Interactions between the Exocrine and the Endocrine Pancreas.

The pancreas has two main functions: to produce and secrete digestive enzymes (exocrine function) and to produce hormones that regulate blood glucose and splanchnic secretion (endocrine function). The endocrine and exocrine portions of the pancreas are central regulators in digestion and metabolism, with continuous crosstalk between their deeply interconnected components, which plays a role in disease. Pancreatic neoplasms, inflammation, trauma, and surgery can lead to the development of type 3c diabetes when an insult simultaneously damages both acini and islets, leading to exocrine and endocrine dysfunction. In diabetes mellitus patients, pancreatic exocrine insufficiency is highly prevalent, yet little is known about the associations between diabetes mellitus and pancreatic exocrine function. This review aims to provide an overview of the physiology of the pancreas, summarize the pathophysiology and diagnostic work-up of pancreatic exocrine insufficiency, and explore the relationships between exocrine pancreatic insufficiency and diabetes mellitus.

Outcome after total pancreatectomy with islet autotransplantation: A European single-center study.

BACKGROUND AND AIMS: Chronic pancreatitis may cause intractable abdominal pain, with total pancreatectomy sometimes being the last resort. To mitigate the subsequent diabetes, total pancreatectomy can be followed by islet autotransplantation (TP-IAT). The primary aim of this study was to assess the outcomes in patients undergoing TP-IAT at Karolinska University Hospital with respect to safety, postoperative complications, and islet graft function. A secondary aim was to compare liver to skeletal muscle as autotransplantation sites. METHODS: Single-center observational cohort study on patients undergoing TP-IAT. Islets were transplanted either into the liver or skeletal muscle. Data on baseline characteristics and pretransplantory conditions were collected. Outcome measures included mortality and major postoperative complications as well as the glycemic measures: insulin use, fasting C-peptide, and HbA1c. RESULTS: Between 2004 and 2020, 24 patients underwent TP-IAT. Islets were transplanted into the liver in 9 patients and into skeletal muscle in 15 patients. There was no 90-day mortality, and major complications (Clavien-Dindo ⩾IIIa) occurred in 26.7%, all related to the procedure of total pancreatectomy. Fasting C-peptide could be detected postoperatively, with higher levels in patients receiving islet autotransplantation into the liver (p = 0.006). Insulin independence was not achieved, although insulin doses at last follow-up were significantly lower in patients receiving islet autotransplantation into the liver compared to skeletal muscle (p = 0.036). CONCLUSION: TP-IAT is safe and associated with tolerable risk, the component of islet autotransplantation being seemingly harmless. Although islet grafts maintain some endocrine function, insulin independence should not be expected. Regarding islet autotransplantation sites, the liver seems superior to skeletal muscle. CLINICAL TRIAL REGISTRATION: Not applicable.

Portomesenteric venous contact ≤180° and overall survival in resectable head and body pancreatic adenocarcinoma treated with upfront surgery.

INTRODUCTION: Upfront surgery is the standard of care for resectable pancreatic cancer, defined as the absence of or ≤180° tumour contact with the portal/superior mesenteric vein. We hypothesized that portomesenteric venous tumour contact is prognostically unfavourable and aimed to assess whether it is associated with poorer survival compared with no venous contact in resectable head and body pancreatic cancer. METHODS: This single-centre retrospective study included patients undergoing upfront surgery for resectable head and body pancreatic cancer in 2010-2020 at Umeå University Hospital, Sweden. No venous contact was compared with portomesenteric venous contact of ≤180° based on preoperative imaging. Overall survival on an intention-to-treat basis was compared with Kaplan-Meier curves, a log-rank test and Cox proportional hazards models. RESULTS: The final study cohort included 39 patients with portomesenteric venous tumour contact and 144 patients without venous tumour contact. Patients with venous tumour contact had a median overall survival of 15.3 months compared to 23.0 months (log rank P = 0.059). Portomesenteric venous tumour contact was an independent negative prognostic factor for survival in the multivariable Cox model (HR 1.68; 95% CI 1.11-2.55, P = 0.014) and was associated with higher rates of microscopically non-radical resections (R1) (50% vs 26.1%, P = 0.012) and pathological lymph node metastasis (76.7% vs 56.8%, P = 0.012). There was no difference in adjuvant chemotherapy receipt or postoperative complications between the groups. CONCLUSIONS: Portomesenteric venous tumour contact is associated with poorer overall survival and higher rates of R1 resections and lymph node metastasis in patients with resectable head and body pancreatic cancer treated with upfront surgery.

