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Pancreatic Neoplasms: HELP
Articles by Carlos F. Fernandez-del Castillo
Based on 107 articles published since 2010
(Why 107 articles?)
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Between 2010 and 2020, C. Fernández Del Castillo wrote the following 107 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
51 Article Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice. 2016

Yamaguchi, Junpei / Mino-Kenudson, Mari / Liss, Andrew S / Chowdhury, Sanjib / Wang, Timothy C / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Warshaw, Andrew L / Thayer, Sarah P. ·Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. · Division of Digestive and Liver Diseases and Irving Cancer Research Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts; Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: sarah.thayer@unmc.edu. ·Gastroenterology · Pubmed #27523981.

ABSTRACT: BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRAS RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2 CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

52 Article Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment. 2016

Huang, Yinshi / Nahar, Sabikun / Nakagawa, Akifumi / Fernandez-Barrena, Maite G / Mertz, Jennifer A / Bryant, Barbara M / Adams, Curtis E / Mino-Kenudson, Mari / Von Alt, Kate N / Chang, Kevin / Conery, Andrew R / Hatton, Charlie / Sims, Robert J / Fernandez-Zapico, Martin E / Wang, Xingpeng / Lillemoe, Keith D / Fernández-Del Castillo, Carlos / Warshaw, Andrew L / Thayer, Sarah P / Liss, Andrew S. ·Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · Constellation Pharmaceuticals, Cambridge, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Departments of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. aliss@mgh.harvard.edu sarah.thayer@unmc.edu. ·Clin Cancer Res · Pubmed #27169995.

ABSTRACT: PURPOSE: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. EXPERIMENTAL DESIGN: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. RESULTS: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. CONCLUSIONS: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259-70. ©2016 AACR.

53 Article Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors. 2016

Villani, Vincenzo / Mahadevan, Krishnan K / Ligorio, Matteo / Fernández-Del Castillo, Carlos / Ting, David T / Sabbatino, Francesco / Zhang, Irene / Vangel, Mark / Ferrone, Soldano / Warshaw, Andrew L / Lillemoe, Keith D / Wargo, Jennifer / Deshpande, Vikram / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medicine and Surgery, University of Salerno, Salerno, Italy. · Doctor of Medicine Program, Harvard Medical School, Boston, MA, USA. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. cferrone@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #27020585.

ABSTRACT: BACKGROUND: The staging of pancreatic neuroendocrine tumors (PNETs) is continuously evolving. Mitotic count, as measured by hematoxylin and eosin (H&E) or Ki67 labeling index (Ki67LI), is the best predictor of disease biology. However, both of these methods have several limitations. Phosphorylated histone H3 (PHH3), a novel mitotic marker, is potentially more accurate and easier to evaluate. This study aimed to evaluate the prognostic impact of PHH3 on patients with PNETs. METHODS: Clinicopathologic data and paraffin-embedded tissue were evaluated for 100 of the 247 PNET patients whose tumors were resected between 1998 and 2010. Mitotic counts were analyzed on H&E-, Ki67-, and PHH3-stained slides by two independent pathologists. Kaplan-Meier curves, log-rank tests, Cox regression models, and time-dependent receiver operative characteristics (ROC) curves were used to evaluate the prognostic power of these markers. An internal data cross-validation was performed to select the best cutoff. RESULTS: Of the 100 PNET patients resected, 53 were men. The median age of the patients was 59 years (range 19-96 years). The median follow-up period was 68 months (range 3-186 months). The median time for evaluation of an H&E- or PHH3-stained slide was 3 min, relative to 15 min for Ki67. The findings showed H&E, Ki67, and PHH3 all to be excellent predictors of disease-specific survival (DSS). However, PHH3 was superior to H&E and Ki67 in predicting both disease-free survival (DFS) (p = 0.006) and DSS (p = 0.001). Evaluation of the PHH3 mitotic count showed 7 mitoses per 10 high-power fields (HPFs) to be the optimal cutoff for differentiating between low- and high-risk PNET patients. CONCLUSIONS: PHH3 is a better predictor of both DFS and DSS than H&E or Ki67 in PNET. In addition, PHH3 appears to be both easier to interpret and more accurate when compared to current prognostic markers.

54 Article Preoperative biliary drainage does not increase major complications in pancreaticoduodenectomy: a large single center experience from the Massachusetts General Hospital. 2016

Sahora, Klaus / Morales-Oyarvide, Vicente / Ferrone, Cristina / Fong, Zhi Ven / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang Ambulatory Care Center 460, 15 Parkman Street, Boston, MA 02114, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang Ambulatory Care Center 460, 15 Parkman Street, Boston, MA 02114, USA. cfernandez@partners.org. ·J Hepatobiliary Pancreat Sci · Pubmed #26768943.

ABSTRACT: BACKGROUND: The impact of preoperative biliary drainage (PBD) on perioperative morbidity and mortality in pancreatic surgery is still under debate. The aim of this study was to investigate outcomes of stented vs. non-stented patients undergoing pancreatoduodenectomy (PD). METHODS: We retrospectively compared 500 consecutive patients who underwent PBD prior to PD with 500 patients who did not. Ninety-day mortality and morbidity were assessed. RESULTS: The overall postoperative morbidity and mortality was 37% and 1.4%, respectively. Major complications (Clavien ≥ III) occurred in 16% of patients. The overall morbidity and mortality was not significantly higher in patients who underwent PBD. However, the rate of wound infection was significantly higher in patients who underwent PBD (19% vs. 9%, P = 0.001). When comparing intraoperative bile cultures of stented patients with and without wound infection, the presence of Enterobacter species (OR 2.4, 95% CI 1.5-4.1, P = 0.001) and Citrobacter species (OR 2.3, 95% CI 1.1-5.2, P = 0.037) in the bile significantly increased the likelihood of wound infection. CONCLUSION: Preoperative biliary drainage is associated with bactobilia and wound infection, but does not affect the overall morbidity and mortality of patients undergoing PD.

