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Objective: Ampullary neoplastic lesions can be resected by endoscopic papillectomy (EP) or transduodenal surgical ampullectomy (TSA) while pancreaticoduodenectomy is reserved for more advanced lesions. We present the largest retrospective comparative study analysing EP and TSA.

Design: Of all patients in the database, lesions with prior interventions, benign histology advanced malignancy (T2 and more), patients with hereditary syndromes and those undergoing pancreatoduodenectomy were excluded. All remaining cases as well as a subgroup of them, after propensity-score matching (nearest-neighbour-method) based on age, gender, anthropometrics, comorbidities, size and histological subtype, were analysed. The median follow-up was 21 months (IQR 10-47) after the primary intervention. Primary outcomes were rates of complete resection (R0) and complications. Groups were compared by Fisher's exact or χ2 test, Mann-Whitney-U-test and log-rank test for survival.

Results: Of 1673 patients in the database, 1422 underwent EP and 251 TSA. Of them, 23.2% were excluded for missing or inconclusive data and 19.8% of patients for prior interventions or hereditary syndromes. Final histology showed in 24.2% of EP and 14.8% of TSA patients a histology other than adenoma or adenocarcinoma while advanced cancers were recorded in 10.9% of EP and 36.6% of TSA patients. Finally, 569 EP and 63 TSA were included in the overall analysis, with a higher rate of more advanced cases and higher R0 resection rates in the TSA groups (90.5% vs 73.1%; p<0.01), with additional ablation in the EP group in 14.4%. Severe adverse event rates were 3.2% (TSA) vs 1.9% (EP). Recurrence after histological R0 resection was 16% (EP) vs 3.2% (TSA; p=0.01), and additional therapy for R1 resection was applied in 67% of the 159 cases. Propensity-score-based matching identified 62 pairs of EP/TSA patients with comparable baseline patient and lesion characteristics. The initial R0-rate was 72.6% (EP) compared with 90.3% (TSA, p=0.02) with recurrences found in 8% (EP) vs 3.2% (TSA; p=0.07); reinterventions were more frequent in the EP group. Overall survival was comparable.

Conclusions: The rate of patients with poor indications due to non-neoplastic disease or advanced cancer is still high for both EP and TSA; multiple retreatments were necessary for EP. Although EP can be considered an appropriate primary therapy for certain ampullary adenomas, case selection for both therapies (especially with regard to the best step-up approach) should be studied further.

Background: Evidence regarding the optimal surgical approach for pancreatic neck/body cancer with portomesenteric vein (PV) involvement is scarce. We aimed to clarify the current practice using an international survey.

Methods: An online survey was distributed to members of nine international associations and study groups. Surgeons who performed pancreatectomy with PV resection (PVR) in the last 12 months were asked about three clinical scenarios with different PV involvement: scenarios A (<90°; length 1 cm), B (<90°; length 3 cm), and C (90–180°; length 3 cm), with or without common hepatic artery (CHA) involvement. PVR was defined according to the ISGPS definition.

Results: Overall, 222 surgeons from 49 countries in 6 continents completed the survey. The most selected procedures were left pancreatectomy with PVR ISGPS-type 1 for scenario A (52.3 %), PVR ISGPS-type 2 for B (28.8 %), and pancreatoduodenectomy with PVR ISGPS-type 3 for C (28.4 %). In patients with CHA involvement, the most selected procedures were left pancreatectomy without arterial reconstruction for A (57.7 %) and B (50.0 %), and total pancreatectomy for C (29.7 %).

Conclusions: The survey illustrates the heterogeneity in surgical management of pancreatic neck/body cancer with PV involvement, indicating the need for prospective studies and guidelines.

Background: Pancreatectomy with venous resection (PVR) is nowadays considered standard. However, there is still concern about increased postoperative morbidity and impaired long-term outcome depending on the type of venous resection and reconstruction. The aim was to investigate the predictors of morbidity and long-term survival in patients undergoing PVR in a high-volume center.

Methods: All consecutive patients undergoing PVR at a single center between January 2008 and January 2019 were retrieved from a prospectively maintained database. Factors associated with postoperative complications and long-term survival were analyzed.

Results: Of 290 patients with isolated PVRs, 188 (65 %) were performed for pancreatic ductal adenocarcinoma (PDAC). Surgical complications developed in 56 % of patients (n = 163), and 11 % (n = 36) had severe complications (Clavien-Dindo>3a). The 90-day mortality was 4.1 %. Venous thrombosis occurred in 4.8 % (n = 14), resulting in one mortality (0.3 %). No technical factors were predictive for the development of severe complications. Longer vein segments >3 cm could be resected with similar short- and long-term outcome as shorter segments. The survival of patients undergoing PVR for resectable, borderline and locally advanced PDAC was similar (median of 18, 14, and 23 months, p = 0.7). On multivariate analysis, elevated CA19-9>200 U/mL and ASA score≥3 were independent predictors of survival (p = 0.02), but not resectability at diagnosis nor type of venous reconstruction.

