Precursor Epithelial Subtypes of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasms (A-IPMN): Clinicopathological Features, Recurrence and Response to Adjuvant Chemotherapy.

BACKGROUND: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown. METHODS: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis. RESULTS: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]. CONCLUSIONS: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype.

Association of Smoking with progression from low-risk to high-risk intraductal papillary mucinous neoplasms and pancreatic cancer.

BACKGROUND: Factors associated with the risk of pancreatic adenocarcinoma (PDAC) may play a role in the development and progression of Intraductal Papillary Mucinous Neoplasms (IPMNs). However, data are limited. AIM: To compare exposome factors in three groups of patients with "high or low-risk" IPMNs, as assessed at diagnosis and during a 24-months follow-up, and with PDAC. METHODS: Patients were matched (same sex, age ±5) 1:1. Exposure variables were compared across groups using Kruskal-Wallis, ANOVA, or Chi-square tests with Bonferroni correction. RESULTS: A total of 151 patients were enrolled in each of the three groups (453 overall). The proportion of current smokers was progressively higher in "low-risk", "high-risk" IPMNs and PDAC patients (8.1 %, 11.2 %, 23.3 %; p = 0.0002). The three groups did not differ in terms of ever or heavy smoking, BMI, history of diabetes, cancer, cholecystectomy or chronic pancreatitis, use of statins or aspirin, and family history of cancer. A history of peptic ulcer was more common in PDAC (7.2 %) than in either "low-risk" (2.0 %) or "high-risk" (2.6%) IPMNs (p = 0.02, not significant after Bonferroni correction). CONCLUSION: Active smoking seems associated with the progression of IPMNs to malignancy, and cessation of active smoking might be advised in patients with IPMN.

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.

Predictors of long-term survival after resection of adenocarcinoma arising from intraductal papillary mucinous neoplasm and derivation of a prognostic model: An international multicenter study (ADENO-IPMN study).

BACKGROUND: Predictors of long-term survival after resection of adenocarcinoma arising from intraductal papillary mucinous neoplasms are unknown. This study determines predictors of long-term (>5 years) disease-free survival and recurrence in adenocarcinoma arising from intraductal papillary mucinous neoplasms and derives a prognostic model for disease-free survival. METHODS: Consecutive patients who underwent pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms in 18 academic pancreatic centers in Europe and Asia between 2010 to 2017 with at least 5-year follow-up were identified. Factors associated with disease-free survival were determined using Cox proportional hazards model. Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In the study, 288 patients (median age, 70 years; 52% male) were identified; 140 (48%) patients developed recurrence after a median follow-up of 98 months (interquartile range, 78.4-123), 57 patients (19.8%) developed locoregional recurrence, and 109 patients (37.8%) systemic recurrence. At 5 years after resection, the overall and disease-free survival was 46.5% (134/288) and 35.0% (101/288), respectively. On Cox proportional hazards model analysis, multivisceral resection (hazard ratio, 2.20; 95% confidence interval, 1.06-4.60), pancreatic tail location (hazard ratio, 2.34; 95% confidence interval, 1.22-4.50), poor tumor differentiation (hazard ratio, 2.48; 95% confidence interval, 1.10-5.30), lymphovascular invasion (hazard ratio, 1.74; 95% confidence interval, 1.06-2.88), and perineural invasion (hazard ratio, 1.83; 95% confidence interval, 1.09-3.10) were negatively associated with long-term disease-free survival. The final predictive model incorporated 8 predictors and demonstrated good predictive ability for disease-free survival (C-index, 0.74; calibration, slope 1.00). CONCLUSION: A third of patients achieve long-term disease-free survival (>5 years) after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms. The predictive model developed in the current study can be used to estimate the probability of long-term disease-free survival.

Impact of age, comorbidities and relevant changes on surveillance strategy of intraductal papillary mucinous neoplasms: a competing risk analysis.

