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Pancreatic Neoplasms: HELP
Articles by Cristina R. Ferrone
Based on 92 articles published since 2008
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Between 2008 and 2019, C. Ferrone wrote the following 92 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Editorial FOLFIRINOX: desert, oasis, or mirage? 2015

Ferrone, Cristina R. ·Massachusetts General Hospital, Surgery, Boston, MA, USA, cFERRONE@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #25490873.

ABSTRACT: -- No abstract --

3 Editorial Lymphadenectomy for pancreatic neuroendocrine tumors: is that the relevant debate? 2014

Ferrone, Cristina R. ·From the Division of General Surgery, Massachusetts General Hospital, Boston, MA. ·Ann Surg · Pubmed #24398923.

ABSTRACT: -- No abstract --

4 Review Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. 2016

Loehrer, Andrew P / Kinnier, Christine V / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address: cferrone@partners.org. ·Adv Surg · Pubmed #27520867.

ABSTRACT: -- No abstract --

5 Review Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. 2016

Loehrer, Andrew P / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, Mass., USA. ·Dig Surg · Pubmed #27216011.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is increasingly common and a leading cause of cancer-related mortality. Surgery remains the only possibility for cure. Upwards of 40% of patients present with locally advanced PDAC (LA-PDAC), where management strategies continue to evolve. In this review, we highlight current trends in neoadjuvant chemotherapy, surgical resection, and other multimodality approaches for patients with LA-PDAC. Despite promising early results, additional work is needed to more accurately and appropriately tailor treatment for patients with LA-PDAC.

6 Review Spectrum and Classification of Cystic Neoplasms of the Pancreas. 2016

Greer, Jonathan B / Ferrone, Cristina R. ·General Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB-425, Boston, MA 02114, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA. Electronic address: cferrone@mgh.harvard.edu. ·Surg Oncol Clin N Am · Pubmed #27013368.

ABSTRACT: As patients are living longer and axial imaging is more widespread, increasing numbers of cystic neoplasms of the pancreas are found. Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are the most common. The revised Sendai guidelines provide a safe algorithm for expectant management of certain cystic neoplasms; however, studies are ongoing to identify further subgroups that can be treated nonoperatively. For those patients with high-risk clinical features or symptoms, surgical resection can be performed safely at high-volume pancreatic centers. Accurate diagnosis is critical for accurate decision making.

7 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.

8 Review Intraductal papillary mucinous neoplasms: does a family history of pancreatic cancer matter? 2012

Nehra, Deepika / Oyarvide, Vicente Morales / Mino-Kenudson, Mari / Thayer, Sarah P / Ferrone, Cristina R / Wargo, Jennifer A / Muzikansky, Alona / Finkelstein, Dianne / Warshaw, Andrew L / Castillo, Carlos Fernández-del. ·Department of Surgery, Massachusetts General Hospital, Boston MA, USA. ·Pancreatology · Pubmed #22898638.

ABSTRACT: BACKGROUND/OBJECTIVES: The purpose of this study is to compare surgically resected intraductal papillary mucinous neoplasms (IPMNs) in patients with and without a family history of pancreatic cancer to gain insight into differences that may suggest the need for differential management. METHODS: A retrospective review of patients who underwent resection of an IPMN at the Massachusetts General Hospital (1990-2011) was conducted. Three hundred and twenty-four patients of whom 45 (13.9%) had a family history of pancreatic cancer were identified. Patients with (PFH) and without (NFH) a family history of pancreatic cancer were compared. RESULTS: There were no differences in demographic characteristics between groups. Extra-pancreatic malignancies diagnosed prior to the IPMN were more common in those with a PFH (35.6% vs 20.1%, p = 0.03). There were no differences in IPMN characteristics between groups including no difference in the presence of invasive disease (p = 0.55). Concurrent pancreatic ductal adenocarcinomas were more common in those with a PFH (11.1% vs 2.9%, p = 0.02). The survival in the PFH group was marginally lower than the NFH group, a difference found to be attributable to the higher prevalence of extra-pancreatic malignancies. CONCLUSION: Characteristics of surgically resected IPMNs are not different between patients with and without a family history of pancreatic cancer. Most importantly, the incidence of invasive disease is not different, suggesting that these lesions may not be more aggressive when they occur in the presence of a family history of pancreatic cancer.

