Bettina M. Rau

Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications

BACKGROUND The time course and relationship between circulating and local cytokine concentrations, pancreatic inflammation, and organ dysfunction in acute pancreatitis are largely unknown. PATIENTS AND METHODS In a prospective clinical study, we measured the proinflammatory cytokines interleukin (IL)-1β, IL-6 and IL-8, the anti-inflammatory cytokine IL-10, interleukin 1β receptor antagonist (IL-1RA), and the soluble IL-2 receptor (sIL-2R), and correlated our findings with organ and systemic complications in acute pancreatitis. In 51 patients with acute pancreatitis admitted within 72 hours after the onset of symptoms, these parameters were measured daily for seven days. In addition, 33 aspirates from ascites and the lesser sac were measured. RESULTS Sixteen patients had mild acute pancreatitis (AP) and 35 severe AP (Atlanta classification); 18 patients developed systemic complications requiring treatment. All mediators were increased in AP. sIL-2R, IL-10, and IL-6 were significantly elevated in patients with distant organ failure. An imbalance in IL-1β/IL-1RA was found in severe AP and pulmonary failure. Peak serum sIL-2R predicted lethal outcome and IL-1RA was an early marker of severity. IL-6 was the best prognostic parameter for pulmonary failure. CONCLUSION Our results suggest that local mediator release, with a probable IL-1β-IL-1RA imbalance in severe cases, is followed by the systemic appearance of pro- and anti-inflammatory mediators. The pattern of local and systemic mediators in complicated AP suggests a role for systemic lymphocyte activation (triggered by local release of mediators) in distant organ complications in severe AP.

Early Assessment of Pancreatic Infections and Overall Prognosis in Severe Acute Pancreatitis by Procalcitonin (PCT): A Prospective International Multicenter Study

Background:Pancreatic infections and sepsis are major complications in severe acute pancreatitis (AP) with significant impact on management and outcome. We investigated the value of Procalcitonin (PCT) for identifying patients at risk to develop pancreatic infections in severe AP. Methods:A total of 104 patients with predicted severe AP were enrolled in five European academic surgical centers within 96 hours of symptom onset. PCT was measured prospectively by a semi-automated immunoassay in each center, C-reactive protein (CRP) was routinely assessed. Both parameters were monitored over a maximum of 21 consecutive days and in weekly intervals thereafter. Results:In contrast to CRP, PCT concentrations were significantly elevated in patients with pancreatic infections and associated multiorgan dysfunction syndrome (MODS) who all required surgery (n = 10) and in nonsurvivors (n = 8) early after onset of symptoms. PCT levels revealed only a moderate increase in patients with pancreatic infections in the absence of MODS (n = 7), all of whom were managed nonoperatively without mortality. A PCT value of ≥3.5 ng/mL on 2 consecutive days was superior to CRP ≥430 mg/L for the assessment of infected necrosis with MODS or nonsurvival as determined by ROC analysis with a sensitivity and specificity of 93% and 88% for PCT and 40% and 100% for CRP, respectively (P < 0.01). The single or combined prediction of the two major complications was already possible on the third and fourth day after onset of symptoms with a sensitivity and specificity of 79% and 93% for PCT ≥3.8 ng/mL compared with 36% and 97% for CRP ≥430 mg/L, respectively (P = 0.002). Conclusion:Monitoring of PCT allows early and reliable assessment of clinically relevant pancreatic infections and overall prognosis in AP. This single test parameter significantly contributes to an improved stratification of patients at risk to develop major complications.

