James J. Farrell

Pancreatic cystic neoplasms: management and unanswered questions.

Approximately 10% of persons 70 years old or older are now diagnosed with pancreatic cysts, but it is not clear which ones require additional analysis, interventions, or follow-up. Primary care doctors rely on gastroenterologists for direction because no one wants to miss a diagnosis of pancreatic cancer, but meanwhile there is pressure to limit use of diagnostic tests and limit costs. We review the different cystic neoplasms of the pancreas and diagnostic strategies based on clinical features and imaging data. We discuss surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines. Intraductal papillary mucinous neoplasm (particularly the branch duct variant) is the lesion most frequently identified incidentally. We report what is known about its pathology, its risk of developing into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk. We also review surgical treatment and strategies for surveillance of pancreatic cysts.

Salivary Biomarkers: Toward Future Clinical and Diagnostic Utilities

SUMMARY The pursuit of timely, cost-effective, accurate, and noninvasive diagnostic methodologies is an endeavor of urgency among clinicians and scientists alike. Detecting pathologies at their earliest stages can significantly affect patient discomfort, prognosis, therapeutic intervention, survival rates, and recurrence. Diagnosis and monitoring often require painful invasive procedures such as biopsies and repeated blood draws, adding undue stress to an already unpleasant experience. The discovery of saliva-based microbial, immunologic, and molecular biomarkers offers unique opportunities to bypass these measures by utilizing oral fluids to evaluate the condition of both healthy and diseased individuals. Here we discuss saliva and its significance as a source of indicators for local, systemic, and infectious disorders. We highlight contemporary innovations and explore recent discoveries that deem saliva a mediator of the bodys physiological condition. Additionally, we examine the current state of salivary diagnostics and its associated technologies, future aspirations, and potential as the preferred route of disease detection, monitoring, and prognosis.

Endoscopically Acquired Pancreatic Cyst Fluid MicroRNA 21 and 221 Are Associated With Invasive Cancer

OBJECTIVES:Pancreatic cysts are a group of lesions with heterogeneous malignant potential. Currently, there are no reliable biomarkers to aid in cyst diagnosis and classification. The objective of this study was to identify potential microRNA (miR) biomarkers in endoscopically acquired pancreatic cyst fluid that could be used to distinguish between benign, premalignant, and malignant cysts.METHODS:A list of candidate miRs was developed using a whole-genome expression array analysis of pancreatic cancer (pancreatic ductal adenocarcinoma) and nonmalignant samples overlapped with existing literature and predicted gene targets. Endoscopically acquired pancreatic cyst fluid samples were obtained from a group of 38 patients who underwent cyst fluid aspiration and surgical resection. Selected miR expression levels in cyst fluid samples were assessed by quantitative real-time-PCR. Additionally, in situ hybridization (ISH) on corresponding cyst tissue samples was performed to identify the source and validate the expression level of fluid miRs.RESULTS:Of the six miRs that were profiled in the study, two showed differential expression in malignant cysts. miR-221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P=0.05). miR-21 was also expressed at significantly higher levels in malignant cysts (P<0.01). Additionally, the expression of miR-21 was significantly higher in premalignant cysts than benign cysts (P=0.03). The differential expression of miR-21 among cyst categories was confirmed by ISH.CONCLUSIONS:In this small single-center study, miRs are potential pancreatic cyst fluid diagnostic biomarkers. In particular, miR-21 is identified as a candidate biomarker to distinguish between benign, premalignant, and malignant cysts. Additionally miR-221 may be of use in the identification of more advanced malignant disease.

Prevalence, Diagnosis and Management of Pancreatic Cystic Neoplasms: Current Status and Future Directions

Cystic neoplasms of the pancreas are found with increasing prevalence, especially in elderly asymptomatic individuals. Although the overall risk of malignancy is very low, the presence of these pancreatic cysts is associated with a large degree of anxiety and further medical investigation due to concerns about malignancy. This review discusses the different cystic neoplasms of the pancreas and reports diagnostic strategies based on clinical features and imaging data. Surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines, is also discussed, with special reference to intraductal papillary mucinous neoplasm (IPMN; particularly the branch duct variant), which is the lesion most frequently identified incidentally. IPMN pathology, its risk for development into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk are discussed. Finally, surgical treatment, strategies for surveillance of pancreatic cysts, and possible future directions are discussed.

Stromal microRNA-21 levels predict response to 5-fluorouracil in patients with pancreatic cancer.

MicroRNA‐21 (miR‐21) is upregulated and inversely associated with survival in many cancer types, including pancreatic ductal adenocarcinoma (PDAC). We studied the predictive value of miR‐21 levels for gemcitabine or 5‐fluorouracil (5‐FU) response in tumor cells (TCs) or cancer associated fibroblasts (CAFs) in a cohort of PDAC patients from the RTOG 9704 trial.

Autoimmune Pancreatitis: An Update on Diagnosis and Management

There is an evolving understanding that autoimmune pancreatitis (AIP) is an immunoglobulin (Ig) G4 systemic disease. It can manifest as primarily a pancreatic disorder or in association with other disorders of presumed autoimmune cause. Classic clinical characteristics include obstructive jaundice, abdominal pain, and acute pancreatitis. Thus, AIP can be difficult to distinguish from pancreatic malignancy. However, AIP may respond to therapy with corticosteroids, and has a strong association with other immune mediated diseases. Although primarily a pathologic diagnosis, attempts have been made to reliably diagnose AIP clinically. AIP can be classified as either type 1 or type 2.

