Jörg Kleeff

Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages.

Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.

Systematic Review and Meta-Analysis of the Role of Defunctioning Stoma in Low Rectal Cancer Surgery

Summary Background Data:The role of a defunctioning stoma in patients undergoing low anterior resection for rectal cancer is still the subject of controversy. Recent studies suggest reduced morbidity after low anterior rectal resection with a defunctioning stoma. Methods:Retrospective and prospective studies published between 1966 and 2007 were systematically reviewed. Randomized controlled trials (RCTs) comparing anterior resections with or without defunctioning stoma were included in a meta-analysis. The pooled estimates of clinically relevant anastomotic leakages and of reoperations were analyzed using a random effects model (odds ratio and 95% confidence interval, CI). Results:Relevant retrospective single (n = 18) and multicenter (n = 9) studies were identified and included in the systematic review. Analysis of incoherent data of the leakage rates in these nonrandomized studies demonstrated that a defunctioning stoma did not influence the occurrence of anastomotic failure but seemed to ameliorate the consequences of the leak. Four RCTs were included in the meta-analysis. The odds ratio for clinically relevant anastomotic leakage was 0.32 (95% CI 0.17–0.59), revealing a statistically significant benefit conferred through a defunctioning stoma (Z = 3.65, P = 0.0003). The odds ratio for reoperation because of leakage-caused complications was 0.27 (95% CI 0.14–0.51), with significantly fewer reoperations in patients with a defunctioning stoma (Z = 3.95, P < 0.0001). Overall mortality rates were comparable regardless of the presence of a defunctioning stoma. Conclusion:A defunctioning stoma reduces the rate of clinically relevant anastomotic leakages and is thus recommended in surgery for low rectal cancers.

Distal pancreatectomy: risk factors for surgical failure in 302 consecutive cases.

Objective:The objective of this study was to identify potential risk factors for mortality and morbidity after distal pancreatectomy, with special focus on the formation of pancreatic fistula. Summary Background Data:Distal pancreatectomy can be performed with low mortality and acceptable morbidity rates. Pancreatic fistulas, occurring in 10% to 20% of cases, remain a problem that contributes significantly to morbidity, length of stay, and overall costs. Methods:From November 1993 to February 2006, perioperative and postoperative data of 302 consecutive patients were recorded. Univariate and multivariate analyses of potential risk factors for morbidity and for the formation of pancreatic fistula were performed. The surgical techniques used for closure were categorized into 4 groups: 1) anastomosis, 2) seromuscular patch, 3) closure by suture, and 4) closure using a stapling device. Results:Indications for resection were pancreatic tumors in 62% of patients, nonpancreatic tumors in 23%, chronic pancreatitis in 12%, and others in 3%. The spleen was preserved in 24% of patients. The morbidity and mortality rates for distal pancreatectomy in this series were 35% and 2%, respectively. The prevalence of pancreatic fistula was 12%. Univariate and multivariate analyses indicated that closure using a stapling device and an operating time ≥480 minutes were associated with a higher incidence of pancreatic fistula (odds ratio = 2.6 and 4.2, respectively). Overall morbidity was mainly influenced by the extent of resection (multivisceral vs. conventional; odds ratio = 1.7). Conclusion:Pancreatic leak remains a common complication after distal pancreatectomy. Our series suggests that stapler closure of the pancreatic remnant is associated with a significantly higher fistula rate.

Systematic review and meta‐analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer

Although some retrospective studies of extended radical lymphadenectomy for pancreatic cancer have suggested a survival advantage, this is controversial.

The role of stroma in pancreatic cancer: diagnostic and therapeutic implications

Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer–stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langtons Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?

Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders

BACKGROUND/AIMS Hepatocellular carcinoma (HCC) is a common malignant tumour worldwide, and its differential diagnosis from benign lesions of the liver is often difficult yet of great clinical importance. In the present study, we analysed whether glypican-3 is useful in differentiating between benign and malignant liver diseases and whether it influences the growth behaviour of HCC. METHODS Northern blot analysis and in situ hybridisation. RESULTS Northern blot analysis indicated that expression of glypican-3 mRNA was either low or absent in normal liver, in focal nodular hyperplasia (FNH), and in liver cirrhosis. In contrast, expression of glypican-3 mRNA was markedly increased in 20 of 30 and moderately increased in five of 30 HCC samples. The average increase in glypican-3 mRNA expression in HCC was significant compared with expression in normal liver (21.7-fold increase, p<0.01). In comparison with FNH or liver cirrhosis, glypican-3 mRNA expression in HCC was increased 7.2- (p<0.05) and 10.8-fold (p<0.01), respectively. In addition, pushing HCCs exhibited significantly higher glypican-3 mRNA expression than invading tumours (p<0.05). In situ hybridisation analysis demonstrated weak expression of glypican-3 mRNA in normal hepatocytes and bile ductular cells, and weak to occasionally moderate signals in hepatocytes forming nodules of liver cirrhosis and in regenerated hepatic nodules of FNH. In contrast, glypican-3 in situ hybridisation signals were intense in hepatic cancer cells with even higher levels in pushing HCCs than in invading HCCs. CONCLUSIONS These findings suggest that glypican-3, in many cases, has the potential to differentiate between benign and malignant liver diseases.

