Understanding metastasis in pancreatic cancer: a call for new clinical approaches.

Although metastasis is a major cause of morbidity and mortality in patients with pancreatic cancer, the requisite events are currently unknown. In this issue of Cell, Haeno et al. and Rhim et al. propose that metastasis occurs much earlier than previously anticipated, with clear implications for improving patient care.

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma.

OBJECTIVE: GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. DESIGN: We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. RESULTS: GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. CONCLUSIONS: GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Distal Bile Duct Cancer: Radical (R0 > 1 mm) Resection Achieves Favorable Survival.

OBJECTIVE: Evaluation of the outcome after resection for distal bile duct cancer (DBC) with focus on the impact of microscopic histopathological resection status R0 (>1 mm) versus R1 (≤1 mm) vs R1 (direct). SUMMARY BACKGROUND DATA: DBC is a rare disease for which oncologic resection offers the only chance of cure. METHODS: Prospectively collected data of consecutive patients undergoing pancreaticoduodenectomy for DBC were analyzed. Histopathological resection status was classified according to the Leeds protocol for pancreatic ductal adeno carcinoma (PDAC) (PDAC; R0 >1 mm margin clearance vs R1 ≤1 mm vs R1 direct margin involvement). RESULTS: A total of 196 patients underwent pancreaticoduodenectomy for DBC. Microscopic complete tumor clearance (R0>1 mm) was achieved in 113 patients (58%). Median overall survival (OS) of the entire cohort was 37 months (5- and 10-year OS rate: 40% and 31%, respectively). After R0 resection, median OS increased to 78 months with a 5-year OS rate of 52%. Negative prognostic factors were age >70 years ( P < 0.0001, hazard ratio (HR) 2.48), intraoperative blood loss >1000 mL ( P = 0.0009, HR 1.99), pN1 and pN2 status ( P = 0.0052 and P = 0.0006, HR 2.14 and 2.62, respectively) and American Society of Anesthesiologists score >II ( P = 0.0259, HR 1.61). CONCLUSIONS: This is the largest European single-center study of surgical treatment for DBC and the first to investigate the prognostic impact of the revised PDAC resection status definition in DBC. The results show that this definition is valid in DBC and that "true" R0 resection (>1 mm) is a key factor for excellent survival. In contrast to PDAC, there was no survival difference between R1 (≤1 mm) and R1 (direct).

A Simple Classification of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery.

OBJECTIVE: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. METHODS: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. RESULTS: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001). CONCLUSION: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Independent Validation and Assay Standardization of Improved Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature. METHODS: We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance. RESULTS: The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-9 >2 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-9 <37 U/mL, 39.7%, 94.1%, and 76.3%, respectively. CONCLUSIONS: The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

A histopathological study of artery wall involvement in pancreatic cancer surgery.

PURPOSE: This study aims to study the depth of artery wall tumour invasion in patients undergoing surgery for pancreatic ductal adenocarcinoma. METHODS: Specimens from 47 pancreatic cancer patients with major arterial (splenic, SA; celiac, CA; common hepatic, CHA) invasion were examined: 45 left (distal) pancreatectomies, including 11 celiac artery resections, and two total pancreatectomies. Dissection of tumour-invaded arteries in 25 fresh specimens was attempted ex vivo using the sub-adventitial dissection technique (SDT). Tumour invasion of 66 arteries was graded using the tumour-free distance (TFD) from the external elastic lamina (EEL): 0 = no arterial invasion; I = TFD ≥ 1 mm; II = TFD < 1 mm; and grade III = EEL invasion. RESULTS: AJCC TNM staging was IA = 1 (2%), IB = 4 (9%), IIA = 5 (11%), IIB = 17(36%) and III = 20 (43%). Grade III tumour invasion was found in 17/47(36%) SAs, in 5/11 (45%) CAs and in 1/8 (13%) CHAs (p = 0.318). Attempted ex vivo SDT undertaken in 33 arteries from 25 specimens was complete in 16 and incomplete in 17 arteries. The median (IQR) TFD was 0.97 (0.11-2.54) mm in dissected and 0.14 (0.10, 0.14) mm in non-dissected SAs (p = 0.034). EEL tumour invasion occurred in 0/12 (0%) dissected compared to 7/13 (54%) non-dissected SAs (p = 0.005). Grades 0, I, II and III invasion were found in four (33%), two (17%) and six (50%), respectively, of 12 dissected SAs and grades II and III in six 6 (46%) and seven (54%), respectively, of 13 non-dissected SAs (p = 0.002). CONCLUSIONS: The grading system described may form the basis for classification to further develop arterial dissection techniques for pancreatic cancer.

Poly(ADP-ribose) polymerase inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Prognostic Factors of Survival After Neoadjuvant Treatment and Resection for Initially Unresectable Pancreatic Cancer.

