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Preoperative risk prediction for intraductal papillary mucinous neoplasms by quantitative CT image analysis.

ABSTRACT: BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) are radiographically identifiable potential precursor lesions of pancreatic adenocarcinoma. While resection is recommended when main duct dilation is present, management of branch duct IPMN (BD-IPMN) remains controversial. This study sought to evaluate whether preoperative quantitative imaging features of BD-IPMNs could distinguish low-risk disease (low- and intermediate-grade dysplasia) from high-risk disease (high-grade dysplasia and invasive carcinoma). METHODS:Patients who underwent resection between 2005 and 2015 with pathologically proven BD-IPMN and a preoperative CT scan were included in the study. Quantitative image features were extracted using texture analysis and a novel quantitative mural nodularity feature developed for the study. Significant features on univariate analysis were combined with clinical variables to build a multivariate prediction model. RESULTS:Within the study group of 103 patients, 76 (74%) had low-risk disease and 27 (26%) had high-risk disease. Quantitative imaging features were prognostic of low-vs. high-risk disease. The model based only on clinical variables achieved an AUC of 0.67 and 0.79 with the addition of quantitative imaging features. CONCLUSION:Quantitative image analysis of BD-IPMNs is a novel method that may enable risk stratification. External validation may provide a reliable non-invasive prognostic tool for clinicians.

SUBMITTER: Attiyeh MA

PROVIDER: S-EPMC6367060 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Preoperative risk prediction for intraductal papillary mucinous neoplasms by quantitative CT image analysis.

Attiyeh Marc A MA Chakraborty Jayasree J Gazit Lior L Langdon-Embry Liana L Gonen Mithat M Balachandran Vinod P VP D'Angelica Michael I MI DeMatteo Ronald P RP Jarnagin William R WR Kingham T Peter TP Allen Peter J PJ Do Richard K RK Simpson Amber L AL

HPB : the official journal of the International Hepato Pancreato Biliary Association 20180807 2

<h4>Background</h4>Intraductal papillary mucinous neoplasms (IPMNs) are radiographically identifiable potential precursor lesions of pancreatic adenocarcinoma. While resection is recommended when main duct dilation is present, management of branch duct IPMN (BD-IPMN) remains controversial. This study sought to evaluate whether preoperative quantitative imaging features of BD-IPMNs could distinguish low-risk disease (low- and intermediate-grade dysplasia) from high-risk disease (high-grade dyspla ...[more]

PMID: 30097414

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Project description:ImportanceIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC).ObjectiveTo fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC.Design, setting, and participants: This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023.Main outcomes and measuresCIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points.ResultsThe CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC.Conclusions and relevanceIn this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

Project description:BackgroundIntraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs.MethodsOur previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case-control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis.ResultsAs compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92.ConclusionDNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers.

Project description:BackgroundThe application of advanced imaging technologies for identifying pancreatic cysts has become widespread. However, accurately differentiating between low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive intraductal papillary mucinous neoplasms (IPMNs) remains a diagnostic challenge with current biomarkers, necessitating the development of novel biomarkers that can distinguish IPMN malignancy.MethodsCyst fluid samples were collected from nine IPMN patients (3 LGD, 3 HGD, and 3 invasive IPMN) during their pancreatectomies. An integrated proteomics approach that combines filter-aided sample preparation, stage tip-based high-pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data of pancreatic cyst fluid and discover marker candidates for IPMN malignancy. Biological processes of differentially expressed proteins that are related to pancreatic cysts and aggressive malignancy were analyzed using bioinformatics tools such as gene ontology analysis and Ingenuity pathway analysis. In order to confirm the validity of the marker candidates, 19 cyst fluid samples were analyzed by western blot.ResultsA dataset of 2992 proteins was constructed from pancreatic cyst fluid samples. A subsequent analysis found 2963 identified proteins in individual samples, 2837 of which were quantifiable. Differentially expressed proteins between histological grades of IPMN were associated with pancreatic diseases and malignancy according to ingenuity pathway analysis. Eighteen biomarker candidates that were differentially expressed across IPMN histological grades were discovered-7 DEPs that were upregulated and 11 that were downregulated in more malignant grades. HOOK1 and PTPN6 were validated by western blot in an independent cohort, the results of which were consistent with our proteomic data.ConclusionsThis study demonstrates that novel biomarker candidates for IPMN malignancy can be discovered through proteomic analysis of pancreatic cyst fluid.

Project description:ImportanceBranch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are common pancreatic preneoplastic lesions, but their surveillance is not personalized.ObjectiveTo investigate patient- and cyst-related factors associated with progression into worrisome features (WFs) or high-risk stigmata (HRS) categories of BD-IPMNs.Design, setting, and participantsCyst- and patient-related factors of consecutive BD-IPMNs without WFs or HRS in 540 patients diagnosed from 2009 to 2018 with at least 12 months' surveillance until February 28, 2020, were registered in a 2-center ambispective cohort study in Italy. In a subgroup, the ABO blood group was studied for the first time in this setting.ExposureCyst-related and patients-related factors and ABO blood group.Main outcomes and measuresThe study outcome was the appearance of WFs or HRS according to the 2017 International Association of Pancreatology guidelines. Survival probability was calculated using Kaplan-Meier curve and risk factors identified by Cox proportional hazards regression. ABO blood group was inferred through genotypes with DNA extraction.ResultsOf 540 patients with BD-IPMNs (median age, 66 years [interquartile range, 58.5-72.0 years]; 337 women [62.4%]) undergoing surveillance for a median of 51.5 months (interquartile range, 28-84 months) for 2758 person-years, 130 patients (24.1%) experienced progression. Probability of progression was 3.7% at 1 year, 23.4% at 5 years, and 43.3% at 10 years; 15 patients (2.8%) underwent surgery, 7 patients (1.3%) had malignant histologic findings, and 3 patients (0.56%) died of pancreatic-associated disease. Initial cyst size greater than 15 mm (hazard ratio [HR], 2.05; 95% CI, 1.44-2.91), body mass index greater than 26.4 (HR, 1.72; 95% CI, 1.19-2.50), and heavy smoking (HR, 1.81; 95% CI, 1.14-2.86) were significant independent factors associated with progression risk. The AA blood genotype was also associated with progression risk (HR, 3.49; 95% CI, 1.04-11.71) compared with the OO genotype in the investigated subgroup.Conclusions and relevanceThis analysis of factors associated with progression of BD-IPMNs according to recent guidelines suggests that cyst size alone is not a reliable factor for estimation of progression risk; however, along with other readily available data, size is helpful for planning personalized surveillance of BD-IPMNs.

Project description:Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dataset Information

Preoperative risk prediction for intraductal papillary mucinous neoplasms by quantitative CT image analysis.

Publications

Preoperative risk prediction for intraductal papillary mucinous neoplasms by quantitative CT image analysis.

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