UK and Ireland Joint Advisory Group (JAG) consensus statements for training and certification in diagnostic endoscopic ultrasound (EUS).

BACKGROUND AND AIMS: International endoscopy societies vary in their approach for credentialing individuals in endoscopic ultrasound (EUS) to enable independent practice; however, there is no consensus in this or its implementation. In 2019, the Joint Advisory Group on GI Endoscopy (JAG) commissioned a working group to examine the evidence relating to this process for EUS. The aim of this was to develop evidence-based recommendations for EUS training and certification in the UK. METHODS: Under the oversight of the JAG quality assurance team, a modified Delphi process was conducted which included major stakeholders from the UK and Ireland. A formal literature review was made, initial questions for study were proposed and recommendations for training and certification in EUS were formulated after a rigorous assessment using the Grading of Recommendation Assessment, Development and Evaluation tool and subjected to electronic voting to identify accepted statements. These were peer reviewed by JAG and relevant stakeholder societies before consensus on the final EUS certification pathway was achieved. RESULTS: 39 initial questions were proposed of which 33 were deemed worthy of assessment and finally formed the key recommendations. The statements covered four key domains, such as: definition of competence (13 statements), acquisition of competence (10), assessment of competence (5) and postcertification mentorship (5). Key recommendations include: (1) minimum of 250 hands-on cases before an assessment for competency can be made, (2) attendance at the JAG basic EUS course, (3) completing a minimum of one formative direct observation of procedural skills (DOPS) every 10 cases to allow the learning curve in EUS training to be adequately studied, (4) competent performance in summative DOPS assessments and (5) a period of mentorship over a 12-month period is recommended as minimum to support and mentor new service providers. CONCLUSIONS: An evidence-based certification pathway has been commissioned by JAG to support and quality assure EUS training. This will form the basis to improve quality of training and safety standards in EUS in the UK and Ireland.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients.

OBJECTIVE: Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking. DESIGN: We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%). RESULTS: Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005). CONCLUSION: In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.

Targeting mTOR dependency in pancreatic cancer.

OBJECTIVE: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. DESIGN: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. RESULTS: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. CONCLUSIONS: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel.

BACKGROUND: Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens. METHODS: Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0-300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve. RESULTS: The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off. CONCLUSION: A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.

'Step-port' laparoscopic cystgastrostomy for the management of organized solid predominant post-acute fluid collections after severe acute pancreatitis.

BACKGROUND: Post-acute pancreatic collections (PAPCs) may require intervention when persistent, large or symptomatic. An open cystgastrostomy is an effective treatment option particularly for larger, solid predominant collections. A laparoscopic cystgastrostomy (LCG) as initially described, could be technically challenging. This report describes the evolution of the operative technique and the results from LCG in a tertiary referral centre. METHODS: Retrospective analysis of the unit's prospectively populated database was conducted. All patients who underwent a surgical cystgastrostomy (SCG) were identified. Patient demographics, outcome and complications were collected and analysed. RESULTS: Forty-four patients underwent SCG: 8 open and 36 laparoscopic. Of the 36 LCG, 6 required open conversion, although with evolution of the technique all of the last 17 cases were completed laparoscopically. The median interquartile range (IQR) length of stay in patients completed laparoscopically was 6 (2-10) compared with 15.5 days (8-19) in those patients who were converted (P = 0.0351). The only peri-operative complication after a LCG was a self-limiting upper gastrointestinal bleed. With a median (IQR) follow-up of 891 days (527-1495) one patient required re-intervention for a residual collection with no recurrent collections identified. CONCLUSION: LCG is a safe and effective procedure in patients with large, solid predominant PAPCs. With increased experience and technical expertise conversion rates can be lowered and outcome optimized.

Serum amylase on the night of surgery predicts clinically significant pancreatic fistula after pancreaticoduodenectomy.