55 Article Operative Versus Nonoperative Management of Nonfunctioning Pancreatic Neuroendocrine Tumors. 2016

Zhang, Irene Y / Zhao, Jing / Fernandez-Del Castillo, Carlos / Braun, Yvonne / Razmdjou, Shadi / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Massachusetts General Hospital, Wang 460, 15 Parkman Street, Boston, MA, USA. · Massachusetts General Hospital, Wang 460, 15 Parkman Street, Boston, MA, USA. cferrone@partners.org. ·J Gastrointest Surg · Pubmed #26691146.

ABSTRACT: INTRODUCTION: Surgical resection is the only curative treatment for pancreatic neuroendocrine tumors (PNETs), but pancreatic operations carry a significant morbidity. We investigated whether the resection of small, asymptomatic nonfunctioning PNETs is beneficial. Clinicopathologic factors were retrospectively reviewed for all PNET cases from 1998 to 2014. METHODS: Kaplan-Meier survival and multivariable regression analyses were performed. A total of 249 patients had nonfunctioning PNETs with adequate follow-up, of whom 193 were resected and 56 were observed. Median age was 56 years, and 48 % of the patients were female. RESULTS: Overall, the resected patients had a significantly longer survival (OS) (p = 0.001). However, for the patients with PNETs ≤2.5 cm in size and without metastasis at presentation, tumor size significantly modified the effect of resection on overall survival (p < 0.05). The protective effect of resection increased as tumor size increased. An operation became a significant predictor of overall survival for tumors >1.5 cm (p = 0.050 or less for larger tumors) but was not significant for tumors <1.5 cm (p = 0.317 or more for smaller tumors), controlling for age-adjusted Charlson comorbidity index. CONCLUSION: Resection of nonfunctioning PNETs over 1.5 cm is independently and significantly associated with a longer survival. However, the benefit of resection for tumors under 1.5 cm is unclear.

56 Article Intraductal papillary mucinous neoplasms of the pancreas with concurrent pancreatic and periampullary neoplasms. 2016

Sahora, K / Crippa, S / Zamboni, G / Ferrone, C / Warshaw, A L / Lillemoe, K / Mino-Kenudson, M / Falconi, M / Fernandez-del Castillo, C. ·Department of Surgery, Massachusetts General Hospital, Boston, USA; Department of Pathology, Massachusetts General Hospital, Boston, USA. · Department of Surgery, Ospedale Sacro Cuore Don Calabria, Negrar (VR), Italy; Department of Pathology, Ospedale Sacro Cuore Don Calabria, Negrar (VR), Italy. · Department of Pathology, Ospedale Sacro Cuore Don Calabria, Negrar (VR), Italy. · Department of Pathology, Massachusetts General Hospital, Boston, USA. · Department of Surgery, Massachusetts General Hospital, Boston, USA; Department of Pathology, Massachusetts General Hospital, Boston, USA. Electronic address: cfernandez@partners.org. ·Eur J Surg Oncol · Pubmed #26687069.

ABSTRACT: BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) have been reported to be associated with concurrent, distinct pancreatic ductal adenocarcinoma (con-PDAC) in about 8% (range, 4-10%) of resected branch duct (BD) lesions. In addition, other pancreatic and ampullary tumors are occasionally diagnosed with IPMN in patients undergoing pancreatic surgery. The objective of this study is to describe the prevalence, clinicopathologic characteristics and prognosis of IPMN with concurrent pancreatic and ampullary neoplasms, especially con-PDAC. METHODS: The combined databases of pancreatic resections from the Massachusetts General Hospital and the Negrar Hospital, Italy, were analyzed for patients who had been diagnosed with IPMN and concurrent pancreatic or ampullary neoplasms. RESULTS: 2762 patients underwent pancreatic surgery from January 2000 to December 2012. Sixteen percent (n = 441) had pathologically confirmed IPMN and 11% of these (n = 50) had a different distinct synchronous pancreatic neoplasm. The majority of these, 62%, were con-PDAC, followed by neuroendocrine neoplasms (10%) and ampullary carcinoma (10%). Less frequently, mucinous (6%) as well as serous cystic neoplasms (6%), adenosquamous carcinoma (4%) and distal bile duct cancer (2%) were diagnosed. Among all patients with synchronous neoplasms, 66% harbored BD-IPMN, 28% combined IPMN and 6% main duct IPMN. Abdominal pain and/or jaundice were the leading symptoms in half of patients. CONCLUSION: IPMN, mainly BD-IPMN, are associated with con-PDAC in about 7% of patients and account for 62% of all concurrent pancreatic/ampullary neoplasms. Other synchronous neoplasms may be found sporadically with IPMN without a suspected association.

57 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.

58 Article Recurrence and Survival After Resection of Small Intraductal Papillary Mucinous Neoplasm-associated Carcinomas (≤20-mm Invasive Component): A Multi-institutional Analysis. 2016

Winter, Jordan M / Jiang, Wei / Basturk, Olca / Mino-Kenudson, Mari / Fong, Zhi Ven / Tan, Wei Phin / Lavu, Harish / Vollmer, Charles M / Furth, Emma E / Haviland, Dana / Klimstra, David S / Jarnagin, William R / Lillemoe, Keith D / Yeo, Charles J / Fernandez-Del Castillo, Carlos / Allen, Peter J. ·*Department of Surgery and the Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA †Department of Pathology, Thomas Jefferson University, Philadelphia, PA ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Pathology, Massachusetts General Hospital, Boston, MA ¶Department of Surgery, Massachusetts General Hospital, Boston, MA ||Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA **Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA ††Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. ·Ann Surg · Pubmed #26135696.