OBJECTIVE: Cost-effectiveness of surveillance for branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. We combined different categories of risks of IPMN progression and of IPMN-unrelated mortality to improve surveillance strategies. DESIGN: Retrospective analysis of 926 presumed BD-IPMNs lacking worrisome features (WFs)/high-risk stigmata (HRS) under surveillance. Charlson Comorbidity Index (CACI) defined the severity of comorbidities. IPMN relevant changes included development of WF/HRS, pancreatectomy or death for IPMN or pancreatic cancer. Pancreatic malignancy-unrelated death was recorded. Cumulative incidence of IPMN relevant changes were estimated using the competing risk approach. RESULTS: 5-year cumulative incidence of relevant changes was 17.83% and 1.6% developed pancreatic malignancy. 5-year cumulative incidences for IPMN relevant changes were 13.73%, 19.93% and 25.04% in low-risk, intermediate-risk and high-risk groups, respectively. Age ≥75 (HR: 4.15) and CACI >3 (HR: 3.61) were independent predictors of pancreatic malignancy-unrelated death. 5-year cumulative incidence for death for other causes was 15.93% for age ≥75+CACI >3 group and 1.49% for age <75+CACI ≤3. 5-year cumulative incidence of IPMN relevant changes were 13.94% in patients with age <75+CACI ≤3 compared with 29.60% in those with age ≥75+CACI >3. In this group 5-year rate of malignancy-free patients was 95.56% with a 5-year survival of 79.51%. CONCLUSION: Although it is not uncommon the occurrence of changes considered by current guidelines as relevant during surveillance of low risk BD-IPMNs, malignancy rate is low and survival is significantly affected by competing patients' age and comorbidities. IPMN surveillance strategy should be tailored based on these features and modulated over time.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

Management of malignant Gastric Outlet Obstruction (mGOO) due to pancreatic cancer in the era of EUS-Gastrojejunostomy: an international practice survey and case vignette study by Pancreas 2000 from the European Pancreatic Club.

BACKGROUND: Malignant Gastric Outlet Obstruction (mGOO) has been standardly treated by surgical Gastrojejunostomy (S-GJ) or Endoscopic Stenting (ES). Recently, EUS-Gastrojejunostomy (EUS-GJ) has emerged as an alternative, despite its worldwide diffusion is heterogeneous. The aim of this survey was to assess clinical decision-making around mGOO and to explore current opinions regarding EUS-GJ. METHODS: An online survey, spread through social networks and EPC newsletter, was created exploring opinions regarding indications, contraindications, benefits/risks, availability of mGOO treatments; 2 case vignettes explored clinical decision-making in different scenarios. RESULTS: Overall, 290 pancreatologists from 44 countries responded, of whom 35% surgeons and 65% gastroenterologists. The most common treatment for mGOO was ES (86%), followed by laparoscopic GJ (76%). EUS-GJ was accessible to 59% of respondents, with 10% proficient in this technique. Gold-standard treatment for mGOO varied by specialty; 45% of gastroenterologists preferred ES, 20% EUS-GJ, and 10% surgical GJ, while among surgeons, these were 24%, 8%, and 25%, respectively. A higher annual volume of mGOO treated correlated with increased EUS-GJ adoption and reduced surgical advice. For 51%, EUS-GJ will become the primary treatment for mGOO, notably higher among gastroenterologists and high-volume centers. For 14%, EUS-GJ spread will be limited in the future, or used only when ES fails (19%). Life expectancy, disease stage and patient's frailty are the main decision driver in therapeutic choice, whereas future surgical resectability does not contraindicate any treatment for 75%. EUS-GJ's main advantages were its minimally invasive nature and clinical efficacy, offset by its steep learning curve. CONCLUSIONS: This survey revealed significant differences in the management of mGOO, depending on specialties, local expertise and treatment volume, suggesting the lack of standardized algorithms. Life expectancy and patients' frailty are the main decision drivers. Regarding EUS-GJ, its availability remains suboptimal, with learning curve as the main perceived barrier.

Long-term Outcomes following Resection of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasm (A-IPMN) versus Pancreatic Ductal Adenocarcinoma (PDAC): A Propensity-score Matched Analysis.

OBJECTIVE: The aim of the present study was to compare long-term post-resection oncological outcomes between A-IPMN and PDAC. SUMMARY BACKGROUND DATA: Knowledge of long term oncological outcomes (e.g recurrence and survival data) comparing between adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) and pancreatic ductal adenocarcinoma (PDAC) is scarce. METHODS: Patients undergoing pancreatic resection (2010-2020) for A-IPMN were identified retrospectively from 18 academic pancreatic centres and compared with PDAC patients from the same time-period. Propensity-score matching (PSM) was performed and survival and recurrence were compared between A-IPMN and PDAC. RESULTS: 459 A-IPMN patients (median age,70; M:F,250:209) were compared with 476 PDAC patients (median age,69; M:F,262:214). A-IPMN patients had lower T-stage, lymphovascular invasion (51.4%vs. 75.6%), perineural invasion (55.8%vs. 71.2%), lymph node positivity (47.3vs. 72.3%) and R1 resection (38.6%vs. 56.3%) compared to PDAC(P<0.001). The median survival and time-to-recurrence for A-IPMN versus PDAC were 39.0 versus19.5months (P<0.001) and 33.1 versus 14.8months (P<0.001), respectively (median follow-up,78 vs.73 months). Ten-year overall survival for A-IPMN was 34.6%(27/78) and PDAC was 9%(6/67). A-IPMN had higher rates of peritoneal (23.0 vs. 9.1%, P<0.001) and lung recurrence (27.8% vs. 15.6%, P<0.001) but lower rates of locoregional recurrence (39.7% vs. 57.8%; P<0.001). Matched analysis demonstrated inferior overall survival (P=0.005), inferior disease-free survival (P=0.003) and higher locoregional recurrence (P<0.001) in PDAC compared to A-IPMN but no significant difference in systemic recurrence rates (P=0.695). CONCLUSIONS: PDACs have inferior survival and higher recurrence rates compared to A-IPMN in matched cohorts. Locoregional recurrence is higher in PDAC but systemic recurrence rates are comparable and constituted by their own distinctive site-specific recurrence patterns.