9 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.

10 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.

11 Article Association Between Very Small Tumor Size and Decreased Overall Survival in Node-Positive Pancreatic Cancer. 2018

Muralidhar, Vinayak / Nipp, Ryan D / Mamon, Harvey J / Punglia, Rinaa S / Hong, Theodore S / Ferrone, Cristina / Fernandez-Del Castillo, Carlos / Parikh, Aparna / Nguyen, Paul L / Wo, Jennifer Y. ·Harvard Radiation Oncology Program, Boston, MA, USA. · Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. jwo@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #30298331.

ABSTRACT: BACKGROUND: In pancreatic adenocarcinoma (PDAC), increasing tumor size usually correlates with a worse prognosis. However, patients with a very small primary tumor who experience lymph node involvement may have a different disease biology. This study sought to determine the interaction between tumor size and lymph node involvement in terms of overall survival (OS). METHODS: The study identified 17,073 patients with a diagnosis of M0 resected PDAC between 1983 and 2013 using the Surveillance, Epidemiology, and End Results database. The patients were stratified by lymph node involvement (N0 vs N+) and T stage (T1a-T1b vs T1c vs T2 vs T3 vs T4). The Kaplan-Meier method was used to estimate OS, and Cox regression analysis was used to compare survival between subgroups after adjustment for patient-specific factors. RESULTS: Lymph node involvement and T stage significantly interacted (p < 0.001). Among the patients with node-negative disease, 5-year OS decreased monotonically with increasing T stage (59.1%, 30.6%, 22.9%, 16.6%, and 8.0%, respectively; p < 0.001). In contrast, among the patients with node-positive disease, those with T1a-T1b tumors (< 10 mm) had worse 5-year OS than those with T1c tumors (7.4% vs 17.6%; adjusted hazard ratio, 0.70; 95% confidence interval, 0.50-0.97; p = 0.034) and similar survival compared with those who had T2, T3, or T4 tumors (9.7%, 8.2%, and 4.8%, respectively; p > 0.2 in all cases). CONCLUSIONS: Among patients with lymph node-positive PDAC, very small primary tumors are associated with decreased OS. This finding raises the possibility that small tumors capable of lymph node metastasis might represent more biologically aggressive cancers.

12 Article Intraoperative Dexamethasone Decreases Infectious Complications After Pancreaticoduodenectomy and is Associated with Long-Term Survival in Pancreatic Cancer. 2018

Sandini, Marta / Ruscic, Katarina J / Ferrone, Cristina R / Warshaw, Andrew L / Qadan, Motaz / Eikermann, Matthias / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. · Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. CFERNANDEZ@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #30298316.