OBJECTIVE: To evaluate the impact of clinical and pathological parameters, including resection margin (R) status, on survival in patients undergoing pancreatic surgery after neoadjuvant treatment for initially unresectable pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Prognostic factors are well documented for patients with resectable PDAC, but have not been described in detail for patients with initially unresectable PDAC undergoing resection after neoadjuvant therapy. METHODS: Prospectively collected data of consecutive patients with initially unresectable pancreatic cancer treated by neoadjuvant treatment and resection were analyzed. The R status was categorized as R0 (tumor-free margin >1 mm), R1 ≤1 mm (tumor-free margin ≤1 mm), and R1 direct (microscopic tumor infiltration at margin). Clinicopathological characteristics and outcomes were compared among these groups and tested for survival prediction. RESULTS: Between January, 2006 and February, 2017, 280 patients with borderline resectable (n = 18), locally advanced (n = 190), or oligometastatic (n = 72) disease underwent tumor resection after neoadjuvant treatment. Median overall survival from the time of surgery was 25.1 months for R0 (n = 82), 15.3 months for R1 ≤1 mm (n = 99), and 16.1 months for R1 direct (n = 99), with 3-year overall survival rates of 35.0%, 20.7%, and 18.5%, respectively (P = 0.0076). The median duration of the neoadjuvant treatment period was 5.1 months. In multivariable analysis, preoperative CA 19-9 levels, lymph node status, metastasis category, and vascular involvement were all significant prognostic factors for overall survival. The R status was not an independent prognostic factor. CONCLUSIONS: In patients undergoing resection after neoadjuvant therapy for initially unresectable PDAC, preoperative CA 19-9 levels, lymph node involvement, metastasis category, and vascular involvement, but not the R status, were independent prognostic factors of overall survival.

Noninvasive Discrimination of Low and High-risk Pancreatic Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To propose a noninvasive diagnostic approach, which allows reliable distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: IPMNs are identifiable precursor lesions of pancreatic cancer, of which surgical resection is warranted prior to the development of invasive carcinoma, but low-grade IPMNs should not be unnecessarily resected. However, diagnostic tools that preoperatively enable accurate risk stratification of IPMNs are missing. METHODS: This single-center, retrospective cohort study included 56 patients who underwent surgical resection for IPMN including 18 low-risk (low-grade) and 38 high-risk (high-grade/invasive carcinoma) IPMNs, from whom clinical features and serum samples were prospectively obtained. An antibody microarray platform was used to analyze the serum proteome. Based on serum markers and selected clinical characteristics support vector machine models were constructed to predict the risk of IPMN malignancy. RESULTS: A serum protein signature discriminating low- and high-risk IPMN patients was identified. Combinations of established clinical features and the newly identified serum biomarkers correctly distinguished low- and high-risk IPMNs in 93% on 1000-fold cross-validation. CONCLUSIONS: This study highlights the synergistic predictive value of combining a novel serum protein signature with conventional clinical characteristics to risk-stratify IPMN patients. If these findings are supported by larger validation studies, they might enable more rational decision-making in clinical management of IPMN patients in conjunction with clinical guidelines.

Severe acute pancreatitis: surgical indications and treatment.

BACKGROUND: Acute pancreatitis (AP) is defined as an acute inflammatory attack of the pancreas of sudden onset. Around 25% of patients have either moderately severe or severe disease with a mortality rate of 15-20%. PURPOSE: The aim of this article was to summarize the advances being made in the understanding of this disease and the important role of surgery. RESULTS AND CONCLUSIONS: An accurate diagnosis should be made a soon as possible, initiating resuscitation with large volume intravenous fluids and oxygen by mask. Predicted severe disease will require intensive monitoring. Most deaths within the first week are due to multi-organ failure; thus, these patients will require intensive therapy unit management. During the second phase of the disease, death is due to local complications arising from the pancreatic inflammation, requiring accurate identification to determine the correct form of treatment. Acute peripancreatic fluid collections arise < 4 weeks after onset of interstitial edematous pancreatitis, not requiring any treatment. Most pancreatic pseudocysts arise > 4 weeks and largely resolve on conservative management. Necrotizing pancreatitis causing acute necrotic collections and later walled-off necrosis will require treatment if symptomatic or infected. Initial endoscopic transgastric or percutaneous drainage will resolve less serious collections but necrosectomy using minimally invasive approaches will be needed for more serious collections. To prevent recurrent attacks of AP, causative factors need to be removed where possible such as cholecystectomy and cessation of alcohol. Future progress requires improved management of multi-organ failure and more effective minimally invasive techniques for the removal of necrosis.

The in situ near-total pancreatectomy (LIVOCADO procedure) for end-staged chronic pancreatitis.

