Shadeah Suleiman

Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis

Objective To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery. Methods In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. Results Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001). Conclusions In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

A population-based assessment of the burden of acute pancreatitis in the United States.

Objectives The aim of this study is to investigate the incidence and mortality of emergency department (ED) visits in the United States attributed to acute pancreatitis (AP) and quantify predictors of admission and mortality. Methods Using the nationwide ED sample, all ED visits between 2006 and 2009 for AP were extracted. Multivariable analyses were fitted for prediction of admission and mortality. Results A weighted sample of 1,224,121 patient visits with AP was captured. Of those, 75.4% resulted in admission and 0.7% died. Between 2006 and 2009, the incidence of AP ED visits increased from 9.9 to 10.6 per 10,000 person-years. Patients were more likely to be admitted if sicker (Charlson Comorbidity Index score ≥3; OR, 6.48; P < 0.001) and if the etiology of pancreatitis was alcoholic versus biliary (OR, 2.20; P < 0.001). They were more likely to die if sicker (Charlson Comorbidity Index score ≥3; OR, 1.51; P < 0.001) and covered with Medicare or Medicaid versus private insurance (OR, 1.40; P < 0.001 and OR, 1.45; P < 0.001, respectively). Conclusions Emergency department visits for AP represent a significant burden on US health care. Although mortality is lower than previously reported, significant disparities exist in patients presenting with AP with regard to admission and mortality rates. Further investigations are needed to assess these disparities.

Investigating MicroRNA Expression Profiles in Pancreatic Cystic Neoplasms

OBJECTIVES:Current diagnostic tools for pancreatic cysts fail to reliably differentiate mucinous from nonmucinous cysts. Reliable biomarkers are needed. MicroRNAs (miRNA) may offer insights into pancreatic cysts. Our aims were to (1) identify miRNAs that distinguish benign from both premalignant cysts and malignant pancreatic lesions using formalin-fixed, paraffin-embedded (FFPE) pathology specimens; (2) identify miRNAs that distinguish mucinous cystic neoplasm (MCN) from branch duct-intraductal papillary mucinous neoplasm (BD-IPMN).METHODS:A total of 69 FFPE pancreatic specimens were identified: (1) benign (20 serous cystadenoma (SCA)), (2) premalignant (10 MCN, 10 BD-IPMN, 10 main duct IPMN (MD-IPMN)), and (3) malignant (19 pancreatic ductal adenocarcinoma (PDAC)). Total nucleic acid extraction was performed followed by miRNA expression profiling of 378 miRNAs interrogated using TaqMan MicroRNA Arrays Pool A and verification of candidate miRNAs. Bioinformatics was used to generate classifiers.RESULTS:MiRNA profiling of 69 FFPE specimens yielded 35 differentially expressed miRNA candidates. Four different 4-miRNA panels differentiated among the lesions: one panel separated SCA from MCN, BD-IPMN, MD-IPMN, and PDAC with sensitivity 85% (62, 97), specificity 100% (93, 100), a second panel distinguished MCN from SCA, BD-IPMN, MD-IPMN, and PDAC with sensitivity and specificity 100% (100, 100), a third panel differentiated PDAC from IPMN with sensitivity 95% (76, 100) and specificity 85% (72, 96), and the final panel diagnosed MCN from BD-IPMN with sensitivity and specificity approaching 100%.CONCLUSIONS:MiRNA profiling of surgical pathology specimens differentiates serous cystadenoma from both premalignant pancreatic cystic neoplasms and PDAC and MCN from BD-IPMN.

Interdisciplinary Management of Cystic Neoplasms of the Pancreas

Cystic neoplasms of the pancreas are increasingly recognized due to the frequent use of abdominal imaging. It is reported that up to 20% of abdominal cross-sectional scans identify incidental asymptomatic pancreatic cysts. Proper characterization of pancreatic cystic neoplasms is important not only to recognize premalignant lesions that will require surgical resection, but also to allow nonoperative management of many cystic lesions that will not require resection with its inherent morbidity. Though reliable biomarkers are lacking, a wide spectrum of diagnostic modalities are available to evaluate pancreatic cystic neoplasms, including radiologic, endoscopic, laboratory, and pathologic analysis. An interdisciplinary approach to management of these lesions which incorporates recent, specialty-specific advances in the medical literature is herein suggested.

