8 months. 5.9 months for stage II, 4.7 months for stage III and 3 months for stage IV disease. Of 90 patients, 46 (51%) had stabilization or reduction in pain, mobility and analgesia scores. Further development and clinical evaluation of matrix metalloproteinase inhibitors for the treatment of pancreatic cancer is warranted.

Aims: To assess the accuracy of brush cytology in patients investigated for pancreatico-biliary strictures., Methods: All pancreatico-biliary brush cytology specimens submitted from two major teaching hospitals over a 6.5 year period were reviewed. Four hundred and forty eight satisfactory specimens from 406 patients with adequate clinical and/or pathological follow up data were examined in the study period., Results: Two hundred and forty six patients (60.6%) were shown to have neoplastic strictures. One hundred and forty seven tumours were identified cytologically, including 87 of 146 pancreatic carcinomas, 29 of 47 cholangiocarcinomas, one of one bile duct adenoma, four of seven carcinomas of the gallbladder, eight of 13 ampullary carcinomas, two of three ampullary adenomas, 10 of 16 malignancies of undetermined origin, none of two islet cell tumours, one of three hepatocellular carcinomas, and five of eight metastatic tumours. The three adenomas identified on brush cytology could not be distinguished from adenocarcinoma morphologically. One hundred and sixty patients (39.4%) had benign strictures, most often as a result of chronic pancreatitis and bile duct stones. There were three false positive cytological diagnoses mainly as a result of the misinterpretation of cases with relatively scant and/or degenerative atypical epithelial cells. Forty one cases were reported as atypical or suspicious of malignancy on brush cytology, of which 29 were ultimately shown to have carcinoma. The overall diagnostic sensitivity and specificity were 59.8% and 98.1%, respectively. The sensitivity increased from 44.3% in the initial third of cases to 70.7% in the final third of cases examined in the series., Conclusions: Brush cytology, in conjunction with other clinical and radiological investigations, is a useful technique in the assessment of patients with suspected pancreatico-biliary neoplasia.

Background: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis., Methods: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate., Findings: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups., Interpretation: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis

Objective: To describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity., Summary Background Data: Surgical intervention for secondary infection of pancreatic necrosis is associated with a death rate of 25% to 40%. Although percutaneous approaches may drain the abscess, they have often failed in the long term as a result of inability to remove the necrotic material adequately., Methods: Fourteen consecutive patients with infected necrosis secondary to acute pancreatitis were studied. The initial four patients underwent sinus tract endoscopy along a drainage tract for secondary sepsis after prior open necrosectomy. This technique was then modified to allow primary debridement for proven sepsis to be carried out percutaneously in a further 10 patients. The techniques and initial results are described., Results: Additional surgery for sepsis was successfully avoided in the initial four patients managed by sinus tract endoscopy, and none died. Of the following 10 patients managed by percutaneous necrosectomy, 2 died. The median inpatient stay was 42 days. There was one conversion for intraoperative bleeding. Eight patients recovered and were discharged from the hospital after a median of three percutaneous explorations. Only 40% of patients required intensive care management after surgery., Conclusions: These initial results in an unselected group of patients are encouraging and show that unlike with percutaneous or endoscopic techniques, both resolution of sepsis and adequate necrosectomy can be achieved. The authors' initial impression of a reduction in postoperative organ dysfunction is particularly interesting; however, the technique requires further evaluation in a larger prospective series.

Background: Severe acute pancreatitis may be protracted and some form of nutritional support is frequently required to maintain the patient's nutritional status. Recent work has suggested that enteral feeding via a jejunal route of delivery may reduce the magnitude of the inflammatory response. Insertion of nasojejunal (NJ) tubes in the patient with severe acute pancreatitis involves both delay and inconvenience. We undertook a prospective, feasibility study to assess the safety and practicability of nasogastric (NG) feeding in patients with severe acute pancreatitis., Patients and Methods: Twenty-six patients with objective evidence of severe acute pancreatitis received nasogastric feeding within 48 h of admission to our unit., Results: Etiology was identified as cholelithiasis (18 patients), ethanol (5), and miscellaneous (3). The median Glasgow score was 4 (range 2-7), APACHE II score 10 (4-28), and C-reactive protein concentration 286 mg/L (79-469). Fifteen patients had pancreatic and/or peripancreatic necrosis. Eleven patients developed severe organ failure, necessitating ventilatory support. Six developed multiple organ system failure, requiring inotropic support and/or renal dialysis. There were four deaths (15.3%). Nine patients underwent early, and nine late, ERCP, respectively; six necrosectomy (5 proven infected necrosis, 1 continued deterioration despite maximal support) and 4 patients internal drainage of a pseudocyst. The feed was well-tolerated in 22 patients. In 3 patients gastric stasis proved troublesome. There was no evidence of clinical or biochemical deterioration on commencing nasogastric feeding., Conclusion: It would appear that early NG feeding is usually possible in severe acute pancreatitis. In most patients it appears safe, well-tolerated, and worthy of further study.