Intraoperative pancreatoscopy can improve the detection of skip lesions during surgery for intraductal papillary mucinous neoplasia: A pilot study.

OBJECTIVES: Intraoperative pancreatoscopy is a promising procedure that might guide surgical resection for suspected main duct (MD) and mixed type (MT) intraductal papillary mucinous neoplasms (IPMNs). The aim of the present study was to assess the diagnostic yield and clinical impact of intraoperative pancreatoscopy in patients operated on for MD and MT-IPMNs. METHODS: This is a retrospective cohort study. Patients undergoing surgery for suspected MD or MT-IPMN underwent intraoperative pancreatoscopy and frozen section analysis. In all patients who required extended resection due to pancreatoscopic findings, we compared the final histology with the results of the intraoperative frozen section analysis. RESULTS: In total, 46 patients, 48% females, mean age (range) 67 years (45-82 years) underwent intraoperative pancreatoscopy. No mortality or procedure related complications were observed. Pancreatoscopy changed the operative course in 30 patients (65%), leading to extended resections in 20 patients (43%) and to parenchyma sparing procedures in 10 patients (22%). Analyzing the group of patients who underwent extended resections, 7 (35%) displayed lesions that needed further surgical treatment (six high grade dysplasia and one with G1 pancreatic neuroendocrine tumor) and among those 7, just 1 (14%) would have been detected exclusively with histological frozen section analysis of the transection margin. The combination of both pancreatoscopy and frozen section analysis lead to 86% sensitivity and 92% specificity for the detection of pathological tissue in the remnant pancreas. CONCLUSION: Intraoperative pancreatoscopy is a safe and feasible procedure and might allow the detection of skip lesions during surgery for suspect MD-involving IPMNs.

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions: a propensity score-matched cohort.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAP-related and sporadic ampullary lesions (SALs). METHODS: This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. RESULTS: Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2 % [95 %CI 71.2-87.3] vs. 46.5 % [95 %CI 36.6-56.4]); P < 0.001). The initial R0 rate was significantly lower in FAP patients (63.4 % [95 %CI 53.8-72.9] vs. 83.2 % [95 %CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1 % [95 %CI 88.0-98.1] vs. SAL 97.0 % [95 %CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7 %. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8 % [95 %CI 12.7-28.8]) and 16 SAL patients (15.8 % [95 %CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). CONCLUSIONS: Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.

BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS. METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression. RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS. CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Adenomatous neoplasia in the papilla of Vater endoscopic and/or surgical resection?

BACKGROUND: Adenomatous neoplasia in the papilla of Vater needs to be resected in order not to progress. It can be challenging to distinguish between early ampullary malignant lesions and non-invasive adenomas, due to the overlap in symptoms and radiological findings. This retrospective study describes the different findings and treatment decisions taken prior to endoscopic and/or surgical resection of ampullary adenomatous lesions. MATERIALS AND METHODS: Patients treated with endoscopic and/or surgical resection for suspected or verified ampullary adenomatous neoplasia, between January 2006 and July 2018, where pre-interventional cross-sectional imaging could not discern an obvious invasive, malignant tumor, were included. Findings were compared against the final diagnosis of the histopathological analysis on the resected specimen. RESULTS: In total, 172 met the inclusion criteria. Patients were treated with either surgical resection (n = 96), endoscopic papillectomy (EP) (n = 55) or both (n = 21). The final diagnosis was in 48% ampullary adenocarcinoma, and the remaining had either ampullary adenoma (38%) or non-neoplastic lesions (14%). In patients where symptoms and cross-sectional imaging were suspicious for malignancy, but with no tissue samples that confirmed neoplasia prior to surgical resection, only 47% had adenocarcinoma. The remaining had either adenoma (9%) or non-neoplastic lesions (44%). Adenocarcinoma was revealed in 27% of the patients where endoscopic biopsies had shown adenoma. Patients with adenoma, treated with EP, were cured in 59%. However, 28% were after EP sent for further surgery due to ductal invasion or a finding of adenocarcinoma. CONCLUSIONS: In patients with a suspicion of ampullary neoplasia on imaging, attempts should be made to get endoscopic tissue samples before deciding on a treatment strategy. If biopsies show ampullary adenoma, patients should be considered for EP, unless there are clear radiologic or endoscopic signs of malignancy. Patients with adenocarcinoma on endoscopic biopsies should undergo surgical resection.