OBJECTIVES: Drainage after pancreaticoduodenectomy (PD) remains controversial because the risk for uncontrolled postoperative pancreatic fistula (POPF) must be balanced against the potential morbidity associated with prolonged and possibly unnecessary drainage. This study investigated the utility of the level of serum amylase on the night of surgery [postoperative day (PoD) 0 serum amylase] to predict POPF. METHODS: A total of 185 patients who underwent PD were studied. Occurrences of POPF were graded using the International Study Group on Pancreatic Fistula (ISGPF) classification. Receiver operating characteristic (ROC) analysis identified a threshold value of PoD 0 serum amylase associated with clinically significant POPF (ISGPF Grades B and C) in a test cohort (n = 45). The accuracy of this threshold value was then tested in a validation cohort (n = 140). RESULTS: Overall, 43 (23.2%) patients developed clinically significant POPF. The threshold value of PoD 0 serum amylase for the identification of clinically significant POPF was ≥ 130 IU/l (P = 0.003). Serum amylase of <130 IU/l had a negative predictive value of 88.8% for clinically significant POPF (P < 0.001). Serum amylase of ≥ 130 IU/l on PoD 0 and a soft pancreatic parenchyma were independent risk factors for clinically significant POPF. CONCLUSIONS: Postoperative day 0 serum amylase of <130 IU/l allows for the early and accurate categorization of patients at least risk for clinically significant POPF and may identify patients suitable for early drain removal.

Pre-operative cardiopulmonary exercise testing predicts adverse post-operative events and non-progression to adjuvant therapy after major pancreatic surgery.

BACKGROUND: Surgery followed by chemotherapy is the primary modality of cure for patients with resectable pancreatic cancer but is associated with significant morbidity. The aim of the present study was to evaluate the role of cardiopulmonary exercise testing (CPET) in predicting post-operative adverse events and fitness for chemotherapy after major pancreatic surgery. METHODS: Patients who underwent a pancreaticoduodenectomy or total pancreatectomy for pancreatic head lesions and had undergone pre-operative CPET were included in this retrospective study. Data on patient demographics, comorbidity and results of pre-operative evaluation were collected. Post-operative adverse events, hospital stay and receipt of adjuvant therapy were outcome measures. RESULTS: One hundred patients were included. Patients with an anaerobic threshold less than 10 ml/kg/min had a significantly greater incidence of a post-operative pancreatic fistula [International Study Group for Pancreatic Surgery (ISGPS) Grades A-C, 35.4% versus 16%, P = 0.028] and major intra-abdominal abscesses [Clavien-Dindo (CD) Grades III-V, 22.4% versus 7.8%, P = 0.042] and were less likely to receive adjuvant therapy [hazard ratio (HR) 6.30, 95% confidence interval (CI) 1.25-31.75, P = 0.026]. A low anaerobic threshold was also associated with a prolonged hospital stay (median 20 versus 14 days, P = 0.005) but not with other adverse events. DISCUSSION: CPET predicts a post-operative pancreatic fistula, major intra-abdominal abscesses as well as length of hospital stay after major pancreatic surgery. Patients with a low anaerobic threshold are less likely to receive adjuvant therapy.

The relationship between tumor inflammatory cell infiltrate and outcome in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The tumor-associated inflammatory cell infiltrate is recognized to have prognostic value in various common solid tumors. However, the prognostic value of the tumor inflammatory cell infiltrate has not been established in pancreatic ductal adenocarcinoma (PDAC) nor has its relationship with the systemic inflammatory response. METHODS: Retrospective study was made of 173 patients who underwent surgery between 1997 and 2009. Routine pathology specimens were scored according to density of the tumor inflammatory cell infiltrate, and biochemical data were collected preoperatively. RESULTS: Low-grade tumor inflammatory cell infiltrate was associated with earlier tumor recurrence (P < 0.001) and particularly in the liver (P = 0.027). It was also associated with T3 tumors (P < 0.05), lymph node involvement (P < 0.05), and resection margin involvement (P < 0.05). On univariate survival analysis, age <65 years (P < 0.05), mGPS (P < 0.001), increased tumor stage (P < 0.01), nodal involvement (P < 0.01), size (P < 0.05), grade (P < 0.05), perineural invasion (P < 0.05), venous invasion (P < 0.01), resection margin involvement (P ≤ 0.001), vascular reconstruction (P < 0.05), and no adjuvant chemotherapy (P < 0.05) were associated with poor survival. In contrast, high-grade tumor inflammatory cell infiltrate was associated with better survival (P < 0.001). On multivariate survival analysis, mGPS [hazard ratio (HR): 1.77, 95% confidence interval (95% CI): 1.19-2.62, P = 0.005], tumor stage (HR: 2.21, 95% CI: 1.16-4.23, P = 0.016), resection margin involvement (HR: 2.19, 95% CI: 1.41-3.44, P = 0.001), venous invasion (HR: 1.79, 95% CI: 1.22-2.63, P = 0.003), tumor inflammatory cell infiltrate (HR: 0.37, 95% CI: 0.25-0.55, P = 0.0001), and adjuvant chemotherapy (P = 0.04) were independently prognostic. CONCLUSIONS: The results of the study show, for the first time, that the presence of a high-grade tumor inflammatory cell infiltrate is an independent predictor of prolonged overall survival following resection for PDAC. Furthermore, measures of the local and the systemic inflammatory response were inversely associated.

Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients.

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.

LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest.

BACKGROUND & AIMS: Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease. METHODS: We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer. RESULTS: We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic KrasG12D to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with KrasG12D to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53. CONCLUSIONS: We have identified a novel LKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo.

A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma.

BACKGROUND: Outcome prediction after resection with curative intent for pancreatic ductal adenocarcinoma remains a challenge. There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients undergoing resection for a variety of common solid tumors. Our aim was to prospectively evaluate the prognostic value of tumor- and patient-related factors including the systemic inflammatory response in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma of the head of pancreas. METHODS: The prognostic impact of tumor factors such as stage and host factors, including the systemic inflammatory response (modified Glasgow Prognostic Score [mGPS]), were evaluated in a prospective study of 135 patients who underwent elective pancreaticoduodenectomy for pancreatic ductal adenocarcinoma from January 2002 to April 2009. RESULTS: In addition to the established tumor-related pathological factors (in particular margin involvement; hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.65-4.84, P < 0.001), an elevated mGPS (HR 2.26, 95% CI 1.43-3.57, P < 0.001) was independently associated with lower overall survival after pancreaticoduodenectomy. Additionally, in an adjuvant therapy subgroup of 74 patients, both margin involvement and an elevated mGPS remained independently associated with reduced overall survival. CONCLUSIONS: We have prospectively validated the influence of tumor-related and patient-related factors. Margin involvement and the preoperative mGPS were the most important determinants of overall survival in patients undergoing potentially curative pancreaticoduodenectomy. Furthermore, both had independent prognostic value in those patients receiving adjuvant chemotherapy. In the future, this may be considered a stratification factor for entry onto therapeutic trials.

Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma.

OBJECTIVE: To determine the prognostic influence of residual tumor at or within 1 mm of the mobilization margins (R1Mobilization) compared with transection margins (R1Transection) following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The prognostic strength of R1 status increases with frequency of margin positivity and is enhanced by protocol driven pathology reporting. Currently, margins are treated uniformly with tumor at or close to any margin considered of equal prognostic significance. The resection involves a mobilization phase freeing the posterior margin and anterior surface then a transection phase requiring lympho-vascular division forming the medial resection and pancreatic transection margin. The comparative assessment of the relative importance of tumor involvement of these different margins has not previously been investigated. METHODS: Retrospective analysis of 148 consecutive resections for PDAC from 1996-2007 was performed. The individual (pancreatic transection, medial, posterior, and anterior surface) margins were separately identified and analyzed by a senior pathologist. An R1 resection was defined as microscopic evidence of tumor < or = 1 mm from a resection margin. R1Mobilization tumor extension included both R1Anterior and R1Posterior cases; while R1Transection included pancreatic neck/body transection, R1Medial and adjacent transection margins. RESULTS: R1 status was confirmed in 109 patients (74%). The medial (46%) and posterior (44%) margins were most commonly involved. R1 status was found to an independent predictor of poor outcome (P < 0.001). R1Mobilization involvement only (n = 48) was associated with a significantly longer median survival of 18.9 months (95% CI, 13.7-24.8) versus 11.1 months (95% CI, 7.1-15.0) for those with R1Transection tumor involvement (n = 61) (P < 0.001). There was no significant difference in the survival of the R1Mobilization compared with R0 group (P = 0.52). CONCLUSIONS: Following pancreaticoduodenectomy for PDAC, involvement of the transection margins in contrast to mobilization margins defines a group whose outcome is significantly worse. This may impact upon the allocation of adjuvant therapy within the setting of randomized controlled trials.

Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.

CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ß) a key regulator of glycolysis. Pharmacological inhibition of GSK3ß results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ß inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

A prognostic Bayesian network that makes personalized predictions of poor prognostic outcome post resection of pancreatic ductal adenocarcinoma.

BACKGROUND: The narrative surrounding the management of potentially resectable pancreatic cancer is complex. Surgical resection is the only potentially curative treatment. However resection rates are low, the risk of operative morbidity and mortality are high, and survival outcomes remain poor. The aim of this study was to create a prognostic Bayesian network that pre-operatively makes personalized predictions of post-resection survival time of 12months or less and also performs post-operative prognostic updating. METHODS: A Bayesian network was created by synthesizing data from PubMed post-resection survival analysis studies through a two-stage weighting process. Input variables included: inflammatory markers, tumour factors, tumour markers, patient factors and, if applicable, response to neoadjuvant treatment for pre-operative predictions. Prognostic updating was performed by inclusion of post-operative input variables including: pathology results and adjuvant therapy. RESULTS: 77 studies (n = 31,214) were used to create the Bayesian network, which was validated against a prospectively maintained tertiary referral centre database (n = 387). For pre-operative predictions an Area Under the Curve (AUC) of 0.7 (P value: 0.001; 95% CI 0.589-0.801) was achieved accepting up to 4 missing data-points in the dataset. For prognostic updating an AUC 0.8 (P value: 0.000; 95% CI:0.710-0.870) was achieved when validated against a dataset with up to 6 missing pre-operative, and 0 missing post-operative data-points. This dropped to AUC: 0.7 (P value: 0.000; 95% CI:0.667-0.818) when the post-operative validation dataset had up to 2 missing data-points. CONCLUSION: This Bayesian network is currently unique in the way it utilizes PubMed and patient level data to translate the existing empirical evidence surrounding potentially resectable pancreatic cancer to make personalized prognostic predictions. We believe such a tool is vital in facilitating better shared decision-making in clinical practice and could be further developed to offer a vehicle for delivering personalized precision medicine in the future.

A systematic review of methodological quality of model development studies predicting prognostic outcome for resectable pancreatic cancer.

OBJECTIVES: To assess the methodological quality of prognostic model development studies pertaining to post resection prognosis of pancreatic ductal adenocarcinoma (PDAC). DESIGN/SETTING: A narrative systematic review of international peer reviewed journals DATA SOURCE: Searches were conducted of: MEDLINE, Embase, PubMed, Cochrane database and Google Scholar for predictive modelling studies applied to the outcome of prognosis for patients with PDAC post resection. Predictive modelling studies in this context included prediction model development studies with and without external validation and external validation studies with model updating. Data was extracted following the Checklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) checklist. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were all components of the CHARMS checklist. Secondary outcomes included frequency of variables included across predictive models. RESULTS: 263 studies underwent full text review. 15 studies met the inclusion criteria. 3 studies underwent external validation. Multivariable Cox proportional hazard regression was the most commonly employed modelling method (n=13). 10 studies were based on single centre databases. Five used prospective databases, seven used retrospective databases and three used cancer data registry. The mean number of candidate predictors was 19.47 (range 7 to 50). The most commonly included variables were tumour grade (n=9), age (n=8), tumour stage (n=7) and tumour size (n=5). Mean sample size was 1367 (range 50 to 6400). 5 studies reached statistical power. None of the studies reported blinding of outcome measurement for predictor values. The most common form of presentation was nomograms (n=5) and prognostic scores (n=5) followed by prognostic calculators (n=3) and prognostic index (n=2). CONCLUSIONS: Areas for improvement in future predictive model development have been highlighted relating to: general aspects of model development and reporting, applicability of models and sources of bias. TRIAL REGISTRATION NUMBER: CRD42018105942.