Tobias Keck

Efficacy of stapler versus hand-sewn closure after distal pancreatectomy (DISPACT): a randomised, controlled multicentre trial

BACKGROUND The ideal closure technique of the pancreas after distal pancreatectomy is unknown. We postulated that standardised closure with a stapler device would prevent pancreatic fistula more effectively than would a hand-sewn closure of the remnant. METHODS This multicentre, randomised, controlled, parallel group-sequential superiority trial was done in 21 European hospitals. Patients with diseases of the pancreatic body and tail undergoing distal pancreatectomy were eligible and were randomly assigned by central randomisation before operation to either stapler or hand-sewn closure of the pancreatic remnant. Surgical performance was assessed with intraoperative photo documentation. The primary endpoint was the combination of pancreatic fistula and death until postoperative day 7. Patients and outcome assessors were masked to group assignment. Interim and final analysis were by intention to treat in all patients in whom a left resection was done. This trial is registered, ISRCTN18452029. FINDINGS Between Nov 16, 2006, and July 3, 2009, 450 patients were randomly assigned to treatment groups (221 stapler; 229 hand-sewn closure), of whom 352 patients (177 stapler, 175 hand-sewn closure) were analysed. Pancreatic fistula rate or mortality did not differ between stapler (56 [32%] of 177) and hand-sewn closure (49 [28%] of 175; OR 0·84, 95% CI 0·53–1·33; p=0·56). One patient died within the fi rst 7 days after surgery in the hand-sewn group; no deaths occurred in the stapler group. Serious adverse events did not differ between groups. INTERPRETATION Stapler closure did not reduce the rate of pancreatic fistula compared with hand-sewn closure for distal pancreatectomy. New strategies, including innovative surgical techniques, need to be identified to reduce this adverse outcome. FUNDING German Federal Ministry of Education and Research.

The Lymph Node Ratio is the Strongest Prognostic Factor after Resection of Pancreatic Cancer

IntroductionSurvival after surgery of pancreatic cancer is still poor, even after curative resection. Some prognostic factors like the status of the resection margin, lymph node (LN) status, or tumor grading have been identified. However, only few data have been published regarding the prognostic influence of the LN ratio (number of LN involved to number of examined LN). We, therefore, evaluated potential prognostic factors in 182 patients after resection of pancreatic cancer including assessment of LN ratio.MethodsSince 1994, 204 patients underwent pancreatic resection for ductal pancreatic adenocarcinoma. Survival was evaluated in 182 patients with complete follow-up evaluations. Of those 182 patients, 88% had cancer of the pancreatic head, 5% of the body, and 7% of the pancreatic tail. Patients underwent pancreatoduodenectomy (85%), distal resection (12%), or total pancreatectomy (3%). Survival was analyzed by the Kaplan–Meier and Cox methods.ResultsIn all 204 resected patients, operative mortality was 3.9% (n = 8). In the 182 patients with follow-up, 70% had free resection margins, 62% had G1- or G2-classified tumors, and 70% positive LN. Median tumor size was 30 (7–80) mm. The median number of examined LN was 16 and median number of involved LN 1 (range 0–22). Median LN ratio was 0.1 (0–0.79). Cumulative 5-year survival (5-year SV) in all patients was 15%. In univariate analysis, a LN ratio ≥ 0.2 (5-year SV 6% vs. 19% with LN ratio < 0.2; p = 0.003), LN ratio ≥ 0.3 (5-year SV 0% vs. 18% with LN ratio < 0.3; p < 0.001), a positive resection margin (p < 0.01) and poor differentiation (G3/G4; p < 0.03) were associated with poorer survival. In multivariate analysis, a LN ratio ≥ 0.2 (p < 0.02; relative risk RR 1.6), LN ratio ≥ 0.3 (p < 0.001; RR 2.2), positive margins (p < 0.02; RR 1.7), and poor differentiation (p < 0.03; RR 1.5) were independent factors predicting a poorer outcome. The conventional nodal status or the number of examined nodes (in all patients and in the subgroups of node positive or negative patients) had no significant influence on survival. Patients with one metastatic LN had the same outcome as patients with negative nodes, but prognosis decreased significantly in patients with two or more LN involved.ConclusionsNot the lymph node involvement per se but especially the LN ratio is an independent prognostic factor after resection of pancreatic cancers. In our series, the LN ratio was even the strongest predictor of survival. The routine estimation of the LN ratio may be helpful not only for the individual prediction of prognosis but also for the indication of adjuvant therapy and herein related outcome and therapy studies.

Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

Objectives:To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. Background:PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. Methods:A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. Results:From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. Conclusions:The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

A simple scoring system based on clinical factors related to pancreatic texture predicts postoperative pancreatic fistula preoperatively.

BACKGROUND Postoperative pancreatic fistula (POPF) is regarded as the most serious complication of pancreatic surgery. The preoperative risk stratification of patients by simple means is of interest in perioperative clinical management. METHODS Based on prospective data, we performed a risk factor analysis for POPF after pancreatoduodenectomy in 62 patients operated between 2006 and 2008 with special focus on clinical parameters that might serve to predict POPF. A predictive score was developed and validated in an independent second dataset of 279 patients operated between 2001 and 2010. RESULTS Several pre- and intraoperative factors, as well as underlying pathology, showed significant univariate correlation with rate of POPF. Multivariate analysis (binary logistic regression) disclosed soft pancreatic texture (odds ratio [OR] 10.80, 95% confidence interval [CI] 1.80-62.20) and history of weight loss (OR 0.15, 95% CI 0.04-0.66) to be the only independent preoperative clinical factors influencing POPF rate. The subjective assessment of pancreatic hardness by the surgeon correlated highly with objective assessment of pancreatic fibrosis by the pathologist (r = -0.68, P < 0.001, two-tailed Spearmans rank correlation). A simple risk score based on preoperatively available clinical parameters was able to stratify patients correctly into three risk groups and was independently validated. CONCLUSIONS Preoperative stratification of patients regarding risk for POPF by simple clinical parameters is feasible. Pancreatic texture, as evaluated intraoperatively by the surgeon, is the strongest single predictive factor of POPF. The findings of the study may have important implications for perioperative risk assessment and patient care, as well as for the choice of anastomotic techniques.

ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat

Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT‐activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR‐203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR‐203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism‐based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.

The Inflammatory Pancreatic Head Mass Significant Differences in the Anatomic Pathology of German and American Patients With Chronic Pancreatitis Determine Very Different Surgical Strategies

Background:The indications for surgery and the surgical strategy selected for chronic pancreatitis (CP) vary widely, perhaps because of unaccounted characteristics of different patient populations such as the “inflammatory mass” in the head of the pancreas, commonly described in Europe but not in America. Methods:We compared the pancreatic morphology, anatomic complications, indications leading to intervention, and the operation performed in 93 consecutive patients with CP operated upon either at a German (n = 48) or an American (n = 45) center specializing in pancreatic surgery. Pretreatment computed tomography/magnetic resonance imaging scans were reevaluated by 2 independent radiologists, especially to measure the anterior-posterior diameter of the pancreatic head (the inflammatory mass). Results:The prevalence of endocrine and exocrine insufficiency was not significantly different. The median diameter of the pancreatic head mass was significantly larger in the German group (4.5 vs. 2.6 cm, P < 0.001). Inflammatory mass-dependent symptoms [gastric outlet obstruction (9/48 vs. 1/45; P = 0.02) and hemorrhage (7/48 vs. 0/45; P = 0.013)] were more frequent in the German group. Bile duct stenosis (19/48 vs. 11/43; P = 0.18) and suspicion of malignancy (5/48 vs. 11/43; P = 0.10) were comparable, whereas chronic pain (15/48 vs. 28/43; P = 0.001) was a more frequent indication for surgery in the US group. Splenic or portal vein thrombosis was found only in the German group. The duration of nonoperative therapy was significantly longer in the German group (median 56 vs. 26 months; P = 0.02). In the US group, a pancreatoduodenectomy with antrectomy was performed in most (89%) cases, whereas in the German group a duodenum-preserving head resection was preferred in more than half (25/47) of the cases (P < 0.001). Conclusions:Symptoms, duration of conservative therapy, and selection of surgical treatment all differed significantly between German and American patients with CP. These differences seem to be dependent upon surprising but unexplained disparities in the pathologic pancreatic anatomy between the 2 populations.