ABSTRACT: BACKGROUND: Early invasive carcinoma may be encountered in association with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The natural history of these early invasive lesions is unknown. METHODS: Pancreatic surgical databases from 4 high-volume centers were queried for IPMNs, with invasive components measuring 20 mm or less. All cases were reviewed by GI gastrointestinal pathologists, and pathologic features were analyzed to identify predictors of recurrence and survival. RESULTS: A total of 70 small IPMN-associated invasive carcinomas (≤20-mm invasion) were identified, comprising 25% of resected IPMN-associated carcinomas (n = 280). Most of these small invasive cancers were multifocal (66%), less than 10 mm in size (73%), and arose in the setting of a main duct IPMN (96%). The most common adenocarcinoma subtypes were tubular (57%) and colloid (29%). Lymph node metastases were present in 19% of cases and 23% were T3 lesions. The overall recurrence rate was 24% (n = 17), and the median time to recurrence was 16 months (range: 4-132 months). Median and 5-year survival rates were 99 months and 59%. Recurrence patterns of invasive disease were local in 35%, distant in 47%, and both in 18%. Lymphatic spread and T3 stage were predictive of recurrence (univariate, P = 0.006), whereas tubular carcinoma type was the most predictive of poor overall survival (multivariate hazard ratio = 3.7, P = 0.04). CONCLUSIONS: This study represents the largest multi-institutional experience of resected small IPMN-associated carcinoma. Although these malignancies may frequently be cured with resection, recurrence risk is significant. Lymphatic spread, increased T stage, and tubular type carcinoma were associated with the poorest outcome.

59 Article Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas). 2016

Jais, B / Rebours, V / Malleo, G / Salvia, R / Fontana, M / Maggino, L / Bassi, C / Manfredi, R / Moran, R / Lennon, A M / Zaheer, A / Wolfgang, C / Hruban, R / Marchegiani, G / Fernández Del Castillo, C / Brugge, W / Ha, Y / Kim, M H / Oh, D / Hirai, I / Kimura, W / Jang, J Y / Kim, S W / Jung, W / Kang, H / Song, S Y / Kang, C M / Lee, W J / Crippa, S / Falconi, M / Gomatos, I / Neoptolemos, J / Milanetto, A C / Sperti, C / Ricci, C / Casadei, R / Bissolati, M / Balzano, G / Frigerio, I / Girelli, R / Delhaye, M / Bernier, B / Wang, H / Jang, K T / Song, D H / Huggett, M T / Oppong, K W / Pererva, L / Kopchak, K V / Del Chiaro, M / Segersvard, R / Lee, L S / Conwell, D / Osvaldt, A / Campos, V / Aguero Garcete, G / Napoleon, B / Matsumoto, I / Shinzeki, M / Bolado, F / Fernandez, J M Urman / Keane, M G / Pereira, S P / Acuna, I Araujo / Vaquero, E C / Angiolini, M R / Zerbi, A / Tang, J / Leong, R W / Faccinetto, A / Morana, G / Petrone, M C / Arcidiacono, P G / Moon, J H / Choi, H J / Gill, R S / Pavey, D / Ouaïssi, M / Sastre, B / Spandre, M / De Angelis, C G / Rios-Vives, M A / Concepcion-Martin, M / Ikeura, T / Okazaki, K / Frulloni, L / Messina, O / Lévy, P. ·Department of Gastroenterology and Pancreatology, Beaujon Hospital, AP-HP, Clichy, France. · The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy. · Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Division of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Departments of Surgery and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. · First Department of Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan. · Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. · Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Department of Surgery, Yonsei University College of Medicine, Pancreaticobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea. · Pancreatic Surgery Unit, Department of Surgery, Polytechnic University of Marche Region, Ancona-Torrette, Italy. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Surgery, Oncology and Gastroenterology, 3rd Surgical Clinic, University of Padua, Padua, Italy. · Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Hepato-Pancreato-Biliary Unit, Pederzoli Hospital, Peschiera del Garda, Italy. · Department of Gastroenterology, Hepatopancreatology and GI Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China. · Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea. · Hepato-Pancreato-Biliary Unit, Freeman Hospital, Newcastle upon Tyne, UK. · National Institute of Surgery and Transplantology named after Shalimov, Kiev, Ukraine. · Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet at Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden. · Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. · Hôpital Privé Mermoz, Gastroentérologie, Lyon, France. · Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. · Gastroenterology Department, Hospital de Navarra, Pamplona, Spain. · Department of Gastroenterology and Hepatology, University College Hospital, London, UK. · Department of Gastroenterology, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain. · Department of Pancreatic Surgery, Humanitas Research Hospital, Rozzano, Milan, Italy. · Gastroenterology and Liver Services, Concord Hospital, Sydney, New South Wales, Australia. · Radiological Department, General Hospital Cá Foncello, Treviso, Italy. · Division of Gastroenterology and Gastrointestinal Endoscopy, San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine, Digestive Disease Center and Research Institute, SoonChunHyang University School of Medicine, Bucheon, Korea. · Department of Gastroenterology, Bankstown-Lidcombe Hospital, Bankstown, New South Wales, Australia. · Department of Digestive Surgery, Timone Hospital, Marseille, France. · Gastrohepatology Department, San Giovanni Battista Molinette Hospital, University of Turin, Turin, Italy. · Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Institut de Reçerca-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. · The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan. · Department of Medicine, Pancreas Center, University of Verona, Verona, Italy. ·Gut · Pubmed #26045140.

