Clem W. Imrie

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial

ObjectiveTo assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Summary Background DataPancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. MethodsESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. ResultsOf 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. ConclusionsResection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

Diagnosis, objective assessment of severity, and management of acute pancreatitis. Santorini consensus conference.

BACKGROUND The diagnosis, early assessment, and management of severe acute pancreatitis remain difficult clinical problems. This article presents the consensus obtained at a meeting convened to consider the evidence in these areas. The aim of the article is to provide outcome statements to guide clinical practice, with an assessment of the supporting evidence for each statement. METHOD Working groups considered the published evidence in the areas of diagnosis, assessment of severity, nonoperative treatment, and surgical treatment of severe acute pancreatitis. Outcome statements were defined to summarize the conclusions on each point considered. The findings were discussed and agreed on by all participants. A careful assessment was made of the strength of the available evidence (proven, probable, possible, unproven, or inappropriate). FINDINGS AND CONCLUSIONS There is reliable evidence to support much current practice. Clear guidance can be given in most areas examined, and several areas were identified where further investigation would be helpful. Diagnosis using plasma concentrations of pancreatic enzymes is reliable. Rapid advances are taking place in the assessment of severity. Several new therapeutic strategies show real promise for the reduction of morbidity and mortality rates. Surgical debridement is required for infected pancreatic necrosis, but is less often necessary for sterile necrosis.

Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome.

In patients with multiple endocrine neoplasia type 1 (MEN-1), gastrinomas are common and thought to occur predominantly in the pancreas. We describe eight patients with MEN-1 and hypergastrinemia (seven with the Zollinger-Ellison syndrome) in whom we searched for neuroendocrine tumors in the pancreas and duodenum. Tumors were found in the proximal duodenum in all eight patients: solitary tumors (diameter, 6 to 20 mm) in three patients and multiple microtumors (diameter, 2 to 6 mm) in the other five. Paraduodenal lymph-node metastases were detected in four patients. Immunocytochemical analysis revealed the presence of gastrin in all the duodenal tumors and in their lymph-node metastases. In contrast, no immunoreactivity for gastrin was present in the endocrine tumors found in the seven pancreatic specimens available for study, except for one tumor with scattered gastrin-positive cells. In four of the six patients whose duodenal gastrinomas were removed, serum gastrin levels returned to normal; in the other two patients gastrin concentrations decreased toward normal. We conclude that in patients with MEN-1 and the Zollinger-Ellison syndrome, gastrinomas occur in the duodenum, but the tumors may be so small that they escape detection.

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.

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 (13/138v 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

Borderline resectable pancreatic cancer: A consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)

BACKGROUND This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability. METHODS An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer. RESULTS The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers. CONCLUSION Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

Diclofenac Reduces the Incidence of Acute Pancreatitis After Endoscopic Retrograde Cholangiopancreatography

BACKGROUND & AIMS Acute pancreatitis following endoscopic retrograde cholangiopancreatography presents a unique opportunity for prophylaxis and early modification of the disease process because the initial triggering event is temporally well defined and takes place in the hospital. We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography. METHODS Entry to the trial was restricted to patients who underwent endoscopic retrograde pancreatography or had manometrically verified sphincter of Oddi hypertension. Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo. Estimation of serum amylase levels and clinical evaluation were performed in all patients. RESULTS A total of 220 patients entered the trial, and 110 received rectal diclofenac. Twenty-four patients developed pancreatitis (11%), of whom 7 received rectal diclofenac and 17 received placebo (P < 0.05). CONCLUSIONS This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease

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.

Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer.

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.

Positive Mobilization Margins Alone Do Not Influence Survival Following Pancreatico-Duodenectomy for Pancreatic Ductal Adenocarcinoma

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 ≤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.

Nasogastric feeding in severe acute pancreatitis may be practical and safe

SummaryBackground. 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.