Intraductal Papillary Mucinous Neoplasia Research Articles

The role of Smad4/TGFB signaling in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC).

748 Background: Pancreatic cancer ranks 4th among cancers as a cause of death in the United States and 85- 90% of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated 2 major types of precursors to PDAC including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN); the mechanisms by which IPMNs give rise to PDAC are incompletely defined. We hypothesize that SMAD4 signaling is specifically involved in IPMN pathway with PanINs and IPMN having partially overlapping signaling pathways and molecular markers. Methods: We performed immunohistochemistry staining on different precursor lesions of mouse pancreatic tissue (PanIN precursor: Ptf1aCre LSL-KrasG12D; IPMN precursor: Ptf1aCreERT LSL- KrasG12D Smad4fl/fl treated with tamoxifen) using markers of different IPMN subtypes and signaling pathways known to be involved in PDAC including, MUC1, MUC2, MUC5AC, SMAD4, ERK1/2, SOX9, and YAP. We treated IPMN cells lines derived from Ptf1aCreERTM LSL-KrasG12D GnasR201C mice with TGF-β, BMP-2, or vehicle control and quantified RNA expression of Smad7, Serpine1, Id2, and normalized to Pmm1 expression. We performed a western blot to detect the protein expression of phospho-SMAD1, phospho-SMAD2, SMAD1, and SMAD2. Results: Both PanIN and IPMN mouse models exhibited strong expression of MUC5AC and MUC1, reflecting the pancreatobiliary subtype. The tumor cells in both models expressed phosphorylated substrates of protein kinase A, phosphorylated ERK1/2, and SOX9. Regional differences were noted for SOX9 signaling with IPMN demonstrating a greater expression around the outer edges of the lesion, compared to the center. PanIN model demonstrated a more prominent nuclear YAP staining. Treatment of BMP2 and TGF-β in pancreatic IPMN cells from Ptf1aCreERTM LSL-KrasG12D GnasR201C cell line significantly increased RNA levels of Serpine1 (2.4 and 199.6, respectively; n = 4; p < 0.05) and Smad7 (2.9 and 6.3, respectively; n = 4; p < 0.05). BMP2 treatment significantly increased RNA levels of Id2 (1.9; n = 4; p < 0.05) while TGF-β significantly decreased Id2 level (0.3; n = 4; p < 0.05). Phosphorylated-SMAD2 was detected only with TGF-β treatment while phosphorylated-SMAD1 was detected with vehicle, TGF-β, and BMP2 treatment with the highest level with BMP2 treatment. Conclusions: Knocking out Smad4, concurrent with activating KrasG12D mutation, induces a specific IPMN progression model that shares similar molecular markers as the PanIN progression model, shown in Kras mutation alone. SMAD4 signaling remains intact in IPMN lesions that arise from activating the KrasG12D GnasR201C mutation, possibly suggesting that Smad4 mutation induces the IPMN-PDAC progression model that differs from Gas-cAMP-PAK-YAP1 cascade found in GNAS signaling.

Pancreatic duct imaging during aging.

As part of the aging process, fibrotic changes, fatty infiltration, and parenchymal atrophy develop in the pancreas. The pancreatic duct also becomes wider with age. This article provides an overview of the diameter of the pancreatic duct in different age groups and different examination methods. Knowledge of these data is useful to avoid misinterpretations regarding the differential diagnosis of chronic pancreatitis, obstructive tumors, and intraductal papillary mucinous neoplasia (IPMN).

Pre-emptive Resection for Intraductal Papillary Mucinous Neoplasia – Long-term Outcome Is Similar between Non-invasive and Early Invasive Lesions

Pre-emptive Resection for Intraductal Papillary Mucinous Neoplasia – Long-term Outcome Is Similar between Non-invasive and Early Invasive Lesions

Outcome after surgery for invasive intraductal papillary mucinous neoplasia compared to conventional pancreatic ductal adenocarcinoma – A Swedish nationwide register-based study

BackgroundThe clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated. ObjectiveThis study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC. MethodsAll patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010–2015, one for patients resected 2016–2019. Median overall survival (OS) was estimated using the Kaplan-Meier method. ResultsWe included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016–2019 cohort, but not in the 2010–2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC. ConclusionIn this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.