ABSTRACT: OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

60 Article Circulating Epithelial Cells in Patients with Pancreatic Lesions: Clinical and Pathologic Findings. 2015

Cauley, Christy E / Pitman, Martha B / Zhou, Jiahua / Perkins, James / Kuleman, Birte / Liss, Andrew S / Fernandez-Del Castillo, Carlos / Warshaw, Andrew L / Lillemoe, Keith D / Thayer, Sarah P. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: ccauley@partners.org. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, Omaha, NE. ·J Am Coll Surg · Pubmed #26209458.

ABSTRACT: BACKGROUND: Circulating epithelial cell (CEC) isolation has provided diagnostic and prognostic information for a variety of cancers, previously supporting their identity as circulating tumor cells in the literature. However, we report CEC findings in patients with benign, premalignant, and malignant pancreatic lesions using a size-selective filtration device. STUDY DESIGN: Peripheral blood samples were drawn from patients found to have pancreatic lesions on preoperative imaging at a surgical clinic. Blood was filtered using ScreenCell devices, which were evaluated microscopically by a pancreatic cytopathologist. Pathologic data and clinical outcomes of these patients were obtained from medical records during a 1-year follow-up period. RESULTS: Nine healthy volunteers formed the control group and were found to be negative for CECs. There were 179 patients with pancreatic lesions that formed the study cohort. Circulating epithelial cells were morphologically similar in patients with a variety of pancreatic lesions. Specifically, CECs were identified in 51 of 105 pancreatic ductal adenocarcinomas (49%), 7 of 11 neuroendocrine tumors (64%), 13 of 21 intraductal papillary mucinous neoplasms (62%), and 6 of 13 patients with chronic pancreatitis. Rates of CEC identification were similar in patients with benign, premalignant, and malignant lesions (p = 0.41). In addition, CEC findings in pancreatic ductal adenocarcinoma patients were not associated with poor prognosis. CONCLUSIONS: Although CECs were not identified in healthy volunteers, they were identified in patients with benign, premalignant, and malignant pancreatic lesions. The presence of CECs in patients presenting with pancreatic lesions is neither diagnostic of malignancy nor prognostic for patients with pancreatic ductal adenocarcinoma.

61 Article Acute pancreatitis in intraductal papillary mucinous neoplasms: A common predictor of malignant intestinal subtype. 2015

Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Ferrone, Cristina R / Gonzalez-Gonzalez, Luis A / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Medicine, Metro West Medical Center, Framingham, MA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: cfernandez@mgh.harvard.edu. ·Surgery · Pubmed #26077509.

ABSTRACT: BACKGROUND: Acute pancreatitis (AP) is a common presenting symptom of intraductal papillary mucinous neoplasms (IPMN). Our objective was to evaluate the clinical and pathologic features of IPMN that present with AP. We hypothesized that the intestinal epithelial subtype, which produces a highly viscous mucin containing MUC2 glycoprotein, is associated with the development of AP. METHODS: We performed a case-control study, evaluating 325 patients with IPMN resected at our institution. Clinicopathologic features were assessed for patients with and without a history of AP and compared between the 2 groups. RESULTS: A history of AP was found in 69 patients (21%). Of those, 33 (48%) experienced a single episode, and some patients had as many as 10 distinct attacks. Three patients presented with necrotizing pancreatitis requiring operative debridement. After resection, recurrent AP occurred in only 14%. A history of AP was associated with younger age (61 vs 70, P < .001), main duct involvement (odds ratio [OR] 1.73, 95% confidence interval [95% CI] 1.00-3.01; P = .049), intestinal subtype (OR 4.84, 95% CI 2.71-8.67; P < .001), and high-grade dysplasia (OR 1.82, 95% CI 1.07-3.11; P = .028). On multivariate analysis, AP was an independent predictor of intestinal subtype (OR 4.69, 95% CI 2.48-8.84, P < .001), malignancy (OR 1.97, 95% CI 1.07-3.63, P = .029), and main duct involvement (OR 1.87, 95% CI 1.02-3.43, P = .044). CONCLUSION: AP is a frequent presenting symptom of IPMN. These patients are younger and have greater odds of harboring malignant intestinal-type IPMN involving the main pancreatic duct.

62 Article Effects of Comorbidities on Outcomes of Patients With Intraductal Papillary Mucinous Neoplasms. 2015

Sahora, Klaus / Ferrone, Cristina R / Brugge, William R / Morales-Oyarvide, Vicente / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: CFERNANDEZ@mgh.harvard.edu. ·Clin Gastroenterol Hepatol · Pubmed #25956837.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas occur mostly in older individuals. Individual life expectancy and risk of death from other factors must be carefully considered in analyzing the risks that IPMNs pose. We investigated whether there is a subset of patients with IPMNs and a high risk of dying from other causes who would not benefit from pancreatic surgery. METHODS: We collected data from 725 patients at Massachusetts General Hospital who underwent resection or have been under observation for IPMNs from 1992 through 2012. Comorbidities were classified according to the age-adjusted Charlson comorbidity index (CACI). Causes of death were recorded, and survival data were analyzed by the Kaplan-Meier method. RESULTS: The patients' median CACI score was 3; 10% of patients had CACI of 7 or more. Of the entire cohort, 55% underwent resection, and the remaining 45% have been under observation. After a median follow-up period of 5 years, 177 patients died (24%, 55% of deaths within 5 years of diagnosis); 78% of deaths were not related to IPMNs. The median survival time for all patients with CACI score of 7 or more was 43 months. Multivariate regression analysis revealed that the chance of non-IPMN-related death within 3 years of diagnosis is 11-fold higher for patients with CACI score of 7 or more than for patients with lower scores. CONCLUSIONS: The CACI can be used to identify patients with a high risk of death from factors other than IPMNs within a few years after diagnosis. These patients are therefore not likely to benefit from further IPMN observation or pancreatic resection.