Clinical Outcomes After Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

OBJECTIVE: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality. BACKGROUND: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice. METHODS: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cutoff values for annual volume of pancreatoduodenectomies (<60 vs ≥60).Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression. RESULTS: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared <60 (4% vs 10%, P = 0.046). In multivariable analysis, annual volume <60 pancreatoduodenectomies (OR 3.78, 95% CI 1.18-12.16, P = 0.026), age (OR 1.07, 95% CI 1.01-1.14, P = 0.046), and estimated blood loss ≥2L (OR 11.89, 95% CI 2.64-53.61, P = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95% CI 1.56-5.26, P = 0.001) and estimated blood loss ≥2L (OR 3.52, 95% CI 1.25-9.90, P = 0.017) were associated with major complications. CONCLUSION: This pan-European prospective snapshot study found a 5% inhospital mortality after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.

Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties.

Emerging research suggests gut microbiome may play a role in pancreatic cancer initiation and progression, but cultivation of the cancer microbiome remains challenging. This pilot study aims to investigate the possibility to cultivate pancreatic microbiome from pancreatic cystic lesions associated with invasive cancer. Intra-operatively acquired pancreatic cyst fluid samples showed culture-positivity mainly in the intraductal papillary mucinous neoplasm (IPMN) group of lesions. MALDI-TOF MS profiling analysis shows Gammaproteobacteria and Bacilli dominate among individual bacteria isolates. Among cultivated bacteria, Gammaproteobacteria, particularly Klebsiella pneumoniae, but also Granulicatella adiacens and Enterococcus faecalis, demonstrate consistent pathogenic properties in pancreatic cell lines tested in ex vivo co-culture models. Pathogenic properties include intracellular survival capability, cell death induction, or causing DNA double-strand breaks in the surviving cells resembling genotoxic effects. This study provides new insights into the role of the pancreatic microbiota in the intriguing link between pancreatic cystic lesions and cancer.

A tug-of-war in intraductal papillary mucinous neoplasms management: Comparison between 2017 International and 2018 European guidelines.

BACKGROUND: 2017 International and 2018 European guidelines are the most recent guidelines for intraductal papillary mucinous neoplasms management. AIM: to evaluate the diagnostic accuracy of these guidelines in identifying malignant IPMN. METHODS: data from resected patients with IPMN were collected in two referral centers. Features of risk associated to cancerous degeneration described in International and European guidelines were retrospectively applied. Sensitivity, specificity, positive and negative predictive value in detecting malignant disease were calculated. RESULTS: the study includes 627 resected patients. European guidelines suggest resection in any patient with at least one feature of moderate-risk. International guidelines suggest that patients with moderate-risk features undergo endoscopic ultrasound before surgery. European guidelines had a higher sensitivity (99.2% vs. 83%) but a lower positive predictive value (59.5% vs. 65.8%) and Specificity (2% vs. 37.5%). European guidelines detected almost all malignancies, but 40% of resected patients had low-grade dysplasia. 297 patients underwent endoscopic ultrasound before surgery. 31/116 (26.7%) tumors radiologically classified as "worrisome features" were reclassified as "high-risk stigmata" by endoscopic ultrasound and 24/31 were malignant IPMN. CONCLUSIONS: European and International guidelines have a relatively low diagnostic accuracy, being European guidelines more aggressive. Endoscopic ultrasound can improve guidelines accuracy in patients with moderate-risk features.

Metabolic Characterization of Plasma and Cyst Fluid from Cystic Precursors to Pancreatic Cancer Patients Reveal Metabolic Signatures of Bacterial Infection.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5 year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here, we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labeled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression-including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products, and trimethylamine-oxide. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g., Helicobacter pylori and gastric cancer).

Metabolic characterization of plasma and cyst fluid from cystic precursors to pancreatic cancer patients reveal metabolic signatures of bacterial infection.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5-year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labelled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression - including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g., Helicobacter pylori and gastric cancer). KEY POINTS: We identified and quantified novel markers of IPMN cyst status and pancreatic cancer disease progression - including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO.We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA.

Circulating and Salivary Antibodies to Fusobacterium nucleatum Are Associated With Cystic Pancreatic Neoplasm Malignancy.