StellaTUM: current consensus and discussion on pancreatic stellate cell research

The field of pancreatic stellate cell (PSC) biology is very young, as the essential in-vitro tools to study these cells (ie, methods to isolate and culture PSC) were only developed as recently as in 1998. Nonetheless, there has been an exponential increase in research output in this field over the past decade, with numerous research groups around the world focusing their energies into elucidating the biology and function of these cells. It is now well established that PSC are responsible for producing the stromal reaction (fibrosis) of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. Despite exponentially increasing data, the methods for studying PSC remain variable. Although within individual laboratories methods are consistent, different methodologies used by various research groups make it difficult to compare results and conclusions. This article is not a review article on the functions of PSC. Instead, members of the Pancreatic Star Alliance (http://www.pancreaticstaralliance.com) discuss here and consolidate current knowledge, to outline and delineate areas of consensus or otherwise (eg, with regard to methodological approaches) and, more importantly, to identify essential directions for future research. Hepatic stellate cells (HSC) were first described by Karl von Kupffer in 1876; however, similar cells in the pancreas were first observed in the 1980s.1–3 In 1998, Apte et al 4 and Bachem et al 5 isolated and cultured PSC.4 5 In the normal pancreas, PSC are located in close proximity to the basal aspect of pancreatic acinar cells. In sections immunostained for the marker desmin (a cytoskeletal protein), quiescent PSC can be seen as cells with a central cell body and long cytoplasmic projections extending along the base of adjacent acinar cells similar to that of pericytes in the mammary gland. …

Transcriptional network governing the angiogenic switch in human pancreatic cancer

A shift of the angiogenic balance to the proangiogenic state, termed the “angiogenic switch,” is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in response to key endogenous pro- and antiangiogenic proteins. This approach reveals a global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signaling components. We also demonstrate that the angiogenic switch is governed by simultaneous regulations of multiple genes organized as transcriptional circuitries. In pancreatic cancer patients, we validate the transcriptome-derived switch of the identified “angiogenic network:” The angiogenic state in chronic pancreatitis specimens is intermediate between the normal (angiogenesis off) and neoplastic (angiogenesis on) condition, suggesting that aberrant proangiogenic environment contributes to the increased cancer risk in patients with chronic pancreatitis. In knockout experiments in mice, we show that the targeted removal of a hub node (peroxisome proliferative-activated receptor δ) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor δ expression levels are correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. Our results therefore also may contribute to the rational design of antiangiogenic cancer agents; whereas “narrow” targeted cancer drugs may fail to shift the robust angiogenic regulatory network toward antiangiogenesis, the network may be more vulnerable to multiple or broad-spectrum inhibitors or to the targeted removal of the identified angiogenic “hub” nodes.

Is there still a role for total pancreatectomy

Objective:To evaluate the perioperative and long-term results of total pancreatectomy (TP), and to assess whether it provides morbidity, mortality, and quality of life (QoL) comparable to those of the pylorus-preserving (pp)-Whipple procedure in patients with benign and malignant pancreatic disease. Summary Background Data:TP was abandoned for decades because of high peri- and postoperative morbidity and mortality. Because selected pancreatic diseases are best treated by TP, and pancreatic surgery and postoperative management of exocrine and endocrine insufficiency have significantly improved, the hesitance to perform a TP is disappearing. Patients and Methods:In a prospective study conducted from October 2001 to November 2006, all patients undergoing a TP (n = 147; 100 primary elective TP [group A], 24 elective TP after previous pancreatic resection [group B], and 23 completion pancreatectomies for complications) were included, and perioperative and late follow-up data, including the QoL (EORTC QLQ-C30 questionnaire), were evaluated. A matched-pairs analysis with patients receiving a pp-Whipple operation was performed. Results:Indications for an elective TP (group A + B) were pancreatic and periampullary adenocarcinoma (n = 71), other neoplastic pancreatic tumors (intraductal papillary mucinous neoplasms, neuroendocrine tumors, cystic tumors; n = 34), metastatic lesions (n = 8), and chronic pancreatitis (n = 11). There were 73 men and 51 women with a mean age of 60.9 ± 11.3 years. Median intraoperative blood loss was 1000 mL and median operation time was 380 minutes. Postoperative surgical morbidity was 24%, medical morbidity was 15%, and mortality was 4.8%. The relaparotomy rate was 12%. Median postoperative hospital stay was 11 days. After a median follow-up of 23 months, global health status of TP patients was comparable to that of pp-Whipple patients, although a few single QoL items were reduced. All patients required insulin and exocrine pancreatic enzyme replacements. The mean HbA1c value was 7.3% ± 0.9%. Conclusion:In this cohort study, mortality and morbidity rates after elective TP are not significantly different from the pp-Whipple. Because of improvements in postoperative management, QoL is acceptable, and is almost comparable to that of pp-Whipple patients. Therefore, TP should no longer be generally avoided, because it is a viable option in selected patients.

The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma

BACKGROUND AND AIMS Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with an innate resistance to therapy. Pancreatic stellate cells (PSCs) produce this excessively desmoplastic microenvironment. The impact of PSC activity on PDAC behavior in vivo is analyzed. METHODS 233 patients who underwent surgery for PDAC were evaluated by immunohistochemistry using antibodies against alpha-smooth muscle actin as a marker of PSC activity. Aniline was used to stain collagen deposition. The ratio of alpha-smooth muscle actin-stained area to collagen-stained area was defined as the activated stroma index (ASI). Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. RESULTS Four major patterns of collagen deposition were defined with regard to PSC activity. The combination of high stromal activity and low collagen deposition was associated with a worse prognosis, whereas the combination of high collagen deposition and low stromal activity indicated a better prognosis. Patients with the lowest ASI had the best median survival rate (25.7 mo). The highest ASI was found in patients with the worst median survival rate (16.1 mo; P = .007; lowest vs highest ASI: hazard ratio, 1.61; 95% confidence interval, 1.014-2.562). ASI was an independent prognostic marker in multivariable survival analysis comparable with the nodal status of cancer. CONCLUSIONS The activated stroma index is a novel independent prognostic marker in PDAC in cases undergoing surgery. This finding highlights the impact of the microenvironment in cancer progression and on patient survival.