Intraductal Papillary Mucinous Neoplasm Patients Research Articles

Older Age as a Worrisome Feature in Patients With Intraductal Papillary Mucinous Neoplasms: a Long-Term Surveillance Study.

Aging has been implicated in the development of various cancer types. No study has specifically investigated age at the diagnosis of intraductal papillary mucinous neoplasms (IPMNs) in relation to the long-term risk of pancreatic carcinogenesis. Within a prospective cohort of 4,104 patients diagnosed with pancreatic cysts, we identified 3,142 IPMN patients and examined an association of age at IPMN diagnosis with the incidence of pancreatic carcinoma. Utilizing the multivariable competing-risks proportional hazards regression model, we estimated subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) for pancreatic carcinoma incidence according to age at IPMN diagnosis. During 22,187 person-years of follow-up, we documented 130 patients diagnosed with pancreatic carcinoma (64 with IPMN-derived carcinoma and 66 with concomitant ductal adenocarcinoma). Older age at IPMN diagnosis was associated with a higher risk of pancreatic cancer incidence (Ptrend = 0.002). Compared to patients aged < 55 years, patients aged 55-64, 65-74, and ≥ 75 years had adjusted SHRs of 1.80 (95% CI, 0.75-4.32), 2.56 (95% CI, 1.10-5.98), and 3.31 (95% CI, 1.40-7.83), respectively. Patients aged ≥ 70 years had a numerically similar adjusted SHR compared to patients aged < 70 years with worrisome features defined by the international consensus guidelines (1.73 [95% CI, 1.01-2.97] and 1.66 [95% CI, 0.89-3.10], respectively). Older patients with IPMNs were at a higher risk of developing pancreatic carcinoma during surveillance. Surgically fit elderly patients may be good candidates for periodic surveillance aimed at a reduction of pancreatic cancer-related deaths.

Abstract 446: Integrated spatial transcriptomics and lipidomics analyses of intraductal papillary mucinous neoplasm identifies enrichment of long chain sulfatide as an early metabolic alteration

Abstract Purpose: To define the metabolic alterations associated with malignant progression of intraductal papillary mucinous neoplasm (IPMN). Experimental Procedures: Matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) was conducted for spatial characterization of lipid profiles on frozen tissue sections from resected human IPMN patients. The specimen set consisted of either low-grade dysplasia (LG) (n=15), high-grade (HG) dysplasia (n=4), or with an associated pancreatic ductal adenocarcinoma (PDAC) (n=4) as well as 15 PDAC tissues. Utilizing serial sections to the same human IPMN cases analyzed with MALDI-MS imaging, we used the Visium Spatial Gene Expression technology platform to characterize the spatiomolecular underpinnings of LG and HG IPMN. H&amp;E images of the same tissue section used for the Visium workflow, were used to annotate the spots in the dataset covering the epithelial lining of the IPMN lesions (“epilesional” areas) and the spots covering the adjacent microenvironment surrounding the lesion (“perilesiopecific” area). Findings were compared with lipidomic analyses of cystic fluid from 89 IPMN patients. The anti-cancer efficacy of UGT8-IN-1, a selective small molecule inhibitor of ceramide galactosyltransferase (CGT, also known as UGT8), was assessed in vitro and in mutant Kras;Gnas allografts. Results: MALDI/MS-based spatial imaging of human resected IPMN tissues and pancreata from a mutant Kras;Gnas mouse model of IPMN revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Visium spatial transcriptomics data confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid from 89 patients with IPMN identified several sulfatide species to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Inhibition of sulfatide metabolism via UGT8-IN-1 reduced viability of Kras;Gnas murine cell lines in vitro and attenuated tumor growth in an allograft IPMN model. UGT8-IN-1 treatment resulted in reduced levels of several sulfatide species, accompanied by a concomitant increase in a subset of quantified sulfatides precursor ceramides, accumulation of mitochondrial mass and reactive oxygen species and time-dependent increases in autophagy/mitophagy markers p62/SQSTM1 and LC-3B, suggesting impaired mitophagy. Conclusion: Enhanced sulfatide metabolism is an early alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception. Citation Format: Yihui Chen, Marta Sans, Fredrik Thege, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, Jianjun Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal Rajapakshe, Mark Hurd, Ricardo León-Letelier, Jody Vykoukal, Jennifer Dennison, Kim-Anh Do, Robert Wolff, Paola Guerrero, Michael Kim, Max Schmidt, Anirban Maitra, Samir Hanash, Johannes Fahrmann. Integrated spatial transcriptomics and lipidomics analyses of intraductal papillary mucinous neoplasm identifies enrichment of long chain sulfatide as an early metabolic alteration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 446.

Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer.

To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.

Identifying predictors for comorbidities related mortality versus pancreatic cancer related mortality in patients with intraductal papillary mucinous neoplasm.

Few data are available for surveillance decisions focusing on factors related to mortality, as the primary outcome, in intraductal papillary mucinous neoplasm (IPMN) patients. We aimed to identify imaging features and patient backgrounds associated with mortality risks by comparing pancreatic cancer (PC) and comorbidities. We retrospectively conducted a multicenter long-term follow-up of 1864 IPMN patients. Competing risk analysis was performed for PC- and comorbidity-related mortality. During the median follow-up period of 5.5years, 14.0% (261/1864) of patients died. Main pancreatic duct ≥5mm and mural nodules were significantly related to all-cause and PC-related mortality, whereas cyst ≥30mm did not relate. In 1730 patients without high-risk imaging features, 48 and 180 patients died of PC and comorbidity. In the derivation cohort, a prediction model for comorbidity-related mortality was created, comprising age, cancer history, diabetes mellitus complications, chronic heart failure, stroke, paralysis, peripheral artery disease, liver cirrhosis, and collagen disease in multivariate analysis. If a patient had a 5 score, 5- and 10-year comorbidity-related mortality is estimated at 18.9% and 50.2%, respectively, more than 7 times higher than PC-related mortality. The model score was also significantly associated with comorbidity-related mortality in a validation cohort. This study demonstrates main pancreatic duct dilation and mural nodules indicate risk of PC-related mortality, identifying patients who need periodic examination. A comorbidity-related mortality prediction model based on the patient's age and comorbidities can stratify patients who do not require regular tests, especially beyond 5years, among IPMN patients without high-risk features. T2022-0046.

Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study

Background and aims Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. Methods Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. Results A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34–10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79–7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). Conclusions We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

Abstract C011: Detection of circulating tumor cells for the early detection of pancreatic cancer

Abstract Introduction The majority of pancreatic cancer patients are diagnosed with advanced, metastatic disease. Biomarkers to detect pancreatic cancer at earlier stages could drastically improve the poor survival rates. Circulating tumor cells (CTCs) are tumor cells that disseminate or are shed into the vascular system and have been detected in patients at pre-malignant stages. However, detecting these rare cells accurately and reliably remains a challenge. The AccuCyte-CyteFinder system uses density-based enrichment of blood nucleated cells followed by detection of CTCs using fluorescence staining, whole slide scanning and automated image analysis. This study aimed to examine whether CTCs could be used to identify patients with pancreatic lesions likely to malignant. Methods 50 patients undergoing an endoscopic ultrasound procedure for a pancreatic mass were recruited at the Royal Prince Alfred Hospital, Sydney, Australia or Chris O’Brien Lifehouse, Sydney, Australia. Peripheral blood was collected prior to the procedure and processed for CTCs on the AccuCyte-CyteFinder platform using a CK+ EpCAM+ CD45- staining panel. Results 28% (14/50) were found to have an intraductal papillary mucinous neoplasm (IPMN), 10% (5/50) pancreatic ductal adenocarcinoma (PDAC), 6% (3/50) pancreatic neuroendocrine tumor (PNET), 42% (21/50) non-neoplastic pancreatic cyst, and 14% (7/50) normal (no mass found). CTCs were highest in the PDAC group with an average of 5 cells/ml, followed by the IPMN (3 cells/ml), pancreatic cyst (2.5 cells/ml), and PNET (0 cells/ml). 86% (12/14) of IPMN patients had detectable CTCs. 2 IPMN patients with CTC counts of more than 5 cells/ml resulted in a resected sample having high-grade dysplasia while 3 IPMN patients with no/low CTC counts resulted in a resected sample having low-grade dysplasia. There was no correlation with the size of the pancreatic mass and CTC number. Conclusions CTCs could be detected in patients with pre-malignant pancreatic cancer and could determine malignancy. CTCs could potentially be used to detect pancreatic cancer early however, larger patient numbers and longer follow-up are required to validate these findings. Citation Format: Dannel Yeo, Vera Klemm, Payal Saxena, Althea Bastian, Heidi Strauss, Charbel Sandroussi, Sara Wahlroos, Peter Grimison, John E.J. Rasko. Detection of circulating tumor cells for the early detection of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C011.