R1 resection in pancreatic cancer has significant impact on long-term outcome in standardized pathology modified for routine use

BACKGROUND The quality of a histopathologic workup after oncologic resection of pancreatic malignancies has changed the central role of surgery substantially for radical tumor clearance over the past years. The development of standardized protocols for pathologic workup increased the rate of R1 resections from around 20% up to 80%. In the present study, we investigated the incidence of R1 and its impact on survival after oncologic pancreatic resections using a standardized pathologic routine protocol. PATIENTS AND METHODS We performed 265 pancreatic resections from September 2003 to September 2010. Among 128 patients with malignant neoplasms, histology revealed ductal pancreatic adenocarcinoma in 97, ampullary cancer in 10, and distal bile duct cancer in 21 patients. Resected specimens were analyzed according to this improved standardized pathology protocol introduced in 2000. Follow-up data on overall and cancer-related survival, presence and site of tumor recurrence, and chemotherapy were obtained from 120 patients. RESULTS Pancreatic resection comprised a pylorus-preserving or classical pancreaticoduodenectomy in 112, a distal pancreatectomy in 8, and a total pancreatectomy in 7 patients. In the overall series, 56 (44%) were classified R1 resections and 68 (43%) R0 resections, 3 patients with R2 resections were excluded, leaving 125 patients for analysis. In pancreatic adenocarcinoma, the rate of R1 was 51% (48/94). R1 resection involved most frequently the circumferential margin in 86% (48/125) of the total group and in 92% (44/48) in pancreatic cancer. Follow-up was performed after a median of 17 months (range, 1-85) postoperatively. Cancer-related death rate in R0 and R1-resected patients was 60% and 83% (P < .02) in all cancers (n = 117) and 66% and 80% in patients with pancreatic adenocarcinoma (n = 88). Median tumor-related survival in R0 and R1 resections was 22 (range, 4-85) vs 14 months (range, 2-48) in all cancers (P < .002), and 19 (range, 4-85) vs 14 months (range, 2-48) in pancreatic adenocarcinoma (P < .04). Kaplan-Meier survival analysis revealed a survival benefit after R0 resection in both all cancers (P = .002) and pancreatic adenocarcinoma (P < .02). The pattern of tumor recurrence had a greater rate of regional metastases in the R1 group (P < .05). CONCLUSION Our 51% rate of R1 resections in ductal pancreatic carcinoma indicates a high quality standard of pathologic evaluation. The vast majority of R1 margins are located at the retroperitoneal dissection surface. Standardization of histopathologic analysis has a clinically relevant impact on survival after oncologic resection of pancreatic cancer and can be achieved by less extensive protocols.

Enhanced ENA-78 and IL-8 Expression in Patients with Malignant Pancreatic Diseases

Background/Aim: Pancreatic cancer is characterized by perineural invasion, early lymph node and liver metastases, and an extremely dismal prognosis. In the present study we aimed at investigating the expression profile of pro-inflammatory and angiogenic CXC chemokines as potential factors contributing to the aggressive biology of this gastrointestinal malignancy. Methods: Protein expression profiles of the CXC chemokines growth-related oncogene alpha (GRO-α/CXCL1), epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5), granulocyte chemoattractant protein-2 (GCP-2/CXCL6), neutrophil-activating protein-2 (NAP-2/CXCL7), and interleukin-8 (IL-8/CXCL8) were assessed by enzyme-linked immunosorbent assay in pancreatic carcinoma, cancer of the papilla of Vater, pancreatic cystadenoma, and chronic pancreatitis specimens. Results: IL-8 and ENA-78 protein expression was most pronounced in pancreatic carcinoma specimens, showing an 11-fold and 17-fold overexpression in comparison with non-affected neighbouring tissues, a 66-fold and 24-fold upregulation compared to pancreatic cystadenoma, and a 6-fold and 9-fold overexpression with respect to chronic pancreatitis, respectively (p < 0.05 between all groups). In addition, a close correlation between IL-8 and ENA-78 protein expression and advanced pancreatic carcinomas in relation to the T category was evident (p < 0.05). Conclusion: Our results demonstrate that ELR+ CXC chemokines are differentially expressed in malignant and non-malignant human pancreatic specimens, suggesting a potential contribution of these chemokines to the pathogenesis of pancreatic carcinoma.

