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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
1 Guideline Pathologic Evaluation and Reporting of Intraductal Papillary Mucinous Neoplasms of the Pancreas and Other Tumoral Intraepithelial Neoplasms of Pancreatobiliary Tract: Recommendations of Verona Consensus Meeting. 2016

Adsay, Volkan / Mino-Kenudson, Mari / Furukawa, Toru / Basturk, Olca / Zamboni, Giuseppe / Marchegiani, Giovanni / Bassi, Claudio / Salvia, Roberto / Malleo, Giuseppe / Paiella, Salvatore / Wolfgang, Christopher L / Matthaei, Hanno / Offerhaus, G Johan / Adham, Mustapha / Bruno, Marco J / Reid, Michelle D / Krasinskas, Alyssa / Klöppel, Günter / Ohike, Nobuyuki / Tajiri, Takuma / Jang, Kee-Taek / Roa, Juan Carlos / Allen, Peter / Fernández-del Castillo, Carlos / Jang, Jin-Young / Klimstra, David S / Hruban, Ralph H / Anonymous6190823. ·*Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA †Department of Pathology, Massachusetts General Hospital, Boston, MA ‡Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Pathology, University of Verona, Verona, Italy ||Department of Surgery, Massachusetts General Hospital, Boston, MA **Department of Surgery, University of Verona, Verona, Italy ††Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD ‡‡Departments of Surgery, University of Bonn, Bonn, Germany §§Departments of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ¶¶Department of Surgery, Edouard Herriot Hospital, HCL, Lyon, France ||||Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands ***Departments of Pathology, Technical University, Munich, Germany †††Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan ‡‡‡Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan §§§Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea ¶¶¶Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile ||||||Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY ****Department of Surgery, Massachusetts General Hospital, Boston, MA ††††Department of Surgery, Seoul National University Hospital, Seoul, Korea ‡‡‡‡Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #25775066.

ABSTRACT: BACKGROUND: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). DESIGN: An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. RESULTS: (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤ 0.5, > 0.5-≤ 1, > 1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic). CONCLUSIONS: These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

2 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.

3 Guideline International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. 2012

Tanaka, Masao / Fernández-del Castillo, Carlos / Adsay, Volkan / Chari, Suresh / Falconi, Massimo / Jang, Jin-Young / Kimura, Wataru / Levy, Philippe / Pitman, Martha Bishop / Schmidt, C Max / Shimizu, Michio / Wolfgang, Christopher L / Yamaguchi, Koji / Yamao, Kenji / Anonymous6680728. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. masaotan@med.kyushu-u.ac.jp ·Pancreatology · Pubmed #22687371.

ABSTRACT: The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated new guidelines. Since the levels of evidence for all items addressed in these guidelines are low, being 4 or 5, we still have to designate them "consensus", rather than "evidence-based", guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required.

4 Editorial Safe surgery for cystic tumors of the pancreas. 2019

Fernández Del Castillo, Carlos. ·Cirugia, Massachusetts General Hospital, United States. ·Rev Esp Enferm Dig · Pubmed #30746958.

ABSTRACT: Cystic tumors of the pancreas are a common indication for pancreatic surgery, and many of them are incidentally-discovered. Some of these tumors are malignant, and many others are pre-malignant. Less than two generations ago, pancreatic surgery was risky business. Surgical mortality, even in some of the best institutions in the world, was about 25%. Complications were very common and not infrequently patients required reoperations and had to remain in the hospital for weeks or even months. They emerged from this highly debilitated, and often went on to have a very poor quality of life. Not surprisingly, for these reasons, pancreatic resection was used only as a "last resort", and mostly for cancer.

5 Editorial Management of pancreatic cysts: the evidence is not here yet. 2015

Fernández-Del Castillo, Carlos / Tanaka, Masao. ·Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan. ·Gastroenterology · Pubmed #25724457.