Objectives: Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic cancer. The presence of oral microbes in pancreatic tissue or cyst fluid has been associated with high-grade dysplasia (HGD) and cancer. The present study aims at investigating if humoral immunity to pancreas-associated oral microbes reflects IPMN severity. Design: Paired plasma (n = 109) and saliva (n = 65) samples were obtained from IPMN pancreatic cystic tumor cases and controls, for anti-bacterial antibody analysis and DNA quantification by enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. Tumor severity was graded by histopathology, laboratory, and clinical data. Circulating plasma and salivary antibody reactivity to a pancreas-associated oral microbe panel were measured by ELISA and correlated to tumor severity. Results: The patient group with high-risk cystic tumors (HGD and/or associated invasive cancer) shows ample circulating IgG reactivity to Fusobacterium nucleatum (F. nucleatum) but not to Granulicatella adiacens (G. adiacens), which is independent of the salivary bacteria DNA levels. This group also shows higher salivary IgA reactivity to F. nucleatum, Fap2 of F. nucleatum, and Streptococcus gordonii (S. gordonii) compared to low-risk IPMN and controls. The salivary antibody reactivity to F. nucleatum and Fap2 are found to be highly correlated, and cross-competition assays further confirm that these antibodies appear cross-reactive. Conclusion: Our findings indicate that humoral reactivity against pancreas-associated oral microbes may reflect IPMN severity. These findings are beneficial for biomarker development.

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment.

IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

INTRODUCTION: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

International validation and update of the Amsterdam model for prediction of survival after pancreatoduodenectomy for pancreatic cancer.

BACKGROUND: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer. METHODS: We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement. RESULTS: Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3-year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001). CONCLUSIONS: This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www.pancreascalculator.com may facilitate use in daily practice and future trials.

Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can progress to invasive pancreatic cancer. Associations between oncogenesis and oral microbiome alterations have been reported. This study aims to investigate a potential intracystic pancreatic microbiome in a pancreatic cystic neoplasm (PCN) surgery patient cohort. DESIGN: Paired cyst fluid and plasma were collected at pancreatic surgery from patients with suspected PCN (n=105). Quantitative and qualitative assessment of bacterial DNA by qPCR, PacBio sequencing (n=35), and interleukin (IL)-1ß quantification was performed. The data were correlated to diagnosis, lesion severity and clinical and laboratory profile, including proton-pump inhibitor (PPI) usage and history of invasive endoscopy procedures. RESULTS: Intracystic bacterial 16S DNA copy number and IL-1ß protein quantity were significantly higher in IPMN with high-grade dysplasia and IPMN with cancer compared with non-IPMN PCNs. Despite high interpersonal variation of intracystic microbiota composition, bacterial network and linear discriminant analysis effect size analyses demonstrated co-occurrence and enrichment of oral bacterial taxa including Fusobacterium nucleatum and Granulicatella adiacens in cyst fluid from IPMN with high-grade dysplasia. The elevated intracystic bacterial DNA is associated with, but not limited to, prior exposure to invasive endoscopic procedures, and is independent from use of PPI and antibiotics. CONCLUSIONS: Collectively, these findings warrant further investigation into the role of oral bacteria in cystic precursors to pancreatic cancer and have added values on the aetiopathology as well as the management of pancreatic cysts.

Pancreatectomy with arterial resection is superior to palliation in patients with borderline resectable or locally advanced pancreatic cancer.

BACKGROUND: Few studies have investigated the outcome of pancreatectomy associated with artery resection (PAR). METHODS: Retrospective analysis of a cohort of operated borderline or locally advanced pancreatic cancer patients with surgically confirmed arterial involvement. Short and long-term outcome were analyzed and compared in patients who underwent PAR (Group 1) and palliative surgery (Group 2). RESULTS: Of 73 patients who underwent surgical exploration with intent of resection, 34 underwent PAR (±venous resection) (Group 1) and 39 underwent palliation (Group 2). 23 patients (67.7%) in Group 1 underwent combined artery-vein resection (AVR). Operation time was longer and blood loss higher in group 1 compared to group 2. There were no differences in post-operative mortality (2.9% vs 2.6%, p = 0.9) and post-operative surgical complications (38.2% vs 25.6%, p = 0.2). The 1, 3 and 5 years survival in Group 1 was superior to Group 2 (63.7%, 23.4% and Q3 23.4% vs 41.7%, 3.2% and 0, p = 0.003). CONCLUSION: PAR seems to be safe and feasible in well selected patients and associated with an advantage of survival compared to palliation, in patients affected by locally advanced pancreatic cancer.

A human protein atlas for normal and cancer tissues based on antibody proteomics.

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, approximately 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.