Liver Resections of Isolated Liver Metastasis in Breast Cancer: Results and Possible Prognostic Factors

Background. Breast cancer liver metastasis is a hematogenous spread of the primary tumour. It can, however, be the expression of an isolated recurrence. Surgical resection is often possible but controversial. Methods. We report on 29 female patients treated operatively due to isolated breast cancer liver metastasis over a period of six years. Prior to surgery all metastases appeared resectable. Liver metastasis had been diagnosed 55 (median, range 1–177) months after primary surgery. Results. Complete resection of the metastases was performed in 21 cases. The intraoperative staging did not confirm the preoperative radiological findings in 14 cases, which did not generally lead to inoperability. One-year survival rate was 86% in resected patients and 37.5% in nonresected patients. Significant prognostic factors were R0 resection, low T- and N-stages as well as a low-grade histopathology of the primary tumour, lower number of liver metastases, and a longer time interval between primary surgery and the occurrence of liver metastasis. Conclusions. Complete resection of metastases was possible in three-quarters of the patients. Some of the studied factors showed a prognostic value and therefore might influence indication for resection in the future.

Human pancreas-specific protein. A diagnostic and prognostic marker in acute pancreatitis and pancreas transplantation.

SummaryConclusionHuman pancreas-specific protein (hPASP) is a very sensitive reflector of the extent of pancreatic necrosis on the cellular level, and is of both diagnostic and prognostic value in acute pancreatitis. Furthermore, it allows the estimation of the severity of graft pancreatitis soon after simultaneous renal and pancreatic transplantation.BackgroundDiagnosis of acute pancreatitis (AP) has been improved in the past 15 yr as new methods for the determination of specific pancreatic enzymes have been developed. However, these enzymes have no prognostic implications. In this prospective study, we evaluated the role of human pancreas-specific protein (hPASP) in comparison with pancreatic amylase and C-reactive protein (CRP) in acute pancreatitis and pancreas transplantation.Patients and MethodsThe study included 40 patients (22 female, 18 male; mean age 51 yr, range 22–88 yr) with AP and 7 patients (2 female, 5 male; mean age 37 yr, range 25–49 yr) with type I diabetes and renal insufficiency who underwent simultaneous kidney and pancreas transplantation. By means of contrast-enhanced computed tomography (CT) and/or intraoperative findings, patients were judged to have edematous-interstitial (AIP,n=20, mean age 55.2 yr, range 24–88 yr) or necrotizing pancreatitis (NP,n=20, mean age 46.3 yr, range 22–81 yr). Serum hPASP concentration was measured daily by a commercial radioimmunoassay technique. In 25 healthy subjects and in several control groups (35 patients with chronic pancreatitis, 20 patients with pancreatic carcinoma and 80 patients with different gastrointestinal diseases) a single blood specimen was taken at hospital admission for the determination of the normal range of hPASP and for specificity analysis.ResultsThe upper normal value for hPASP in healthy subjects was found to be 52 ng/mL. Serum hPASP was elevated in all patients suffering from AP, with a median of 343 ng/mL (lower-upper quartile: 192–478 ng/mL) at hospital admission. In the daily serum monitoring with respect to the onset of symptoms, significantly higher hPASP levels were found in NP compared with AIP after day 2 (p<0.001). In patients with NP, peak values of hPASP correlated significantly with the extent of pancreatic necroses measured by contrast-enhanced CT-scanning, whereas CRP did not. Six patients of the transplantation group had the same serum hPASP course as AIP, with almost normal values on the third postoperative day. One patient had elevated levels throughout the observation period. This patient suffered from necrotizing graft pancreatitis, confirmed by relaparotomy, and died because of subsequent septic complications.

Toll-like receptor 4 polymorphisms in German and US patients are not associated with occurrence or severity of acute pancreatitis

In a recent paper published in Gut Sharif and co-workers have investigated the role of toll-like receptor 4 (TLR4) and its co-receptor CD14 in experimental pancreatitis. Using genetically modified strains of mice in which TLR4 or CD14 had been deleted the authors found significantly less pancreatic injury and systemic inflammation in the milder, caerulein-induced pancreatitis as well as the more severe L-arginine-induced variety.1 Toll-like receptors belong to a family of pattern recognition receptors that mediate innate immune recognition and inflammatory responses. They are activated by products of microbial metabolism and for TLR4 the best established ligand is lipopolysaccharide (LPS), a major component of Gram-negative bacteria. Surprisingly, the beneficial effect of TLR4 or CD14 deletion on pancreatitis was completely independent of either the presence of LPS, or the translocation of bacteria.1 If TLR4 were to have a …

