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Pancreatic Neoplasms: HELP
Articles by William R. Brugge
Based on 49 articles published since 2010
(Why 49 articles?)
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Between 2010 and 2020, W. Brugge wrote the following 49 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines. 2014

Pitman, Martha B / Centeno, Barbara A / Ali, Syed Z / Genevay, Muriel / Stelow, Ed / Mino-Kenudson, Mari / Fernandez-del Castillo, Carlos / Max Schmidt, C / Brugge, William / Layfield, Lester / Anonymous9540785. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Diagn Cytopathol · Pubmed #24554455.

ABSTRACT: 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.

2 Editorial Pancreatic cyst guidelines: Which one to live by? 2017

Basar, Omer / Brugge, William R. ·Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #28411756.

ABSTRACT: -- No abstract --

3 Editorial Which guidelines should be used for branch-duct intraductal papillary mucinous neoplasms? 2016

Basar, Omer / Brugge, William R. ·Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Gastroenterology, Hacettepe Medical School, Ankara, Turkey. · Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #27530478.

ABSTRACT: -- No abstract --

4 Editorial Pancreatic cyst surveillance: Threat or opportunity? 2016

Brugge, William R. ·Pancreas Biliary Center, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #27206581.

ABSTRACT: -- No abstract --

5 Editorial Cyst fluid: moving beyond the carcinoembryonic antigen. 2015

Brugge, William R. ·Pancreas Biliary Center, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #26264436.

ABSTRACT: -- No abstract --

6 Editorial Cystic lesions of the pancreas: more reliable differentiation with in situ high-resolution optical imaging? 2012

Iftimia, Nicusor / Yoon, Won Jae / Brugge, William R. · ·Expert Rev Gastroenterol Hepatol · Pubmed #22375515.

ABSTRACT: -- No abstract --

7 Review EUS and related technologies for the diagnosis and treatment of pancreatic disease: research gaps and opportunities-Summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop. 2017

Lee, Linda S / Andersen, Dana K / Ashida, Reiko / Brugge, William R / Canto, Mimi I / Chang, Kenneth J / Chari, Suresh T / DeWitt, John / Hwang, Joo Ha / Khashab, Mouen A / Kim, Kang / Levy, Michael J / McGrath, Kevin / Park, Walter G / Singhi, Aatur / Stevens, Tyler / Thompson, Christopher C / Topazian, Mark D / Wallace, Michael B / Wani, Sachin / Waxman, Irving / Yadav, Dhiraj / Singh, Vikesh K. ·Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. · Departments of Cancer Survey and Gastrointestinal Oncology, Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Osaka, Japan. · Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Comprehensive Digestive Disease Center, Department of Gastroenterology and Hepatology, University of California at Irvine Health, Orange, California, USA. · Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Gastroenterology, Indiana University Health Medical Center, Indianapolis, Indiana, USA. · Department of Medicine, University of Washington, Seattle, Washington, USA. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Department of Pathology, University of Pittsburgh Medical Center, Sewickley, Pennsylvania, USA. · Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida, USA. · Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. · Department of Medicine, The University of Chicago Comprehensive Cancer Center, University of Chicago School of Medicine, Chicago, Illinois, USA. ·Gastrointest Endosc · Pubmed #28941651.

ABSTRACT: A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to address the research gaps and opportunities in pancreatic EUS. The event occurred on July 26, 2017 in 4 sessions: (1) benign pancreatic diseases, (2) high-risk pancreatic diseases, (3) diagnostic and therapeutics, and (4) new technologies. The current state of knowledge was reviewed, with identification of numerous gaps in knowledge and research needs. Common themes included the need for large multicenter consortia of various pancreatic diseases to facilitate meaningful research of these entities; to standardize EUS features of different pancreatic disorders, the technique of sampling pancreatic lesions, and the performance of various therapeutic EUS procedures; and to identify high-risk disease early at the cellular level before macroscopic disease develops. The need for specialized tools and accessories to enable the safe and effective performance of therapeutic EUS procedures also was discussed.

8 Review My Treatment Approach: Pancreatic Cysts. 2017

Basar, Omer / Brugge, William R. ·Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA. Electronic address: obasar@mgh.harvard.edu. · Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA. ·Mayo Clin Proc · Pubmed #28890216.

ABSTRACT: Our treatment approach for either symptomatic or incidentally found pancreatic cysts continues to improve. The true incidence of pancreatic cysts is not known, and pancreatic cystic neoplasms, especially intraductal papillary mucinous neoplasms, are currently most commonly diagnosed and resected. This is a result of increasing awareness, widespread availability of imaging, and better understanding of the nature of pancreatic cysts as well. Recent studies on molecular analysis and devices such as microbiopsy forceps help us better define and select the treatment approach to alleviate symptoms and to prevent malignant tumors while avoiding unnecessary surgery.

