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Background: A delayed post-pancreatoduodenectomy haemorrhage is associated with a significant increase in peri-operative mortality. Endovascular techniques are frequently used for a delayed haemorrhage. However, limited data exists on the short- and long-term outcomes of this approach. A retrospective review over a 10-year period at a quaternary-referral pancreatic centre was performed., Methods: Between 2002-2012, 1430 pancreatoduodenectomies were performed, and 32 patients had a delayed haemorrhage (occurring >24 h post-operatively) managed by endovascular techniques. The clinicopathological variables related to a haemorrhage were investigated., Results: A total of 42 endovascular procedures were performed at a median of 25 days, with the majority of delayed haemorrhages occurring after 7 days. There were four deaths (13%) with three occurring in patients with a grade C haemorrhage. Seven patients (22%) experienced rebleeding, and two patients developed hepatic abscesses., Conclusion: A delayed haemorrhage post-pancreaticoduodenectomy can be managed by endovascular techniques with acceptable morbidity and mortality. Rebleeding and hepatic abscesses may occur and can be managed non-operatively in most cases. The association of a delayed haemorrhage with a pancreatic fistula makes this a challenging clinical problem., (© 2015 International Hepato-Pancreato-Biliary Association.)

Background: Elderly patients undergoing open pancreatoduodenectomy (OPD) are at increased risk for surgical morbidity and mortality. Whether totally laparoscopic pancreatoduodenectomy (TLPD) mitigates these risks has not been evaluated., Methods: A retrospective review of outcomes in patients submitted to pancreatoduodenectomy during 2007-2014 was conducted (n = 860). Outcomes in elderly patients (aged ≥70 years) were compared with those in non-elderly patients with respect to risk-adjusted postoperative morbidity and mortality. Differences in outcomes between patients submitted to OPD and TLPD, respectively, were evaluated in the elderly subgroup., Results: In elderly patients, the incidences of cardiac events (odds ratio [OR] 3.21, P < 0.001), respiratory events (OR 1.68, P = 0.04), delayed gastric emptying (DGE) (OR 1.73, P = 0.003), increased length of stay (LoS, 1 additional day) (P < 0.001), discharge disposition other than home (OR 8.14, P < 0.001) and blood transfusion (OR 1.48, P = 0.05) were greater than in non-elderly patients. Morbidity and mortality did not differ between the OPD and TLPD subgroups of elderly patients. In elderly patients, OPD was associated with increased DGE (OR 1.80, P = 0.03), LoS (1 additional day; P < 0.001) and blood transfusion (OR 2.89, P < 0.001) compared with TLPD., Conclusions: Elderly patients undergoing TLPD experience rates of mortality, morbidity and cardiorespiratory events similar to those in patients submitted to OPD. In elderly patients, TLPD offers benefits by decreasing DGE, LoS and blood transfusion requirements., (© 2015 International Hepato-Pancreato-Biliary Association.)

