Abstract

This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC) from malignant diseases, such as biliary tract cancer (BTC), intraductal papillary mucinous carcinoma (IPMC), and various benign pancreaticobiliary diseases. Capillary electrophoresis−mass spectrometry was used to analyze charged metabolites. We repeatedly analyzed serum samples (n = 41) of different storage durations to identify metabolites showing high quantitative reproducibility, and subsequently analyzed all samples (n = 140). Overall, 189 metabolites were quantified and 66 metabolites had a 20% coefficient of variation and, of these, 24 metabolites showed significant differences among control, benign, and malignant groups (p < 0.05; Steel–Dwass test). Four multiple logistic regression models (MLR) were developed and one MLR model clearly discriminated all disease patients from healthy controls with an area under receiver operating characteristic curve (AUC) of 0.970 (95% confidential interval (CI), 0.946–0.994, p < 0.0001). Another model to discriminate PC from BTC and IPMC yielded AUC = 0.831 (95% CI, 0.650–1.01, p = 0.0020) with higher accuracy compared with tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), pancreatic cancer-associated antigen (DUPAN2) and s-pancreas-1 antigen (SPAN1). Changes in metabolomic profiles might be used to screen for malignant cancers as well as to differentiate between PC and other malignant diseases.

Highlights

  • Pancreatic cancer (PC) has a poor prognosis

  • The study population was composed of 27 patients with pancreatic cancer (PC), 10 with biliary tract cancer (BTC), two with intraductal papillary mucinous carcinoma (IPMC), six with chronic pancreatitis (CP), three with intraductal papillary mucinous adenoma (IPMA), 55 with benign pancreatobiliary diseases such as bile duct stone, ampullary adenoma or pancreatic pseudocyst and 46 healthy controls (C)

  • PC, BTC, and IPMC were categorized into malignant disease (M), IPMA and other benign pancreatobiliary diseases were categorized into benign diseases (B)

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Summary

Introduction

Pancreatic cancer (PC) has a poor prognosis. Its overall five-year survival rate is less than 5%, the lowest of all cancers [1]. Discrimination between PC and chronic pancreatitis (CP) is difficult during mass forming pancreatitis and autoimmune pancreatitis despite the use of tissue diagnosis using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) [12,13] These tumor markers do not help with decision-making for a diagnosis until surgery. Identification of metabolites to detect PC and BTC using a serum metabolomic profile has been conducted intensively [16,17,18,19,20,21]. Most of these comparisons included only healthy controls and PC patients, and in some cases with the addition of chronic pancreatitis. We developed and evaluated four mathematical models to discriminate these diseases from the other groups

Results
C Healthy control
Patient Selection and Serum Collection
Sample Preparation
Measurement Conditions and Processing of Raw Data
Stability Analysis of Metabolomic Profiles
Data Analysis to Discriminate Disease Groups
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