Conclusion: The type of venous resection/reconstruction does not influence outcome and should be tailored according to patients' and tumors’ characteristics during PVR. The long-term survival after PVR for PDAC is influenced by tumor-and patient-related characteristics, and not technical vascular-resection associated factors.

Introduction: Tumor-residing microbiota poses a new challenge in cancer progression and therapy; however, the functional behavior of patient tumor-derived microbes remains poorly understood. We previously reported the presence of tumor microbiota in intraductal papillary mucinous neoplasms (IPMNs), which are precursors of pancreatic cancer.

Methods: We examined the metabolic and pathogenic potential of clinical microbiota strains obtained from IPMN tumors using various pancreatic cell lines and 3D spheroid models.

Results: Our findings revealed that several strains from IPMNs with invasive cancer or high-grade dysplasia, such as E. cloacae, E. faecalis, and K. pneumoniae, induced a cancer metabolite signature in human pancreatic cells when infected ex vivo. Bacterial invasiveness was significantly correlated with DNA damage in spheroids derived from normal and tumor-derived pancreatic cells, particularly in strains derived from advanced neoplasia IPMN and under hypoxic conditions. Additionally, microbial metabolites activate human mucosal-associated invariant T (MAIT) cells and restrict the infection, both extra- and intracellularly, in hypoxic tumor conditions and in synergy with antibiotics.

Discussion: Immune sensing of tumor microbiota metabolites may have clinical implications in cancer management.

Objective: To investigate whether tangential versus segmental portomesenteric venous resection (PVR) impacts surgical and oncological outcome in patients undergoing pancreatoduodenectomy for pancreatic cancer with portomesenteric vein (PMV) involvement.

Summary Background Data: Current comparative studies on tangential versus segmental PVR as part of pancreatoduodenectomy for pancreatic cancer include all degrees of PMV involvement, including cases where tangential PVR may not be a feasible approach, limiting the clinical applicability.

Methods: International retrospective study in 10 centers from 5 countries, including all consecutive patients after pancreatoduodenectomy with PVR for pancreatic cancer with ≤180° PMV involvement on cross-sectional imaging at diagnosis (2014-2020). Cox and logistic regression analyses were performed to investigate the association of tangential versus segmental PVR with overall survival (OS) from surgery, recurrence-free survival (RFS), locoregional recurrence, and in-hospital/30-day major morbidity, adjusting for potential confounders.

Results: Overall, 357 patients who underwent pancreatoduodenectomy with PVR were included (42% tangential PVR, 58% segmental PVR). The adjusted risk for in-hospital/30-day major morbidity was 23% (95%CI, 17-32) after tangential and 23% (95%CI, 17-30) after segmental PVR (P=0.98). After adjusting for confounders, PVR type was not associated with OS (HR=0.94 [95%CI, 0.69-1.30]), RFS (HR=0.94 [95% CI, 0.69 to 1.28), and locoregional recurrence (OR=0.76 [95%CI, 0.40-1.46]).

Conclusions: In patients undergoing pancreatoduodenectomy for pancreatic cancer with ≤180° PMV involvement, the type of PVR (i.e., tangential vs. segmental) was not associated with differences in surgical and oncological outcome. This suggest that if both procedures are technically feasible, surgeons can choose the type of PVR based on their preference.

Background: Left-sided pancreatic cancer is associated with worse overall survival (OS) compared with right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with resectable pancreatic cancer (RPC), current randomized trials included mostly patients with right-sided RPC. The purpose of this study was to assess the association between neoadjuvant therapy and OS in patients with left-sided RPC compared with upfront surgery.

Patients and methods: This was an international multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). The primary endpoint was OS from diagnosis. Time-dependent Cox regression analysis was carried out to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at the time of diagnosis. Adjusted OS probabilities were calculated.

Results: Overall, 2282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared with upfront surgery (adjusted hazard ratio 0.69, 95% confidence interval 0.58-0.83) with an adjusted median OS of 53 versus 37 months (P = 0.0003) and adjusted 5-year OS rates of 47% versus 35% (P = 0.0001) compared with upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction = 0.003) and higher serum carbohydrate antigen 19-9 (CA19-9; Pinteraction = 0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction = 0.43), splenic vein (Pinteraction = 0.30), retroperitoneal (Pinteraction = 0.84), and multivisceral (Pinteraction = 0.96) involvement.

Conclusions: Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared with upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.

Aim: To validate the prognostic value of the PAncreatic NeoAdjuvant MAssachusetts (PANAMA)-score and to determine its predictive ability for survival benefit derived from adjuvant treatment in patients after resection of pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant FOLFIRINOX.

Background: The PANAMA-score was developed to guide prognostication in patients after neoadjuvant therapy and resection for PDAC. As this score focuses on the risk for residual disease after resection, it might also be able to select patients who benefit from adjuvant after neoadjuvant therapy.