Association of autoimmune pancreatitis and intraductal papillary mucinous neoplasm. A retrospective analysis from a tertiary care referral center.

BACKGROUND: Autoimmune Pancreatitis (AIP) is a rare chronic inflammatory disease affecting the pancreas. Chronic pancreatic inflammation represents a risk factor for pre-neoplastic conditions such as Intraductal Papillary Mucinous Neoplasia (IPMN). Due to the rarity of AIP, the incidence, and clinical features of IPMN occurring in AIP patients remains unknown. AIMS: In the present study we aimed to explore the relationship between AIP and IPMN and to characterize the clinical features and outcomes of IPMN occurring in the context of AIP. METHODS: We retrospectively (2008-2020) analyzed the clinical and radiological records of a large single center cohort of patients with AIP and investigated the prevalence of IPMN. We then compared the clinical, laboratory and radiological characteristics of patients with IPMN and AIP with a cohort of patients with isolated IPMN. RESULTS: Five hundred and nineteen patients were included in this retrospective study. Sixteen patients had concomitant IPMN and AIP(3%); 61 patients had isolated AIP (12%); 442 patients had isolated IPMN (85%). The prevalence of IPMN in patients with AIP was higher than that observed in the general population (21%vs8-10%). Worrisome Features and High-Risk Stigmata were more frequently observed in IPMN occurring together with AIP compared to isolated IPMN(p < 0.05). Based on radiological features IPMN in the context of AIP was more frequently of main-duct type compared to isolated IPMN(p < 0.05). CONCLUSION: Our data suggest that AIP represents a chronic inflammatory condition that might favor IPMN development with high-risk features. Prolonged surveillance of these patients and longitudinal studies are required to further test the association with AIP and malignant and pre-malignant conditions.

The Italian registry of families at risk for pancreatic cancer (IRFARPC): implementation and evolution of a national program for pancreatic cancer surveillance in high-risk individuals.

Screening programs for early detection and treatment of pancreatic cancer (PC) and its precursor lesions are increasingly implemented worldwide to reduce disease-specific lethality. Given the relatively low prevalence of the disease, the ideal target of such approaches is an enriched cohort of individuals harboring a lifetime risk of developing PC significantly higher compared to the general population, given either a substantial aggregation of PC cases in their family (i.e. familial pancreatic cancer) or a genomic landscape enriched with pathogenic variants associated with pancreatic carcinogenesis (i.e. mutation carriers). In Italy, a national registry for the census and surveillance of high-risk individuals for PC was launched in 2015, enrolling some 1200 subjects as of today. In this perspective, the scientific background, multi-level structure, and evolution of IRFARPC are outlined, as well as its long-term results, future developments, and areas for improvement.

Opioid analgesia and severity of acute pancreatitis: An international multicentre cohort study on pain management in acute pancreatitis.

BACKGROUND: The effect of analgesic modalities on short-term outcomes in acute pancreatitis remains unknown. However, preclinical models have raised safety concerns regarding opioid use in patients with acute pancreatitis. OBJECTIVE: This study aimed to assess the association between analgesics, particularly opioids, and severity and mortality in hospitalised patients with acute pancreatitis. METHODS: This prospective multicentre cohort study recruited consecutive patients admitted with a first episode of acute pancreatitis between April 1 and 30 June 2022, with a 1-month follow-up. Data on aetiology, clinical course, and analgesic treatment were collected. The primary outcome was the association between opioid analgesia and acute pancreatitis severity, which was analysed using univariate and multivariate analyses. RESULTS: Among a total of 1768 patients, included from 118 centres across 27 countries, 1036 (59%) had opioids administered on admission day, and 167 (9%) received opioids after admission day. On univariate analysis, moderately severe or severe acute pancreatitis was associated with male sex, Asian ethnicity, alcohol aetiology, comorbidity, predicted severe acute pancreatitis, higher pain scores, longer pain duration and opioid treatment (all p < 0.001). On multivariate analysis, comorbidity, alcohol aetiology, longer pain duration and higher pain scores increased the risk of moderately severe or severe acute pancreatitis (all p < 0.001). Furthermore, opioids administered after admission day (but not on admission day) doubled the risk of moderately severe or severe disease (OR 2.07 (95% CI, 1.29-3.33); p = 0.003). Opioid treatment for 6 days or more was an independent risk factor for moderately severe or severe acute pancreatitis (OR 3.21 (95% CI, 2.16-4.79; p < 0.001). On univariate analysis, longer opioid duration was associated with mortality. CONCLUSION: Opioid treatment increased the risk of more severe acute pancreatitis only when administered after admission day or for 6 days or more. Future randomised studies should re-evaluate whether opioids might be safe in acute pancreatitis.