Background: Inflammation and oxidative stress are believed to be important in the development of the systemic complications of acute pancreatitis. The fat-soluble vitamins A and E, and the carotenoids have antioxidant properties. The aim of this study was to assess the effect of acute pancreatitis on serum concentrations of vitamin antioxidants and to relate such changes to the degree of the inflammatory response., Methods: Thirteen consecutive patients with predicted severe acute pancreatitis were compared with 26 matched healthy controls. Five patients developed severe acute pancreatitis and three of these died. Vitamin antioxidant and C-reactive protein (CRP) levels were measured daily for up to 7 days., Results: Patients had significantly lower levels of antioxidants throughout the course of the study (P < 0.017). In patients there was a significant correlation between peak CRP and trough antioxidant levels (P < 0. 01). In patients with mild acute pancreatitis, the concentrations of retinol and beta-carotene at final review were significantly higher than those in patients with severe acute pancreatitis (P < 0.05). This coincided with a reduction in CRP level., Conclusion: In acute pancreatitis, circulating concentrations of vitamin antioxidants are reduced and are inversely related to the rise in CRP level.

Background: Death from acute pancreatitis within the first week after admission is usually a consequence of multiple organ dysfunction. Reports from specialist centres suggest that, with improvements in resuscitation and supportive care, such deaths are becoming uncommon but it is unclear if this is reflected in a decrease in early mortality rate from acute pancreatitis in the general population., Methods: Data concerning patients discharged with a diagnosis of acute pancreatitis (International Classification of Disease-9 code 577.0) between 1984 and 1995 were obtained from the Information and Statistics Division, National Health Service in Scotland, and analysed on a computer database., Results: The incidence of acute pancreatitis in Scotland continues to increase in both sexes. The in-hospital mortality rate (death from all causes) was 7.5 per cent and showed a slight but significant downward trend over the period of study. Death within 7 days of hospital admission accounted for 53.7 per cent of all deaths and the proportion of early deaths did not decline over the study interval., Conclusion: These results suggest that scope remains for considerable improvement in the early management of acute pancreatitis. There is an urgent need to improve the early recognition of severe pancreatitis coupled to a willingness on behalf of clinicians to transfer these patients at an early stage to a centre with high-dependency and intensive care facilities supervised by a multidisciplinary team with expertise in the endoscopic, radiological and surgical management of these patients.

For a 30-year period beginning in 1958, the general basis of medical therapy of acute pancreatitis had as its focus the provision of supplementary antiprotease therapy usually given intravenously. This concept was based on the belief that the body's natural antiprotease defense mechanism, which relies heavily on alpha 2-macroglobulin, together with alpha 1-antiprotease (alpha 1-antitrypsin), was inadequate to cope with the vast enzyme release that occurred with the onset of the more severe forms of the disease. This article examines recent studies and emerging theories on the medical therapy of acute pancreatitis.

Staging of acute pancreatitis is important for selection of patients for clinical trials, comparison of results between centers, and the early identification of patients who may benefit from therapeutic intervention or transfer to a specialist unit. The APACHE-II score and other multiple-factor scoring systems are widely used for the first two indications, and of these, the APACHE-II score provides the best accuracy at an early stage in the course of the illness. Presently, however, no system provides sufficient predictive power to facilitate clinical decision making. At a time of increasing pressure to involve specialist units at an early stage in the management of these complex patients, a pressing need to identify a system for accurate early staging of acute pancreatitis remains.

Background: Pain relief after distal pancreatectomy for chronic pancreatitis is reportedly satisfactory in 50-80 per cent of patients. This study attempted to determine clinical and radiological features that might select patients likely to benefit from distal pancreatectomy, and whether splenic preservation influenced the outcome., Methods: Thirty-eight patients with chronic pancreatitis, who underwent distal pancreatectomy between 1982 and 1998, were reviewed retrospectively. The outcome of surgery was correlated with the aetiology of pancreatitis and radiological appearance on endoscopic retrograde cholangiopancreatography and computed tomography., Results: Good results were achieved in 23 of 36 patients for whom follow-up (median 48 months) was available, including all 11 with obstructive pancreatitis. The spleen was preserved in 22 patients. Twelve patients became diabetic after surgery: three of 20 in whom the spleen was preserved and nine of 16 who underwent splenectomy., Conclusion: Non-alcoholic patients with a normal pancreas proximal to a dominant ductal stricture had a consistently good outcome from surgery. Spleen-preserving distal pancreatectomy, although technically demanding, can be performed safely with results equivalent to those of distal pancreatectomy with splenectomy or autotransplantation. Splenic preservation, apart from preventing postsplenectomy sepsis, might also delay the onset of diabetes.

The purpose of this chapter is to examine the possible role of platelet-activating factor (PAF) antagonist therapy as a means of modifying the systemic inflammatory response syndrome (SIRS) and multi-organ dysfunction syndrome (MODS) in the management of patients with severe acute pancreatitis (AP). Supposed specific treatments of AP have not shown clinical benefit, with antiprotease agents such as aprotinin and gabexate mesilate, as well as fresh frozen plasma, being ineffective. In addition, early peritoneal lavage, intravenous glucagon, somatostatin and octreotide have shown no benefit.