9 Review EUS. 2013

Brugge, William R. ·GI Endoscopy Unit, Massachusetts General Hospital, Boston, Massachusetts 02214, USA. ·Gastrointest Endosc · Pubmed #23948189.

ABSTRACT: -- No abstract --

10 Review Endoscopic approach to the diagnosis and treatment of pancreatic disease. 2013

Brugge, William R. ·Massachusetts General Hospital, GI Unit, Boston, MA 02114, USA. WBrugge@partners.org ·Curr Opin Gastroenterol · Pubmed #23872485.

ABSTRACT: PURPOSE OF REVIEW: The purpose of this review is to examine the recent developments in the use of endoscopic retrograde cholangio-pancreatography (ERCP) and endoscopic ultrasound (EUS) in the management of patients with pancreatic-biliary disease. RECENT FINDINGS: The use of ERCP to guide selective placement of pancreatic sphincterotomes, stone extraction balloons, and stents enables clinicians to treat pancreatic sphincteric and ductal disorders. Pancreatic stones are a remediable cause of recurrent pancreatitis and small calculi can be easily removed. The gold standard for the diagnosis of pancreas divisum remains ERCP and sphincterotomy is highly effective in the treatment of relapsing pancreatitis. Intraductal papillary mucinous neoplasms are the most common pancreatic malignancy and ERCP, as well as EUS can identify and sample the solid and cystic lesions. Mural nodules can be detected and sampled effectively by EUS-fine needle aspiration (FNA). The sensitivity of EUS-FNA for pancreatic adenocarcinoma is excellent (more than 85%). Although cyst fluid carcinoembryonic antigen is a very good marker for the presence of a mucinous cystic lesion, it is not an indicator of malignancy. SUMMARY: In summary, ERCP and EUS are important tools for the management of benign and malignant lesions of the pancreas.

11 Review Endoscopic ultrasonography-guided tumor ablation. 2012

Yoon, Won Jae / Brugge, William R. ·Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. ·Gastrointest Endosc Clin N Am · Pubmed #22632957.

ABSTRACT: With the introduction of curvilinear endosonoscopes, endoscopic ultrasonography (EUS) has achieved the role of a therapeutic modality as well as diagnostic procedure. EUS-guided tumor ablation is one such therapeutic modality. Various techniques of EUS-guided tumor ablation have been described, including radiofrequency ablation, photodynamic therapy, laser ablation, and ethanol injection. Most of the currently described techniques are experimental. Development and continuous improvement of devices, as well as establishment of indications for EUS-guided tumor ablations, are mandatory.

12 Review Pancreatic cystic neoplasms: diagnosis and management. 2012

Yoon, Won Jae / Brugge, William R. ·Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA. ·Gastroenterol Clin North Am · Pubmed #22341252.

ABSTRACT: PCNs are composed of a wide range of lesions from benign cysts to malignancies . Although a cross-sectional imaging provides a sensitive screening test, EUS with FNA and cyst fluid analysis greatly increase the diagnostic certainty. Cyst fluid CEA offers the greatest accuracy in the differentiation between mucinous and nonmucinous PCNs. In the future, endoscopic ablation therapy might offer an alternative to the traditional surgical approach.

13 Clinical Trial Imaging of pancreatic cystic lesions with confocal laser endomicroscopy: an ex vivo pilot study. 2017

Kadayifci, Abdurrahman / Atar, Mustafa / Yang, Michelle / Fernandez-Del Castillo, Carlos / Mino-Kenudson, Mari / Brugge, William R. ·Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. kadayifci@hotmail.com. · Division of Gastroenterology, University of Gaziantep, University street, 27060, Gaziantep, Turkey. kadayifci@hotmail.com. · Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ·Surg Endosc · Pubmed #28444494.