Background & Aims: In gastrointestinal muscles, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) is predominantly expressed by interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor-α (PDGFRA) polypeptide is expressed by so-called fibroblast-like cells. KIT and PDGFRA have been reported to be coexpressed in ICC precursors and gastrointestinal stromal tumors (GISTs), which originate from the ICC lineage. PDGFRA signaling has been proposed to stimulate growth of GISTs that express mutant KIT, but the effects and mechanisms of selective blockade of PDGFRA are unclear. We investigated whether inhibiting PDGFRA could reduce proliferation of GIST cells with mutant KIT via effects on the KIT-dependent transcription factor ETV1., Methods: We studied 53 gastric, small intestinal, rectal, or abdominal GISTs collected immediately after surgery or archived as fixed blocks at the Mayo Clinic and University of California, San Diego. In human GIST cells carrying imatinib-sensitive and imatinib-resistant mutations in KIT, PDGFRA was reduced by RNA interference (knockdown) or inhibited with crenolanib besylate (a selective inhibitor of PDGFRA and PDGFRB). Mouse ICC precursors were retrovirally transduced to overexpress wild-type Kit. Cell proliferation was analyzed by methyltetrazolium, 5-ethynyl-2'-deoxyuridine incorporation, and Ki-67 immunofluorescence assays; we also analyzed growth of xenograft tumors in mice. Gastric ICC and ICC precursors, and their PDGFRA(+) subsets, were analyzed by flow cytometry and immunohistochemistry in wild-type, Kit(+/copGFP), Pdgfra(+/eGFP), and NOD/ShiLtJ mice. Immunoblots were used to quantify protein expression and phosphorylation., Results: KIT and PDGFRA were coexpressed in 3%-5% of mouse ICC, 35%-44% of ICC precursors, and most human GIST samples and cell lines. PDGFRA knockdown or inhibition with crenolanib efficiently reduced proliferation of imatinib-sensitive and imatinib-resistant KIT(+)ETV1(+)PDGFRA(+) GIST cells (50% maximal inhibitory concentration = 5-32 nM), but not of cells lacking KIT, ETV1, or PDGFRA (50% maximal inhibitory concentration >230 nM). Crenolanib inhibited phosphorylation of PDGFRA and PDGFRB, but not KIT. However, Kit overexpression sensitized mouse ICC precursors to crenolanib. ETV1 knockdown reduced KIT expression and GIST proliferation. Crenolanib down-regulated ETV1 by inhibiting extracellular-signal-regulated kinase (ERK)-dependent stabilization of ETV1 protein and also reduced expression of KIT and PDGFRA., Conclusions: In KIT-mutant GIST, inhibition of PDGFRA disrupts a KIT-ERK-ETV1-KIT signaling loop by inhibiting ERK activation. The PDGFRA inhibitor crenolanib might be used to treat patients with imatinib-resistant, KIT-mutant GIST., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The 7th edition of the American Joint Committee on Cancer (AJCC) staging system has recently been validated and shown to predict survival in patients with intrahepatic cholangiocarcinoma (ICC). The present study attempted to investigate the validity of these findings., Methods: A single-centre, retrospective cohort study was conducted. Histopathological restaging of disease subsequent to primary surgical resection was carried out in all consecutive ICC patients. Overall survival was compared using Kaplan-Meier estimates and log-rank tests., Results: A total of 150 patients underwent surgery, 126 (84%) of whom met the present study's inclusion criteria. Of these 126 patients, 68 (54%) were female. The median length of follow-up was 4.5 years. The median patient age was 58 years (range: 24-79 years). Median body mass index was 27 kg/m(2) (range: 17-46 kg/m(2) ). Staging according to the AJCC 7th edition categorized 33 (26%) patients with stage I disease, 27 (21%) with stage II disease, five (4%) with stage III disease, and 61 (48%) with stage IVa disease. The AJCC 7th edition failed to accurately stratify survival in the current cohort; analysis revealed significantly worse survival in those with microvascular invasion, tumour size of >5 cm, grade 4 disease, multiple tumours and positive lymph nodes (P < 0.001). A negative resection margin was associated with improved survival (P < 0.001)., Conclusions: The AJCC 7th edition did not accurately predict survival in patients with ICC. A multivariable model including tumour size and differentiation in addition to the criteria used in the AJCC 7th edition may offer a more accurate method of predicting survival in patients with ICC., (© 2014 International Hepato-Pancreato-Biliary Association.)

Background: New-onset diabetes mellitus after a pancreaticoduodenectomy (PD) remains poorly defined. The aim of this study was to define the incidence and predictive factors of immediate post-resection diabetes mellitus (iPRDM)., Methods: Retrospective review of patients undergoing PD from January 2004 through to July 2010. Immediate post-resection diabetes mellitus was defined as diabetes requiring pharmacological treatment within 30 days post-operatively. Logistic regression was conducted to identify factors predictive of iPRDM., Results: Of 778 patients undergoing PD, 214 were excluded owing to pre-operative diabetes (n= 192), declined research authorization (n= 14) or death prior to hospital discharge (n= 8); the remaining 564 patients comprised the study population. iPRDM occurred in 22 patients (4%) who were more likely to be male, have pre-operative glucose intolerance, or an increased creatinine, body mass index (BMI), pre-operative glucose, operative time, tumour size or specimen length compared with patients without iPRDM (P < 0.05). On multivariate analysis, pre-operative impaired glucose intolerance (P < 0.001), pre-operative glucose ≥ 126 (P < 0.001) and specimen length (P= 0.002) were independent predictors of iPRDM. A predictive model using these three factors demonstrated a c-index of 0.842., Discussion: New-onset, post-resection diabetes occurs in 4% of patients undergoing PD. Factors predictive of iPRDM include pre-operative glucose intolerance, elevated pre-operative glucose and increased specimen length. These data are important for patient education and predicting outcomes after PD., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Primary gastrointestinal stromal tumours (GISTs) of the duodenum are rare. The aim of this study was to review the surgical management of GISTs in this anatomically complex region., Methods: Retrospective review from January 1999 to August 2011 of patients with primary GISTs of the duodenum., Results: Forty-one patients underwent resection of duodenal GISTs. All operations were performed with intent to cure with negative margins of resection. The most common location of origin was the second portion of the duodenum. Local excision (n= 19), segmental resection with primary anastomosis (n= 11) and a pancreatoduodenectomy (n= 11) were performed. Two patients underwent an ampullectomy with local excision. Peri-operative mortality and overall morbidity were 0 and 12, respectively. Patients with high-risk GISTs (P= 0.008) and those who underwent a pancreatoduodenectomy (P= 0.021) were at a greater risk for morbidity. The median follow-up was 18 months. Eight patients developed recurrence. High-risk GISTs and neoplasms with ulceration had the greatest risk for recurrence (P= 0.017, P= 0.029 respectively). The actuarial 3- and 5-year survivals were 85% and 74%, respectively., Conclusion: The choice and type of resection depends on the proximity to the ampulla of Vater, involvement of adjacent organs and the ability to obtain negative margins. The morbidity depends on the type of procedure for GIST., (© 2012 International Hepato-Pancreato-Biliary Association.)