Preliminary clinical exome evaluation of intraductal papillary mucinous neoplasm patients by next generation sequencing

Preliminary clinical exome evaluation of intraductal papillary mucinous neoplasm patients by next generation sequencing

Evaluation of intraductal papillary mucinous neoplasms detected incidentally with magnetic resonance cholangiopancreatography

Objectives: The aim of this study was to estimate the prevalence of coincidentally found intraductal papillary mucinous neoplasms (IPMNs) and assess their features with magnetic resonance cholangiopancreatography (MRCP) imaging. Methods: The prevalence of incidentally detected IPMN was evaluated in 951 patients who underwent MRCP examination for various indications. MRCP images were assessed to analyze the number, size, location, and internal structure of lesions in patients with IPMN. Furthermore, the association between IPMN prevalence and age and gender was evaluated. Results: IPMN was detected in 102 (10.7%) of 951 patients. Solitary IPMNs were located in different parts of the pancreas: in the uncinate process in 8 (7.8%), in the head and neck in 19 (18.6%), in the corpus in 10 (9.8%), and in the tail in 7 (6.9%) patients. IPMN was multiple in 58 (56.9%) patients. IPMN was identified in 41 (6.18%) patients under 65 years and 61 (21.18%) patients over 65 years, and the variance was statistically substantial (p &amp;lt; 0.001). IPMN diameter was 7.22 ± 4.3 mm in patients under 65 years and 9.21 ± 4.74 mm in those over 65 years, which was statistically significant (p = 0.048). Patients who were older were more likely to have multiple IPMNs (p = 0.010). Conclusions: IPMNs increase in frequency, quantity, and size with age. MRCP is the most essential sequence for determining main pancreatic duct (MPD) involvement or communication, a critical finding for diagnosis. Since MRCP is capable of screening patients at very short intervals, it may be utilized for follow-up imaging in IPMN patients.

Clinical trajectory of intraductal papillary mucinous neoplasms progressing to pancreatic carcinomas during long-term surveillance: a prospective series of 100 carcinoma cases.

Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms (IPMNs). Using a prospective cohort of 3437 IPMN patients, we identified 100 IPMN patients who developed pancreatic carcinomas during long-term surveillance. We examined serial changes of blood markers (carbohydrate antigen 19-9 [CA19-9], hemoglobin A1c [HbA1c], and pancreatic enzymes) and morphological features (worrisome features and high-risk stigmata) during the prediagnostic period of pancreatic carcinomas, overall and by carcinoma types (IPMN-derived vs. concomitant pancreatic carcinomas). CA19-9 elevation was observed in 39 patients and was associated with a metastatic stage. Compared to IPMN-derived carcinomas, concomitant carcinomas were more likely to represent CA19-9 elevation (60% vs. 30%, respectively; P = 0.005). HbA1c levels elevated only in 3 patients. Pancreatic enzyme elevation was observed in 18 patients with no differences in frequencies between the carcinoma types. All patients with elevated levels of blood markers had positive findings on cross-sectional imaging. High-risk stigmata or worrisome features were observed in all patients but one with concomitant carcinoma. The most common types of worrisome features were the main pancreatic duct dilatation and CA19-9 elevation in IPMN-derived and concomitant carcinomas, respectively. Compared to IPMN-derived carcinomas, concomitant carcinomas were less likely to harbor high-risk stigmata (16% vs. 86%, respectively; P < 0.001). The usefulness of currently available blood biomarkers was limited in early detection of pancreatic carcinomas related to IPMNs. Morphological alterations were well correlated with long-term risk of IPMN-derived carcinomas, but not with that of concomitant carcinomas.

Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasm of the Pancreas.

Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cyst and a precursor of pancreatic cancer (PDAC). Since PDAC has a devastatingly high mortality rate, the early diagnosis and treatment of any precursor lesion are rational. The safety of the existing guidelines on the clinical management of IPMN has been criticized due to unsatisfactory sensitivity and specificity, showing the need for further markers. Blood obtained from patients with IPMN was therefore subjected to size-based isolation of circulating epithelial cells (CECs). We isolated CECs and evaluated their cytological characteristics. Additionally, we compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CECs and the primary IPMN tissue, since KRAS mutations are very typical for PDAC. Samples from 27 IPMN patients were analyzed. In 10 (37%) patients, CECs were isolated and showed a hybrid pattern of surface markers involving both epithelial and mesenchymal markers, suggesting a possible EMT process of the cells. Especially, patients with high-grade dysplasia in the main specimen were all CEC-positive. KRAS mutations were also present in CECs but less common than in IPMN tissue. The existence of CEC in IPMN patients offers additional blood-based research possibilities for IMPN biology.

