A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer.

BACKGROUND: We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC. METHODS: A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated. RESULTS: Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19-9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02). CONCLUSIONS: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.

The Impact of Hepaticojejunostomy Leaks After Pancreatoduodenectomy: a Devastating Source of Morbidity and Mortality.

INTRODUCTION: Hepaticojejunostomy leaks are less frequent than pancreatic leaks after pancreatoduodenectomy, and the current literature suggests comparable outcomes. The purpose of this study was to determine if the hepaticojejunostomy leak adversely affected patient outcomes. METHODS: Consecutive cases of pancreatoduodenectomy (n = 924) were reviewed at a single high-volume institution over an 8-year period (2006-2014). RESULTS: Pancreaticojejunostomy leaks were identified in 217 (23%) patients and hepaticojejunostomy leaks were identified in 24 patients (3%); combined hepaticojejunostomy/pancreaticojejunostomy leaks were identified in 31 patients (3%). Those with hepaticojejunostomy leaks or combined leaks had a significantly increased risk of morbidity when compared to pancreaticojejunostomy leaks or no leak (54 and 58 vs. 34 and 24%, respectively, p < 0.05). The median length of stay was significantly greater for hepaticojejunostomy leaks or combined leaks when compared to pancreatojejunostomy leaks (17 or 14 vs. 9 days, p = 0.001) and those with no leak (17 or 14 vs. 7 days, p = 0.001). Ninety-day mortality for all patients was 3.6%. Hepaticojejunostomy leaks and combined leaks significantly increased 90-day mortality rate (17 and 32%, respectively, p < 0.05). CONCLUSIONS: Hepaticojejunostomy and combined leaks after pancreatoduodenectomy are rarer than pancreaticojejunostomy leaks; these patients are at a significantly increased risk of major morbidity and mortality.

DEEPEN: A negation detection system for clinical text incorporating dependency relation into NegEx.

In Electronic Health Records (EHRs), much of valuable information regarding patients' conditions is embedded in free text format. Natural language processing (NLP) techniques have been developed to extract clinical information from free text. One challenge faced in clinical NLP is that the meaning of clinical entities is heavily affected by modifiers such as negation. A negation detection algorithm, NegEx, applies a simplistic approach that has been shown to be powerful in clinical NLP. However, due to the failure to consider the contextual relationship between words within a sentence, NegEx fails to correctly capture the negation status of concepts in complex sentences. Incorrect negation assignment could cause inaccurate diagnosis of patients' condition or contaminated study cohorts. We developed a negation algorithm called DEEPEN to decrease NegEx's false positives by taking into account the dependency relationship between negation words and concepts within a sentence using Stanford dependency parser. The system was developed and tested using EHR data from Indiana University (IU) and it was further evaluated on Mayo Clinic dataset to assess its generalizability. The evaluation results demonstrate DEEPEN, which incorporates dependency parsing into NegEx, can reduce the number of incorrect negation assignment for patients with positive findings, and therefore improve the identification of patients with the target clinical findings in EHRs.

Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines.

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and postbiopsy treatment and management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings over an 18-month period and synthesis of online comments of the draft document on the Papanicolaou Society of Cytopathology web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on a proposed standardized terminology scheme for pancreatobiliary specimens that correlate cytological diagnosis with biological behavior and increasingly conservative patient management of surveillance only. The proposed terminology scheme recommends a six-tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (benign or other), Suspicious and Positive. Unique to this scheme is the "Neoplastic" category separated into "benign" (serous cystadenoma), or "Other" (premalignant mucinous cysts, neuroendocrine tumors, and solid-pseudopapillary neoplasms). The positive or malignant category is reserved for high-grade, aggressive malignancies including ductal adenocarcinoma, acinar cell carcinoma, poorly differentiated neuroendocrine carcinomas, pancreatoblastoma, lymphoma, and metastases. Interpretation categories do not have to be used. Some pathology laboratory information systems require an interpretation category, which places the cytological diagnosis into a general category. This proposed scheme provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology. In addition, this terminology scheme attempts to provide maximum flexibility for patient management, which has become increasingly conservative for some neoplasms.