Background & Aims: The incidence of intraductal papillary mucinous neoplasm (IPMN) is believed to be increasing; we investigated whether this is the result of increasing burden of disease or more diagnostic scrutiny., Methods: In a retrospective cohort study, we calculated a trend in reported incidence of IPMN using data collected from Olmsted County, Minnesota, from 1985 to 2005. Total IPMN cases from the Olmsted database were identified through a keyword and International Classification of Diseases, 9th revision, search using a database from the Rochester Epidemiology Project, with all cases verified by subsequent chart review. The subsequent rate of IPMN-related carcinoma was calculated using data from the national Surveillance Epidemiology and End Results-9 database, reflecting trends from 1982 to 2007. Cases of IPMN-related carcinoma were identified in the Surveillance Epidemiology and End Results-9 database by limiting the search to histology codes for noninvasive and invasive IPMN., Results: Between 1985 and 2005, there was a 14-fold increase in the age- and sex-adjusted incidence of IPMN, from 0.31 to 4.35 per 100,000 persons. From 2000 to 2001, the rate of reported carcinoma increased from 0.008 to 0.032 per 100,000 persons, but stabilized afterward, with a rate of 0.06 per 100,000 persons in 2007. Mortality from all causes of pancreatic cancer was stable between 1975 and 2007 (approximately 11 deaths per 100,000 individuals)., Conclusions: The incidence of IPMN has increased in the absence of an increase in IPMN-related or overall pancreatic cancer-related mortality, so it likely results from an increase in diagnostic scrutiny, rather than greater numbers of patients with clinically relevant disease., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.

Objectives: Although lymphatic spread is common in intrahepatic cholangiocarcinoma (ICC), lymphadenectomy is not widely performed as part of operative resection in this disease. The objectives of this study were to assess national trends for lymphadenectomy and its impact on survival in patients with ICC., Methods: The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) registry was queried to identify patients with ICC (n=4893) reported during 1988-2007. Kaplan-Maier and Cox proportional hazards regression were used to analyse survival., Results: Five-year overall survival (OS) was 5.2%. Lymph node (LN) status was available for 48.9% (n=2391) of patients. Histologic LN evaluation was performed in 13.5% (n=658) of patients for a median of two (interquartile range: 1-3) LNs. During the study period, the frequency of histologic LN assessment (P=0.78) did not change in liver resection patients. In the 733 resected patients, positive vs. negative LN status was associated with worse 5-year OS of 8.4% vs. 25.9%, respectively (hazard ratio=1.8; P<0.001)., Conclusions: Nodal status is an important prognostic factor for survival in patients diagnosed with ICC. In the USA, few patients undergo hepatic resection with lymphadenectomy; therefore, the clinical benefit of formal lymphadenectomy in ICC remains unknown., (© 2011 International Hepato-Pancreato-Biliary Association.)

Background: Recent reports support an association between chronic inflammation and progression to pancreatic cancer (PC)., Methods: This case-control, candidate gene association study evaluated 1,354 Caucasian patients with pancreatic ductal adenocarcinoma and 1,189 healthy Caucasian controls. We genotyped 1,538 single nucleotide polymorphism (SNP) in 102 genes from inflammatory pathways involving NF-κB. Primary tests of association assumed a multiplicative (log-additive) genotype effect; secondary analyses examined dominant, additive, and recessive SNP effects., Results: After adjusting for known risk factors for PC, single SNP analysis revealed an association between four SNPs in NOS1 and one in the CD101 gene with PC risk. These results, however, were not replicated in a PC case-control and cohort population., Conclusion: NOS1 and CD101 may be associated with a risk of PC; however, these findings did not replicate in other PC populations. Future research is needed into the possible role of NOS1 and CD101 for PC., Impact: This research shows a lack of association between genetic variation in 102 inflammation-related genes and PC. Future research is needed into the possible role of other inflammation-related genes and PC risk., (©2011 AACR.)