ABSTRACT: -- No abstract --

6 Review Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. 2017

Tanaka, Masao / Fernández-Del Castillo, Carlos / Kamisawa, Terumi / Jang, Jin Young / Levy, Philippe / Ohtsuka, Takao / Salvia, Roberto / Shimizu, Yasuhiro / Tada, Minoru / Wolfgang, Christopher L. ·Department of Surgery, Shimonoseki City Hospital, Shimonoseki, Japan. Electronic address: masaotan@med.kyushu-u.ac.jp. · Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Gastroenterology, Komagome Metropolitan Hospital, Tokyo, Japan. · Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea. · Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hopital Beaujon, Clichy Cedex, France. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. · Dept. of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Cameron Division of Surgical Oncology and The Sol Goldman Pancreatic Cancer Research Center, Department of Surgery, Johns Hopkins University, Baltimore, MD, USA. ·Pancreatology · Pubmed #28735806.

ABSTRACT: The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required.

7 Review Intraductal Papillary Mucinous Neoplasm of the Pancreas. 2016

Fong, Zhi Ven / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114-3117, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114-3117, USA. Electronic address: cfernandez@partners.org. ·Surg Clin North Am · Pubmed #27865286.

ABSTRACT: The incidence of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has been rising in the past 2 decades, driven mainly by the widespread use of cross-sectional imaging. IPMNs are intraductal mucin-producing neoplasms that involve the main pancreatic duct or its side branches and lack the ovarian stroma typically seen in mucinous cystic neoplasms. The International Association of Pancreatology released consensus guidelines in 2006 and 2012 providing clinical algorithms based on IPMN features and risk of malignancy. In this article, we review the different classifications of IPMNs, their natural history, and clinical management and address recent controversies in the literature.

8 Review Intraductal Papillary Mucinous Neoplasm of the Pancreas: Current State of the Art and Ongoing Controversies. 2016

Fong, Zhi Ven / Ferrone, Cristina R / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #26727096.

ABSTRACT: With the widespread use and advances in radiographic imaging, Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are identified with increasing frequency. Although many studies have addressed its biology and treatment, true understanding of its natural history continues to elude us. Its malignant potential places careproviders in a clinical dilemma of balancing the morbidity of pancreatectomy against the risk of malignant transformation while under continuous surveillance. Recently, there have been conflicting data published in the literature, generating more uncertainty in the field. In this article, we critically analyze the contrasting consensus guidelines from the International Association of Pancreatology and the American Gastroenterology Association, and address lingering questions and controversies. We also synthesize newly published data in the context of current standard of care, and provide a comprehensive review and recommendations for the clinical diagnosis, treatment, and follow-up strategy in the management of patients with Intraductal Papillary Mucinous Neoplasms.

9 Review Diagnosis and Management of Pancreatic Cystic Neoplasms. 2015

Kim, Teresa S / Fernandez-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, GRB-425, Boston, MA 02114, USA. · Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, WAC-460, Boston, MA 02114, USA. Electronic address: cfernandez@partners.org. ·Hematol Oncol Clin North Am · Pubmed #26226903.

ABSTRACT: Incidentally discovered pancreatic cystic lesions are increasingly common, affecting up to 10% to 15% of patients undergoing cross-sectional imaging. Although some pancreatic cystic neoplasms harbor invasive malignancy or the potential to progress over time, a majority are benign and can be observed safely. Accurate diagnosis is key to appropriate management. Diagnosis requires a multidisciplinary and multimodal approach. This review discusses each type of pancreatic cystic neoplasm and the current data on diagnosis and treatment.

10 Review Intraductal papillary mucinous neoplasms. 2015

Sahora, Klaus / Fernández-del Castillo, Carlos. ·aDepartment of Surgery, Medical University Vienna, Vienna, Austria bDepartment of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA. ·Curr Opin Gastroenterol · Pubmed #26125316.

