Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis.

Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.

[Neoadjuvant and adjuvant treatment of pancreatic cancer]. / Neoadjuvante und adjuvante Therapie beim Pankreaskarzinom.

BACKGROUND: Resection is the only curative treatment option for pancreatic cancer patients. Adjuvant chemotherapy can improve disease-free survival and overall survival after resection. Furthermore, neoadjuvant treatment protocols are currently being investigated in a large number of studies. OBJECTIVE: Summary of the current evidence for adjuvant and neoadjuvant treatment. MATERIAL AND METHODS: Review of the current scientific literature and guidelines. RESULTS AND CONCLUSION: After resection for pancreatic cancer patients should receive intensive chemotherapy with mFOLFIRINOX, gemcitabine plus capecitabine or gemcitabine/5-fluorouracil (5-FU) monotherapy. Neoadjuvant treatment concepts are promising but have to be further evaluated in prospective studies.

Prognostic Nomogram for Resected Pancreatic Adenocarcinoma: A TRIPOD-Compliant Retrospective Long-Term Survival Analysis.

BACKGROUND: Prognostic prediction had been widely used in various cancer entities, from early screening to end-stage patient caring. Currently, there is hardly any well-validated nomogram which exists for long-term survival prediction in pancreatic adenocarcinoma (PC) patients in a post-surgery setting. Our objectives are to identify possible prognostic factors in PC patients following radical resection and to develop a prognostic nomogram based on independent survival predictors. METHODS: From 2009 to 2014, a total of 432 PC patients who underwent curative intended surgeries with complete follow-up data were included in this current retrospective long-term survival analysis. Clinicopathological data were extracted from medical records, and all missing values (percentage 0.9-8.3%) were imputed five times with the "PMM" method. Cox proportional hazards models were utilized. A nomogram was formulated based on results from the multivariate regression model so as to predict OS at 1-, 2- and 3-year as well as median OS. Validations, including discrimination and calibration, were carried out with 1000 bootstrap resamples. External validation was conducted in order to verify the accuracy of our nomogram at 1 and 2 years by utilizing the clinicopathological data of 122 PC patients who underwent curative intended surgeries in 2015 in our centre. RESULTS: Age, abdominal pain, back pain, tumour location, preoperative neutrophil-lymphocyte ratio, preoperative CA19-9, tumour differentiation, microscopic nerve invasion, microscopic vascular invasion, T stage, lymph node ratio, M stage and adjuvant chemotherapy were all assembled into nomogram. The concordance index (C-index) of internal and external validation was 0.702 and 0.688, respectively. The C-index of the TNM staging system was 0.572 (P < 0.001 vs. nomogram). CONCLUSION: Our prognostic nomogram based on clinicopathological parameters shows good performance in long-term survival prediction in PC patients following radical surgery and could play a role in further clinical utilization.

The Liverpool duodenum-and spleen-preserving near-total pancreatectomy can provide long-term pain relief in patients with end-stage chronic pancreatitis.

PURPOSE: Total pancreatectomy may improve symptoms in patients with severe end-stage chronic pancreatitis. This might be achieved whilst preserving both the duodenum- and spleen-(DPSPTP). Mature clinical outcomes of this approach are presented. METHODS: Single-centre prospective cohort study performed between September 1996 and May 2016. Demographic, clinical details, pain scores and employment status were prospectively recorded during clinic attendance. RESULTS: Fifty-one patients (33 men, 18 women) with a median (interquartile range) age of 40.8 (35.3-49.4) years, a median weight of 69.8 (61.0-81.5) Kg and a median body mass index of 23.8 (21.5-27.8), underwent intended duodenum-and spleen-preserving near-total pancreatectomy for end-stage chronic pancreatitis. Aetiology was excess alcohol in 25, idiopathic (no mutation) in 15, idiopathic (SPINK-1/CFTR mutations) in two, hereditary (PRSS1 mutation) in seven and one each post-necrotising pancreatitis and obstructive pancreatic duct divisum in 1. The main indication for surgery was severe pain. Findings included parenchymal calcification in 79% and ductal calculi in 24%, a dilated main pancreatic duct in 57% and a dilated main bile duct in 17%, major vascular involvement in 27% and pancreato-peritoneal fistula in 2%. Postoperative complications occurred in 20 patients with two deaths. Median pain scores were 8 (7-8) preoperatively and 3 (0.25-5.75) at 5 years (p = 0.013). Opiate analgesic use was significantly reduced postoperatively (p = 0.048). Following surgery, 22 (63%) of 38 patients of working age re-entered employment compared with 12 (33%) working preoperatively (p = 0.016). CONCLUSION: Duodenum-and spleen-preserving near-total pancreatectomy provided long-term relief in adult patients with intractable chronic pancreatitis pain, with improved employment prospects.

Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging.

BACKGROUND: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. METHODS: Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. RESULTS: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. CONCLUSION: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy.

BACKGROUND: Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine-based adjuvant chemotherapy. METHODS: A systematic review was performed, searching databases from January 1997 to January 2016. Articles pertaining to hENT1 immunohistochemical analysis in resected PDAC specimens from patients who subsequently underwent adjuvant gemcitabine-based chemotherapy were identified. Eligible studies were required to contain survival data, reporting specifically overall survival (OS) and disease-free survival (DFS) with associated hazard ratios (HRs) stratified by hENT1 status. RESULTS: Of 42 articles reviewed, eight were suitable for review, with seven selected for quantitative meta-analysis. The total number of patients included in the meta-analysis was 770 (405 hENT1-negative, 365 hENT1-positive). Immunohistochemically detected hENT1 expression was significantly associated with both prolonged DFS (HR 0·58, 95 per cent c.i. 0·42 to 0·79) and OS (HR 0·52, 0·38 to 0·72) in patients receiving adjuvant gemcitabine but not those having fluoropyrimidine-based adjuvant therapy. CONCLUSION: Expression of hENT1 is a suitable prognostic biomarker in patients undergoing adjuvant gemcitabine-based chemotherapy.

Evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer.

Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case­control sets: 1) samples from patients diagnosed with pancreatic cancer (n = 40), chronic pancreatitis (n = 20), benign jaundice due to gall stones (n = 20) and healthy subjects (n = 20); 2) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0­12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0­12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers. BIOLOGICAL SIGNIFICANCE: Pancreatic cancer is usually diagnosed when at an advanced stage which greatly limits therapeutic options. Biomarkers that could facilitate earlier diagnosis are urgently sought.

iTRAQ reveals candidate pancreatic cancer serum biomarkers: influence of obstructive jaundice on their performance.

BACKGROUND: The aims of our study were to identify serum biomarkers that distinguish pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) patients from benign pancreatic disease patients and healthy subjects, and to assess the effects of jaundice on biomarker performance. METHODS: Isobaric tags for relative and absolute quantification were used to compare pooled serum and pancreatic juice samples from a test set of 59 and 25 subjects, respectively. Validation was undertaken in 113 independent subjects. RESULTS: Candidate proteins Complement C5, inter-α-trypsin inhibitor heavy chain H3, α1-ß glycoprotein and polymeric immunoglobulin receptor were elevated in cancer, as were the reference markers CA19-9 and Reg3A. Biliary obstruction had a significant effect on the performance of the markers, in particular within the PDAC group where the presence of jaundice was associated with a significant increase in the levels of all six proteins (P<0.01). Consequently, in the absence of jaundice, proteins showed reduced sensitivity for PDAC patients over benign subjects and healthy controls (HCs). Similarly, in the presence of jaundice, markers showed reduced specificity for PDAC patients over benign subjects with jaundice. Combining markers enabled improved sensitivity for non-jaundiced PDAC patients over HCs and improved specificity for jaundiced PDAC patients over jaundiced benign disease subjects. CONCLUSIONS: The presence-absence of jaundice in the clinical scenario severely impacts the performance of biomarkers for PDAC diagnosis and has implications for their clinical translation.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel.

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer.

BACKGROUND: The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining. RESULTS: Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups. CONCLUSION: These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.

Current status of GV1001 and other telomerase vaccination strategies in the treatment of cancer.