Diffuse Intraductal Papillary Mucinous Neoplasia in Both Native and Transplant Pancreases Despite Normal Residual Pancreas in the Respective First-Degree Donor.

Diffuse Intraductal Papillary Mucinous Neoplasia in Both Native and Transplant Pancreases Despite Normal Residual Pancreas in the Respective First-Degree Donor.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

Impact of spatio-temporal recurrence pattern on overall survival for invasive intraductal papillary mucinous neoplasia – A comparison with pancreatic ductal adenocarcinoma

BackgroundResections for intraductal papillary mucinous neoplasia (IPMN) have increased dramatically during the last decade. Recurrence pattern and impact of adjuvant chemotherapy for solid pancreatic ductal adenocarcinoma (PDAC) is well known, but not for invasive IPMN (inv-IPMN). ObjectivesTo elucidate the impact of spatio-temporal recurrence pattern and adjuvant chemotherapy on overall survival for inv-IPMN compared with PDAC. MethodsWe conducted a retrospective single-center observational study of consecutive patients ≥18 years of age who underwent resection for inv-IPMN or PDAC at Karolinska University Hospital, between 2009 and 2018. Different initial recurrence sites and time frames as well as predictors for death were assessed with multivariable Cox and logistic regressions. Survival analyses were performed using the Kaplan-Meier model and log rank test. ResultsOf 396 resected patients, 92 were inv-IPMN and 304 PDAC. Both recurrence rate and death rate within three-years were lower for inv-IPMN compared to PDAC (p = 0.006 and p = 0.007 respectively). Across the whole cohort, the most common recurrence patterns were multi-site (25%), single-site liver (21%) and single-site locoregional (10%) recurrence. The most prominent predictors for death in multivariable Cox regression, especially if occurred within the first year, were multi-site (HR 17.0), single-site peritoneal (HR 13.6) and single-site liver (HR 13.1) recurrence. These predictors were less common in inv-IPMN compared to PDAC (p = 0.007). The effect of adjuvant chemotherapy was similar in the two groups. ConclusionResected inv-IPMN exhibits a less aggressive recurrence pattern than PDAC that translates into a more favorable overall survival.

Circulating IgG4+ Plasmablast Count as a Diagnostic Tool in Autoimmune Pancreatitis

<h3>Background & Aims</h3> Type 1 autoimmune pancreatitis (AIP) is an IgG4-related disease whose diagnosis is challenging. The aim of this study was to investigate the diagnostic value of circulating total and IgG4⁺ plasmablasts in differentiating this condition from the other main pancreatic diseases. <h3>Methods</h3> Patients with type 1 AIP (n = 19) were prospectively enrolled in a tertiary center together with patients suffering from type 2 or not otherwise specified (NOS) AIP (n = 10), pancreatic adenocarcinoma (n = 17), chronic pancreatitis (n = 20), and intraductal papillary mucinous neoplasia or chronic asymptomatic pancreatic hyperenzymemia (n = 21) as control groups. Flow cytometry was used to measure the total plasmablast and IgG4⁺ plasmablast number by gating peripheral blood CD45⁺CD19⁺CD38^hiCD20^-CD24^-CD27⁺ and CD45⁺CD19⁺CD38^hiCD20^-CD24^-CD27⁺IgG4⁺ cells, respectively. In patients with AIP, these cell populations were also evaluated after 1 month of therapy, after 2–4 months from the end of treatment, and after 1 year from the enrollment. The study was approved by the local ethics committee (protocol number: 59133, 30/11/2017). <h3>Results</h3> Total plasmablast quantification was capable of discriminating type 1 AIP from all the other pancreatic disorders with a sensitivity of 47% and a specificity of 81%, according to a cutoff of 4500 cells/mL (AUC = 0.738), whereas IgG4⁺ plasmablast count distinguished type 1 AIP from all the other pancreatic disorders with a sensitivity of 80% and a specificity of 97% when applying a cutoff of 210 IgG4⁺ cells/mL (AUC = 0.879). The basal IgG4⁺ plasmablast number was significantly higher (<i>P</i> = .0001) in type 1 AIP than in type 2/NOS AIP, decreased after steroid therapy, and increased at disease relapse. <h3>Conclusion</h3> IgG4⁺ plasmablast count represents a potentially useful biomarker to differentiate type 1 from type 2/NOS AIP and from other pancreatic diseases.