ABSTRACT: BACKGROUND: The differential diagnosis of pancreatic cystic lesions (PCLs) is an increasingly common clinical challenge. Confocal laser endomicroscopy (CLE) may differentiate PCLs by imaging of the cyst wall. However, clinical experience is still limited, and better image definition and characterization of the cyst wall in a spectrum of cysts are needed. This experimental study aimed to expose detailed imaging characteristics of PCLs by CLE. METHODS: Patients who underwent surgery of a PCL were enrolled. During surgery, intravenous fluorescein (2.5 ml of 10%) was injected just prior to the ligation of blood vessels supplying the pancreas. The freshly excised specimens were transected along the long axis to fully expose the luminal surface. A Gastroflex-UHD CLE probe (pCLE) was used manually to acquire images directly from the surface of cyst wall. The specimen subsequently underwent cross-sectional histology. All recorded data were analyzed by two investigators for predefined and original image findings of PCLs. RESULTS: Ten cases were recruited into the study. All patients underwent surgery because of a mucinous cyst with worrisome features or a symptomatic PCL. Imaging was successful in all patients and differently shaped papillary projections (PP) were visualized in eight patients. Pathological examination of those patients confirmed 6 cases with Intraductal Papillary Mucinous Neoplasm (IPMN) and 2 cases with Mucinous Cystic Neoplasm (MCN). In two patients with serous cystadenoma, typical vascular network was visualized in one patient, and microcystic structures in the other. Three of the IPMNs were malignant. The loss of papillary margin integrity and significant fragmentation together with irregularity was detected in malignant IPMNs by CLE. CONCLUSIONS: Pancreatic cyst epithelial wall can be visualized successfully by pCLE in ex vivo surgical specimens. Different papillary projections have been seen in all cases of IPMNs and MCNs. CLE has potential for identifying IPMN subtypes and for grading dysplasia.

14 Article Moray micro forceps biopsy improves the diagnosis of specific pancreatic cysts. 2018

Zhang, M Lisa / Arpin, Ronald N / Brugge, William R / Forcione, David G / Basar, Omer / Pitman, Martha B. ·Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. ·Cancer Cytopathol · Pubmed #29660844.

ABSTRACT: BACKGROUND: Making a specific diagnosis of pancreatic cysts preoperatively is difficult. The new disposable Moray micro forceps biopsy (MFB) device allows tissue sampling from the pancreatic cyst wall/septum and aims to improve diagnosis. This study compares the diagnostic performance of the MFB with the current conventional analysis of pancreatic cyst fluid (PCF). METHODS: A total of 48 patients sampled with MFB were identified. Cysts were classified as mucinous on PCF based on extracellular mucin/mucinous epithelium, carcinoembryonic antigen (CEA) levels ≥192 ng/mL, or KRAS/GNAS mutation. A diagnosis of intraductal papillary mucinous neoplasm was supported by GNAS mutation; a diagnosis of serous cystadenoma was supported by Von Hippel-Lindau tumor suppressor (VHL) mutation. A diagnosis of mucinous cystic neoplasm required the presence of subepithelial ovarian-type stroma. A high-risk cyst was defined as a mucinous cyst with high-grade dysplasia or an adenocarcinoma. Comparisons in diagnostic performance between PCF and MFB were made. RESULTS: The mean age of the patients was 69.6 years (range, 27-90 years); 25 of 48 patients (52.1%) were female. Cysts were in the pancreatic head (13 patients), neck (2 patients), body (20 patients), and tail (13 patients), averaging 3.1 cm (range, 1.2-6.0 cm). There was concordance with mucinous versus nonmucinous classification (60.4% for PCF vs 58.3% for MFB; P = .949). Three high-risk cysts were detected by PCF and 2 were detected by MFB (P = .670). However, MFB diagnosed significantly more specific cysts compared with PCF (50.0% for MFB vs 18.8% for PCF; P<.001). CONCLUSIONS: PCF analysis and MFB have comparable performance in distinguishing between mucinous and nonmucinous cysts and for detecting high-risk cysts. However, MFB was found to be superior for diagnosing specific cyst subtypes, thus adding significant value to preoperative patient management. Cancer Cytopathol 2018;126:414-20. © 2018 American Cancer Society.

15 Article Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts. 2018

Basar, Omer / Yuksel, Osman / Yang, Dennis J / Samarasena, Jason / Forcione, David / DiMaio, Christopher J / Wagh, Mihir S / Chang, Kenneth / Casey, Brenna / Fernandez-Del Castillo, Carlos / Pitman, Martha B / Brugge, William R. ·Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Gastroenterology, Eryaman Private Hospital, Ankara, Turkey. · Division of Gastroenterology, University of Florida Health, Gainesville, Florida. · Division of Gastroenterology and Hepatology, University of California, Aurora, California. · Division of Gastroenterology, Mount Sinai Medical Center, New York, New York. · Division of Gastroenterology and Hepatology, University of Colorado, Denver, Colorado, USA. · Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #29510146.

ABSTRACT: BACKGROUND AND AIMS: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology. METHODS: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS-FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis. RESULTS: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%). CONCLUSION: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis.

