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Background: Neoadjuvant treatment for pancreatic ductal adenocarcinoma (PDAC) has increased, necessitating histopathologic confirmation of cancer. This study evaluates the performance of endoscopic tissue acquisition (TA) procedures for borderline resectable and resectable PDAC. Methods: Pathology reports of patients included in two nationwide randomized controlled trials (PREOPANC and PREOPANC-2) were reviewed. The primary outcome was sensitivity for malignancy (SFM), considering both “suspicious for” and “malignant” as positive. Secondary outcomes were rate of adequate sampling (RAS) and diagnoses other than PDAC. Results: Overall, 892 endoscopic procedures were performed in 617 patients, including endoscopic ultrasonography (EUS)-guided TA in 550 (89.1%), endoscopic retrograde cholangiopancreatography (ERCP)-guided brush cytology in 188 (30.5%), and periampullary biopsies in 61 patients (9.9%). The SFM was 85.2% for EUS, 88.2% for repeat EUS, 52.7% for ERCP, and 37.7% for periampullary biopsies. The RAS ranged 94–100%. Diagnoses other than PDAC were other periampullary cancers in 24 (5.4%), premalignant disease in five (1.1%), and pancreatitis in three patients (0.7%). Conclusions: EUS-guided TA of patients with borderline resectable and resectable PDAC included in RCTs had an SFM above 85% for both first and repeat procedures, meeting international standards. Two percent had false positive result for malignancy and 5% had other (non-PDAC) periampullary cancers.

Background The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed. Methods The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration. Results Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points. Conclusion The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis.METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133.FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group.INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis.FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Background: Early recognition of postoperative pancreatic fistula might decrease the risk of subsequent life threatening complications. The aim of this review was to systematically evaluate the accuracy of postoperative clinical, biochemical and radiologic variables for early recognition of clinically relevant postoperative pancreatic fistula. Methods: A systematic literature search was performed up to August 2018. Clinical studies reporting on the association between postoperative variables and clinically relevant postoperative pancreatic fistula were included. Variables were stratified: early prediction (postoperative day 1–2) versus early diagnosis (day 3) and had to be reported in 2 cohorts. Results: Overall, 37 included studies reported on 17 different diagnostic variables after 8701 pancreatic resections. Clinically relevant postoperative pancreatic fistula occurred in 1532/8701 patients (18%). Early prediction variables included elevated serum and drain amylase (day 1). Identified variables for early diagnosis were: non-serous drain efflux (day 3); positive drain culture (day 3); elevated temperature (any day); elevated C-Reactive Protein (CRP; day 4); elevated white blood cell count (day 4) and peripancreatic collections on computed tomography (CT; day 5–10). Conclusion: This review provides a comprehensive overview of postoperative variables associated with clinically relevant pancreatic fistula. Incorporation of variables in future algorithms could potentially mitigate the clinical impact of postoperative pancreatic fistula.

Introduction: FOLFIRINOX chemotherapy showed promising results in treating patients with pancreatic ductal adenocarcinoma (PDAC). However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single cycle of FOLFIRINOX, in combination with a granulocyte colony-stimulating factor (G-CSF), on the blood immune transcriptome of PDAC patients. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response. Methods Blood samples of 68 patients from all PDAC disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. Patients were divided into “disease control” and “progressive disease” following the RECIST criteria 1.1. RNA was isolated and targeted immune-gene expression profiling was performed using the PanCancer Immune profiling panel of NanoString. The FOLFIRINOX delta Gene Expression Profiling (FFX-ΔGEP) score was calculated using the weight of eight genes following LASSO multivariate regression analysis. Results Comparing the immune gene expression profile of samples at baseline to after a single FOLFIRINOX cycle resulted in the identification of 395 differentially expressed genes (BH.P BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1, and TGFB2), could predict the lack of FOLFIRINOX response with a leave-one-out cross-validated AUC [95% CI] of 0.87 [0.60–0.98]. Our FFX-ΔGEP score outperformed the predictiveness of absolute and proportional ΔCA19-9 values with an AUC [95% CI] of 0.70 [0.27–1.0] and 0.52 [0.24–0.80], respectively. Notably, immune-gene expression profiles of baseline samples could not predict the lack of FOLFIRINOX response. Conclusions A single FOLFIRINOX cycle, combined with G-CSF, alters the peripheral immune transcriptome indisputably. We revealed a novel multigene FFX-ΔGEP score which is, to our knowledge, the first gene expression-based early circulating biomarker that predicts the lack of FOLFIRINOX response after only a single cycle. Validation in a larger independent cohort of samples is crucial before clinical implementation.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor clinical prognosis and is usually a metastatic disease. In the last decades, oncolytic viro-immunotherapy has shown a promise as treatment strategy with encouraging results for a variety of tumors. Newcastle Disease Virus (NDV) is an oncolytic virus which selectively infects and damages tumors either by directly killing tumor cells or by promoting an anti-tumor immune response. Several studies have demonstrated that NDV strains with a multi-basic cleavage site (MBCS) in the fusion protein (F) have increased anti-tumor efficacy upon intratumoral injection in murine tumor models. However, intravenous injections, in which the oncolytic virus spreads systemically, could be more beneficial to treat metastasized PDAC in addition to the primary tumor. In this study, we compared the oncolytic efficacy and safety of intratumoral and intravenous injections with NDV containing an MBCS in F (NDV F3aa) in an immune deficient murine xenograft (BxPC3) model for PDAC. In this model, both intratumoral and intravenous injections with NDV F3aa induced anti-tumor efficacy as measured at 10 days after the first injection. Upon intravenous injection virus was detected in some of the tumors, indicating the systemic spread of the virus. Upon both treatments, mice did not display weight loss or abnormalities and treated mice did not secrete virus to the environment. These data demonstrate that intravenous injections of NDV F3aa can be applicable to treat metastasized cancers in immune deficient hosts without inflicting adverse effects.

Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p

Background: Radiotherapy is an established treatment for malignant localised disease. Pancreatic cancer however seems relatively insensitive to this form of therapy. Methods: Pancreatic cancer cell lines MiaPaca-2 and Panc-1 were pre-treated with 3000 IU/ml IFN alpha or 100 IU/ml IFN beta followed by 0, 2, 4, or 6 Gray (Gy) irradiation. Colony forming assay was used to assess the effects on cellgrowth. To measure the surviving fraction at the clinically relevant dose of 2 Gy (SF2), cells were pre-treated with 1000-10.000 IU/ml IFN alpha or 50-500 IU/ml IFN beta followed by 2 Gy irradiation. Results: The plating efficiency was 49% for MiaPaca-2 and 22% for Panc-1. MiaPaca-2 was more radiosensitive than Panc-1 (surviving fraction of 0.28 versus 0.50 at 4 Gray). The SF2 of MiaPaca-2 was 0.77 while the SF2 of Panc-1 was 0.70. The SF2 significantly decreased after pretreatment with IFN alpha 1000 IU/ml (p < 0.001) and IFN beta 100 IU/ml (p < 0.001) in MiaPaca-2 and with IFN alpha 5000 IU/ml (p < 0.001) and IFN beta 100 IU/ml (p < 0.01) in Panc-1. The sensitising enhancement ratio (SER) for IFN alpha 3000 IU/ml was 2.15 in MiaPaca-2 and 1.90 in Panc-1. For IFN beta 100 IU/ml the SER was 1.72 for in MiaPaca-2 and 1.51 in Panc-1. Conclusions: Type I interferons have radiosensitising effects in pancreatic cancer cell lines. This radiosensitising property might lead to an improved response to treatment in pancreatic cancer. Interferon beta is the most promising drug due to its effect in clinically obtainable doses. (C) 2011 Elsevier Ltd. All rights reserved.

The high mortality rate and minimal progress made in the treatment of pancreatic cancer over the last few decades, warrant an alternative approach. Treatment protocols should be individualised to the patient guided by prognostic markers. A particularly interesting target would be the architectural transcription factor high mobility group A1 (HMGA1), that is low or undetectable in normal tissue, induced during neoplastic transformation and consequently often exceptionally high in cancer. The aim of the current study was therefore to determine the differential expression of HMGA1 in pancreatic head and periampullary cancer and investigate its relation with outcome. HMGA1 expression was determined by immunohistochemistry on original paraffin embedded tissue from 99 pancreatic head- and 112 periampullary cancers (with R0). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS) and conventional prognostic factors. HMGA1 was expressed in 47% and 26% of pancreatic head- and periampullary cancer, respectively and associated with poor RFS, CSS and OS in periampullary cancer. CSS 5 years following surgery was 25% and 44% for patients with tumours which were positive or negative for HMGA1 protein, respectively. HMGA1 expression was not associated with survival in pancreatic head cancer. In conclusion HMGA1 was identified as an independent prognostic marker predicting poor outcome in periampullary cancer. Although expressed to a higher extent as compared to periampullary cancer, HMGA1 was not associated with survival in pancreatic head cancer. (c) 2010 Elsevier Ltd. All rights reserved.