Inflammatory protein profiling of pancreatic cyst fluid using EUS-FNA in tandem with cytokine microarray differentiates between branch duct IPMN and inflammatory cysts

BACKGROUND Diagnosis of pancreatic cystic neoplasms remains problematic. We hypothesize that inflammatory mediator proteins in pancreatic cyst fluid can differentiate branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) and pancreatic inflammatory cysts. We aim to 1) detect inflammatory mediator proteins (IMPs) using a multiplexed IMP-targeted microarray in pancreatic cyst fluid obtained during endoscopic ultrasound fine needle aspiration (EUS-FNA) and 2) compare IMP profiles in pancreatic cyst fluid from BD-IPMNs and inflammatory cysts. Pancreatic cyst fluid from ten patients (5 BD-IPMN and 5 inflammatory cysts) was obtained by EUS-FNA and analyzed directly with a multiplexed microarray assay to determine concentrations of 89 IMPs. Statistical analysis was performed using non-parametric methods. RESULTS Eighty-three of the 89 assayed IMPs were detected in at least one of the 10 patient samples. Seven IMPs were detected in BD-IPMN but not inflammatory cysts, while eleven IMPs were identified in inflammatory cysts but not BD-IPMN. Notably, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression was present in all five inflammatory cyst samples. Hepatocyte growth factor (HGF) was present in significantly higher concentrations in inflammatory cysts compared to BD-IPMN. CONCLUSION Our exploratory analysis reveals that GM-CSF and HGF in EUS-FNA-collected pancreatic cyst fluid can distinguish between BD-IPMN and inflammatory cyst. Coupling microarray molecular techniques to EUS-FNA may represent a major step forward to our understanding complex pancreatic disease.

The Atlanta Classification, Revised Atlanta Classification, and Determinant-Based Classification of Acute Pancreatitis: Which Is Best at Stratifying Outcomes?

Objectives To determine which classification is more accurate in stratifying severity. Methods The study used a retrospective analysis of a prospective acute pancreatitis database (June 2005–December 2007). Acute pancreatitis severity was stratified according to the Atlanta classification (AC) 1992, the revised Atlanta classification (RAC) 2012, and the determinant-based classification (DBC) 2012. Receiver operating characteristic analysis (area under the curve) compared the accuracy of each classification. Logistic regression identified predictors of mortality. Results 338 patients were analyzed: 13% had persistent organ failure (POF) (>48 hours), of whom 37% had multisystem POF, and 11% had pancreatic necrosis, of whom 19% had infected necrosis. Mortality was 4.1%. For predicting mortality (area under the curve), the RAC (0.91) and DBC (0.92) were comparable (P = 0.404); both outperformed the AC (0.81) (P < 0.001). For intensive care unit admission, the RAC (0.85) and DBC (0.85) were comparable (P = 0.949); both outperformed the AC (0.79) (P < 0.05). There were 2 patients in the critical category of the DBC. Multisystem POF was an independent predictor of mortality (odds ratio, 75.0; 95% confidence interval, 13.7–410.6; P < 0.001), whereas single-system POF, sterile necrosis, and infected necrosis were not. Conclusion The RAC and DBC were generally comparable in stratifying severity. The paucity of patients in the critical category in the DBC limits its utility. Neither classification accounts for the impact of multisystem POF, which was the strongest predictor of mortality.

Pancreatic Juice Prostaglandin E2 Concentrations Are Elevated in Chronic Pancreatitis and Improve Detection of Early Disease

Objectives:Chronic pancreatitis (CP) may be difficult to diagnose in early stages. We aimed to measure pancreatic juice (PJ) prostaglandin E2 (PGE2) concentrations to determine whether they are elevated in CP and improve diagnosis of early disease.Methods:We measured PJ PGE2 in 10 patients with established CP, 25 patients who met criteria for “minimal change” chronic pancreatitis (MCCP), and 10 normal control participants.Results:Median PJ PGE2 was elevated in CP (307 pg/ml, IQR (249–362)) and MCCP (568 pg/ml, (418–854)) compared with normal controls (104 pg/ml, (68–206)) (P≤ 0.001). Area under receiving operator curve (AUROC) for diagnosis of CP and MCCP was 0.9 and 0.62, respectively, for PJ bicarbonate concentration alone; AUROC was 1.0 and 0.94 for the combination of PJ bicarbonate and PGE2 concentrations.Conclusions:PJ PGE2 appears to be a biomarker for CP and is elevated in both established and “minimal change” chronic pancreatitis.