ABSTRACT: PURPOSE OF REVIEW: Our understanding of intraductal papillary mucinous neoplasm (IPMN) of the pancreas has remarkably grown within the last decade; nonetheless there is still an ongoing controversy if the majority of these potentially malignant neoplasms need to be resected or if observation in a subset is well tolerated. RECENT FINDINGS: Novel cyst fluid biomarkers, like Gnas mutations or mab DAS-1, could play a pivotal role in the distinction of IPMN vs. other cystic lesions, in the sub-classification of IPMN and in the detection of IPMN with high-grade dysplasia or invasive cancer. Other recent studies focused on natural history of minimal- and extensive-mixed IPMN and the safety of the 2012 AIP guidelines. Small series also described that observation can be an option in selected frail patients with MD-IPMN. Further, data from a large European multicenter study analysis indicated that patients with IPMN do not have an increased frequency of extrapancreatic malignancies. SUMMARY: Increasing knowledge about the nature of IPMN and their subtypes has resulted in an individualized approach in diagnosis and treatment. Owing to the availability of accurate diagnostic instruments, timing and indication for pancreatic resection have become more selective, sparing patients with harmless IPMN from major surgery.

11 Review Is it safe to follow side branch IPMNs? 2014

Marchegiani, Giovanni / Fernández-del Castillo, Carlos. · ·Adv Surg · Pubmed #25293604.

ABSTRACT: Management of Bd-IPMN remains challenging. Critical appraisal of the published literature reveals that the actual treatment of what is presumed to be Bd-IPMN remains unsatisfactory, with a high rate of surgically overtreated patients. Until we accrue more precise knowledge of the natural history of Bd-IPMN, management of patients with this presumed diagnosis should be individually tailored and preferably carried out in centers with a high expertise. For now, the authors strongly think that the old guidelines should be followed in most patients because these have proven to correctly identify lesions that can be safely followed. Although the new guidelines allow for follow-up of lesions greater than 3 cm, and for the most part this is safe, they should be used cautiously in younger patients because very close surveillance would be required for their long remaining lifespan.

12 Review Pancreatic cystic neoplasms: management and unanswered questions. 2013

Farrell, James J / Fernández-del Castillo, Carlos. ·Yale Pancreas Center and Interventional Endoscopy, Yale School of Medicine, New Haven, Connecticut, USA. james.j.farrell@yale.edu ·Gastroenterology · Pubmed #23622140.

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

13 Review Diagnosis and management of cystic pancreatic lesions. 2013

Sahani, Dushyant V / Kambadakone, Avinash / Macari, Michael / Takahashi, Noaki / Chari, Suresh / Fernandez-del Castillo, Carlos. ·Department of Radiology, Division of Abdominal Imaging and Intervention, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, White 270, Boston, MA 02114, USA. dsahani@partners.org ·AJR Am J Roentgenol · Pubmed #23345356.

ABSTRACT: OBJECTIVE: The purpose of this review is to outline the management guidelines for the care of patients with cystic pancreatic lesions. CONCLUSION: The guidelines are as follows: Annual imaging surveillance is generally sufficient for benign serous cystadenomas smaller than 4 cm and for asymptomatic lesions. Asymptomatic thin-walled unilocular cystic lesions smaller than 3 cm or side-branch intraductal papillary mucinous neoplasms should be followed up with CT or MRI at 6 and 12 months interval after detection. Cystic lesions with more complex features or with growth rates greater than 1 cm/year should be followed more closely or recommended for resection if the patient's condition allows surgery. Symptomatic cystic lesions, neoplasms with high malignant potential, and lesions larger than 3 cm should be referred for surgical evaluation. Endoscopic ultrasound with fine-needle aspiration (FNA) biopsy can be used preoperatively to assess the risk of malignancy.

14 Review Preoperative evaluation and management of the pancreatic head mass. 2013

Conrad, Claudius / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021114, USA. cconrad@partners.org ·J Surg Oncol · Pubmed #22674403.

ABSTRACT: The differential diagnosis of a pancreatic head mass encompasses a wide range of clinical entities that include both solid and cystic lesions. This chapter focuses on our approach to the patient presenting with a newly found pancreatic head mass with the main goals of determining the risk of the lesion being malignant or premalignant, resectability if the patient is appropriate for surgical intervention, assessment of need for multimodality treatment and determination the patient's surgical risk.

15 Review Pancreatic surgery for adenocarcinoma. 2012

Warshaw, Andrew L / Lillemoe, Keith D / Fernandez-del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. awarshaw@partners.org ·Curr Opin Gastroenterol · Pubmed #22782020.