16 Article Ex vivo human bile duct radiofrequency ablation with a bipolar catheter. 2018

Atar, Mustafa / Kadayifci, Abdurrahman / Daglilar, Ebubekir / Hagen, Catherine / Fernandez-Del Castillo, Carlos / Brugge, William R. ·Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, 3-H GI Associates, Zero Emerson Place, Blossom St., Boston, MA, 02114, USA. · Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, 3-H GI Associates, Zero Emerson Place, Blossom St., Boston, MA, 02114, USA. kadayifci@hotmail.com. · Unit of Gastroenterology, Reyap Istanbul Hospital, Istanbul, Turkey. kadayifci@hotmail.com. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ·Surg Endosc · Pubmed #29264758.

ABSTRACT: BACKGROUND: Management of the primary and secondary tumors of the bile ducts still remains as a major clinical challenge. Radiofrequency (RF) ablation (RFA) of these tumors is feasible but the effect of RF energy on the human common bile duct (CBD) and surrounding tissues has not been investigated. This pilot study aimed to determine the relationship between RF energy and the depth of ablation in the normal human CBD. METHODS: The study was performed on fresh ex vivo human biliary-pancreatic tissue which had been resected for a pancreatic cyst or mass. The study was conducted within 15 min after resection. A bipolar Habib RFA catheter was placed into the middle of the intact CBD, and three different (5, 7, 10 W) power settings were applied over a 90-s period by an RF generator. Gross and histological examinations were performed. The depth of coagulation necrosis in CBD and the effect of RFA on CBD wall and surrounding pancreas tissue were determined by microscopic examination. RESULTS: The study included eight tissue samples. 5 W power was applied to three sites and RFA caused only focal epithelial necrosis limited to the CBD mucosa. 7 and 10 W were applied to five sites and coagulation necrosis occurred in all cases. Microscopically, necrosis was transmural, involved accessory bile duct glands, and extended to the surrounding pancreatic tissue in four of these cases. Macroscopically, RFA resulted in circumferential white-yellowish color change extending approximately 2 cm of the CBD. CONCLUSION: Bipolar RF energy application with 5 W resulted in limited ablation on CBD wall. However, 7 and 10 W generated tissue necrosis which extended through the CBD wall and into surrounding pancreas tissue. Endoscopic biliary RFA is an effective technique for local biliary tissue ablation but the use of high energy may injure surrounding tissue.

17 Article Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms. 2018

Franses, Joseph W / Basar, Omer / Kadayifci, Abdurrahman / Yuksel, Osman / Choz, Melissa / Kulkarni, Anupriya S / Tai, Eric / Vo, Kevin D / Arora, Kshitij S / Desai, Niyati / Licausi, Joseph A / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A / Ryan, David P / Brugge, William R / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA. · Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. · Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA brugge.william@mgh.harvard.edu dting1@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA brugge.william@mgh.harvard.edu dting1@mgh.harvard.edu. ·Oncologist · Pubmed #28860411.

ABSTRACT: BACKGROUND: Recent work has demonstrated early shedding of circulating epithelial cells (CECs) from premalignant intraductal papillary mucinous neoplasms (IPMNs). However, the potential use of CECs as a "liquid biopsy" for patients with IPMNs has been limited by antigen dependence of CEC isolation devices and the lack of robust detection biomarkers across CEC phenotypes. MATERIALS AND METHODS: We utilized a negative depletion microfluidic platform to purify CECs from contaminating leukocytes and coupled this platform with immunofluorescence, RNA in situ hybridization, and RNA sequencing (RNA-seq) detection and enumeration. RESULTS: Using established protein (EpCAM, cytokeratins) and novel noncoding RNA (HSATII, cytokeratins) biomarkers, we detected CECs in 88% of patients bearing IPMN lesions. RNA-seq analysis for MUC genes confirm the likely origin of these CECs from pancreatic lesions. CONCLUSION: Our findings increase the sensitivity of detection of these cells and therefore could have clinical implications for cancer risk stratification. IMPLICATIONS FOR PRACTICE: This work describes a high-sensitivity platform for detection of epithelial cells shed from preneoplastic lesions at high risk of malignant transformation. Further research efforts are underway to define the transcriptional programs that might allow discrimination between circulating cells released from tumors that will become malignant and cells released from tumors that will not. After further refinement, this combination of technologies could be deployed for monitoring and early detection of patients at high risk for developing new or recurrent pancreatic malignancies.

18 Article Long-term Risk of Pancreatic Malignancy in Patients With Branch Duct Intraductal Papillary Mucinous Neoplasm in a Referral Center. 2017

Pergolini, Ilaria / Sahora, Klaus / Ferrone, Cristina R / Morales-Oyarvide, Vicente / Wolpin, Brian M / Mucci, Lorelei A / Brugge, William R / Mino-Kenudson, Mari / Patino, Manuel / Sahani, Dushyant V / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Universita' Politecnica delle Marche, Ancona, Italy. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: cfernandez@partners.org. ·Gastroenterology · Pubmed #28739282.