Methods: This retrospective international multicenter study is endorsed by the European-African Hepato-Pancreato-Biliary Association (E-AHPBA). Patients with PDAC who underwent resection after neoadjuvant FOLFIRINOX were included. Mantel-Cox regression with interaction analysis was performed to assess the impact of adjuvant chemotherapy.

Results: Overall, 383 patients after resection of PDAC following neoadjuvant FOLFIRINOX were included of whom 187 (49%), 137 (36%), and 59 (15%) had a low-risk, intermediate-risk, and high-risk PANAMA-score, respectively. A discrimination in median OS was observed stratified by risk groups (48.5, 27.6, and 22.3 months, Log-Rank-Plow-intermediate=0.004, Log-Rank-Pintermediate-high=0.027). Adjuvant therapy was not associated with an OS difference in the low-risk group (HR 1.50, 95%CI:0.92-2.50), whereas improved OS was observed in the intermediate (HR 0.58, 95%CI:0.34-0.97) and high-risk groups (HR 0.47, 95%CI:0.24-0.94) (p-interaction=0.008).

Conclusions: The PANAMA 3-tier risk groups (low-risk, intermediate-risk, and high-risk, available via pancreascalculator.com) correspond with differential survival in patients with resected PDAC following neoadjuvant FOLFIRINOX. The risk groups also differentiate between survival benefit associated with adjuvant treatment, with only the intermediate- and high-risk groups associated with improved OS.

Background: Intraductal papillary mucinous neoplasms (IPMNs) display four histological subtypes: gastric foveolar, pancreaticobiliary, intestinal, and oncocytic. All of these subtypes harbor a different risk of cancer development. The clinical impact of these subtypes concerning the occurrence of high-grade dysplasia (HGD)/cancer (C) in specific morphological types, such as branch-duct (BD), main-duct (MD), and mixed-type (MT) IPMNs, has been less investigated. Hence, our aim was to investigate the prevalence of histological subtypes and their possible association with HGD/C concerning morphologically different IPMNs.

Methods: This was a retrospective review of demographics, risk factors, and histological features in a surgical cohort of patients having undergone resection for suspect malignant IPMNs at a high-volume tertiary center from 2007 to 2017.

Results: A total of 273 patients were resected for IPMNs from during the study period, of which 188 were included in the final analysis. With sex- and age-adjusted multivariable logistic regression analysis across the entire cohort, gastric foveolar subtypes were associated with a reduced prevalence of HGD/C (OR = 0.30; 0.11–0.81, 95% CI, 95%CI; p = 0.01). With univariable logistic regression analysis, in the BD-IPMN subgroup, the pancreaticobiliary subtype was associated with an increased prevalence of HGD/C (OR = 18.50, 1.03–329.65, 95% CI; p = 0.04). In MD- and MT-IPMNs, the gastric foveolar subtype was associated with a decreased prevalence of HGD/cancer (OR = 0.30, 0.13–0.69, 95% CI; p = 0.004).

Conclusions: In MD and MT-IPMNs, the gastric-foveolar subtype is associated with a lower prevalence of HGD/C, possibly identifying in such a high-risk group, a subgroup with more indolent behavior. In BD-IPMNs, the pancreaticobiliary subtype is associated with a higher prevalence of HGD/C, conversely identifying among those patients, a subgroup deserving special attention.

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.

Background: The introduction of the 1 mm cut-off for resection margin according to the Leeds Pathology Protocol has transformed the concept of surgical radicality. Its impact on nodal-positive resected pancreatic ductal adenocarcinoma patients is unclear. The aim of this study was to analyse the effect of margin clearance on survival among resected, nodal-positive pancreatic ductal adenocarcinoma patients whose specimens were analysed according to the Leeds Pathology Protocol.

Methods: Data were collected retrospectively from multicentre clinical databases. Resected patients with nodal involvement were included. Overall survival and disease-free survival were analysed according to minimum reported margin clearances of 0, 0.5, 1, and 2 mm. The results are reported separately for patients who had not undergone venous resection and for patients for whom data were available regarding the superior mesenteric vein-facing margin or the vein specimen. The eighth edition of TNM classification by the AJCC was used.

Results: The study comprised 290 stage IIB patients and 215 stage III patients without venous resection. The superior mesenteric vein margin analysis comprised 127 stage IIB patients and 198 stage III patients. The different resection margin distances were not associated with overall survival and disease-free survival among patients without venous resection (P > 0.050). Receiving adjuvant therapy was associated with longer overall survival among stage IIB patients (P = 0.034) and stage III patients (P = 0.003) and with longer disease-free survival among stage III patients (P < 0.001).

Conclusions: In this study, a margin clearance greater than 1 mm showed no clear effect on overall survival in pancreatic ductal adenocarcinoma patients with nodal involvement, whereas adjuvant therapy was confirmed to be essential to ensure longer overall survival.