ABSTRACT: PURPOSE OF REVIEW: Pancreatic resection remains among the most formidable and complex of abdominal surgical operations. Nonetheless, recent observations have continued to provide incremental improvement in both our evidence for treatment regimens and the technology, resulting in better outcomes. RECENT FINDINGS: Neoadjuvant regimens appear to have promise, at least in local control and perhaps in long-term survival. More extensive operations focusing on perineural invasion along with minimally invasive laparoscopic and robotic techniques are attracting increasing attention. The effectiveness of major vascular resection remains controversial. Concentration of patients in centers of expertise has contributed to improved outcomes. SUMMARY: Improved management of pancreatic resections for cancer with more extensive and less-invasive surgical techniques has increased the number of patients who are candidates for effective surgical treatment.

16 Review Intraductal papillary mucinous neoplasms of the pancreas. 2010

Fernández-del Castillo, Carlos / Adsay, N Volkan. ·Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. cfernandez@partners.org ·Gastroenterology · Pubmed #20650278.

ABSTRACT: -- No abstract --

17 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. 2018

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Blaszkowsky, Lawrence S / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Lillemoe, Keith D / DeLaney, Thomas F / Fernández-Del Castillo, Carlos / Ferrone, Cristina R / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston. ·JAMA Oncol · Pubmed #29800971.

ABSTRACT: Importance: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. Objective: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. Design, Setting, and Participants: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. Interventions: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. Main Outcomes and Measures: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). Results: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. Conclusions and Relevance: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01591733.

18 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.

19 Clinical Trial The proteome of postsurgical pancreatic juice. 2015

Marchegiani, Giovanni / Paulo, Joao A / Sahora, Klaus / Fernández-Del Castillo, Carlos. ·From the *Department of Surgery, Massachusetts General Hospital, Harvard Medical School; and †Department of Cell Biology, Harvard Medical School, Boston, MA. ·Pancreas · Pubmed #25875796.

ABSTRACT: OBJECTIVE: This study aimed to evaluate the proteome of the pancreatic juice after pancreatectomy. METHODS: Pancreatic juice samples were obtained during surgery and the postoperative period. Proteins were identified by mass spectrometry-based protein quantification technology and compared with published data of the nonoperated pancreas. Subgroup analyses were done in patients with pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant chemotherapy and in smokers. RESULTS: Five hundred eighteen proteins were identified in the postoperative pancreatic juice, encompassing all of the main organ functions. Sixty-seven of these were also present in the published data of the nonoperated pancreas and 7 of these had significant variation of concentration after surgery. Growth factors that have been described in postsurgical regeneration of the liver were not found to be overexpressed, whereas clusterin did, confirming the finding of previous experimental studies on pancreatic regeneration. Several proteins involved in immunomodulation and organ functions were differently expressed, depending on PDAC, neoadjuvant therapy, and smoking. CONCLUSIONS: The proteome of the pancreas after surgical resection contains factors related to all main organ functions, changes over time, and is different in patients with PDAC receiving neoadjuvant therapy and in smokers. The pancreas reacts to the surgical trauma by producing proteins that protect the organ and stimulate the restoration of its function.

20 Clinical Trial Circulating tumor cells found in patients with localized and advanced pancreatic cancer. 2015

Kulemann, Birte / Pitman, Martha B / Liss, Andrew S / Valsangkar, Nakul / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Hoeppner, Jens / Mino-Kenudson, Mari / Warshaw, Andrew L / Thayer, Sarah P. ·From the *Department of Surgery and †Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ‡Department of Surgery, University Hospital Freiburg, Freiburg, Germany; §Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and ║Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE. ·Pancreas · Pubmed #25822154.

ABSTRACT: OBJECTIVES: Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis. RESULTS: Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (≤American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (≥ American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors. CONCLUSIONS: Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC.