ABSTRACT: BACKGROUND & AIMS: Little is known about the development of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). We evaluated long-term outcomes of a large cohort of patients with BD-IPMNs to determine risk of malignancy and define a subset of low-risk BD-IPMNs. METHODS: We performed a retrospective analysis of data from 577 patients with suspected or presumed BD-IPMN under surveillance at the Massachusetts General Hospital. Patients underwent cross-sectional imaging analysis at 3 months or later after their initial diagnosis. The diagnosis of BD-IPMN was based on the presence of unilocular or multilocular cysts of the pancreas and a non-dilated main pancreatic duct (<5 mm). We collected demographic, clinical, and pathology data. Cysts were characterized at the time of diagnosis and during the follow-up period. Follow-up duration was time between initial cyst diagnosis and date of last visit or death for patients without development of pancreatic cancer, date of surgery for patients with histologically confirmed malignancy, or date of first discovery of malignancy by imaging analysis for patients with unresectable tumors or who underwent neoadjuvant treatment before surgery. The primary outcome was risk of malignancy, with a focus on patients followed for 5 years or more, compared with that of the US population, based on standardized incidence ratio. RESULTS: Of the 577 patients studied, 479 (83%) were asymptomatic at diagnosis and 363 (63%) underwent endoscopic ultrasound at least once. The median follow-up time was 82 months (range, 6-329 months) for the entire study cohort; 363 patients (63%) underwent surveillance for more than 5 years, and 121 (21%) for more than 10 years. Malignancies (high-grade dysplasia or invasive neoplasm) developed after 5 years in 20 of 363 patients (5.5%), and invasive cancer developed in 16 of 363 patients (4.4%). The standardized incidence ratio for patients with BD-IPMNs without worrisome features of malignancy at 5 years was 18.8 (95% confidence interval, 9.7-32.8; P < .001). One hundred and eight patients had cysts ≤1.5 cm for more than 5 years of follow-up; only 1 of these patients (0.9%) developed a distinct ductal adenocarcinoma. By contrast, among the 255 patients with cysts >1.5 cm, 19 (7.5%) developed malignancy (P = .01). CONCLUSIONS: In a retrospective analysis of patients with BD-IPMNs under surveillance, their overall risk of malignancy, almost 8%, lasted for 10 years or more, supporting continued surveillance after 5 years. Cysts that remain ≤1.5 cm for more than 5 years might be considered low-risk for progression to malignancy.

19 Article Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos). 2017

Krishna, Somashekar G / Brugge, William R / Dewitt, John M / Kongkam, Pradermchai / Napoleon, Bertrand / Robles-Medranda, Carlos / Tan, Damien / El-Dika, Samer / McCarthy, Sean / Walker, Jon / Dillhoff, Mary E / Manilchuk, Andrei / Schmidt, Carl / Swanson, Benjamin / Shah, Zarine K / Hart, Phil A / Conwell, Darwin L. ·Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Pancreas Biliary Center, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Division of Gastroenterology, Department of Medicine, Indiana University Hospital, Indianapolis, Indiana, USA. · Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand. · Department of Gastroenterology, Ramsay Générale de Santé, Hôpital privé Jean Mermoz, Lyon, France. · Gastroenterology and Endoscopy Division, Instituto Ecuatoriano de Enfermedades Digestivas, University Hospital OMNI, Guayaquil, Ecuador. · Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore. · Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Department of General Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. ·Gastrointest Endosc · Pubmed #28286093.