63 Article Oncocytic-type intraductal papillary mucinous neoplasms: a unique malignant pancreatic tumor with good long-term prognosis. 2015

Marchegiani, Giovanni / Mino-Kenudson, Mari / Ferrone, Cristina R / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: cfernandez@partners.org. ·J Am Coll Surg · Pubmed #25840549.

ABSTRACT: BACKGROUND: The different epithelial phenotypes of intraductal papillary mucinous neoplasms (IPMNs) are predictors of tumor biology and post-surgical outcomes. Oncocytic-type IPMN (O-IPMN) seems to have a unique natural history, but not much information is available because of its rarity. We sought to describe the characteristics of a cohort of patients resected for O-IPMNs, focusing on their long-term outcomes after surgery. STUDY DESIGN: We conducted a retrospective review of the demographics, clinical presentation, pathology, and survival of a cohort of patients resected for IPMN between 1990 and 2013, comparing O-IPMN with other IPMN subtypes. RESULTS: Eighteen of 400 patients (4.5%) who underwent resection for IPMN had the oncocytic subtype. Compared with other IPMN patients, those with O-IPMNs were more likely to be male (72% vs 45%; p = 0.02) and to have main pancreatic duct involvement (72% vs 42%; p = 0.01). Oncocytic IPMNs occurred in asymptomatic individuals in 67% of cases. They had either invasive carcinoma (61%) or high-grade dysplasia (39%), and the proportions in other epithelial subtypes were 19% and 21%, respectively (p < 0.001). After resection, the 10-year recurrence rate for O-IPMNs was 46%. Recurrences occurred up to 11 years after the initial resection and a completion total pancreatectomy was performed in 4 patients. At a median follow-up of 7 years, no patients with O-IPMN had died from the disease. CONCLUSIONS: Oncocytic IPMN is a unique tumor subtype that occurs mostly in the main pancreatic duct and is malignant. Recurrences after resection are not uncommon and can occur more than 10 years after the initial resection. Reoperations for recurrent O-IPMN are often feasible and have excellent results in terms of survival.

64 Article The Charlson age comorbidity index predicts early mortality after surgery for pancreatic cancer. 2015

Dias-Santos, Daniela / Ferrone, Cristina R / Zheng, Hui / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA; Chronic Diseases Research Centre, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. · Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA. · Biostatistics Center, Massachusetts General Hospital, Boston, MA. · Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA. Electronic address: CFERNANDEZ@mgh.harvard.edu. ·Surgery · Pubmed #25704415.

ABSTRACT: BACKGROUND: Although operative resection represents the only hope for cure in pancreatic cancer, it is associated with significant morbidity and mortality. Furthermore, in some patients disease progression occurs very early postoperatively and no tangible benefit is seen from the operation. Identification of preoperative predictors of death within the first year of surgery could help in the counseling of patients diagnosed with pancreatic cancer. METHODS: We studied retrospectively patients who underwent resection for pancreatic adenocarcinoma from 2002 to 2012. We calculated the age-adjusted Charlson Age Comorbidity Index (CACI) and used logistic regression models to determine predictors of mortality within 1 year of surgery. Kaplan-Meier curves and Cox proportional hazards models were developed to determine hazard ratios on survival. RESULTS: Surgery with curative intent was performed in 497 patients; 136 (27%) died within the first year. A CACI score of >4 was predictive of increased duration of stay (P < .001), postoperative complications (P = .042), and mortality within 1 year of pancreatic resection (P < .001). A CACI score of ≥ 6 increased 3-fold the odds of death within the first year. CONCLUSION: CACI is useful to predict outcome after pancreatectomy for pancreatic cancer. Patients with a high CACI score have a <50% likelihood of being alive 1 year postoperatively. This information should be used when considering the appropriateness of pancreatic resection in patients with multiple comorbidities.

65 Article Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. 2015

Ferrone, Cristina R / Marchegiani, Giovanni / Hong, Theodore S / Ryan, David P / Deshpande, Vikram / McDonnell, Erin I / Sabbatino, Francesco / Santos, Daniela Dias / Allen, Jill N / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Faris, Jason E / Goyal, Lipika / Kwak, Eunice L / Murphy, Janet E / Ting, David T / Wo, Jennifer Y / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·*Department of Surgery †Department of Radiation Oncology; and ‡Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #25599322.

ABSTRACT: PURPOSE: On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. PATIENTS AND METHODS: Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. RESULTS: Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. CONCLUSIONS: After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

66 Article Early Drain Removal--The Middle Ground Between the Drain Versus No Drain Debate in Patients Undergoing Pancreaticoduodenectomy: A Prospective Validation Study. 2015

Ven Fong, Zhi / Correa-Gallego, Camilo / Ferrone, Cristina R / Veillette, Gregory R / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #25563864.

ABSTRACT: OBJECTIVE: To perform an unbiased assessment of first postoperative day (POD 1) drain amylase level and pancreatic fistula (PF) after pancreaticoduodenectomy (PD). BACKGROUND: Recent evidence demonstrated that drain abandonment in PD is unsafe. Early drain amylase levels have been proposed as predictors of PF after PD, allowing for selection of patients for early drain removal. METHODS: Daily drain amylase levels were correlated with the development of PF in 2 independent cohorts of patients undergoing PD: training cohort (n = 126; year 2008) and validation cohort (n = 369; years 2009-2012). RESULTS: POD 1 drain amylase level had the highest predictive ability (concordance index: 0.911) for PF in the training cohort. An amylase level of 612 U/L or higher showed the best accuracy (86%), sensitivity (93%), and specificity (79%). Thus, a cutoff value of 600 U/L was utilized. In the validation cohort, 229 (62.1%) patients had a POD 1 drain amylase level of lower than 600 U/L, and PF developed in only 2 (0.9%) cases; whereas in patients with POD 1 drain amylase level of 600 U/L or higher (n = 140) the PF rate was 31.4% (odds ratio [OR] = 52, P < 0.0001). On multivariate analysis, POD 1 drain amylase level of lower than 600 U/L (OR = 0.0192, P < 0.0001) was a stronger predictor of the absence of PF than pancreatic gland texture (OR = 0.193, P = 0.002) and duct diameter (OR = 0.861, P = 0.835). CONCLUSIONS: After PD, the risk of PF is less than 1% if POD 1 drain amylase level is lower than 600 U/L. We propose that in this group, which comprise more than 60% of patients, drains should be removed on POD 1.