Duodenum-Preserving Subtotal and Total Pancreatic Head Resections for Inflammatory and Cystic Neoplastic Lesions of the Pancreas

IntroductionFor treatment of inflammatory and benign neoplastic lesions of the pancreatic head, a subtotal or total pancreatic head resection is a limited surgical procedure with the impact of replacing the application of a Whipple procedure. The objective of this work is to describe the technical modifications of subtotal and total pancreatic head resection for inflammatory and neoplastic lesions of the pancreas. The advantages of this limited surgical procedure are the preservation of the stomach, the duodenum and the extrahepatic biliary ducts for treatment of benign lesions of the pancreatic head, papilla, and intrapancreatic segment of the common bile duct. For chronic pancreatitis with an inflammatory mass complicated by compression of the common bile duct or causing multiple pancreatic main duct stenoses and dilatations, a subtotal pancreatic head resection results in a long-lasting pain control. Performing, in addition, a biliary anastomosis or a Partington Rochelle type of pancreatic main duct drainage, respectively, is a logic and simple extension of the procedure. The rationale for the application of duodenum-preserving total pancreatic head resection for cystic neoplastic lesions are complete exstirpation of the tumor and, as a consequence, interruption of carcinogenesis of the neoplasia preventing development of pancreatic cancer. Duodenum-preserving total head resection necessitates additional biliary and duodenal anastomoses. For mono-centric IPMN, MCN, and SCA tumors, located in the pancreatic head, total duodenum-preserving pancreatic head resection can be performed without hospital mortality and resurgery for recurrency. Based on controlled clinical trials, duodenum-preserving pancreatic head resection is superior to the Whipple-type resection with regard to lower postoperative morbidity, almost no delay of gastric emptying, preservation of the endocrine function, lower frequency of rehospitalization, early professional rehabilitation, and establishment of a predisease level of quality of life.ConclusionThe limited surgical procedures of subtotal or total pancreatic head resection are simple, safe, ensures free tumour margins and replace in the authors institution the application of a Whipple-type head resection.

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial.

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.

Intensified neoadjuvant radiochemotherapy for rectal cancer enhances surgical complications

BackgroundNeoadjuvant radiochemotherapy has proven superior to adjuvant treatment in reducing the rate of local recurrence without impairing cancer related survival or the incidence of distant metastases. The present study aimed at addressing the effects of an intensified protocol of neoadjuvant treatment on the development of postoperative complications.MethodsA total of 387 patients underwent oncological resection for rectal cancer in our institution between January 2000 and December 2009. 106 patients received an intensified radiochemotherapy. Perioperative morbidity and mortality were analyzed retrospectively with special attention on complication rates after intensified radio-chemotherapy. Therefore, for each patient subjected to neoadjuvant treatment a patient without neoadjuvant treatment was matched in the following order for tumor height, discontinuous resection/exstirpation, T-category of the TNM-system, dividing stoma and UICC stage.ResultsOf all patients operated for rectal cancer, 27.4% received an intensified neoadjuvant treatment. Tumor location in the matched patients were in the lower third (55.2%), middle third (41.0%) and upper third (3.8%) of the rectum. Postoperatively, surgical morbidity was higher after intensified neoadjuvant treatment. In the subgroup with low anterior resection (LAR) the anastomosis leakage rate was higher (26.6% vs. 9.7%) and in the subgroup of patients with rectal exstirpations the perineal wound infection rate was increased (42.2% vs. 18.8%) after intensified radiochemotherapy.ConclusionsIn rectal cancer the decision for an intensified neoadjuvant treatment comes along with an increase of anastomotic leakage and perineal wound infection. Quality of life is often reduced considerably and has to be balanced against the potential benefit of intensifying neoadjuvant radiochemotherapy.