ABSTRACT: BACKGROUND AND AIMS: EUS-guided needle-based confocal laser endomicroscopy (nCLE) characteristics of common types of pancreatic cystic lesions (PCLs) have been identified; however, surgical histopathology was available in a minority of cases. We sought to assess the performance characteristics of EUS nCLE for differentiating mucinous from non-mucinous PCLs in a larger series of patients with a definitive diagnosis. METHODS: Six endosonographers (nCLE experience >30 cases each) blinded to all clinical data, reviewed nCLE images of PCLs from 29 patients with surgical (n = 23) or clinical (n = 6) correlation. After 2 weeks, the assessors reviewed the same images in a different sequence. A tutorial on available and novel nCLE image patterns was provided before each review. The performance characteristics of nCLE and the κ statistic for interobserver agreement (IOA, 95% confidence interval [CI]), and intraobserver reliability (IOR, mean ± standard deviation [SD]) for identification of nCLE image patterns were calculated. Landis and Koch interpretation of κ values was used. RESULTS: A total of 29 (16 mucinous PCLs, 13 non-mucinous PCLs) nCLE patient videos were reviewed. The overall sensitivity, specificity, and accuracy for the diagnosis of mucinous PCLs were 95%, 94%, and 95%, respectively. The IOA and IOR (mean ± SD) were κ = 0.81 (almost perfect); 95% CI, 0.71-0.90; and κ = 0.86 ± 0.11 (almost perfect), respectively. The overall specificity, sensitivity, and accuracy for the diagnosis of serous cystadenomas (SCAs) were 99%, 98%, and 98%, respectively. The IOA and IOR (mean ± SD) for recognizing the characteristic image pattern of SCA were κ = 0.83 (almost perfect); 95% CI, 0.73-0.92; and κ = 0.85 ± 0.11 (almost perfect), respectively. CONCLUSIONS: EUS-guided nCLE can provide virtual histology of PCLs with a high degree of accuracy and inter- and intraobserver agreement in differentiating mucinous versus non-mucinous PCLs. These preliminary results support larger multicenter studies to evaluate EUS nCLE. (Clinical trial registration number: NCT02516488.).

20 Article Needle-Based Confocal Laser Endomicroscopy for Evaluation of Cystic Neoplasms of the Pancreas. 2017

Kadayifci, Abdurrahman / Atar, Mustafa / Basar, Omer / Forcione, David G / Brugge, William R. ·Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, 3-H GI Associates, Zero Emerson Place, Blossom st., Boston, MA, 02114, USA. kadayifci@hotmail.com. · Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, 3-H GI Associates, Zero Emerson Place, Blossom st., Boston, MA, 02114, USA. ·Dig Dis Sci · Pubmed #28281172.

ABSTRACT: BACKGROUND: The accurate diagnosis of cystic neoplasms of the pancreas (CNP) with current diagnostic methods is limited. Endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) is a new technique which can obtain images from the cyst wall during EUS-fine needle aspiration (EUS-FNA). The aim of this study was to assess the safety, feasibility, and diagnostic value of nCLE for CNP. METHODS: Patients who underwent EUS-FNA to evaluate a CNP larger than 2 cm were enrolled. The cyst was punctured with 19-G FNA needle preloaded with an nCLE probe. The images from different areas of the cyst wall were recorded. Using the final diagnosis defined by surgery or EUS-FNA cyst fluid analysis, the accuracy of the confocal images was defined. RESULTS: The procedure and image acquisition was successful in 18 of the 20 patients. Predefined typical structures for mucinous cysts were visualized in 8 of 12 (66%) cysts but none of the non-mucinous cysts. The superficial vascular network which is a typical finding of serous cysts was observed in 2 of 3 patients. The sensitivity, specificity, and diagnostic accuracy of the findings of epithelial structures by nCLE were 66, 100, and 80%, respectively, for a mucinous cyst diagnosis. All patients tolerated the procedure well, and no adverse effects were determined. CONCLUSION: nCLE was found to be safe and feasible with high technical success, in this pilot study. With an overall accuracy of 80%, it has the potential to contribute to the diagnosis of CNP with specific imaging.

21 Article Preoperative characteristics and cytological features of 136 histologically confirmed pancreatic mucinous cystic neoplasms. 2017

Scourtas, Aristana / Dudley, Jonathan C / Brugge, William R / Kadayifci, Abdurrahman / Mino-Kenudson, Mari / Pitman, Martha B. ·Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Stanford University Medical Center, Palo Alto, California. · Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. · Division of Gastroenterology, Gaziantep University School of Medicine, Gaziantep, Turkey. ·Cancer Cytopathol · Pubmed #27926784.

ABSTRACT: BACKGROUND: Mucinous cystic neoplasms (MCNs) of the pancreas present a management conundrum. The majority are benign but all are resected due to their malignant potential. Recent studies have recommended nonsurgical management. In the current study, the authors analyzed the preoperative imaging, cytology, and cyst fluid characteristics of 136 histologically confirmed MCNs to assess predictors of a high-risk (HR) cyst for surgical triage. METHODS: MCNs resected at the Massachusetts General Hospital between 1990 and 2014 formed the study cohort. Patient demographics, cyst size, and mural nodules (MNs) by endoscopic ultrasound, cytology, and cyst fluid carcinoembryonic antigen and amylase levels were correlated with histological grade. A HR cyst was defined as high-grade dysplasia or invasive carcinoma on histology. Performance characteristics were assessed for each parameter, with a cyst size ≥3 cm or a MN on imaging and malignant cytology considered to be "true-positive" results for predicting malignancy. RESULTS: Only 15 of the 136 cysts had HR histology (11%). On average, patients with HR cysts were older than those with low-risk cysts (55 years vs 49 years, respectively). High-grade cytology was the most accurate predictor of malignancy (95%) followed by MN and cyst size together (88%) and MN alone (83%). The average carcinoembryonic antigen level (in ng/mL) increased with the grade of dysplasia but the ranges overlapped between low risk and HR cysts. CONCLUSIONS: To the authors' knowledge, the current study is the largest series to date analyzing the cytological features of histologically confirmed MCN. Cytology is insensitive but very specific for detecting a HR MCN and outperformed imaging for the detection of HR MCN. Endoscopic ultrasound-guided fine-needle aspiration and cytology should be performed on any clinically suspected MCN that is being considered for conservative management. Cancer Cytopathol 2017;125:169-177. © 2016 American Cancer Society.