Item does not contain fulltext BACKGROUND & AIMS: The prevalence of pancreatic cysts is not known, but asymptomatic pancreatic cysts are diagnosed with increasing frequency. We investigated the prevalence of pancreatic cysts in individuals who were screened by magnetic resonance imaging (MRI) as part of a preventive medical examination. METHODS: Data from consecutive persons who underwent abdominal MRI (n = 2803; 1821 men; mean age, 51.1 +/- 10.8 y) at an institute of preventive medical care were included from a prospective database. All individuals had completed an application form including questions about possible abdominal complaints and prior surgery. MRI reports were reviewed for the presence of pancreatic cysts. Original image sets of all positive MRI reports and a representative sample of the negative series were re-assessed by a blinded, independent radiologist. RESULTS: Pancreatic cysts were reported in 66 persons (2.4%; 95% confidence interval, 1.9-3.0); prevalence correlated with increasing age (P < .001). There was no difference in prevalence between sexes (P = .769). There was no correlation between abdominal complaints and the presence of pancreatic cysts (P = .542). Four cysts (6%) were larger than 2 cm and 3 (5%) were larger than 3 cm. Review of the original image sets by the independent radiologist did not significantly change these findings. CONCLUSIONS: The prevalence of pancreatic cysts in a large consecutive series of individuals who underwent an MRI at a preventive medical examination was 2.4%. Prevalence increased with age, but did not differ between sexes. Only a minority of cysts were larger than 2 cm. 01 september 2010

In the 1980s, the In-111-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst(2)) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PART) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr(3)-octreotate (DOTATATE) and DOTA, Tyr(3)-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst(2), have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PART. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PART with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PART could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PART. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PART and describes clinical and preclinical studies regarding PRRT optimizing strategies. Semin Nucl Med 40:209-218 (C) 2010 Elsevier Inc. All rights reserved.

Summary Background & aims Pneumatosis intestinalis (PI), characterised by the presence of intramural air in the bowel wall, is seen in various diseases, in some cases leading to explorative laparotomy and resection of the involved bowel. Here, we describe three cases of PI after pancreaticoduodenectomy (PD) associated with post-operative feeding through a needle catheter jejunostomy (NCJ). Method Retrospective analysis of three cases of PI after PD with clinical and radiological findings. Results All patients underwent a PD for periampullary cancer and an NCJ was performed for post-operative feeding. PI was observed 8–32 days after surgery. None of the patients had an acute abdomen or hemodynamical instability necessitating acute surgery. After excluding associated causes of PI, immediate discontinuation of enteral feeding and initiation of parenteral nutrition resulted in a rapid recovery. None of the patients required surgery. Conclusion In patients with an NCJ for post-operative nutritional support who develop PI, we advise to take these measures as a first step, while excluding associated complications and other causes for PI.

Pancreatic cancer is a devastating disease. Radical surgical resection offers the only chance for cure. In search of improved survival, more extended resections have been advocated. On the other hand, pylorus-preserving pancreaticoduodenectomy (PPPD) has emerged as an organ-preserving alternative to a standard Whipple resection (SW). However, its oncologic safety has been under debate. Furthermore, reports of increased rates of delayed gastric emptying have been made. We performed a Medline-PubMed search for relevant articles. In addition to nonrandomized reports, we found 3 randomized controlled trials (RCTs) comparing SW or PPPD with SW with extended lymphadenectomy and 4 RCTs comparing SW with PPPD. For resection of pancreatic cancer, SW and PPPD are probably equally effective. Extended resections are not warranted on the basis of the current evidence and should only be offered in an experimental setting.

G A A b st ra ct s on rifaximin. The cumulative incidence for EVB over five years was 10.9%, (4% on rifaximin compared to 16% not on rifaximin; P=0.004). Patients taking rifaximin had a lower hazard of first EVB then those not taking the medication (Figure 1). In multivariable analysis patients taking rifaximin had an 81% lower risk of bleeding within five years (HR 0.19 (0.06-0.57); P=0.003). There was no difference in survival between patients taking rifaximin and those not on the medication (P=0.18). Conclusion: The use of rifaximin in addition to standard medical therapy for the primary prophylaxis of EVB was associated with significantly reduced time to first EVB. This study potentially describes another use for rifaximin in decompensated cirrhosis, however, further prospective randomized control trial are necessary to validate the results.