Impact of Initial Recurrence Pattern on Overall Survival for Intraductal Papillary Mucinous Neoplasia

Introduction: Resections for intraductal papillary mucinous neoplasia (IPMN) have increased dramatically. Recurrence pattern and impact of adjuvant chemotherapy for conventional pancreatic adenocarcinoma (PDAC) is well known, but not for invasive IPMN (inv-IPMN). This study aims to elucidate the impact of adjuvant chemotherapy and tempo-spatial recurrence pattern on overall survival (OS) for inv-IPMN compared with PDAC.

Digital Cholangioscopy Visualized a Pancreaticobiliary Fistula Associated With Intraductal Papillary Mucinous Neoplasm

An 83-year-old woman presented with jaundice at our hospital. Contrast-enhanced computed tomography revealed a large intraductal papillary mucinous neoplasia (IPMN) with ectasia of the main pancreatic duct and intrahepatic bile ducts. An inferior common bile duct pancreaticobiliary fistula was also detected (Figure A: arrow). Subsequently, magnetic resonance cholangiopancreatography showed signal changes in the region, signifying massive amounts of mucus (Figure B).

Pancreatic Adenocarcinoma Associated to Intraductal Papillary Mucinous Neoplasia: Histopathological Particularities and Clinical Implications

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor, known for an aggressive evolution. Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor, considered a premalignant lesion with the possibility of carcinogenesis towards PDAC. The clinical, surgical and histopathological particularities of the association between PDAC and IPMN are yet unknown, further research being needed. Methods: We have conducted a retrospective descriptive study, on a nine-year period (2012-2020), with the aim of comparing the characteristics of patients that underwent curative surgical interventions for solitary PDAC and PDAC associated to IPMN. Results: Fifteen patients with PDAC associated with IPMN (Group 1) and 386 patients with solitary PDAC (Group 2) were included in our study. Group 1 had a younger average age (61.8 years) compared to Group 2 (63.89 years). Total pancreatectomy was more frequently performed for Group 1 than Group 2 (33.33% vs 12.43%). Group 1 had a higher percentage of cases with positive perineural, perilymphatic and perivascular invasion. Group 1 registered a worse overall survival, as well as a worse short-time survival compared to Group 2. Conclusions: PDAC associated to IPMN registers distinct epidemiological, clinical and histopathological characteristics compared to solitary PDAC.

Noninvasive risk stratification of intraductal papillary mucinous neoplasia with malignant potential by serum apolipoprotein-A2-isoforms.

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic cancer. An accurate serum biomarker, which allows earlier identification of asymptomatic individuals with high-risk for developing cancer, is of urgent need. Apolipoprotein A2-isoforms (apoA2-i) have previously been identified as biomarkers in pancreatic cancer. This study investigates a potential clinical application of the serum apoA2-i for risk stratification of IPMN and associated cancer. The concentrations of apoA2-i were retrospectively determined in 523 patient sera specimen, composed of 305 IPMNs with preinvasive lesions with different grades of dysplasia and invasive cancer, 140 pancreatic ductal adenocarcinoma, 78 with other cystic lesions and healthy controls cohorts, using an apoA2-i enzyme-linked immunosorbent assay kit. The diagnostic performance of serum apoA2-i was assessed and compared to routine clinical marker CA 19-9. ApoA2-i levels were significantly reduced in all IPMN samples regardless of stage compared to healthy controls. Receiver operating characteristic curve analysis of IPMNs with high-grade dysplasia and IPMN with associated carcinoma revealed the area under curve (AUC) of 0.91 and >0.94, respectively. The respective sensitivities were 70% and 83% with a specificity of 95%, and significantly higher than the gold standard biomarker CA 19-9. AUC values of apoA2-i for detecting IPMN-associated carcinoma of colloid and ductal subtypes were 0.990 and 0.885, respectively. ApoA2-i has the potential to early detect the risk of malignancy of patients with IPMN. The serological apoA2-i test in combination with imaging modalities could help improve the diagnosis of IPMN malignancy. Further validation in larger and independent international cohort studies is needed.