Short- and long-term results of duodenum preservation versus resection for the management of chronic pancreatitis: a prospective, randomized study.

BACKGROUND Individualization of operations for chronic pancreatitis (CP) offers tailored operative approaches for the management of complications of CP. For the management of the inflammatory head mass and its complications, duodenum-preserving procedures (Frey and Beger operations) compete in efficacy and quality of life with pancreatoduodenectomy procedures (PPPD and Whipple operations). Our aim was to compare the short- and long-term results of duodenum-preserving and duodenum-resecting techniques in a prospective, randomized trial. METHODS Eighty-five patients with CP were randomized to undergo either pylorus-preserving (PPPD) or duodenum-preserving pancreatic head resection (DPPHR). Perioperative and long term results were evaluated. RESULTS Although the duodenum-preserving operations had a lesser median operating time (360 vs 435 minutes; P = .002), there were no differences in the need for intraoperative blood transfusion (76% vs 79%) or the duration of hospital stay (13 vs 14 days). Postoperative complications in general (33% vs 30%), surgical complications (21% vs 23%), and severe complications such as pancreatic leakage (10% vs 5%) or the need for reoperation (2% vs 2%) did not differ between the DPPHR and the PPPD groups, and there was no mortality (0%). The long-term outcome after a median of >5 years showed no differences between the DPPHR and PPPD regarding quality of life, pain control (67% vs 67%), endocrine status (45% vs 44%), and exocrine insufficiency (76% vs 61%). CONCLUSION Both types of pancreatic head resections are equally effective in pain relief and eventual quality of life after long-term follow-up (>5 years) without differences in endocrine or exocrine function.

Pancreatic Proteases in Serum Induce Leukocyte-Endothelial Adhesion and Pancreatic Microcirculatory Failure

Background: Neutrophil-mediated tissue injury in acute pancreatitis includes a severe reduction of the functional microcirculation via interaction of adhesion molecules on leukocytes (MAC-1) and endothelium (ICAM-1). The hypothesis of the study was that trypsin and elastase in serum alone lead to the expression of these complementary adhesion molecules and result in increased leukocyte-endothelial interaction (LEI). In addition we evaluated the preventative benefit of protease inhibition on these mechanisms. Materials and Methods: In vitro: Cultured endothelial cells (HUVEC) and human leukocytes (PMN) were stimulated with increasing doses of trypsin and elastase. In addition, pre-treatment of PMN or HUVEC was performed with protease inhibitors (Nafamostat mesilate, FUT and gabexate mesilate, FOY). The expression of ICAM-1 or MAC-1 was evaluated by flow cytometry. In vivo: Severe pancreatitis was induced in rats. Microcirculatory disturbances were evaluated by real-time confocal microscopy at 9 h in controls and acute pancreatitis with or without anti-protease treatment. Additionally, the effect of continuous trypsin and elastase infusion on pancreatic microcirculation and LEI were evaluated by intravital fluorescence videomicroscopy. Results: Up-regulation of MAC-1 and ICAM-1 expression requires the presence of serum. The maximal increase of MAC-1 and ICAM-1 expression was found at concentrations of trypsin or elastase characteristic for acute pancreatitis. FUT or FOY significantly reduced protease-induced expression of MAC-1 and ICAM-1. Real-time in-vivo microscopy revealed that functional capillary density in acute pancreatitis was significantly reduced (267.1 ± 2.95/mm2 vs. 91.29 ± 12.81/mm2) and treatment with FUT significantly reduced this effect (134.6 ± 4.6/mm2; p < 0.05 vs. untreated pancreatitis). Infusion of trypsin or elastase alone increased LEI in vivo and reduced pancreatic perfusion. Conclusion: Both trypsin and elastase up-regulate the expression of adhesion molecules on leukocytes and endothelial cells in the presence of serum. Increased LEI and reduced perfusion of the pancreas, characteristic of acute pancreatitis, is induced in vivo by infusion of pancreatic proteases and this effect is partially abrogated by their inhibitors. These results support the role of circulating trypsin and elastase in promoting pancreatic microcirculatory failure in experimental acute pancreatitis.

Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive biology and poor prognosis. Experimental evidence has suggested a role for the transcriptional repressor Zinc finger E-box binding homeobox 1 (ZEB1) in epithelial-mesenchymal transition, invasion, and metastasis in PDAC. ZEB1 expression has been observed in cancer cells as well as stromal fibroblasts. Our study aimed to evaluate the prognostic value of ZEB1 expression in PDAC tissue. METHODS Patient baseline and follow-up data were extracted from a prospectively maintained database. After clinicopathologic re-review, serial sliced tissue slides were immunostained for ZEB1, E-cadherin, vimentin, and pan-cytokeratin. ZEB1 expression in cancer cells and adjacent stromal fibroblasts was graded separately and correlated to routine histopathologic parameters and survival after resection. RESULTS A total of 117 cases of PDAC were included in the study. High ZEB1 expression in cancer cells and in stromal cancer-associated fibroblasts was associated with poor prognosis. There was also a trend for poor prognosis with a lymph node ratio of greater than 0.10. In line with its role as an inducer of epithelial-mesenchymal transition, ZEB1 expression in cancer cells was positively correlated with Vimentin expression and negatively with E-Cadherin expression. In multivariate analysis, stromal ZEB1 expression grade was the only independent factor of survival after resection. CONCLUSION Our data suggest that ZEB1 expression in cancer cells as well as in stromal fibroblasts are strong prognostic factors in PDAC. Stromal ZEB1 expression is identified for the first time as an independent predictor of survival after resection of PDAC. This observation suggests that therapies targeting ZEB1 and its downstream pathways could hit both cancer cells and supporting cancer-associated fibroblasts.

Inhibition of matrix metalloproteinase-9 with doxycycline reduces pancreatitis-associated lung injury.

Background/Aims: Severe lung injury, responsible for up to 15% of mortality in acute necrotizing pancreatitis patients, is promoted by neutrophil (PMN) migration into the lung. We have previously demonstrated that pulmonary injury in acute pancreatitis is mediated by PMN-derived matrix metalloproteinase-9 (MMP-9). This study was conducted to evaluate the ability of the broad-spectrum MMP inhibitor doxycycline to prevent secondary pulmonary injury in acute pancreatitis. Methods: Eighteen rats were randomized into three groups: severe pancreatitis (SAP), severe pancreatitis + doxycycline (SAP+Dox) (30 mg/kg body mass) or control. Acute pancreatitis was induced by intraductal glycodesoxycholic acid and i.v. stimulation with cerulein. Lung sections were histologically graded for edema, microthrombi, atelectasis and hemorrhage. Active MMP-9 in lung tissue was measured with fluorescent assay (ELISA). Naphtol-AS-D-chloroacetate esterase staining was used to determine pulmonary PMN infiltration. The inhibitory effect of doxycycline on MMP-9-induced transmigration was confirmed in a Matrigel transmigration assay. Results: Addition of doxycycline significantly reduced TNF-α-induced PMN transmigration across Matrigel membrane (12.6 ± 2.6 vs. 20.1 ± 3.9 PMNs; p < 0.05). SAP+Dox showed decreased concentration of active MMP-9 in lung tissue (37.89 ± 1.75 vs. 46.29 ± 3.68 ng/ml; p < 0.05) and as a result decreased pulmonary infiltration of PMNs (21.2 ± 5.1 vs. 32.5 ± 6.8; p < 0.05). Histological evaluation revealed decreased pulmonary edema (1.83 ± 0.41 vs. 2.33 ± 0.51, p < 0.05), atelectasis (1.67 ± 0.52 vs. 2.33 ± 0.52; p < 0.05) and pulmonary hemorrhage (2.5 ± 0.55 vs. 1.83 ± 0.41; p < 0.05) in SAP+Dox vs. SAP. These findings were paralleled by reduced pulmonary expression of active MMP-9. Conclusions: Inhibition of MMP-9 activity with doxycycline reduced pancreatitis-associated lung injury and expression of MMP-9 in pulmonary tissue. Doxycycline reduced PMN migration in vitro and in vivo and therefore might represent a novel strategy for the prevention of secondary pulmonary complications in acute pancreatitis.