22 Article Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms. 2017

Kadayifci, Abdurrahman / Atar, Mustafa / Wang, Jessica L / Forcione, David G / Casey, Brenna W / Pitman, Martha B / Brugge, William R. ·Division of Gastroenterology, Gaziantep University School of Medicine, Gaziantep, Turkey. · Division of Gastroenterology, Harvard Medical School, Boston, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. ·Dig Endosc · Pubmed #27514845.

ABSTRACT: BACKGROUND AND AIM: Molecular analysis of pancreatic cyst fluid (PCF) has been proposed as a novel method for differentiating pancreatic cystic lesions (PCL). The present study aimed to investigate the value of GNAS testing when added to KRAS and carcinoembryonic antigen (CEA) testing of PCF for the diagnosis of intraductal papillary mucinous neoplasms (IPMN). METHODS: Prospectively collected endoscopic ultrasonography fine-needle aspiration (EUS-FNA) data were analyzed retrospectively for GNAS and KRAS mutations and CEA results. IPMN were histologically confirmed or supported by imaging and EUS-FNA findings (KRAS, CEA, cytology). Performance characteristics of GNAS added to KRAS and CEA for the diagnosis of IPMN were calculated. RESULTS: The study population consisted of 197 patients with cyst fluid test results. Cysts were histologically classified in 33 patients and by clinical criteria in 164 patients. The IPMN group included 108 patients and the non-IPMN group included 89 patients. GNAS was positive in 51 patients (47.2%) with IPMN. Forty-two of these patients (82.3%) also had a KRAS mutation. Adding GNAS to KRAS increased the diagnostic accuracy from 76.6% to 79.1% (P > 0.05). Adding GNAS to CEA increased the diagnostic accuracy from 66.4% to 80.7 % (P < 0.05), but did not achieve a diagnostic superiority to KRAS testing alone (80.7% vs 76.6%, P > 0.05). The diagnostic accuracy of the triple combination was significantly better than all single tests (P < 0.05). CONCLUSION: GNAS mutation is a highly specific test for IPMN. When GNAS testing is added to CEA and KRAS, a significantly greater overall accuracy (86.2%) is achieved.

23 Article Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size: Positive Implications for Future Targeted Screening. 2016

Hur, Chin / Tramontano, Angela C / Dowling, Emily C / Brooks, Gabriel A / Jeon, Alvin / Brugge, William R / Gazelle, G Scott / Kong, Chung Yin / Pandharipande, Pari V. ·From the *Institute for Technology Assessment and †Gastroenterology Division, Department of Medicine, Massachusetts General Hospital; ‡Harvard Medical School; §Department of Radiology, Massachusetts General Hospital; and ∥Dana Farber Cancer Institute, Boston, MA. ·Pancreas · Pubmed #26692444.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has not experienced a meaningful mortality improvement for the past few decades. Successful screening is difficult to accomplish because most PDACs present late in their natural history, and current interventions have not provided significant benefit. Our goal was to identify determinants of survival for early PDAC to help inform future screening strategies. METHODS: Early PDACs from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database (2000-2010) were analyzed. We stratified by size and included carcinomas in situ (Tis). Overall cancer-specific survival was calculated. A Cox proportional hazards model was developed and the significance of key covariates for survival prediction was evaluated. RESULTS: A Kaplan-Meier plot demonstrated significant differences in survival by size at diagnosis; these survival benefits persisted after adjustment for key covariates in the Cox proportional hazards analysis. In addition, relatively weaker predictors of worse survival included older age, male sex, black race, nodal involvement, tumor location within the head of the pancreas, and no surgery or radiotherapy. CONCLUSIONS: For early PDAC, we found tumor size to be the strongest predictor of survival, even after adjustment for other patient characteristics. Our findings suggest that early PDAC detection can have clinical benefit, which has positive implications for future screening strategies.