Esophagogastroduodenal Findings in Patients with Intraductal Papillary Mucinous Neoplasms.

The association between intraductal papillary mucinous neoplasms (IPMNs) and extra-pancreatic malignancies is controversial. This cross-sectional study compared esophagogastroduodenal findings in 340 IPMN patients to those of age- and gender-matched controls without known IPMNs who underwent esophagogastroduodenoscopies (EGDs) for similar clinical reasons. The presence of gastric and esophageal cancer, Barrett's esophagus, neuroendocrine tumors (NETs), gastrointestinal stromal tumors (GISTs), gastric adenomas, and ampullary tumors was assessed. The results showed that 4/340 (1.2%) of the IPMN patients had gastric cancer and 1/340 (0.3%) had esophageal cancer. The matched control group had a similar incidence of gastric cancer (5/340) (1.5%), with no esophageal cancer cases (p > 0.999). The overall incidence of other esophagogastroduodenal conditions did not significantly differ between the IPMN patients and the controls. However, the incidence of gastric cancer in the IPMN patients was higher than expected based on national cancer registry data (standardized incidence ratio of 31.39; p < 0.001; CI 8.38-78.76). In conclusion, IPMN patients have a significantly higher incidence of gastric cancer compared to the general population. However, the incidence of esophagogastroduodenal findings, including gastric and esophageal cancer, is similar between IPMN patients and those who undergo an EGD for similar clinical indications. Further research is needed to determine optimal surveillance strategies for IPMN patients regarding their risk of developing gastric cancer.

Role of pancreatic ductal adenocarcinoma risk factors in intraductal papillary mucinous neoplasm progression.

Pancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is prevention. Intraductal papillary mucinous neoplasms (IPMNs) are precursors of PDAC. It is difficult to estimate the incidence of IPMNs because they are asymptomatic. Two recent studies reported pancreatic cysts in 3% and 13% of scanned subjects. The possibility of identifying a subgroup of IPMN patients with a higher probability of progression into cancer could be instrumental in increasing the survival rate. In this study, genetic and non-genetic PDAC risk factors were tested in a group of IPMN patients under surveillance. A retrospective study was conducted on 354 IPMN patients enrolled in two Italian centres with an average follow-up of 64 months. With the use of DNA extracted from blood, collected at IPMN diagnosis, all patients were genotyped for 30 known PDAC risk loci. The polymorphisms were analysed individually and grouped in an unweighted polygenic score (PGS) in relation to IPMN progression. The ABO blood group and non-genetic PDAC risk factors were also analysed. IPMN progression was defined based on the development of worrisome features and/or high-risk stigmata during follow-up. Two genetic variants (rs1517037 and rs10094872) showed suggestive associations with an increment of IPMN progression. After correction for multiple testing, using the Bonferroni correction, none of the variants showed a statistically significant association. However, associations were observed for the non-genetic variables, such as smoking status, comparing heavy smokers with light smokers (HR = 3.81, 95% 1.43-10.09, p = 0.007), and obesity (HR = 2.46, 95% CI 1.22-4.95, p = 0.012). In conclusion, this study is the first attempt to investigate the presence of shared genetic background between PDAC risk and IPMN progression; however, the results suggest that the 30 established PDAC susceptibility polymorphisms are not associated with clinical IPMN progression in a sample of 354 patients. However, we observed indications of cigarette smoking and body mass index (BMI) involvement in IPMN progression. The biological mechanism that could link these two risk factors to progression could be chronic inflammation, of which both smoking and obesity are strong promoters.

Comparison of Invasive Pancreatic Ductal Adenocarcinoma versus Intraductal Papillary Mucinous Neoplasm: A National Cancer Database Analysis