Indications for the surgical management of pancreatic neoplasms

Due to its rising incidence, pancreatic neoplasia, which mainly include adenocarcinomas, neuroendocrine and cystic neoplasia of the pancreas, is becoming increasingly relevant in everyday clinical practice.Based on a systematic literature search, a working group of pancreatic experts developed evidence-based recommendations for surgical indications in pancreatic neoplasia to improve the quality.There is a clear surgical indication for primary or secondary resectable pancreatic carcinomas without metastasis, for functionally active, symptomatic and functionally inactive neuroendocrine neoplasia of more than 2 cm in size and for cystic neoplasm with symptoms or signs of malignancy including all intraductal papillary-mucinous neoplasia (IPMN) of the main duct and mixed type, all mucinous-cystic neoplasia (MCN) > 4 cm and all solid pseudopapillary neoplasia (SPN). Surgery can be indicated for pancreatic carcinomas with isolated arterial vascular infiltration or for long periods of stable oligometastasis, regarding neuroendocrine neoplasias for metastasis or debulking surgery as well as for branch-duct IPMN with risk criteria and MCN <4 cm. There is no primary indication for surgery in locally advanced and metastatic pancreatic cancer or asymptomatic serous-cystic neoplasia (SCN).The indication for surgery should always be individualized taking into account age, comorbidities and patient wishes.

Abstract PO-103: Cellular origin influences immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of Kras

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of merely 9%. Although mouse studies in the past decade have made progress towards a better understanding of how PDAC cellular origin affects tumorigenesis, there hasn’t been study on the immune microenvironment differences between precursor lesions and PDAC derived from acinar and ductal cells. Following our previous study that showed loss of Pten with oncogenic KrasG12D mutations in the ductal cells (KPtenDuct/+) resulted the formation of intraductal papillary mucinous neoplasias (IPMN) as the precursor lesion in mice, we further found siminar mutations in the acinar cells (KPtenAcinar/+) formed pancreatic intraepithelial neoplasia (PanIN) instead. We subsequently used the KPtenDuct/+ and KPtenAcinar/+ models to elucidate the effect of cellular origin on the immune microenvironment by performing immunohistochemistry. We looked at immune cell infiltration densities between precursor lesions and PDAC derived from KPtenDuct/+ and KPtenAcinar/+ models and will present the data during the conference. Additionally, macrophages polarized by conditioned media derived from KPtenDuct/+ and KPtenAcinar/+ PDAC cells showed distinctive polarization status, indicating cellular origin could result in PDAC with different cytokine and chemokine profiles that affect the immune microenvironment. Our study is the first to directly compare immune cell population between acinar- and ductal-derived PDAC originating from different types of precursor lesions with the same genetic background. Our study suggests the potential role of cellular origin on influencing PDAC immune heterogeneity. Citation Format: Yan Dou, Wesley Hunt, Justin Chhuor, Farnaz Taghizadeh, Atefeh Samani, Karnjit Sarai, Claire Dubois, David F. Schaeffer, Maike Sander, Janel L. Kopp. Cellular origin influences immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of Kras [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-103.