ABSTRACT: BACKGROUND: Dexamethasone is administered intraoperatively to prevent anesthesia-related nausea and vomiting and to reduce postoperative opioid administration. However, the adverse effects of corticosteroids on anastomotic healing and wound infection as well as oncologic outcomes remain unclear. We analyzed the effect of intraoperative dexamethasone administration on surgical outcomes after pancreaticoduodenectomy and on long-term survival in pancreatic cancer patients. METHODS: A total of 679 pancreaticoduodenectomies from a prospectively maintained database were analyzed. Surgical outcomes were compared between patients who received intraoperative dexamethasone and those who did not. Kaplan-Meier curves and Cox-regression survival analysis were performed in patients with pancreatic cancer. A propensity analysis was done to reduce the inherent bias of retrospective design. RESULTS: Patients who received dexamethasone (117, 17.2%) were younger and more likely to be female than those who did not (p = 0.001). Overall and 30-day major morbidity were similar among all resected patients, although there were fewer infectious complications in the dexamethasone group (18.8% vs. 28.5%, p = 0.032). In pancreatic cancer patients, dexamethasone was associated with significantly improved median overall survival (46 vs. 22 months, p = 0.017). This effect occurred independently of stage, pathologic characteristics, or adjuvant therapy, with adjusted hazard ratios, derived from pre-propensity and post-propensity analysis, of 0.67 (0.47-0.97) and 0.57 (0.37-0.87), respectively. CONCLUSIONS: A single intraoperative dose of dexamethasone did not increase morbidity after pancreaticoduodenectomy and, in fact, was associated with a decrease in infectious complications. The treatment was independently associated with improved overall survival in patients with pancreatic adenocarcinoma, an effect that cannot be explained and needs further validation in a prospective setting.

13 Article Are Staging Computed Tomography (CT) Scans of the Chest Necessary in Pancreatic Adenocarcinoma? 2018

Mehtsun, Winta T / Chipidza, Fallon E / Fernández-Del Castillo, Carlos / Hemingway, Katherine / Fong, Zhi Ven / Chang, David C / Pandharipande, Pari / Clark, Jeffrey W / Allen, Jill / Hong, Theodore S / Wo, Jennifer Y / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. · Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA. · Department of Radiology, Massachusetts General Hospital, Boston, MA, USA. · Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. cferrone@partners.org. ·Ann Surg Oncol · Pubmed #30276641.

ABSTRACT: BACKGROUND: There is no consensus on the use of chest imaging in pancreatic ductal adenocarcinoma (PDAC) patients. Among PDAC patients, we examined the use of chest computed tomography (CT) over time and determined whether the use of chest CT led to a survival difference or change in management via identification of indeterminate lung nodules (ILNs). METHODS: Retrospective clinical data was collected for patients diagnosed with PDAC from 1998 to 2014. We examined the proportion of patients undergoing staging chest CT scan and those who had ILN, defined as ≥ 1 well-defined, noncalcified lung nodule(s) ≤ 1 cm in diameter. We determined time to overall survival (OS) using multivariate Cox regression. We also assessed changes in management of PDAC patients who later developed lung metastasis only. RESULTS: Of the 2710 patients diagnosed with PDAC, 632 (23%) had greater than one chest CT. Of those patients, 451 (71%) patients had ILNs, whereas 181 (29%) had no ILNs. There was no difference in median overall survival in patients without ILNs (16.4 [13.6, 19.0] months) versus those with ILN (14.8 [13.6, 15.8] months, P = 0.18). Examining patients who developed isolated lung metastases (3.3%), we found that staging chest CTs did not lead to changes in management of the primary abdominal tumor. CONCLUSIONS: Survival did not differ for PDAC patients with ILNs identified on staging chest CTs compared with those without ILNs. Furthermore, ILN identification did not lead to changes in management of the primary abdominal tumor, questioning the utility of staging chest CTs for PDAC patients.

14 Article Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. 2018

Erstad, Derek J / Sojoodi, Mozhdeh / Taylor, Martin S / Ghoshal, Sarani / Razavi, Allen A / Graham-O'Regan, Katherine A / Bardeesy, Nabeel / Ferrone, Cristina R / Lanuti, Michael / Caravan, Peter / Tanabe, Kenneth K / Fuchs, Bryan C. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States derstad@partners.org bfuchs@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. · Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. · Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02114, United States. ·Dis Model Mech · Pubmed #29903803.