Current evidence on overall survival (OS) between invasive pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) is limited to single-center reports. We aimed to compare the characteristics, management, and OS of invasive PDAC vs. IPMN using a national United States (US) database. Invasive PDAC or IPMN adult (≥18 years) patients were identified in the National Cancer Database (2004-2016). OS was assessed with the Kaplan-Meier method and the stratified log-rank test. We included 101,190 patients (100,834 PDAC, 356 IPMN). A higher proportion of PDAC vs. IPMN patients had clinical N1 (36.8% vs. 15.7%, p < 0.001) and M1 disease (41.2% vs. 5.9%, p < 0.001). A lower proportion of PDAC patients underwent surgery (25.5% vs. 80.3%, p < 0.001), but a higher proportion received chemotherapy (65.4% vs. 46.1%, p < 0.001) or radiation (25.3% vs. 20.5%, p = 0.04). A higher proportion of surgical patients with PDAC vs. IPMN underwent margin-positive resection (23.0% vs. 14.0%, p = 0.001). The median OS for PDAC vs. IPMN was 8.3 vs. 33.4 months. In the stratified analysis for N0M0 disease, the median OS for PDAC vs. IPMN was 12.8 vs. 43.3 months, for N1M0, it was 11.5 vs. 17.0 months, while for M1, it was 4.0 vs. 7.0 months. In both diagnoses, surgery yielded improved OS, while stratified analysis in the surgical cohort demonstrated similar findings. Invasive PDAC is more aggressive than invasive IPMN, yet in the case of metastasis, OS is equally poor. Excellent long-term OS is achievable with surgical resection in highly selected cases, and efforts should focus on facilitating surgical treatment.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct

Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD= 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD= 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

Intraductal Papillary Mucinous Neoplasm of Pancreas with High-Risk Stigmata or Worrisome Features: What do You Do? Physician’s View

There are still debated about surveillance interval, duration, diagnostic modality and treatment for intraductal papillary mucinous neoplasm (IPMN) of the pancreas. In recent guidelines, ‘high risk stigmata (HRS)’ and ‘worrisome feature (WF)’ are defined as predictive factors for malignancy in IPMN. IPMNs with HRS and main duct- IPMN are more likely to accompany malignancies, thus require surgery. However, in the case of only WF, since the risk of malignancy is different for each factor, the management decision can be variable according to the number of overlapping WFs. In addition, for segmental main pancreatic duct dilatation without enhancing mural nodules, careful surveillance might be considered rather than immediate surgery. In IPMN patients with elderly or severe comorbidities, treatment strategy should be determined based on surgical and malignant risk assessment. To date, the natural course of IPMN patients with HRS and WF is not well understood, thus further studies with a large number of patients are needed.

Health-related quality of life and anxiety levels among patients under surveillance for intraductal papillary mucinous neoplasm

BackgroundBecause of the premalignant nature of intraductal papillary mucinous neoplasms (IPMNs), patients should undergo surveillance as long as they remain fit for surgery. This surveillance, with imaging and laboratory tests every 6 to 12 months, is expensive and may psychologically burden patients. This study aimed to determine the effects of IPMN surveillance on patients´ health-related quality of life (HRQoL) and anxiety levels.MethodsWe included a random subgroup of all IPMN patients undergoing a follow-up check-up at Helsinki University Hospital (HUH) between August 2017 and November 2018. Patients were asked to complete the 15D HRQoL and state-trait anxiety inventory (STAI) questionnaires just before and three months after an IPMN control.ResultsAmong 899 patients in IPMN follow-up, 232 participated. The 15D HRQoL results showed differences in some IPMN patients’ 15 analyzed dimensions compared to a sex- and age-standardized general population cohort, but the clinical relevance of these differences appear doubtful. We detected no significant difference in the anxiety levels determined using the STAI questionnaires before or three months after the IPMN control.ConclusionSurveillance should be less harmful than the risk of disease. Among our patients, the recommended IPMN follow-up carried minimal negative impact on patients’ HRQoL or anxiety levels. This result is important, because the number of patients under IPMN surveillance is rapidly increasing and the cancer risk among the majority of these patients remains small.Trial registration: The Surgical Ethics Committee of Helsinki University Hospital approved this study (Dnro HUS 475/2017) and it was registered at ClinicalTrials.gov (NCT03131076) before patient enrollment began.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms

BackgroundAn intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose.MethodsWe prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups.ResultsPartial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method.ConclusionPESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Threshold of Main Pancreatic Duct Diameter in Identifying Malignant Intraductal Papillary Mucinous Neoplasm by Magnetic Resonance Imaging.