GV1001 is a telomerase-specific, promiscuous class II peptide vaccine which is currently in an advanced stage of clinical development. This article reviews the biological rationale underpinning the design of ongoing studies with the vaccine as well as its immunogenicity and clinical activity. It places GV1001 in the context of other immunotherapeutic approaches targeting telomerase and assesses the chances of the vaccine becoming a future standard of care in the treatment of cancer.

PALB2 mutations in European familial pancreatic cancer families.

Recently, PALB2 was reported to be a new pancreatic cancer susceptibility gene as determined by exomic sequencing, as truncating PALB2 mutations were identified in 3 of 96 American patients with familial pancreatic cancer (FPC). Representing the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) and the German National Case Collection for Familial Pancreatic Cancer (FaPaCa), we evaluated whether truncating mutations could also be detected in European FPC families. We have directly sequenced the 13 exons of the PALB2 gene in affected index patients of 81 FPC families. An index patient was defined as the first medically identified patient, stimulating investigation of other members of the family to discover a possible genetic factor. None of these patients carried a BRCA2 mutation. We identified three (3.7%) truncating PALB2 mutations, each producing different stop codons: R414X, 508-9delAG and 3116delA. Interestingly, each of these three families also had a history of breast cancer. Therefore, PALB2 mutations might be causative for FPC in a small subset of European families, especially in those with an additional occurrence of breast cancer.

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer.

BACKGROUND: Enzyme-linked immunoassays of full-length (M65) and/or caspase-cleaved (M30) cytokeratin 18 (CK18) released from epithelial cells undergoing necrosis and/or apoptosis, respectively, may have prognostic or predictive biomarker utility in a range of solid tumour types. Characterisation of baseline levels of circulating full length and cleaved CK18 specifically in patients with pancreatic cancer. METHODS: Plasma samples from 103 patients with pancreatic cancer stored at -80 degrees C were assayed for M65 and M30 levels. The median (inter-quartile range (IQR)) duration of plasma storage was 34 (23-57) months. Patients with metastatic disease (n=19) were found to have greater median (IQR) M65 levels (1145 (739-1698) U l(-1)) compared with the locally advanced (n=20; 748 (406-1150) U l(-1)) and resected (n=64; 612 (331-987) U l(-1)) patients (P=0.002). Elevated M65 levels were associated with poorer overall survival on univariate (P<0.001) but not multivariate (P=0.202) analysis. M65 concentrations also exhibited significant associations with concurrent serum-bilirubin levels (P<0.001) and the duration of plasma storage (P<0.001). CONCLUSIONS: Baseline plasma CK18 levels in pancreatic cancer are affected by the presence of obstructive jaundice and prolonged plasma storage. Clinical biomarker studies utilising serial CK18 levels are warranted in pancreatic cancer, provided consideration is given to these potentially confounding factors.

S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility.

BACKGROUND: High levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood. METHODS: Immunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays. RESULTS: Our proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin beta and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens (n=55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells (P=0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells. CONCLUSION: These findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.

Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

An open randomized comparison of clinical effectiveness of protocol-driven opioid analgesia, celiac plexus block or thoracoscopic splanchnicectomy for pain management in patients with pancreatic and other abdominal malignancies.

UNLABELLED: In inoperable malignancy, pain relief with opioids is often inadequate. Nerve block procedures may improve symptom control. Our aim was to assess celiac plexus block (CPB) and thoracoscopic splanchnicectomy (TS) in patients receiving appropriate medical management (MM). METHODS: Patients with confirmed irresectable malignancy of the pancreas or upper abdominal viscera who required opioid analgesia were randomized to MM alone, MM+CPB, or MM+TS. Randomization was stratified by treatment centre, tumour type and previous opioid medication. The primary endpoint was pain relief at 2 months. RESULTS: 65 patients (58 pancreas cancer) were randomized, 18 withdrew or died within 2 months. Effective pain relief was achieved in only one third of subjects at 2 weeks, and just under half at 2 months (MM: 6/19 and 5/12 evaluable patients; CPB: 5/14 and 5/9; TS 4/14 and 4/11). There were no significant differences between the groups in pain scores or opioid consumption, and there was no correlation between continued use of opioids and effective pain relief. DISCUSSION: Previous randomized studies have shown small differences in pain scores, but no difference in opioid consumption and quality of life. The absence of any benefit from interventions in the present study questions their value.