Clinical evaluation, imaging studies, indications for cytologic study, and preprocedural requirements for duct brushing studies and pancreatic FNA: the Papanicolaou Society of Cytopathology recommendations for pancreatic and biliary cytology.

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing, and post-biopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings, and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed.

Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.

BACKGROUND: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls. METHODS: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC. RESULTS: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues. CONCLUSIONS: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis.

Adipokines and cytokines in human pancreatic juice: unraveling the local pancreatic inflammatory milieu.

BACKGROUND: Differential adipokine expression in obesity influences the inflammatory milieu, and may explain in part obesity's negative impact on pancreatic disease. Pancreatic juice analysis may provide a good means to evaluate the local pancreatic inflammatory milieu. The presence of adipokines in pancreatic juice is unknown. AIMS: This proof-of-concept study was designed to determine the presence of adipokines and cytokines in human pancreatic juice. METHODS: With institutional review board approval, pancreatic juice was obtained from ten patients with a broad range of diagnoses at the time of endoscopic retrograde cholangiopancreatography. Pancreatic juice was assayed using enzyme-linked immunosorbent assay (ELISA) for insulin, the proinflammatory adipokine leptin, the anti-inflammatory adipokine adiponectin, and the inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and monocyte chemoattractant protein-1 (MCP-1). Correlation between adipokine and inflammatory mediator expression was determined by linear regression analysis. Data are presented as mean +/- standard error of the mean (SEM); P < 0.05 was considered statistically significant. RESULTS: Leptin (0.16 +/- 0.05 ng/ml) and adiponectin (0.63 +/- 0.02 microg/ml) were both present, as were the inflammatory mediators IL-6 (112.6 +/- 28.1 pg/ml), TNF-alpha (49.0 +/- 18.8 pg/ml), and MCP-1 (32.2 +/- 0.9 pg/ml). Paradoxically, the expression of the anti-inflammatory adipokine adiponectin correlated strongly with that of the proinflammatory cytokine IL-6 (R(2) = 0.98, P < 0.001). CONCLUSIONS: This report is the first to describe adipokine expression in human pancreatic juice. Human pancreatic juice inflammatory mediators and adipokines may provide an important measurement of the local pancreatic inflammatory milieu.

Laparoscopic left pancreatectomy: complication risk score correlates with morbidity and risk for pancreatic fistula.

BACKGROUND: Surgeons are performing laparoscopic left pancreatectomy (LLP) with increasing frequency; however, determinants of perioperative outcome after LLP are not well defined. We evaluated factors contributing to morbidity after LLP. METHODS: Records from patients undergoing LLP from 2000 to 2008 from nine academic medical centers were evaluated to assess risk factors for perioperative complications. Extent of pancreatic resection was determined by the length of the gross pancreatic specimen. Complications and pancreatic fistula rates were assessed, and a model was developed to identify those at risk of postoperative adverse events. RESULTS: Among the 219 LLP cases, indications were cystic neoplasms in 122 (56%), solid neoplasms in 83 (38%), and chronic pancreatitis in 14 (6%). Thirty-day morbidity and mortality were 39% and 0, respectively. Major complications occurred in 11%. Pancreatic fistulae were detected in 23%, with clinically important fistulae (International Study Group on Pancreatic Fistula Definition grade B/C) seen in 10%. On multivariate analysis, only greater estimated blood loss (EBL), higher body mass index (BMI), and longer length of resected pancreas were associated with major complications. A complication risk score consisting of 1 point each for BMI >27, pancreatic specimen length >8 cm, or EBL > or =150 mL predicted an increased risk of complications and pancreatic fistulae. CONCLUSIONS: The risk of major complications after LLP is 11%, with clinically important pancreatic fistulae occurring in 10%. A complication risk score incorporating BMI, extent of pancreatic resection, and EBL correlates with all end points evaluated. The complication risk score should be used when quality outcome measures are evaluated.