Clinical Management of Pancreatic Premalignant Lesions

Clinical Management of Pancreatic Premalignant Lesions

S27 Association Between Pancreatic Intraductal Papillary Mucinous Neoplasms and Extrapancreatic Malignancies: A Systematic Review and Meta-Analysis

Introduction: It is still unclear whether patients with intraductal papillary mucinous neoplasia (IPMN) harbor a higher risk of developing extrapancreatic malignancies (EPMs). Aim of this meta-analysis is to provide a pooled estimate of the incidence of EPM in patients with IPMN, with a particular focus on the comparison to the general population. Methods: Computerized bibliographic search on the main databases was performed through February 2021. Pooled effects were calculated using a random-effects model by means of DerSimonian and Laird test. Primary endpoint was the pooled incidence of EPM in IPMN patients. Additional outcome was the comparison of EPM occurrence between IPMN patients and general population, expressed in terms of standardized incidence ration (SIR) along with 95% confidence intervals (CIs). Results: Eighteen studies with 8709 patients were included. Pooled rate of EPM in patients with IPMN was 27.3% (95% CI: 20.5%-34.1%), with a pooled rate of 14.7% (9.4%-20.1%) of EPM detected previous to IPMN diagnosis and 6.6% (4.5%-8.7%) of synchronous EPM. Pooled rate of metachronous EPM was 10 (95% CI: 6-13)/1000 persons-year. No difference was observed according to IPMN histology and sex, whereas a significantly superior incidence of EPM was observed in patients with main-duct IPMN (36.7%, 25.4%-48% as compared to 26.2%, 17.6%-34.8% in branch-duct IPMN; P=0.03) and in Eastern studies (36.1%, 31.1%-41.1% versus 20.8%, 12.7%-28.9%; P=0.02). Pooled SIR of comparison with expected rates in general population was 1.01 (0.79-1.29); no difference was observed concerning rates of metachronous gastric cancer (SIR 1.60, 0.72-3.54) and colorectal cancer (SIR 1.29, 0.92-1.18), whereas biliary cancer was observed more frequently in IPMN patients (SIR 2.29, 1.07-4.93). EPM-related and IPMN-related mortality rates ere 6% (3%-9.1%) and 6.3% (4.2%-8.5%), respectively. Conclusion: Our meta-analysis demonstrates that IPMN patients harbor an overall rate of EPM as high as 27.3%, but rate of metachronous EPM is not superior to the general population.Figure 1.: Forest plot comparing observed/expected incidence of metachronous extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia. Standardized incidence ratio was 1.01 (0.79-1.29), with moderate evidence of heterogeneity (I2=22%).Table 1.: Analysis concerning gastric, colorectal, biliary cancer, and mortality.

Mucinous Pancreatic Cysts: Comparison of Cyst Size and Location in Certain Mucinous Cyst Subgroups

There are studies reporting that the location of intraductal papillary mucinous neoplasia (IPMN) predicts malignancy. Therefore, we evaluated the cyst location's relationship with malignancy, and the possibility of using cyst size and location to distinguish between non-main duct (non-MD)-IPMNs, mucinous cystic neoplasia (MCN), and cystic pancreatic ductal adenocarcinoma (PDAC).We performed a retrospective analysis of data from 122 patients with a definite cyto-histological diagnosis of non-MDIPMNs, LR-MCNs, and cystic PDACs via endoscopic ultrasound fine-needle aspiration between October 2011 and October 2020. We grouped the cyst locations as head, uncinate, neck (HUN), and corpus or tail (CT). On histology, low-grade dysplasia and intermediategrade dysplasia were considered low risk (LR), whereas high-grade dysplasia and invasive carcinoma were considered high risk (HR).Of the 122 patients (61 (50%) women, median age 61.5 years (range 19-85), there were 34 (27.9%) LR-non-MD-IPMNs, 33 (27%) HR-non-MD-IPMNs, 19 (15.6%) LR-MCNs, and 36 (29.5%) cystic PDACs. We found no significant difference between LRand HR-non-MD-IPMN locations (P = .803). Low-risk non-MD-IPMNs were significantly smaller than HR-non-MD-IPMNs (P < .001), LR-MCNs (P = .002), and cystic PDACs (P < .001). The area under the receiver operating characteristic curve (AUROC) was 0.819 (95% CI: 0.716-0.902; P < .0001), and demonstrated a cyst size cut-off <2.2 cm to differentiate LR cysts, while cysts <1.6 cm had a negative predictive value (NPV) of 100% in non-MD-IPMNs.Cyst location is not predictive of malignancy in non-MD-IPMNs. Low-risk non-MD-IPMNs were smaller than HR-non MDIPMNs, LR-MCNs, and cystic PDACs. The cyst size cut-off was 2.2 cm; however, <1.6 cm had a 100% NPV differentiating LR- from HR-non-MD-IPMNs.