24 Article Next-Generation Sequencing and Fluorescence in Situ Hybridization Have Comparable Performance Characteristics in the Analysis of Pancreaticobiliary Brushings for Malignancy. 2016

Dudley, Jonathan C / Zheng, Zongli / McDonald, Thomas / Le, Long P / Dias-Santagata, Dora / Borger, Darrell / Batten, Julie / Vernovsky, Kathy / Sweeney, Brenda / Arpin, Ronald N / Brugge, William R / Forcione, David G / Pitman, Martha B / Iafrate, A John. ·Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts. · Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts; Department of Gastroenterology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: mpitman@partners.org. · Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: aiafrate@partners.org. ·J Mol Diagn · Pubmed #26596524.

ABSTRACT: Cytological evaluation of pancreatic or biliary duct brushings is a specific, but insensitive, test for malignancy. We compared adjunctive molecular testing with next-generation sequencing (NGS) relative to fluorescence in situ hybridization (FISH) for detection of high-risk neoplasia or malignancy. Bile duct brushings from 81 specimens were subjected to cytological analysis, FISH using the UroVysion probe set, and targeted NGS. Specimens were placed into negative/atypical (negative) or suspicious/positive (positive) categories depending on cytology and negative or positive categories on the basis of FISH and NGS results. Performance characteristics for each diagnostic modality were calculated on the basis of clinicopathologic follow-up and compared in a receiver operating characteristic analysis. There were 33 high-risk neoplasia/malignant strictures (41%) and 48 benign (59%). NGS revealed driver mutations in 24 cases (30%), including KRAS (21 of 24 cases), TP53 (14 of 24 cases), SMAD4 (6 of 24 cases), and CDKN2A (4 of 24 cases). Cytology had a sensitivity of 67% (95% CI, 48%-82%) and a specificity of 98% (95% CI, 89%-100%). When added to cytology, NGS increased the sensitivity to 85% (95% CI, 68%-95%), leading to a significant increase in the area under the curve in a receiver operating characteristic analysis (P = 0.03). FISH increased the sensitivity to 76% (95% CI, 58%-89%), without significantly increasing the area under the curve. These results suggest that ancillary NGS testing offers advantages over FISH, although studies with larger cohorts are needed to verify these findings.

25 Article Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. 2016

Jones, Martin / Zheng, Zongli / Wang, Jessica / Dudley, Jonathan / Albanese, Emily / Kadayifci, Abdurrahman / Dias-Santagata, Dora / Le, Long / Brugge, William R / Fernandez-del Castillo, Carlos / Mino-Kenudson, Mari / Iafrate, A John / Pitman, Martha B. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. ·Gastrointest Endosc · Pubmed #26253016.

ABSTRACT: BACKGROUND AND AIMS: The value of next-generation sequencing (NGS) of pancreatic cyst fluid relative to the clinical and imaging impression has not been well-studied. The aim of this study was to assess the impact of NGS on the clinical diagnosis from imaging and carcinoembryonic antigen (CEA) and thus the management of pancreatic cysts. METHODS: Ninety-two pancreatic cyst fluids from 86 patients were analyzed by cytology, CEA, and targeted NGS. Cysts were classified by imaging as nonmucinous, mucinous, or not specified. NGS results were compared with the imaging impression stratified by CEA and cytology. RESULTS: NGS impacted the clinical diagnosis by defining a cyst as mucinous in 48% of cysts without elevated CEA levels. The VHL gene in 2 intraductal papillary mucinous neoplasms (IPMNs) supported a serous cystadenoma. Twenty percent of cysts that were nonmucinous by imaging were mucinous by NGS. Of the 14 not-specific cysts, CEA levels were not elevated in 12 (86%), and NGS established a mucinous etiology in 3 (25%). A KRAS or GNAS mutation supported an IPMN with nonmucinous CEA in 71%. A KRAS mutation reclassified 19% of nonneoplastic cysts with nonmucinous CEA as mucinous. Seven cyst fluids (8%) had either a TP53 mutation or loss of CDKN2A or SMAD4 in addition to KRAS and/or GNAS mutations; 5 of 7 (71%) were clinically malignant, and high-grade cytology was detected in all 5. Overall, CEA was more specific for a mucinous etiology (100%), but NGS was more sensitive (86% vs 57%). CONCLUSIONS: NGS of pancreatic cyst fluid impacts clinical diagnosis and patient management by defining, supporting, or changing the clinical diagnosis based on imaging and CEA. NGS was most valuable in identifying mucinous cysts with nonmucinous CEA. An added benefit is the potential to detect mutations late in the progression to malignancy that may increase the risk classification of the cyst based on imaging and cytology.

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