Endoscopic diagnosis and treatment of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are rare pancreatic neoplasms comprising only 1% to 2% of all pancreatic tumors. In recent years, the number of incidentally discovered PNETs has greatly increased given the widespread use of axial imaging. However, a significant proportion of PNETs may not be visualized on conventional imaging such as computed tomography, magnetic resonance imaging, and somatostatin receptor scintigraphy. Endoscopic ultrasound (EUS) has become an integral part of the diagnosis of PNETs because of its high sensitivity for detecting, localizing, and diagnosing PNETs. EUS-guided tissue acquisition provides histologic and immunologic confirmation, and may also allow prognostication about tumor behavior. In addition to preoperative assessment of these tumors, EUS has also been shown to have an important role in nonoperative management of small nonfunctional PNETs. Finally, recent developments suggest that interventional EUS may be used to aid intraoperative localization of PNETs and to deliver therapeutic agents for the treatment of PNETs. This review will discuss the endoscopic diagnosis and treatment of PNETs, with focus on recent advances in the utility of EUS in the clinical management of these tumors.

Precision Medicine and Pancreatic Cancer

Objectives There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2. Methods Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine. Tumor DCK, RRM1, RRM2, and p53R protein expressions were analyzed using a tissue microarray and immunohistochemistry and correlated with treatment outcome (overall survival and disease-free survival) by unconditional logistic regression analysis. Results There were 229 patients eligible for analysis from both the 5-fluorouracil and gemcitabine arms. Only RRM2 protein expression, and not DCK, RRM1, or p53R2 protein expression, was associated with survival in the gemcitabine treatment arm. Conclusions Despite limited data from other nonrandomized treatment data, our data do not support the predictive value of DCK, RRM1, or p53R2. Efforts should focus on human equilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.

Comparison of the diagnostic accuracy of three current guidelines for the evaluation of asymptomatic pancreatic cystic neoplasms.

Abstract Asymptomatic pancreatic cysts are a common clinical problem but only a minority of these cases progress to cancer. Our aim was to compare the accuracy to detect malignancy of the 2015 American Gastroenterological Association (AGA), the 2012 International Consensus/Fukuoka (Fukuoka guidelines [FG]), and the 2010 American College of Radiology (ACR) guidelines. We conducted a retrospective study at 3 referral centers for all patients who underwent resection for an asymptomatic pancreatic cyst between January 2008 and December 2013. We compared the accuracy of 3 guidelines in predicting high-grade dysplasia (HGD) or cancer in resected cysts. We performed logistic regression analyses to examine the association between cyst features and risk of HGD or cancer. A total of 269 patients met inclusion criteria. A total of 228 (84.8%) had a benign diagnosis or low-grade dysplasia on surgical pathology, and 41 patients (15.2%) had either HGD (n = 14) or invasive cancer (n = 27). Of the 41 patients with HGD or cancer on resection, only 3 patients would have met the AGA guidelines indications for resection based on the preoperative cyst characteristics, whereas 30/41 patients would have met the FG criteria for resection and 22/41 patients met the ACR criteria. The sensitivity, specificity, positive predictive value, negative predictive value of HGD, and/or cancer of the AGA guidelines were 7.3%, 88.2%, 10%, and 84.1%, compared to 73.2%, 45.6%, 19.5%, and 90.4% for the FG and 53.7%, 61%, 19.8%, and 88% for the ACR guidelines. In multivariable analysis, cyst size >3 cm, compared to ⩽3 cm, (odds ratio [OR] = 2.08, 95% confidence interval [CI] = 1.11, 4.2) and each year increase in age (OR = 1.07, 95% CI = 1.03, 1.11) were positively associated with risk of HGD or cancer on resection. In patients with asymptomatic branch duct-intraductal papillary mucinous neoplasms or mucinous cystic neoplasms who underwent resection, the prevalence rate of HGD or cancer was 15.2%. Using the 2015 AGA criteria for resection would have missed 92.6% of patients with HGD or cancer. The more “inclusive” FG and ACR had a higher sensitivity for HGD or cancer but lower specificity. Given the current deficiencies of these guidelines, it will be important to determine the acceptable rate of false-positives in order to prevent a single true-positive.

Editorial: Stopping Pancreatic Cyst Surveillance?

Abstract: The management of patients with pancreatic cysts, especially presumed branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), remains a challenge. BD-IPMNs carry a very low risk of malignancy and occur in predominantly older individuals who often die from causes not related to their pancreatic disease. The specific decision to stop surveillance of presumed low risk BD-IPMNs (those without either worrisome features (WF) or high risk stigmata (HRS)) is controversial, and needs to balance the real risk of malignancy or developing malignancy and IPMN-related mortality, with the patient’s life expectancy, quality of life expectations, and mortality from non-pancreatic-related causes. With improved life expectancy, improved survival from non-pancreatic malignancies, rising health costs, and growing detection of ever smaller presumed BD-IPMNs, this issue is becoming ever more critical.