Communication, understanding and engagement of patients with pancreatic cancer at time of diagnosis.

BACKGROUND: Objectives: To investigate communication clarity and understanding at the time of pancreatic adenocarcinoma (PDAC) diagnosis and whether they can influence patient engagement and compliance. METHODS: Consecutive PDAC patients were enrolled at the time of diagnosis after obtaining informed consent in a single-center study. The patients completed a validated scale (PHE-s®), and the understanding rate was assessed using standardized tools. Patient compliance was evaluated, and the correlation between the PHE-s®, understanding, and compliance was calculated. RESULTS: Thirty patients were enrolled (15 female) with a mean age 64.4, 13 were metastatic. The mean visit time was 31 min, being longer if visiting doctor was an oncologist (p = 0.002). The engagement level was high in 70% of the patients, and all but one were compliant. The analysis of doctor-patient interactions showed a median of 121 conversational turns for doctors, 75 for patients, and 20 for caregivers (p < 0.0001), and the median percentage of speaking time was 77% for doctors, 13% for patients, and 2% for caregivers (p < 0.0001). Female caregivers spent more time speaking than did male caregivers (median 11.6% vs. 1.3%; p = 0.06). There were 290 instances of problematic understanding, most of which occurred during the taking of patients' personal medical history for doctors, while for patients and caregivers, these occurred mainly during the discussion of diagnosis/treatment (p < 0.0001). In a multivariable analysis, only origin from central or southern Italy was associated with high engagement (p = 0.0087). CONCLUSION: In this first attempt to measure clarity of communication and engagement in patients with PDAC, typical features of conversation and problematic understanding emerged, which deserves further investigation.

An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature associated with prognosis in PDAC and the splicing factor Quaking (QKI) as a determinant of the basal-like signature. Single-cell sequencing analyses highlight QKI as a marker of the basal-like phenotype. QKI represses splicing events associated with the classical subtype while promoting basal-like events associated with shorter survival. QKI favors a plastic, quasi-mesenchymal phenotype that supports migration and chemoresistance in PDAC organoids and cell lines, and its expression is elevated in high-grade primary tumors and metastatic lesions. These studies identify a splicing signature that defines PDAC subtypes and indicate that QKI promotes an undifferentiated, plastic phenotype, which renders PDAC cells chemoresistant and adaptable to environmental changes.

Same-session endoscopic diagnosis and symptom palliation in pancreato-biliary malignancies: Clinical impact of rapid on-site evaluation (ROSE).

Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 [interquartile range 63-78]; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19-1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2-7) and median time to chemotherapy was 33 days (range, 24-47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk.

BACKGROUND AND AIMS: In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs. METHODS: We performed annual surveillance of Dutch HRIs, involving carriers of germline pathogenic variants (PVs) and PV-negative familial pancreatic cancer kindreds. HRIs with IPMNs were compared with Italian individuals without familial risk under surveillance for sporadic IPMNs. RESULTS: A total of 457 HRIs were followed for 48 (range 2-172) months; the estimated cumulative IPMN incidence was 46% (95% confidence interval, 28%-64%). In comparison with 442 control individuals, IPMNs in HRIs were more likely to grow ≥2.5 mm/y (31% vs 7%; P < .001) and develop worrisome features (32% vs 19%; P = .010). PV carriers with IPMNs more often displayed neoplastic progression (n = 3 [11%] vs n = 6 [1%]; P = .011), while familial pancreatic cancer kindreds did not (n = 0 [0%]; P = 1.000). The malignancy risk in a PV carrier with an IPMN was 23% for growth rates ≥2.5 mm/y (n = 13), 30% for ≥5 mm/y (n = 10), and 60% for ≥10 mm/y (n = 5). CONCLUSIONS: The cumulative incidence of IPMNs in HRIs is higher than previously reported in the general population. Compared with sporadic IPMNs, they have an increased growth rate. PV carriers with IPMNs are suggested to be at a higher malignancy risk. Intensive follow-up should be considered for PV carriers with an IPMN growing ≥2.5 mm/y, and surgical resection for those growing ≥5 mm/y.

Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.