ABSTRACT: Syngeneic, immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics. Here, we describe surgical techniques for orthotopic and heterotopic pancreatic ductal adenocarcinoma (PDAC) tumor implantation and characterize phenotypes based on implantation site.Mice (

15 Article None 2018

Kasten, Benjamin B / Gangrade, Abhishek / Kim, Harrison / Fan, Jinda / Ferrone, Soldano / Ferrone, Cristina R / Zinn, Kurt R / Buchsbaum, Donald J. ·Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: benjaminkasten@uabmc.edu. · Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. · Institute for Quantitative Health Science and Engineering, Department of Radiology, Michigan State University, East Lansing, MI, United States. ·Nucl Med Biol · Pubmed #29413459.

ABSTRACT: INTRODUCTION: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with METHODS: In vitro Scatchard assays assessed the specific binding of CONCLUSION: Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with

16 Article Staging Laparoscopy Not Only Saves Patients an Incision, But May Also Help Them Live Longer. 2018

Sell, Naomi M / Fong, Zhi Ven / Del Castillo, Carlos Fernandez / Qadan, Motaz / Warshaw, Andrew L / Chang, David / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. cferrone@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #29388123.

ABSTRACT: BACKGROUND: Approximately 20-40% of patients with "resectable" pancreatic adenocarcinoma (PDAC) by imaging criteria have metastatic disease on exploration. Our aim was to assess the potential impact of staging laparoscopy versus upfront laparotomy in "resectable" patients found to have metastatic PDAC. METHODS: Clinicopathologic data was retrospectively collected for all patients with PDAC undergoing an operation with curative intent between 2001-2015 at a single institution. RESULTS: Of the 1001 patients undergoing surgical evaluation, 151 had unsuspected metastatic PDAC. Staging laparoscopy was performed in 59% (89/151) of patients, while 41% (62/151) underwent an exploratory laparotomy with or without prophylactic bypass. There were no differences in patient demographics and preoperative CA 19-9 levels between the staging laparoscopy and exploratory laparotomy groups. However, staging laparoscopy was more often performed for pancreatic body/tail lesions (85% vs 60% for pancreatic head lesions, p < 0.001). Patients who only underwent laparoscopy started palliative chemotherapy more quickly (17.9 days vs 39.9 days in the laparotomy group, p < 0.001). There was no difference in the 30 day or lifetime incidence of postoperative cholangitis, gastric outlet obstruction, or biliary stent placement between groups. The median overall survival for the staging laparoscopy group (11.4 months) was significantly longer than the laparotomy group (8.3 months, p < 0.001). In a cox regression analysis adjusting for clinicopathologic variables, staging laparoscopy was associated with significantly improved overall survival when compared to the laparotomy group (HR 0.53, 95% C.I. 0.34-0.82, p = 0.005). CONCLUSION: For patients diagnosed with metastatic PDAC at the time of surgical exploration, staging laparoscopy was associated with a shorter time to chemotherapy and improved overall survival when compared to those explored without laparoscopy.

17 Article Intraductal Papillary Mucinous Neoplasm of the Pancreas in Young Patients: Tumor Biology, Clinical Features, and Survival Outcomes. 2018

Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Ferrone, Cristina R / Warshaw, Andrew L / Lillemoe, Keith D / Sahani, Dushyant V / Pergolini, Ilaria / Attiyeh, Marc A / Al Efishat, Mohammad / Rezaee, Neda / Hruban, Ralph H / He, Jin / Weiss, Matthew J / Allen, Peter J / Wolfgang, Christopher L / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Wang Ambulatory Care Center 460, Boston, MA, 02114, USA. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Wang Ambulatory Care Center 460, Boston, MA, 02114, USA. cfernandez@partners.org. ·J Gastrointest Surg · Pubmed #29047068.