PURPOSE: Total pancreatectomy for severe pain in end-stage chronic pancreatitis may be the only option, but with vascular involvement, this is usually too high risk and/or technically not feasible. The purpose of the study was to present the clinical outcomes of a novel procedure in severe chronic pancreatitis complicated by uncontrollable pain and vascular involvement. METHODS: We describe an in situ near-total pancreatectomy that avoids peripancreatic vascular dissection (Livocado procedure) and report on surgical and clinical outcomes. RESULTS: The Livocado procedure was carried out on 18 (3.9%) of 465 patients undergoing surgery for chronic pancreatitis. There were 13 men and 5 women with a median (IQR) age of 48.5 (42.4-57) years and weight of 60.7 (58.0-75.0) kg. All had severe pain and vascular involvement; 17 had pancreatic parenchymal calcification; the median (IQR) oral morphine equivalent dose requirement was 86 (33-195) mg/day. The median (IQR) maximal pain scores were 9 (9-10); the average pain score was 6 (IQR 4-7). There was no peri-operative or 90-day mortality. At a median (IQR) follow-up of 32.5 (21-45.75) months, both maximal and average pain scores were significantly improved post-operatively, and at 12 months, two-thirds of patients were completely pain free. Six (33%) patients had employment pre-operatively versus 13 (72%) post-operatively (p = 0.01). CONCLUSIONS: The Livocado procedure was safe and carried out successfully in patients with chronic pancreatitis with vascular involvement where other procedures would be contraindicated. Perioperative outcomes, post-operative pain scores, and employment rehabilitation were comparable with other procedures carried out in patients without vascular involvement.

Sub-adventitial divestment technique for resecting artery-involved pancreatic cancer: a retrospective cohort study.

PURPOSE: To introduce sub-adventitial divestment technique (SDT), a procedure to remove the tumor while preserving the artery during curative pancreatectomy. Peri-operative safety profile was also evaluated. METHODS: In a single center consecutive series of pancreatectomy for pancreatic cancer, the outcome of patients who had pancreatectomy with SDT was compared to standard pancreatic surgery. RESULTS: From June 2014 to June 2016, 72 patients had pancreatectomy with SDT and 235 had standard surgery. Tumor stage was T4 in all 72 (100%) tumors removed using SDT compared to four (2%) with standard pancreatectomy (p < 0.001). All 72 (100%) tumors in the SDT group were stage III compared to 24 (10%) in the standard surgery group (p < 0.001). Both groups had a high proportion of poorly differentiated tumors (52 (72%) and 163 (69%) respectively) and perineural tumor invasion (62 (86%) and 186 (79%) respectively). R1 (< 1 mm) was found in 24 (86%) of 28 tumors in the SDT group, and in 72 (60%) out of 120 standard pancreatectomy tumors (p = 0.01). Complications occurred in 29 (40%) of the SDT group and in 88 (37%) of the standard group. The in-hospital mortality was four (6%) in the SDT group and one (0.4%) in the standard group (p = 0.01), with a 90-day mortality of 5 (8%)/60 and 6 (3%)/209 (p = 0.07) respectively. CONCLUSIONS: The sub-adventitial divestment technique appeared to be an effective surgical technique to remove the tumor while preserving the artery. This approach warrants further validation in prospective studies.

TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial.

BACKGROUND: TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma. METHODS: Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay. RESULTS: Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months. CONCLUSIONS: TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at ClinicalTrials.gov (NCT02261714).

Pancreatic cancer incidence and survival and the role of specialist centres in resection rates in England, 2000 to 2014: A population-based study.

BACKGROUND: The aim was to compare population-based survival for exocrine pancreatic cancer in England in the 23 regions covered by specialist centres. The centres were initiated in 2001, covering populations of 2-4 million. METHODS: We examined incidence for adults diagnosed with a pancreatic exocrine cancer during 1995-2014 and age-standardised net survival up to five years after diagnosis for patients diagnosed during 2000-2013. We examined variation in regional resection rates and survival for patients diagnosed during 2010-2013. The data were extracted from the National Cancer Registration and Analysis Service. RESULTS: Age-standardised annual incidence rates of exocrine pancreatic cancer increased from 17.1 per 100,000 during 1995-1999 to 18.7 during 2010-2014. Age-standardised one-year and five-year net survival increased from 17.9% and 3.6%, respectively, for 2000-2009, to 21.6% and 4.2% during 2010-2013. There were 2086 (8.9%) resections among 23,415 patients diagnosed with an exocrine tumour in 2010-2013. The proportion ranged from 5.1% to 19.6% between centres. Among resected patients, survival was 73.0% at one year and 20.2% at five years. Of the total 2118 resected patients, 18 (0.9%) were at stage 1; 34 (1.6%) at stage 2; 791 (37.3%) at stage 3 and 140 (6.6%) at stage 4, although 53.6% of stage information was missing. Five-year survival was 2.1% for those who were not resected. The number of resections performed in each centre was not correlated with one-year survival. CONCLUSIONS: Despite improvements in the management of pancreatic cancer in England with the introduction of specialist centres, resection rates remain relatively low, and survival remains lower than in comparably wealthy countries.

Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.

BACKGROUND: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP). METHODS: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated. RESULTS: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP. CONCLUSIONS: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.