21 Clinical Trial A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. 2014

Hong, Theodore S / Ryan, David P / Borger, Darrell R / Blaszkowsky, Lawrence S / Yeap, Beow Y / Ancukiewicz, Marek / Deshpande, Vikram / Shinagare, Shweta / Wo, Jennifer Y / Boucher, Yves / Wadlow, Raymond C / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Zhu, Andrew X / Ferrone, Cristina R / Mamon, Harvey J / Adams, Judith / Winrich, Barbara / Grillo, Tarin / Jain, Rakesh K / DeLaney, Thomas F / Fernandez-del Castillo, Carlos / Duda, Dan G. ·Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: tshong1@partners.org. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. ·Int J Radiat Oncol Biol Phys · Pubmed #24867540.

ABSTRACT: PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

22 Clinical Trial Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. 2014

Wo, Jennifer Y / Mamon, Harvey J / Ferrone, Cristina R / Ryan, David P / Blaszkowsky, Lawrence S / Kwak, Eunice L / Tseng, Yolanda D / Napolitano, Brian N / Ancukiewicz, Marek / Swanson, Richard S / Lillemoe, Keith D / Fernandez-del Castillo, Carlos / Hong, Theodore S. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. Electronic address: jwo@partners.org. · Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. · Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Harvard Radiation Oncology Program, Boston, United States. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Department of General Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. ·Radiother Oncol · Pubmed #24231241.

ABSTRACT: PURPOSE: In this phase I study, we sought to determine the feasibility and tolerability of neoadjuvant short course radiotherapy (SC-CRT) delivered with photon RT with concurrent capecitabine for resectable pancreatic adenocarcinoma. MATERIALS AND METHODS: Ten patients with localized, resectable pancreatic adenocarcinoma were enrolled from December 2009 to August 2011. In dose level I, patients received 3 Gy × 10. In dose level 2, patients received 5 Gy × 5 (every other day). In dose level 3, patients received 5 Gy × 5 (consecutive days). Capecitabine was given during weeks 1 and 2. Surgery was performed 1-3 weeks after completion of chemotherapy. RESULTS: With an intended accrual of 12 patients, the study was closed early due to unexpected intraoperative complications. Compared to the companion phase I proton study, patients treated with photons had increased intraoperative RT fibrosis reported by surgeons (27% vs. 63%). Among those undergoing a Whipple resection, increased RT fibrosis translated to an increased mean OR time of 69 min. Dosimetric comparison revealed significantly increased low dose exposure to organs at risk for patients treated with photon RT. CONCLUSIONS: This phase I experience evaluating the tolerability of neoadjuvant SC-CRT with photon RT closed early due to unexpected intraoperative complications.

23 Clinical Trial Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. 2011

Hong, Theodore S / Ryan, David P / Blaszkowsky, Lawrence S / Mamon, Harvey J / Kwak, Eunice L / Mino-Kenudson, Mari / Adams, Judith / Yeap, Beow / Winrich, Barbara / DeLaney, Thomas F / Fernandez-Del Castillo, Carlos. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. tshong1@partners.org ·Int J Radiat Oncol Biol Phys · Pubmed #20421151.

ABSTRACT: PURPOSE: To evaluate the safety of 1 week of chemoradiation with proton beam therapy and capecitabine followed by early surgery. METHODS AND MATERIALS: Fifteen patients with localized resectable, pancreatic adenocarcinoma of the head were enrolled from May 2006 to September 2008. Patients received radiation with proton beam. In dose level 1, patients received 3 GyE × 10 (Week 1, Monday-Friday; Week 2, Monday-Friday). Patients in Dose Levels 2 to 4 received 5 GyE × 5 in progressively shortened schedules: level 2 (Week 1, Monday, Wednesday, and Friday; Week 2, Tuesday and Thursday), Level 3 (Week 1, Monday, Tuesday, Thursday, and Friday; Week 2, Monday), Level 4 (Week 1, Monday through Friday). Capecitabine was given as 825 mg/m(2) b.i.d. Weeks 1 and 2 Monday through Friday for a total of 10 days in all dose levels. Surgery was performed 4 to 6 weeks after completion of chemotherapy for Dose Levels 1 to 3 and then after 1 to 3 weeks for Dose Level 4. RESULTS: Three patients were treated at Dose Levels 1 to 3 and 6 patients at Dose Level 4, which was selected as the MTD. No dose limiting toxicities were observed. Grade 3 toxicity was noted in 4 patients (pain in 1; stent obstruction or infection in 3). Eleven patients underwent resection. Reasons for no resection were metastatic disease (3 patients) and unresectable tumor (1 patient). Mean postsurgical length of stay was 6 days (range, 5-10 days). No unexpected 30-day postoperative complications, including leak or obstruction, were found. CONCLUSIONS: Preoperative chemoradiation with 1 week of proton beam therapy and capecitabine followed by early surgery is feasible. A Phase II study is underway.