ABSTRACT: AIM: The aim of this paper is to describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in young patients. METHODS: We evaluated 1693 patients from the Pancreatic Surgery Consortium who underwent resection for IPMN and classified them as younger or older than 50 years of age at the time of surgery. We assessed the relationship of age with clinical, radiological, pathological, and prognostic features. RESULTS: We identified 90 (5%) young patients. Age was not associated with differences in main pancreatic duct size (P = 0.323), presence of solid components (P = 0.805), or cyst size (P = 0.135). IPMNs from young patients were less likely to be of gastric type (37 vs. 57%, P = 0.005), and more likely to be of oncocytic (15 vs. 4%, P = 0.003) and intestinal types (44 vs. 26%, P = 0.004). Invasive carcinomas arising from IPMN were less common in young patients (17 vs. 27%, P = 0.044), and when present they were commonly of colloid type (47 vs. 31% in older patients, P = 0.261) and had better overall survival than older patients (5-year, 71 vs. 37%, log-rank P = 0.031). CONCLUSION: Resection for IPMN is infrequent in young patients, but when they are resected, IPMNs from young patients demonstrate different epithelial subtypes from those in older patients and more favorable prognosis.

18 Article Pancreatic neuroendocrine tumor: Correlations between MRI features, tumor biology, and clinical outcome after surgery. 2018

Canellas, Rodrigo / Lo, Grace / Bhowmik, Sreejita / Ferrone, Cristina / Sahani, Dushyant. ·Department of Radiology, Division of Abdominal Imaging and Intervention, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. ·J Magn Reson Imaging · Pubmed #28480609.

ABSTRACT: PURPOSE: To assess which magnetic resonance imaging (MRI) features are associated with pNETs (pancreatic neuroendocrine tumors) grade based on the WHO classification, as well as identify MRI features related to disease progression after surgery. MATERIALS AND METHODS: In this Institutional Review Board (IRB)-approved study, 1.5T and 3.0T MRI scans of 80 patients with surgically verified pNETs were assessed. The images were evaluated for tumor location; size; pattern; predominant signal intensity on precontrast T RESULTS: The MRI features that were associated with aggressive tumors were: size >2.0 cm (odds ratio [OR] = 4.8, P = 0.002), "T CONCLUSION: MRI features can be used to assess pNETs aggressiveness and identify patients at risk for early disease progression after surgical resection. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:425-432.

19 Article Tolerability and Long-term Outcomes of Dose-Painted Neoadjuvant Chemoradiation to Regions of Vessel Involvement in Borderline or Locally Advanced Pancreatic Cancer. 2018

Wo, Jennifer Y / Niemierko, Andrzej / Ryan, David P / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Kwak, Eunice L / Lillemoe, Keith D / Drapek, Lorraine N / Zhu, Andrew X / Allen, Jill N / Faris, Jason E / Murphy, Janet E / Nipp, Ryan / Fernandez-Del Castillo, Carlos / Ferrone, Cristina R / Hong, Theodore S. ·Departments of Radiation Oncology. · Medical Oncology. · General Surgery, Massachusetts General Hospital, Boston, MA. ·Am J Clin Oncol · Pubmed #28134673.

ABSTRACT: PURPOSE: We reviewed our experience involving patients with borderline resectable or locally advanced pancreatic cancer, treated with the dose-painted (DP) boost technique to regions of vessel involvement which preclude upfront surgical resection. We evaluated patient outcomes with respect to tolerability and treatment outcomes. MATERIALS AND METHODS: We retrospectively reviewed 99 patients with borderline resectable (n=25) or locally advanced pancreatic cancer (n=74) treated with DP-neoadjuvant chemoradiation from 2010 to 2015. Tumor and regional lymph nodes were prescribed 50.4 Gy and the region around the involved blood vessel was boosted to 58.8 Gy in 28 fractions. The primary outcome was acute toxicity and late duodenal toxicity. Secondary outcomes included conversion to surgical resectability, local failure, disease-free survival, and overall survival (OS). Cox proportional hazards models were performed to evaluate for predictors of survival. RESULTS: All but 1 patient completed chemoradiation. The rates of grade 2+ and 3+ nausea were 40% and 12%, respectively. With regards to late toxicity, 5 patients developed potential RT-related grade 3+ duodenal complications including duodenal ulceration/bleeding (n=3) and duodenal stricture (n=2). With a median follow-up of 15 months, the median OS was 18.1 months. Among 99 patients in our study, 37 patients underwent surgical resection. For patients who underwent surgical resection (n=37), the median OS was 30.9 months. On multivariate analysis, only normalization of CA 19-9 post-RT was associated with improved OS. CONCLUSIONS: We found that DP-neoadjuvant chemoradiation to regions of vessel involvement is both feasible and well tolerated. In addition, we demonstrated that over one third of patients with initially deemed unresectable disease were able to undergo surgical resection after receiving neoadjuvant therapy including DP-chemoradiation.