Outcome after resection for invasive intraductal papillary mucinous neoplasia is similar to conventional pancreatic ductal adenocarcinoma

Background/objectivesResections for intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Overall survival (OS) for conventional pancreatic ductal adenocarcinoma (PDAC) is well known but OS for invasive IPMN (inv-IPMN) is not as conclusive. This study aims to elucidate potential differences in clinicopathology and OS between these tumor types and to investigate if the raised number of resections have affected outcome. MethodsConsecutive patients ≥18 years of age resected for inv-IPMN and PDAC at Karolinska University Hospital between 2009 and 2018 were included. Clinicopathological variables were analyzed in multivariable regression models. Outcome was assessed calculating two-year OS, estimating OS using the Kaplan-Meier model and comparing survival functions with log-rank test. Results513 patients were included, 122 with inv-IPMN and 391 with PDAC. During the study period both the proportion resected inv-IPMN and two-year OS, irrespective of tumor type, increased (2.5%–45%; p < 0.001 and 44%–57%; p = 0.005 respectively). In Kaplan-Meier survival analysis inv-IPMN had more favorable median OS (mOS) compared to PDAC (33.6 months vs 19.3 months, p = 0.001). However, in multivariable Cox Regression analysis, tumor type was not a predictor for death, but so were resection period, tumor subtype and N-stage (all p < 0.001). ConclusionIn this large single center observational cohort study, inv-IPMN seemed to have favorable survival outcome compared to PDAC, but after adjusting for predictors for death this benefit vanished. The combination of a pronounced increase in resected inv-IPMN and a concurrent hazard abatement for death within 2 years during the study period proved to be a principal factor.

Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations for diagnosis of intraductal papillary mucinous neoplasia and mucinous cystic lesions: a systematic review and meta-analysis

Although molecular analysis of pancreatic cyst fluid may aid pancreatic cyst classification, clinical practice remains highly variable. Therefore, we performed a systematic review and meta-analysis to evaluate the diagnostic performance of KRAS and GNAS mutations in EUS-acquired pancreatic cyst fluid for diagnosis of intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic lesions (MCLs). Individualized searches were developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and meta-analysis analyzed according to the Cochrane Diagnostic Test Accuracy working group methodology. A bivariate model was used to compute the pooled sensitivity and specificity and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence interval (95% CI). Six studies (785 lesions) were included. For IPMNs and MCLs, KRAS + GNAS (combination) had significantly higher diagnostic accuracy than KRAS alone and GNAS alone (all P< .001). The pooled sensitivity, specificity, and diagnostic accuracy of KRAS + GNAS mutations for diagnosis of IPMNs were 94% (95% CI, 72-99; I2= 86.74%), 91% (95% CI, 72-98; I2= 89.83), and 97% (95% CI, 95-98), respectively, with each significantly higher compared with carcinoembryonic antigen (CEA) alone (all P< .001). For diagnosis of MCLs, KRAS + GNAS had a similar sensitivity and specificity compared with CEA alone; however, diagnostic accuracy was significantly improved (97% [95% CI, 95-98] vs 89% [95% CI, 86-91]; P< .001). Molecular analysis for KRAS + GNAS mutations in EUS-acquired pancreatic cyst fluid has high sensitivity and specificity with significantly improved diagnostic accuracy for diagnosis of IPMNs and MCLs when compared with CEA alone.

Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations for diagnosis of intraductal papillary mucinous neoplasia and mucinous cystic lesions：a systematic review and meta-analysis 1）.

Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations for diagnosis of intraductal papillary mucinous neoplasia and mucinous cystic lesions：a systematic review and meta-analysis^1）.