67 Article IPMN involving the main pancreatic duct: biology, epidemiology, and long-term outcomes following resection. 2015

Marchegiani, Giovanni / Mino-Kenudson, Mari / Sahora, Klaus / Morales-Oyarvide, Vicente / Thayer, Sarah / Ferrone, Cristina / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Departments of *Surgery; and †Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #24979607.

ABSTRACT: OBJECTIVES: To describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) with predominant involvement of the main pancreatic duct (MPD), analyzing predictors for survival and recurrence. BACKGROUND: IPMNs involving the MPD harbor a high likelihood of malignancy and different biological features. The appropriateness of including cases with minimal noncircumferential MPD involvement has been challenged because these show clinicopathological features that are similar to branch duct IPMN. Accordingly, their exclusion has led to a redefinition of MPD IPMN (MD-IPMN). METHODS: Retrospective review of resected MD-IPMN from 1990 to 2013. All slides were reviewed by a single pancreatic pathologist and classified on the basis of epithelial type and invasive component. RESULTS: A total of 223 patients underwent resection for IPMN involving the MPD. Of these, 50 were excluded because of minimal MPD involvement. Among the 173 patients analyzed, median age was 68 years and 55% were males. Predominant epithelial phenotype was intestinal (50%). Forty-eight patients (28%) had low- or intermediate-grade dysplasia, whereas 125 (72%) had either high-grade dysplasia (33%) or invasive carcinoma (39%). Of the 67 invasive IPMNs, 39 were tubular carcinomas (58%) and invasion was minimal (<5 mm) in 28 (42%). The 5-year overall survival rate was 69% and the disease-specific survival rate was 83%. The estimated recurrence rate at 10 years was 25%. Size and type of the invasive component, lymph node positivity, and a positive resection margin were predictors for both survival and recurrence (P < 0.05). CONCLUSIONS: MD-IPMN is mainly intestinal-type and malignant. After resection, it has a very favorable prognosis, especially in the absence of macroscopic invasive carcinoma.

68 Article High performing whipple patients: factors associated with short length of stay after open pancreaticoduodenectomy. 2014

Lee, Grace C / Fong, Zhi Ven / Ferrone, Cristina R / Thayer, Sarah P / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA, 02114-3117, USA. ·J Gastrointest Surg · Pubmed #25091843.

ABSTRACT: INTRODUCTION: Despite the decreasing mortality of pancreaticoduodenectomy (PD), it continues to be associated with prolonged length of postoperative hospital stay (LOS). This study aimed to determine factors that could predict short LOS after PD. Additionally, as preliminary data of minimally invasive PD emerges, we sought to determine the average LOS after open PD at a high-volume center to set a standard to which minimally invasive PD can be compared. METHODS: A total of 634 consecutive patients who underwent open PD between January 2007 and December 2012 at the Massachusetts General Hospital comprised the study cohort. "High performers" were defined as patients with postoperative LOS ≤5 days. RESULTS: Median LOS was 7 days. A total of 61 patients (9.6%) had LOS ≤5 days and were deemed "high performing." In multivariate logistic regression analysis, male gender (p = 0.032), neoadjuvant chemoradiation (p = 0.001), epidural success (p = 0.019), epidural duration ≤3 days (p = 0.001), lack of complications (p < 0.001), surgery on Thursday or Friday (p = 0.001), and discharge on Monday through Wednesday (p < 0.001) were independently associated with LOS ≤5 days. Readmission rate, time to readmission, and mortality were not different between the two groups. The proportion of patients with pancreatic ductal adenocarcinoma who went on to receive adjuvant therapy was no different if LOS was ≤5 or >5 days, but high performance was predictive of beginning therapy <8 weeks after surgery (p = 0.010). CONCLUSION: In our experience, median LOS was 7 days, and early discharge (≤5 days) after open PD is safe and feasible in about 10 % of patients. These high performers are more likely to be male, have received neoadjuvant therapy, and had successful epidural analgesia. High performers with cancer are more likely to start chemotherapy <8 weeks after surgery. Minimally invasive PD should be compared to this high standard for median LOS, among other quality metrics, to justify its increased cost, operative duration, and learning curve.

69 Article Not all mixed-type intraductal papillary mucinous neoplasms behave like main-duct lesions: implications of minimal involvement of the main pancreatic duct. 2014

Sahora, Klaus / Fernández-del Castillo, Carlos / Dong, Fei / Marchegiani, Giovanni / Thayer, Sarah P / Ferrone, Cristina R / Sahani, Dushyant V / Brugge, William R / Warshaw, Andrew L / Lillemoe, Keith D / Mino-Kenudson, Mari. ·Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Boston, MA. · Department of Radiology, Massachusetts General Hospital, Boston, MA; Department of Radiology, Harvard Medical School, Boston, MA. · Division of Gastroenterology, Massachusetts General Hospital, Boston, MA; Department of Internal Medicine, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Boston, MA; Department of Pathology, Harvard Medical School, Boston, MA. Electronic address: mminokenudson@partners.org. ·Surgery · Pubmed #25081232.