24 Article Diabetes mellitus is associated with unfavorable pathologic features, increased postoperative mortality, and worse long-term survival in resected pancreatic cancer. 2020

Hank, Thomas / Sandini, Marta / Qadan, Motaz / Weniger, Maximilian / Ciprani, Debora / Li, Annie / Ferrone, Cristina R / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: CFernandez@mgh.harvard.edu. ·Pancreatology · Pubmed #31706821.

ABSTRACT: BACKGROUND: The risk of pancreatic ductal adenocarcinoma (PDAC) is increased in patients with diabetes mellitus (DM), particularly in those with new-onset DM. However, the impact of DM on outcomes following pancreatic surgery is not fully understood. We sought to explore the effects of DM on post-resection outcomes in patients undergoing either upfront resection or following neoadjuvant treatment (NAT). METHODS: Resections for PDAC between 2007 and 2016 were identified from a prospectively-maintained database. Data on demographics, pathology, and perioperative outcomes were compared between patients with or without DM. Survival analysis was performed using Kaplan-Meier curves and adjusted for confounders by a Cox-proportional hazards model. RESULTS: 662 patients were identified, of whom 277 (41.8%) had DM. Diabetics were more likely to be male, had higher BMI, and higher ASA-scores. At pathology, DM was associated with larger tumors (30 vs. 26 mm; p = 0.041), higher rates of lymph-node involvement (69% vs. 59%; p = 0.031) and perineural invasion (88% vs. 82%; p = 0.026). Despite having similar rates of complications, diabetics experienced higher 30-day mortality (3.2% vs. 0.8%; p = 0.019). Median overall survival was worse in diabetic patients (18 vs. 34 months; p < 0.001); this effect was more pronounced in patients with NAT (18 vs. 54 months; p < 0.001). At multivariate analysis, DM was confirmed as an independent predictor of post-resection survival. CONCLUSION: DM is a common comorbidity in PDAC and is associated with unfavorable pathology, as well as worse postoperative and oncologic outcomes. The blunted effect on survival is more pronounced in patients who undergo resection following NAT.

25 Article Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. 2019

Ligorio, Matteo / Sil, Srinjoy / Malagon-Lopez, Jose / Nieman, Linda T / Misale, Sandra / Di Pilato, Mauro / Ebright, Richard Y / Karabacak, Murat N / Kulkarni, Anupriya S / Liu, Ann / Vincent Jordan, Nicole / Franses, Joseph W / Philipp, Julia / Kreuzer, Johannes / Desai, Niyati / Arora, Kshitij S / Rajurkar, Mihir / Horwitz, Elad / Neyaz, Azfar / Tai, Eric / Magnus, Neelima K C / Vo, Kevin D / Yashaswini, Chittampalli N / Marangoni, Francesco / Boukhali, Myriam / Fatherree, Jackson P / Damon, Leah J / Xega, Kristina / Desai, Rushil / Choz, Melissa / Bersani, Francesca / Langenbucher, Adam / Thapar, Vishal / Morris, Robert / Wellner, Ulrich F / Schilling, Oliver / Lawrence, Michael S / Liss, Andrew S / Rivera, Miguel N / Deshpande, Vikram / Benes, Cyril H / Maheswaran, Shyamala / Haber, Daniel A / Fernandez-Del-Castillo, Carlos / Ferrone, Cristina R / Haas, Wilhelm / Aryee, Martin J / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Clinic of Surgery, UKSH Campus Lübeck, Germany. · Institute of Pathology, University Medical Center Freiburg, Germany. · Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu. ·Cell · Pubmed #31155233.

ABSTRACT: Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

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