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Purpose: Only small, potentially benign pancreatic tumors located ≥3 mm distant from the main pancreatic duct (MPD) are considered good candidates for enucleation. This study evaluates the outcome of enucleations with regard to their distance to the MPD., Methods: Clinical characteristics, complications, and outcomes of prospectively documented patients with small (≤30 mm), potentially benign pancreatic tumors, who underwent enucleation, were retrospectively analyzed. Patients were divided in two groups, either deep enucleation (DE, distance ≤3 mm) or standard enucleation (SE, distance >3 mm), as determined by intraoperative ultrasonography (IOUS)., Results: Sixty patients underwent DE (n = 30) or SE (n = 30) with IOUS. Both groups did not differ regarding age, tumor size, pathology, and operating time. Complications occurred in 24/30 (80 %) patients of the DE group compared to 15/30 (50 %) patients after SE (P = 0.029). Mortality was nil. The most frequent complication was pancreatic fistula (POPF) occurring in 22/30 (73.3 %) patients after DE and 9/30 (30 %) patients undergoing SE (P = 0.002). Especially, the rate of clinically significant POPF types B and C was higher after DE (21 of 30 patients) compared to SE (7 of 30 patients, P = 0.0006). Univariate and multivariate analyses revealed DE as the only significant factor that negatively influenced the occurrence of POPF. Postoperative hospital stay tended to be longer after DE (15 vs. 11.5 days, P = 0.050). All but two patients with metastatic gastrinoma and two patients, who died of unrelated causes, showed no evidence of disease after a median follow-up of 24 (3-235) months., Conclusions: Deep enucleation of small, potentially benign pancreatic tumors should be considered with caution given the high rate of clinically relevant POPF.

Background and Aims: Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival. Since then, the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Only the addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival, coming along with a very uncomfortable rash in the patients. Therefore, new adjuvant agents with very low toxic levels are needed. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemotherapeutic potential of aspirin as an adjuvant agent to gemcitabine., Methods: Drug treatment was initiated at the age of 3 months. LsL-Kras (G12D) ; Pdx1-Cre or LsL-Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, gemcitabine, or a combination of gemcitabine and aspirin. All mice were treated until death. The effect of aspirin was evaluated by histopathological analyses and immunostaining., Results: Gemcitabine prolonged overall median survival of LsL-Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre mice by 31 days as compared to mock-treated animals (median survival, 190 vs. 159 days; p = 0.396). Addition of aspirin to gemcitabine even extended the survival for ten more days, leading to a prolonged survival by 41 days, reaching virtually statistical significance versus the control group (median survival, 200 vs. 159 days; p = 0.05). Furthermore, we found that administration of aspirin in combination with gemcitabine reduced the number of Foxp3(+) regulatory T cells significantly., Conclusion: In conclusion, we identified aspirin as an effective adjuvant agent to gemcitabine in the treatment of PDAC. While fundamental differences in biology suggest the need for caution in equating mouse tumors with their human counterparts, mouse models nevertheless represent an important source of insight regarding human neoplasia. Further studies are necessary to confirm the hypothesis that aspirin might be an effective well-tolerated chemotherapeutic adjuvant agent for pancreatic cancer.

Background: This study aimed to evaluate the outcome of patients with abdominal, thoracic or vascular operations and long-term intensive care unit (ICU) treatment., Patients and Methods: The present retrospective observational cohort study was performed at the authors' surgical ICU at the Marburg University Medical Centre. All patients who stayed at the ICU longer than 48 h and underwent visceral, thoracic or vascular surgery between January 2005 and December 2006 were retrospectively analysed. Patients with an ICU stay of 20 or more days were defined as the long-term study group. Clinical variables were tested for prognostic value., Results: In 2 years, 852 patients were treated at the intensive care unit. Follow-up was available in 502 patients, with 219 patients treated for two and more days and a median of 16.4 days. Sixty-seven long-term patients were compared to 152 (69.4 %) patients treated between 2 and 20 days. Overall survival after 12 months was 50.2 % (110/219), while 65.8 % (144/219) were discharged from ICU. Older age, longer treatment at the ICU and increased simplified acute physiology score (SAPS) at admission were associated with decreased 12-month survival, while no statistical differences were observed for the underlying and malignant disease by univariate analysis. The risk of death was 29, 56 and 61 % for patients treated 2-4, 5-19 and ≥20 days at the ICU. Decreased survival of patients treated for 5-19 and ≥20 days were confirmed by logrank test (p = 0.001)., Conclusions: Patients with long-term ICU stay showed decreased survival than patients who are treated less than 5 days but similar survival as patients which stayed between 5 and 19 days. Malignant disease is not associated with an unfavourable 12-month survival while older age, higher SAPS index at discharge and longer stay at ICU are. Long-term ICU survivors have no increased risk to succumb after discharge from ICU.