Randomized Noninferiority Trial Comparing Diagnostic Yield of Cytopathologist-guided versus 7 passes for EUS-FNA of Pancreatic Masses.

To improve diagnostic yield of endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) in solid pancreatic lesions, on‐site cytology review has been recommended. Because this is not widely available throughout the world, the aim of the present study was to compare the diagnostic yield of EUS‐FNA carried out with rapid on‐site evaluation (ROSE) versus seven FNA passes without ROSE in pancreatic masses.

Differential Expression of GNAS and KRAS Mutations in Pancreatic Cysts

CONTEXT KRAS mutations play an important role in pancreatic cancer. GNAS mutations were discovered in intraductal papillary mucinous neoplasms (IPMN). OBJECTIVES Our aim was to identify the frequency of KRAS and GNAS mutations in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma (PDAC). METHODS Sixty-eight surgically resected formalin fixed, paraffin embedded pancreatic specimens were analyzed, including: 1) benign (20 serous cystadenoma (SCA)), 2) pre-malignant (10 mucinous cystic neoplasm (MCN), 10 branch duct intraductal papillary mucinous neoplasm (BD-IPMN), 9 main duct IPMN (MD-IPMN)), 3) malignant (19 PDAC). Total nucleic acid extraction was performed. KRAS codon 12/13 and GNAS codon 201 mutations were interrogated via targeted sequencing using the Ion Torrents Personal Genome Machine (PGM). RESULTS Mean age of 68 patients was 61.9±8.4 with 72% female. KRAS and GNAS mutations were more common in PDAC and IPMN. KRAS mutations predominated in PDAC compared to pancreatic cysts (16/19, 84% versus 10/49, 20%; P<0.001). GNAS mutations were more common in IPMN compared to non-IPMN lesions (8/19, 42% versus 2/49, 4%; P=0.0003). No GNAS mutations were detected in PDAC and MCN while 2 SCA carried GNAS mutations. Double mutations with KRAS and GNAS were only present in IPMN (5/19 versus 0/30 SCA and MCN, P=0.006). CONCLUSIONS KRAS and GNAS mutations were more common in PDAC and IPMN with KRAS mutations primarily in PDAC and GNAS mutations more frequent in IPMN. No GNAS mutations occurred in MCN and double mutations were only present in IPMN.

Differentiating Branch Duct and Mixed IPMN in Endoscopically Collected Pancreatic Cyst Fluid via Cytokine Analysis

Background. Differentiating branch duct from mixed intraductal papillary mucinous neoplasm (BD-IPMN) is problematic, but clinically important as mixed IPMNs are managed surgically, while some BD-IPMN may be followed. Inflammatory mediator proteins (IMPs) have been implicated in acute and chronic inflammatory and malignant pancreatic diseases. Aim. To compare IMP profile of pancreatic cyst fluid collected endoscopically from BD-IPMN and mixed IPMN. Methods. Pancreatic cyst fluid from ten patients (5 BD-IPMN and 5 mixed IPMN) was collected by endoscopic ultrasound-guided fine needle aspiration or endoscopic retrograde cholangiopancreatography. Concentrations of 89 IMPs in these samples were determined using a multiplexed bead-based microarray protein assay and compared between BD-IPMN and mixed IPMN. Results. Eighty-six of 89 IMPs were detected in at least one of the 10 samples. Fourteen IMPs were detected only in mixed IPMN, while none were only in BD-IPMN. Of these, TGF-β1 was most prevalent, present in 3 of 5 mixed IPMNs. Seventy-two IMPs were detected in both BD-IPMN and mixed IPMNs. Of these, only G-CSF (P < 0.05) was present in higher concentrations in mixed IPMNs. Conclusion. TGF-β1 and G-CSF detected in endoscopically collected pancreatic cyst fluid are potential diagnostic biomarkers capable of distinguishing mixed IPMN from BD-IPMN.