ABSTRACT: BACKGROUND: The malignant potential of intraductal mucinous neoplasm of the pancreas (IPMN) is associated closely with main pancreatic duct (MPD) involvement. Because mixed-type IPMN is thought to have the same malignant potential as that of main-duct (MD)-IPMN, resection is recommended; however, the biological nature of mixed-type IPMN with only minimal involvement of MPD (min-mix-IPMN) may be different. METHODS: A prospective database of 404 resected IPMNs was re-reviewed to subclassify mixed-type IPMNs. We defined min-mix-IPMN as absence of gross abnormalities (except for dilatation) of MPD and noncircumferential microscopic involvement of MPD limited to few sections. RESULTS: We identified 46 min-mix-IPMNs, 163 IPMNs with extensive involvement of MPD (ex-mix-IPMN), 175 branch-duct (BD)-IPMNs, and 20 MD-IPMNs. The majority of min-mix-IPMNs were found incidentally and increased cyst size on surveillance was the leading operative indication. The median diameter of MPD was 2 mm in min-mix-IPMN versus 9 mm in ex-mix-IPMN (P < .0001), and cysts ≥10 mm were present in 62% of ex-mix-IPMNs versus 93% of min-mix-IPMNs (P < .0001). Most importantly, the vast majority of min-mix-IPMNs exhibited gastric-type epithelium, similar to BD-IPMNs, whereas intestinal-type epithelium was present in half of ex-mix-IPMNs, similar to MD-IPMNs. The prevalence of high-grade lesions was less in min-mix-IPMN than ex-mix-IPMN (P < .0001). These differences were reflected in better disease-specific outcomes of min-mix-IPMN compared with ex-mix-IPMN (P = .046). CONCLUSION: Min-mix-IPMN often presents with no MPD dilation and is an incidental finding by microscopic examination. min-mix-IPMN shares the pathologic features and less aggressive biology with BD-IPMN. We propose that min-mix-IPMN be categorized differently than ex-mix-IPMN.

70 Article Delaying chemoradiation until after completion of adjuvant chemotherapy for pancreatic cancer may not impact local control. 2014

Wo, Jennifer Y / Childs, Stephanie K / Szymonifka, Jackie / Mamon, Harvey J / Ryan, David P / Blaszkowsky, Lawrence S / Kwak, Eunice L / Ferrone, Cristina R / Allen, Jill N / Zhu, Andrew X / Wolpin, Brian M / Chan, Jennifer A / Abrams, Thomas A / McCleary, Nadine J / Fernandez-Del Castillo, Carlos / Hong, Theodore S. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: jwo@partners.org. · Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Pract Radiat Oncol · Pubmed #24890357.

ABSTRACT: BACKGROUND: Timing of administration of adjuvant chemoradiation (CRT) for pancreatic cancer has varied across studies. To date, the impact of timing of adjuvant CRT on long-term outcomes has not been evaluated. This study evaluates the effect of timing of adjuvant CRT on locoregional control (LRC) and overall survival (OS). METHODS AND MATERIALS: We performed a review of 159 patients with resected pancreatic adenocarcinoma who received adjuvant CRT between 1998 and 2010. Median dose of CRT was 50.4 Gy. The primary study variable was timing of CRT, dichotomized as immediate CRT versus delayed CRT. Consistent with Radiation Therapy Oncology Group (RTOG) 9704, immediate chemoradiation was defined as after ≤1 cycle of chemotherapy, whereas delayed CRT was defined as after >1 cycle. Cox multivariate analysis (MVA) was performed. RESULTS: Median follow-up was 55 months. Seventy-four percent of patients received immediate CRT, and 26% patients received delayed CRT. Patients treated with delayed CRT were more likely to receive adjuvant gemcitabine (100% vs 53%; P < .001). Timing of adjuvant CRT was not associated with LRC or OS on univariate or MVA. Preoperative carcinoembryonic antigen ≥1.3 ng/mL (hazard ratio, 3.18; P = .017) and positive margins (hazard ratio, 5.35; P < .001) were associated with lower rates LRC on MVA. Higher lymph node positivity ratio and not receiving adjuvant gemcitabine were independently associated with worse OS. CONCLUSIONS: Timing of adjuvant CRT for resectable pancreatic cancer may not significantly affect LRC or OS. These findings support the ongoing RTOG 0848 trial design, and provide reassurance that delaying CRT until completion of chemotherapy should not significantly impact LRC.

71 Article Standardized cytopathology reporting for the pancreas: the time is right. 2014

Fernández-del Castillo, Carlos. ·Pancreas and Biliary Surgery Program, Harvard Medical School, Boston, Massachusetts. ·Cancer Cytopathol · Pubmed #24826942.

ABSTRACT: -- No abstract --

72 Article Enhanced primary tumor delineation in pancreatic adenocarcinoma using ultrasmall super paramagnetic iron oxide nanoparticle-ferumoxytol: an initial experience with histopathologic correlation. 2014

Hedgire, Sandeep S / Mino-Kenudson, Mari / Elmi, Azadeh / Thayer, Sarah / Fernandez-del Castillo, Carlos / Harisinghani, Mukesh G. ·Department of Abdominal Imaging and Intervention, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. ·Int J Nanomedicine · Pubmed #24790431.