Objective: Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic lesion. The identification of malignancy is critical for the establishment of treatment strategies. Main pancreatic duct (MPD) diameter is one critical feature for malignant IPMNs. However, the threshold of 1.0 cm is challenged. In this study, we explored independent risk factors and further calculated the threshold of MPD in identifying malignant IPMNs. Method: A total of 151 IPMN patients were included in this retrospective study. Demographic information, clinicopathological features, laboratory testing, and preoperative radiological characteristics by magnetic resonance imaging were collected. The receiver operating characteristic (ROC) curves were performed to determine the MPD diameter's cutoff levels and evaluate the predicted factors' diagnostic ability. Results: A cutoff value of 0.77 cm MPD (an area under the curve (AUC) = 0.746) in all IPMNs and 0.82 cm (AUC = 0.742) in the main duct involved IPMNs was obtained. MPD diameter (odds ratio (OR), 12.67; 95% confidence interval (CI), 4.80-33.48) and the mural nodule (OR, 12.98; 95% CI, 3.18-52.97) were the independent associated factors with high-risk IPMNs. The combined model with MPD and mural nodule showed a better predictive performance than mural nodule or MPD diameter alone (AUC = 0.803 vs 0.619, 0.746). A nomogram was developed and showed good performance (C index = 0.803). Conclusion: Our data show that mural nodule and MPD diameter are independent risk factors in identifying malignant intraductal papillary mucinous neoplasms. A cutoff value of 0.77 cm of MPD diameter may be a threshold value in identifying malignant intraductal papillary mucinous neoplasms or undergoing surgical resection.

Carcinoembryonic antigen levels in pancreatic juice are associated with histological subtypes of intraductal papillary mucinous neoplasm of the pancreas.

BackgroundThe present study aimed to examine the correlation between preoperative carcinoembryonic antigen levels in pancreatic juice (PJ‐CEA) and the histological subtype of intraductal papillary mucinous neoplasm (IPMN).MethodsWe enrolled IPMN patients who underwent endoscopic retrograde pancreatography between March 2002 and March 2018. Clinical factors associated with IPMN histological subtypes of 67 patients who underwent surgery were analyzed. Furthermore, the relationship between CEA immunohistochemistry findings and histological subtypes was investigated.ResultsMedian PJ‐CEA were 15 ng/ml in the gastric type, 150 ng/ml in the intestinal type, and 175 ng/ml in the pancreatobiliary type. Both intestinal and pancreatobiliary types had significantly higher PJ‐CEA than the gastric type (p = 0.001). In the analysis of histological subtype predictors, high PJ‐CEA (≥63 ng/ml) only showed a significant difference in multivariate analyses (95% confidence interval 4.8–70.2; p < 0.001). Immunohistochemistry findings revealed significantly higher CEA expression in the non‐gastric type than in the gastric type (p < 0.001). The non‐gastric type showed a significantly worse prognosis than the gastric type (p = 0.017).ConclusionPJ‐CEA was an independent predictor of IPMN histological subtypes in a preoperative setting. High PJ‐CEA predict the non‐gastric type, while low PJ‐CEA predict the gastric type.

The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients.

Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precancerous lesion, with increasing incidence in recent years. However, the mechanisms of IPMN progression into invasive cancer remain unclear. The mRNA expression data of IPMN/PAAD patients were extracted from the TCGA and GEO databases. First, based on GSE19650, we analyzed the molecular alterations, tumor stemness, immune landscape, and transcriptional regulation of IPMN progression. The results indicated that gene expression changed dramatically, specifically at the intraductal papillary-mucinous adenoma (IPMA) stage. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Kyoto Encyclopedia of Genes and Genomes (GSEA) pathway analyses showed that glycoprotein-related, cell cycle, and P53 pathways displayed the most significant changes during progression. With IPMN progression, tumor stemness increased continuously, and KRAS, ERBB3, RUNX1, and ELF3 are essential driver genes affecting tumor stemness. Motif analysis suggested that KLF4 may be a specific transcription factor that regulates gene expression in the IPMA stage, while MYB and MYBL1 control gene expression in the IPMC and invasive stages, respectively. Then, GSE19650 and GSE71729 transcriptome data were combined to perform the least absolute shrinkage and selection operator (LASSO) method and Cox regression analysis to develop an 11-gene prediction model (KCNK1, FHL2, LAMC2, CDCA7, GPX3, C7, VIP, HBA1, BTG2, MT1E, and LYVE1) to predict the prognosis of pancreatic cancer patients. The reliability of the model was validated in the GSE71729 and TCGA databases. Finally, 11 additional IPMN patients treated in our hospital were included, and the immune microenvironment changes during IPMN progression were analyzed by immunohistochemistry (IHC). IHC results suggest that Myeloid-derived suppressor cells (MDSCs) and macrophages may be key in the formation of immunosuppressive microenvironment of IPMN progression. Our study deepens our understanding of IPMN progression, especially the changes in the immune microenvironment. The findings of this work may contribute to the development of new therapeutic strategies for IPMN.