Colin J. McKay

Percutaneous Necrosectomy and Sinus Tract Endoscopy in the Management of Infected Pancreatic Necrosis: An Initial Experience

ObjectiveTo describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity. Summary Background DataSurgical 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. MethodsFourteen 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. ResultsAdditional 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. ConclusionsThese 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.

A Randomized Study of Early Nasogastric versus Nasojejunal Feeding in Severe Acute Pancreatitis

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.

European experts consensus statement on cystic tumours of the pancreas.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression

Summary Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.

RE: nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer: Long-Term Survival From a Phase III Trial.

We read with interest the article by Goldstein and colleagues that reports the long-term results of the large phase III randomized trial (IMPACT) of nab-paclitaxel plus gemcitabine or gemcitabine alone in patients with metastatic pancreatic cancer, extending support for the superior efficacy of this combination therapy (1). They reported that the presence of a systemic inflammatory response, as evidenced by an elevated neutrophil lymphocyte ratio (NLR), effectively stratified survival independent of the trial treatment. A pooled treatment analysis demonstrated that patients with an NLR of 5 or less had a statistically significantly prolonged survival compared with patients with an NLR of more than 5 (median = 9.1 vs 5.0 months, P < .001). In the nab-Paclitaxel plus gemcitabine arm there was a statistically significantly longer overall survival vs the gemcitabine arm alone in patients with an NLR of 5 or less (P < .001). Furthermore, when there was evidence of a raised systemic inflammatory response, a trend was evident favoring prolonged survival in the nab-paclitaxel plus gemcitabine arm vs the gemcitabine alone group (P = .079). These results confirm our previous observations in patients with pancreatic adenocarcinoma, that an elevated NLR is an important independent prognostic factor (2). However, there is good evidence that assessment of the systemic inflammatory response using acute phase proteins, in particular C-reactive protein (CRP) and albumin (Glasgow Prognostic Score [GPS]) has superior prognostic value in a variety of common solid tumors (3), including pancreatic cancer both in resectable and nonresectable forms (2). Therefore, it is clear that even in such a poor-prognosis tumor as pancreatic cancer outcomes can be stratified according to the systemic inflammatory response. This new knowledge offers the possibility for simple and effective stratification for patients with this difficult-to-treat cancer. For heterogeneous cancers, in particular pancreatic cancer, a stratified medicine approach offers potential to target an individual’s cancer with the right treatment for the right patient (4). This strategy could improve overall outcomes and quality of life for patients by minimizing unnecessary side effects arising from ineffective therapies. However, as demonstrated in the present study, the concept of stratification should not be limited to tumoror gene-centric aspects but extended to consider patient or host aspects including the burden of the systemic inflammatory response. Moreover, beyond stratification there is also an opportunity for therapeutic targeting of the systemic inflammatory response. Given the role of JAK-STAT signaling in the inflammatory responses of patients with pancreatic cancer (5), it is of interest that a recent randomized phase II trial of the JAK1/JAK2 inhibitor ruxolitinib combined with capecitabine in patients with metastatic pancreatic cancer revealed a statistically significantly prolonged survival for those patients who were administered ruxolitinib with coexisting evidence of an elevated systemic inflammatory response, as measured by CRP and/or the modified GPS (6). It is also of interest that nab-paclitaxel itself has potential to alter the tumor stroma and immune environment (7). In summary, the work of Goldstein and colleagues (1) confirms the prognostic value of the systemic inflammatory response in patients with metastatic pancreatic cancer. Furthermore, it heralds a new era in which the systemic inflammatory response becomes a legitimate target for treatment of these patients.

MicroRNA Molecular Profiles Associated with Diagnosis, Clinicopathologic Criteria, and Overall Survival in Patients with Resectable Pancreatic Ductal Adenocarcinoma

Purpose: MicroRNAs (miRNA) have potential as diagnostic and prognostic biomarkers and as therapeutic targets in cancer. We sought to establish the relationship between miRNA expression and clinicopathologic parameters, including prognosis, in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Global miRNA microarray expression profiling of prospectively collected fresh-frozen PDAC tissue was done on an initial test cohort of 48 patients, who had undergone pancreaticoduodenectomy between 2003 and 2008 at a single institution. We evaluated association with tumor stage, lymph node status, and site of recurrence, in addition to overall survival, using Cox regression multivariate analysis. Validation of selected potentially prognostic miRNAs was done in a separate cohort of 24 patients. Results: miRNA profiling identified expression signatures associated with PDAC, lymph node involvement, high tumor grade, and 20 miRNAs were associated with overall survival. In the initial cohort of 48 PDAC patients, high expression of miR-21 (HR = 3.22, 95% CI: 1.21–8.58) and reduced expression of miR-34a (HR = 0.15, 95% CI: 0.06–0.37) and miR-30d (HR = 0.30, 95% CI: 0.12–0.79) were associated with poor overall survival following resection independent of clinical covariates. In a further validation set of 24 patients, miR-21 and miR-34a expression again significantly correlated with overall survival (P = 0.031 and P = 0.001). Conclusion: Expression patterns of miRNAs are significantly altered in PDAC. Aberrant expression of a number of miRNAs was independently associated with reduced survival, including overexpression of miR-21 and underexpression of miR-34a. Summary: miRNA expression profiles for resected PDAC were examined to identify potentially prognostic miRNAs. miRNA microarray analysis identified statistically unique profiles, which could discriminate PDAC from paired nonmalignant pancreatic tissues as well as molecular signatures that differ according to pathologic features. miRNA expression profiles correlated with overall survival of PDAC following resection, indicating that miRNAs provide prognostic utility. Clin Cancer Res; 18(2); 534–45. ©2011 AACR.

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.

Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas.

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 ⩽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.