ABSTRACT: PURPOSE: To evaluate the role of ferumoxytol-enhanced magnetic resonance imaging (MRI) in delineating primary pancreatic tumors in patients undergoing preoperative neoadjuvant therapy. MATERIALS AND METHODS: Eight patients with pancreatic adenocarcinoma were enrolled in this study, and underwent MRI scans at baseline, immediate post, and at the 48 hour time point after ferumoxytol injection with quantitative T2* sequences. The patients were categorized into two groups; group A received preoperative neoadjuvant therapy and group B did not. The T2* of the primary pancreatic tumor and adjacent parenchyma was recorded at baseline and the 48 hour time point. After surgery, the primary tumors were assessed histopathologically for fibrosis and inflammation. RESULTS: The mean T2* of the primary tumor and adjacent parenchyma at 48 hours in group A were 22.11 ms and 16.34 ms, respectively; in group B, these values were 23.96 ms and 23.26 ms, respectively. The T2* difference between the tumor and adjacent parenchyma in group A was more pronounced compared to in group B. The tumor margins were subjectively more distinct in group A compared to group B. Histopathologic evaluation showed a rim of dense fibrosis with atrophic acini at the periphery of the lesion in group A. Conversely, intact tumor cells/glands were present at the periphery of the tumor in group B. CONCLUSION: Ferumoxytol-enhanced MRI scans in patients receiving preoperative neoadjuvant therapy may offer enhanced primary tumor delineation, contributing towards achieving disease-free margin at the time of surgery, and thus improving the prognosis of pancreatic carcinomas.

73 Article Peritoneal seeding in intraductal papillary mucinous neoplasm of the pancreas patients who underwent endoscopic ultrasound-guided fine-needle aspiration: the PIPE Study. 2014

Yoon, Won Jae / Daglilar, Ebubekir S / Fernández-del Castillo, Carlos / Mino-Kenudson, Mari / Pitman, Martha B / Brugge, William R. ·Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Harvard Medical School, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Endoscopy · Pubmed #24619804.

ABSTRACT: BACKGROUND AND STUDY AIMS: There have been concerns about peritoneal seeding after endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of mucinous pancreatic cystic lesions. The aims of this study were to determine the frequency of postoperative peritoneal seeding in patients with intraductal papillary mucinous neoplasm (IPMN) who had undergone pre-operative EUS-FNA and to compare it with that of patients with IPMN who had surgery with no pre-operative tissue sampling. PATIENTS AND METHODS: A total of 175 patients who had undergone resection of IPMNs with pre-operative EUS-FNA (EUS-FNA group) were analyzed and compared with 68 patients who had undergone resection with no pre-operative tissue sampling (No Sampling group). Patient characteristics, pathology, and frequency of peritoneal seeding after surgery were analyzed and compared. Peritoneal seeding was diagnosed based on pathology or image findings. RESULTS: The two groups were comparable with respect to sex, age, follow-up duration, involvement of the pancreatic head, involvement of the main duct, grade of dysplasia, and size of histologically proven branch-duct IPMNs. Four patients (2.3 %) with invasive IPMN developed peritoneal seeding in the EUS-FNA group, whereas three (4.4 %, two with invasive IPMN and one with high-grade dysplasia) developed peritoneal seeding in the No Sampling group (P  = 0.403). No peritoneal seeding was noted during surgery in these cases. Except for one patient in the EUS-FNA group, no spillage occurred during resection in these patients. CONCLUSIONS: In this cohort of patients undergoing resection of IPMN, the difference in the frequency of peritoneal seeding in the EUS-FNA group and the No Sampling group was not significant.

74 Article Cystic pancreatic neuroendocrine tumors: the value of cytology in preoperative diagnosis. 2014

Morales-Oyarvide, Vicente / Yoon, Won Jae / Ingkakul, Thun / Forcione, David G / Casey, Brenna W / Brugge, William R / Fernández-del Castillo, Carlos / Pitman, Martha B. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Cancer Cytopathol · Pubmed #24591417.

ABSTRACT: BACKGROUND: Cystic pancreatic neuroendocrine tumors (cPanNETs) account for 13% to 17% of PanNETs. Although the value of endoscopic ultrasound (EUS) imaging and cyst fluid analysis (CFA) in their preoperative diagnosis has been well described, limited information is available about the diagnostic role of cytology samples obtained from fine-needle aspiration (FNA). METHODS: Cytopathology records between 1992 and 2013 were searched for all reports of cysts interpreted as PanNET. Patient demographics, clinical and radiologic information, CFA, histopathology, and cytopathology findings were recorded. Performance characteristics of cytology and EUS for the accurate diagnosis of cPanNET were calculated. RESULTS: In total, 35 FNAs from 33 patients with cPanNETs were identified, and 34 EUS were performed. Cytology made a specific diagnosis of a cPanNET in 71% of the biopsies compared with a specific diagnosis by EUS in 38% of cases. An interpretation of suspicious for cPanNET was given in 77% of cases by cytology and in 47% by EUS. Cytology identified 86% of the lesions as high-risk pancreatic cysts compared with 56% by EUS. Diagnostic morphology was present on both cytology and cell block preparations in 60% of aspirates, on cytology only in 20%, and on cell block only in 20%. CFA was performed on 51% cyst fluids. All cysts but 1 revealed low carcinoembryonic antigen levels (range, 0.2 to >500 ng/mL; mean, 29.5 ng/mL), and amylase levels were <500 U/L in all but 2 cases (range, 16-1493 U/L; mean, 205 U/L). CONCLUSIONS: Cytology is the most accurate test for preoperative diagnosis of cPanNETs. EUS is insufficiently accurate for independent diagnosis, and carcinoembryonic antigen and amylase analyses are noncontributory.

75 Article mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN). 2014

Das, Koushik K / Xiao, Hong / Geng, Xin / Fernandez-Del-Castillo, Carlos / Morales-Oyarvide, Vicente / Daglilar, Ebubekir / Forcione, David G / Bounds, Brenna C / Brugge, William R / Pitman, Martha B / Mino-Kenudson, Mari / Das, Kiron M. ·Department of Internal Medicine, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. · Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. · Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. · Department of Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. · Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA Department of Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. · Division of Gastroenterology, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. ·Gut · Pubmed #24277729.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. DESIGN: mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. RESULTS: Immunohistochemistry-Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignant IPMNs were 85% and 95%, respectively. Lesional fluid-Samples from low- and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. CONCLUSIONS: mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification.

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