Oliver Strobel

Pancreatic cancer surgery in the new millennium: better prediction of outcome.

Background: Surgery is the only therapy with potentially curative intention in pancreatic cancer. This analysis aimed to determine prognostic parameters in a patient cohort with resected pancreatic adenocarcinoma with a special focus on the revised R1-definition. Methods: Between October 2001 and August 2009, data from 1071 consecutively resected patients with pancreatic adenocarcinoma were prospectively collected in an electronical database. Parameters tested for survival prediction in univariate analysis included patient, tumor, and resection characteristics as well as adjuvant therapy. The parameters with significant results were used for multivariate survival analysis. Identified parameters with positive or negative prognostic effect were used to define risk groups and to assess the effects on patient survival. Results: Age, ASA-score, CEA and CA19–9 levels, preoperative insulin-dependent diabetes mellitus, T-, N-, M-, R-, G-tumor classification, advanced disease, and LNR were all significant in univariate analysis, whereas gender, NYHA score, BMI, insurance status, type of surgical procedure, and adjuvant therapy were not. In multivariate analysis, age ≥70 years, preoperative insulin-dependent diabetes, CA19–9 ≥400 U/mL, T4-, M1- or G3-status, and LNR > 0.2 were independent negative predictors, whereas Tis/T1/T2-status, G1-differentiation, and R0-status (revised definition) were independently associated with good prognosis. Using these risk factors, patients were stratified into 4 risk-groups with significantly different prognosis; 5-year survival varied between 0% and 54.5%. Risk stratification resulted in improved survival prognostication within the predominant AJCC IIA and AJCC IIB stages. Conclusions: A newly defined prognostic profiling including the revised R1-definition discriminates survival of patients with resectable pancreatic adenocarcinoma better than the AJCC staging system, and may be of particular relevance for patient-adjusted therapy in the heterogeneous group of AJCC stage II tumors.

Small (Sendai negative) branch-duct IPMNs: not harmless.

Objective:The aim of this study was to evaluate existing management guidelines for branch-duct intraductal papillary mucinous neoplasms (IPMNs). Background:According to current treatment guidelines (Sendai criteria), patients with asymptomatic branch-duct type IPMNs of the pancreas less than 3 cm in diameter without suspicious features in preoperative imaging should undergo conservative treatment with yearly follow-up examinations. Nevertheless, the risk of harboring malignancy or invasive cancer remains a significant matter of consequence. Methods:All patients who were surgically resected for branch-duct IPMNs between January 2004 and July 2010 at the University Clinic of Heidelberg were analyzed. Clinical characteristics of the patients and preoperative imaging were examined with regard to the size of the lesions, presence of mural nodules, thickening of the wall, dilation of the main pancreatic duct, and tumor markers. Results were correlated with histopathological features and were discussed with regard to the literature. Results:Among a total of 287 consecutively resected IPMNs, 123 branch-duct IPMNs were identified analyzing preoperative imaging. Some 69 branch-duct IPMNs were less than 3 cm in size, without mural nodules, thickening of the wall, or other features characteristic for malignancy (“Sendai negative”). Of all the Sendai negative branch-duct IPMNs, 24.6% (17/69) showed malignant features (invasive carcinoma or carcinoma in situ) upon histological examination of the surgical specimen. Conclusions:Although many branch-duct IPMNs are small and asymptomatic, they harbor a significant risk of malignancy. We believe that both main-duct and branch-duct IPMNs represent premalignant lesions. This should be taken into account for adequate therapeutic management. With regard to these results, the current Sendai criteria for branch-duct IPMNs need to be adjusted.

Risk of Malignancy in Serous Cystic Neoplasms of the Pancreas

Background: In contrast to mucinous cystic neoplasms of the pancreas, which are known to have considerable malignant potential, the serous variant is generally thought to be benign. There are, however, several reports of malignancy in serous cystic neoplasms of the pancreas. Aims: To assess the risk of malignancy of serous cystic tumors of the pancreas and to investigate specific clinical and histological features. Methods: Clinical and pathological characteristics of benign and malignant serous cystic neoplasms of the pancreas were investigated by a review of the literature and documented by a case of a serous cystadenocarcinoma and immunohistochemical analysis of a series of serous cystadenomas. Reviewing the literature prevalence, age and sex distribution of serous cystic neoplasms were analyzed. Results: The prevalence of cancer among serous cystic neoplasms reported since 1989 was 3%. Serous cystadenoma of the pancreas present at an earlier age (61 years) than serous cystadenocarcinoma (66 years; p = 0.056) and are symptomatic in the majority of patients.Pathological examination of the primary tumor was not able to distinguish cystadenoma from cystadenocarcinoma in 38% of cases. In 25% the diagnosis of cancer was established only after growth of metachronous metastases. In the present case, nuclear atypia, papillary structures, proliferation marker Ki-67 and p53 protein were increased in the primary tumor and/or metachronous metastasis. Conclusion: Serous cystic neoplasms of the pancreas do have malignant potential with a risk of malignancy of 3% and should be surgically treated if the operative risk is acceptable. Routine analysis of genetic and proliferation markers may improve diagnosis of malignancy in these tumors.

Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome.

Objective:To evaluate the safety and outcome of multivisceral pancreatic resections for primary pancreatic malignancies. Background:Curative resection is the only potential cure for patients with pancreatic cancer, but some patients present with advanced tumors that are not resectable by a standard pancreatic resection. Data on risk and survival analysis of extended pancreatic resections is limited. Methods:One hundred one patients who had a multivisceral pancreatic resection between 10/2001 and 12/2007 were identified from a prospective database, and perioperative and long-term results were compared with those of 202 matched patients with a standard pancreatic resection. Uni- and multivariate regression analysis were performed to identify parameters that are associated with perioperative morbidity. Long-term survival was evaluated. Results:Colon, stomach, adrenal gland, liver, hepatic or celiac artery, kidney, or small intestine were resected in 37.6%, 33.7%, 27.7%, 18.8%, 16.8%, 11.9%, and 6.9% of the 101 patients with multivisceral resection, respectively. Additional portal vein resection was performed in 20.8% of patients. Overall and surgical morbidity but not mortality was significantly increased compared with standard pancreatic resections (55.5% vs. 42.8%, 37.6 vs. 25.3%, and 3.0% vs. 1.5%, respectively). Uni- and multivariate analysis identified a long operative time and the extended multivisceral resection of 2 or more additional organs as independent risk factors for intraabdominal complications or need for relaparotomy. Median survival was comparable to that of standard pancreatic resections. Conclusions:Multivisceral resections can be performed with increased morbidity but comparable mortality and long-term prognosis as compared with standard pancreatic resections at high volume centers. Increased morbidity is related to extended multivisceral resections with a long operative time.

Pancreatic Duct Glands Are Distinct Ductal Compartments That React to Chronic Injury and Mediate Shh-Induced Metaplasia

BACKGROUND & AIMS Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. METHODS The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. RESULTS Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. CONCLUSIONS PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia.

Enucleation in pancreatic surgery: indications, technique, and outcome compared to standard pancreatic resections

PurposePancreatic surgery is a technically challenging intervention with high demands for preoperative diagnostics and perioperative management. A perioperative mortality rate below 5% is achieved in high-volume centers due to the high level of standardization in surgical procedures and perioperative care. Besides standard resections, certain indications may require individualized surgical concepts such as tumor enucleations. The aim of the study was to evaluate the indications, technique, and outcome of this limited local approach compared to major resections.Materials and methodsData from patients undergoing pancreatic surgery were prospectively recorded. All patients with tumor enucleations were compared with classical resections (pancreaticoduodenectomy or left resection) in a matched-pair analysis (1:2). Tumor type, localization, operative parameters, complications, and outcome were evaluated.ResultsFifty-three patients underwent pancreatic tumor enucleation between October 2001 and December 2009. Indications included cystic lesions, IPMNs, and neuroendocrine pancreatic tumors. Enucleations were associated with shorter operation time, less blood loss as well as shorter ICU and hospital stay compared to pancreaticoduodenectomy and left resections. The overall surgical morbidity of enucleations was 28.3% without major complications. Leading clinical problems were ISGPF type A fistulas (20.8%) requiring prolonged primary drainage. No surgical revisions were necessary, and no deaths occurred.ConclusionsPancreatic tumor enucleations can be carried out with good results and no mortality. Decisions regarding enucleations are highly individual compared to standard resections, underlining the importance of treatment in experienced high-volume institutions. Enucleations should be carried out whenever possible and oncologically feasible to prevent the typical complications of major pancreatic resection.