Intraductal papillary mucinous neoplasm (IPMN) was first recognized in the 1980s with increasing publications over the last decade as the incidence increased sharply, especially at tertiary-care referral centers. Population-based studies have estimated the age and sex-adjusted cumulative incidence of IPMN to be 2.04 per 100 000 person-years (95% confidence interval: 1.28-2.80). It is now understood that IPMN can be classified anywhere along the spectrum of the adenoma to carcinoma sequence and often harbors mutations in genes such as KRAS early in the disease process. Many patients are diagnosed incidentally after imaging of the abdomen for other diagnostic purposes. Patients that present with a history of symptoms such as pancreatitis and abdominal pain are at high risk of harboring a malignancy. Clinicopathologic features such as involvement of the main pancreatic duct, presence of mural nodules, and side branch disease > 3.0 cm in size may indicate that there is an underlying invasive component to the IPMN. In addition, the incidence of extra-pancreatic neoplasms is higher in patients with IPMN, with reported rates of 25% to 50%. There are no current screening recommendations to detect and diagnose IPMN but once the diagnosis is made, screening for extrapancreatic neoplasms such as colon polyps and colorectal cancer should be considered. Surgical resection is the recommend treatment for patients with high-risk features while close observation can be offered to patients without worrisome signs and symptoms of carcinoma.

Background: Hepatic epithelioid haemangioendothelioma (HEH) is a rare vascular neoplasm with unpredictable clinical behaviour., Aim: To compare overall survival (OS) and disease-free survival (DFS) between liver resection (LR) and orthotopic liver transplantation (OLT) for the treatment of HEH., Methods: Retrospective review of 30 patients with HEH treated at Mayo Clinic during 1984 and 2007., Results: Median age was 46 years with a female predominance of 2:1. Treatment included LR (n= 11), OLT (n= 11), chemotherapy (n= 5) and no treatment (n= 3). LR was associated with a 1-, 3- and 5-year OS of 100%, 86% and 86% and a DFS of 78%, 62% and 62%, respectively. OLT was associated with a 1-, 3- and 5-year OS of 91%, 73% and 73% and a DFS 64%, 46% and 46%, respectively. Metastases were present in 37% of patients but did not significantly affect OS. Important predictors of a favourable OS and DFS were largest tumour ≤ 10 cm and multifocal disease with ≤ 10 nodules., Conclusion: LR and OLT achieve comparable results in the treatment of HEH. LR is appropriate for patients with resectable disease and favourable prognostic factors. OLT is appropriate for patients with unresectable disease and possibly those with unfavourable prognostic factors. Metastases may not be a contraindication to surgical treatment., (© 2010 International Hepato-Pancreato-Biliary Association.)

Background: Despite increasing numbers of reports, biliary tract intraductal papillary mucinous neoplasm (BT-IPMN) is not yet recognized as a unique neoplasm. The aim of the present study was to define the presence of BT-IPMN in a large series of resected biliary neoplasms., Methods: From May 1994 to December 2006, BT-IPMN cases were identified by reviewing pathology specimens of all resected cholangiocarcinomas and other biliary neoplasms when cystic, papillary or mucinous features were cited in pathology reports., Results: BT-IPMN was identified in 23 out of 253 (9%) specimens using the strict histopathological criteria of IPMN. The most common presenting symptom was abdominal discomfort which was present in 15 patients (65%). Only one of the original operative pathology reports used the term IPMN; 16 (70%) used the terms cystic, mucinous and/or papillary. BT-IPMN was isolated to non-hilar extra-hepatic ducts in 12 (52%), intra-hepatic ducts in 6 (26%) and hilar extra-hepatic ducts in 5 patients (22%). Carcinoma was found in association with BT-IPMN in 19 patients (83%); 5-year survival was 38% after resection., Conclusion: BT-IPMN occurs throughout the intra- and extra-hepatic biliary system and can be identified readily as a unique neoplasm. Broader acceptance of BT-IPMN as a unique neoplasm may lead to a better understanding of the pathogenesis of biliary malignancies.