Background: Since for pancreatic cancer the mortality rate approaches the incidence rate with only 1-4% of all patients surviving 5 years, it would be would be of great value to provide chemopreventive treatment for high-risk individuals., Discussion: The preclinical study of pancreatic intraepithelial neoplasia (PanINs) has recently been made possible by the generation of genetically modified animal models, which recapitulate human PanINs and invasive pancreatic cancer on a genetic and histomorphologic level. Very recently, several groups have reported first evidence of chemoprevention of pancreatic cancer.

Background: To evaluate the role of somatic TP53 mutations and to correlate somatic and germline mutations with results of immunostaining, a large cohort of ACC patients was analyzed., Patients and Methods: Patients with ACC who underwent potential curative surgery at the authors' department were screened for TP53 somatic and germline mutations in exons 5, 6, 7, 8, and 10 by DHPLC analysis. Aberrant samples were further analyzed by direct sequencing. Immunostaining was performed on corresponding paraffin sections in all patients. Complete clinical and follow-up data were correlated with the status of TP53., Results: Thirty ACC patients were included. Four of 30 patients showed aberrant DHPLC configuration and direct sequencing confirmed 2 (7%) germline mutations (R337H, R248W), 1 (3%) somatic mutation (R213X), and 1 (3%) noncoding polymorphism (g.17708 A>T). The only patient with a positive family history harbored a TP53 mutation. Tumors of the three patients with mutations showed aberrant p53 expression in more than 10% of cells by immunostaining, compared to only 3 of 27 patients without mutations (p = 0.009). Aberrant p53 expression (>5%) was detected in 12/30 (40%) ACCs. The latter was associated with an increased Ki67 and van Slooten index (p ≤ 0.001; p = 0.020). Disease-free survival decreased significantly in patients with aberrant p53 IHC of more than 5% of cells (65.7 ± 12.4 vs. 26.6 ± 8.7 months; p = 0.043 log rank test)., Conclusions: Patients with ACC revealed aberrant expression of p53 in 40%, and mutations were identified in 25% of these patients. Therefore aberrant p53 expression should be considered an indicator for genetic testing. A subgroup of apparently sporadic ACC is caused by TP53 germline mutations, and family history is a strong indicator for p53 germline mutations.

Purpose: This study was made to evaluate long-term results of an aggressive surgical approach for pancreaticoduodenal neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1)., Methods: MEN1 patients with either biochemical evidence of functioning or non-functioning pNENs larger than 1 cm in size on imaging underwent duodenopancreatic surgery. Since 1997, patients were followed annually by biochemical testing and imaging studies., Results: Thirty-eight genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 22) or non-functioning (n = 16) pNENs, nine patients were yet not operated. Malignant disease occurred in 12 (35%) patients defined by either lymph node (12 patients) and/or distant metastases (2 patients). Six patients with Zollinger-Ellison syndrome (ZES) required pylorus-preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure and 32 patients underwent other duodenopancreatic resections. Ten (26%) patients underwent up to four reoperations for either recurrent or metastatic disease that resulted in completion pancreatectomy in four patients. After median 109 months, 44 patients were alive and three patients died, one due to thymic carcinoid and two of unrelated causes. All eight patients with organic hyperinsulinism and 7 of 13 patients with ZES were biochemically cured. However, 24 of 38 (78%) patients developed new pNENs in the pancreatic remnant, but none developed distant metastases., Conclusions: Early resection of pNENs in MEN1 may prevent the development of distant metastases. However, the majority of patients develop new pNENs in the duodenopancreatic remnant which may require completion pancreatectomy in the long term.

Background: Sporadic malignant non-functioning pancreatic endocrine tumors (NF-PETs) are an important subset of pancreatic neoplasms. The aim of this study was to assess the impact of improved imaging on these features in a tertiary referral centre within a 20-year follow-up., Patients and Methods: From 1988 to 2009, 51 patients were treated for sporadic malignant NF-PETs. Forty-one patients who underwent tumor resection were retrospectively attributed according to the date of the initial diagnosis, group 1: 1988-1999 vs. group 2: 2000-2009., Results: Cross-sectional imaging led to positive prediction of NF-PETs in all patients. Curative resection was achieved in 76%. Synchronous metastases were present in 56% with a positive prediction of 43%. In group 1, the mean reported CT-determined tumor size was 56 vs. 54 mm in group 2 (p = 0.89). Synchronous metastases were present in 61% in group 1 vs. 57% (p = 0.99) in group 2. Metachronous metastases were recorded in 39% in group 1 vs. 43% (p = 0.84) in group 2. The mean interval from initial resection to diagnosis of metastatic disease was significantly shorter (p = 0.01) in patients from group 1 (14 vs. 61 months). Cumulative 5- and 10-year survival rates were 77% and 72% in group 1 vs. a 5-year survival rate of 66% in group 2., Conclusion: So far, improved CT-based imaging has no impact on earlier detection of initial synchronous metastases in sporadic malignant NF-PETs, while metachronous metastases are detected earlier.

Introduction: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as nonfunctional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Nonfunctional tumors do not secrete a hormone resulting in a clinical syndrome., Methods: The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach in patients with advanced disease may also prolong survival., Conclusions: This review focuses on the current standards of surgical treatment of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given.