Bacterial translocation and infected pancreatic necrosis in acute necrotizing pancreatitis derives from small bowel rather than from colon

BACKGROUND The clinical course of acute necrotizing pancreatitis (ANP) is determined by the superinfection of pancreatic necrosis. To date, the pathophysiology of the underlying bacterial translocation is poorly understood. The present study investigated the bacterial source of translocation. METHODS A terminal loop ileostomy was applied in rats. Selective digestive decontamination (SDD) of either the small bowel or the colon was performed. After 3 days of SDD, severe ANP was induced. At 24 hours, bacterial translocation was assessed by cultures of bowel mucosa, mesenteric lymph nodes, and pancreas using a scoring system (0-4). RESULTS Without SDD, pancreatic infection was present in all cases with an average score of 2.67. Colon SDD reduced pancreatic superinfection to 1.67 (not significant). SDD of the small bowel significantly reduced superinfection to 1.0 (P < .005). CONCLUSIONS Bacterial translocation from the colon is less frequent than translocation from the small bowel. Thus, the small bowel seems to be the major source of enteral bacteria in infected pancreatic necrosis.

Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19–1.34, P = 1.42 × 10−14), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84–0.92, P = 1.41 × 10−8) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85–0.93, P = 2.35 × 10−8). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09–1.19, P = 3.36 × 10−9), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories.

OBJECTIVE To determine the prognostic value of PLN and LNR based on a large series with standardized lymphadenectomy and pathological workup. BACKGROUND Lymph node (LN) involvement is a major prognostic factor in pancreatic adenocarcinoma. However, the distinction N0/N1 is not sufficient to accurately predict prognosis. To improve prognostic accuracy in N1 tumors, different LN parameters have been tested. Previous studies were based on series with variable numbers of examined lymph nodes (ELN) and came to inconsistent conclusions as to the value of the number of positive lymph nodes (PLN) and the lymph node ratio (LNR). METHODS 811 patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma between October 2001 and June 2012 were identified from a prospective database. Clinicopathological parameters included LN status (N0/N1), ELN, PLN, and LNR. Univariate and multivariate survival analyses were performed. RESULTS The median number of ELN was 24 (interquartile range: 18-32). By univariate analysis, both PLN and LNR were significantly associated with survival in N1 tumors. However, by multivariate analysis, only the number of PLN was confirmed as independent predictor of survival. Median survival in patients with only 1 PLN was 31.1 months and comparable to the survival in N0 (33.2 months). With increasing numbers of PLN median survival significantly decreased (2-3 PLN: 26.1 months, 4-7 PLN: 21.9 months, ≥8 PLN: 18.3 months, P < 0.0001). CONCLUSIONS This study demonstrates that, based on high numbers of ELN, PLN is superior to LNR in predicting survival and allows to distinguish several N-categories that improve prognostic accuracy in LN-positive resectable pancreatic adenocarcinoma.

Pancreatic main-duct involvement in branch-duct IPMNs: an underestimated risk.

Objectives:This study aimed to analyze a large single-center population of resected intraductal papillary mucinous neoplasms (IPMN) of the pancreas with respect to risk factors of malignant transformation. Background:There is international consensus that main-duct (MD) as well as mixed-type IPMNs should be treated surgically due to a high risk of malignancy. In contrast, there is an ongoing controversy about surgery of branch-duct type IPMN (BD-IPMN). Methods:All consecutive patients who underwent surgery for IPMN between January 2004 and December 2012 were included. Clinical characteristics and preoperative imaging were correlated with histopathological features. Results:A total of 512 patients underwent pancreatic surgery and had a histological proof of IPMN. According to preoperative imaging, 74 patients had MD-IPMN (14%), 205 mixed-type (40%), and 233 suspected BD-IPMN (46%). On histopathology, 162 of 512 patients revealed low-grade, 105 moderate, and 52 high-grade dysplasia. One hundred ninety-three IPMN patients (38%) suffered from invasive carcinoma. Among invasive IPMNs, the majority (58%) were mixed-type lesions according to preoperative imaging. Of 141 Sendai negative BD-IPMNs, a malignancy rate of 18% (high-grade dysplasia and invasive carcinoma) was found. Most interesting, 29% of suspected BD-IPMNs (67/233) revealed histological involvement of the main pancreatic duct not evident in preoperative imaging. Conclusions:All subtypes of IPMNs display a relevant risk for malignant transformation. By abdominal imaging, many IPMNs are misclassified as BD-IPMNs but reveal mixed-type lesions in histopathology. Because currently available preoperative diagnostics are not sufficient to reliably diagnose BD-IPMNs, surgical resection for suspected small branch-duct IPMN should be considered in patients fit for surgery.