20 Article Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium. 2018

Attiyeh, Marc A / Fernández-Del Castillo, Carlos / Al Efishat, Mohammad / Eaton, Anne A / Gönen, Mithat / Batts, Ruqayyah / Pergolini, Ilaria / Rezaee, Neda / Lillemoe, Keith D / Ferrone, Cristina R / Mino-Kenudson, Mari / Weiss, Matthew J / Cameron, John L / Hruban, Ralph H / D'Angelica, Michael I / DeMatteo, Ronald P / Kingham, T Peter / Jarnagin, William R / Wolfgang, Christopher L / Allen, Peter J. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, Massachusetts General Hospital, Boston, MA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #28079542.

ABSTRACT: OBJECTIVE: Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA: IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS: Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS: We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS: For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

21 Article Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma. 2018

Keane, Florence K / Wo, Jennifer Y / Ferrone, Cristina R / Clark, Jeffrey W / Blaszkowsky, Lawrence S / Allen, Jill N / Kwak, Eunice L / Ryan, David P / Lillemoe, Keith D / Fernandez-Del Castillo, Carlos / Hong, Theodore S. ·Harvard Radiation Oncology Program, Harvard Medical School. · Departments of Radiation Oncology. · Surgery. · Medicine, Division of Medical Oncology, Massachusetts General Hospital, Boston, MA. ·Am J Clin Oncol · Pubmed #27740973.

ABSTRACT: OBJECTIVES: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. METHODS: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. RESULTS: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. CONCLUSIONS: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

22 Article Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. 2017

Geller, Leore T / Barzily-Rokni, Michal / Danino, Tal / Jonas, Oliver H / Shental, Noam / Nejman, Deborah / Gavert, Nancy / Zwang, Yaara / Cooper, Zachary A / Shee, Kevin / Thaiss, Christoph A / Reuben, Alexandre / Livny, Jonathan / Avraham, Roi / Frederick, Dennie T / Ligorio, Matteo / Chatman, Kelly / Johnston, Stephen E / Mosher, Carrie M / Brandis, Alexander / Fuks, Garold / Gurbatri, Candice / Gopalakrishnan, Vancheswaran / Kim, Michael / Hurd, Mark W / Katz, Matthew / Fleming, Jason / Maitra, Anirban / Smith, David A / Skalak, Matt / Bu, Jeffrey / Michaud, Monia / Trauger, Sunia A / Barshack, Iris / Golan, Talia / Sandbank, Judith / Flaherty, Keith T / Mandinova, Anna / Garrett, Wendy S / Thayer, Sarah P / Ferrone, Cristina R / Huttenhower, Curtis / Bhatia, Sangeeta N / Gevers, Dirk / Wargo, Jennifer A / Golub, Todd R / Straussman, Ravid. ·Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. · Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA. · Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Department of Mathematics and Computer Science, Open University of Israel, Raanana, Israel. · Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. · Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. · Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. · Small Molecule Mass Spectrometry Facility, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge, MA 02138, USA. · Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. · Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. · Department of Biomedical Engineering, Columbia University, New York City, NY 10027, USA. · Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Harvard T. H. Chan School of Public Health, Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Boston, MA 02115, USA. · Department of Pathology, Sheba Medical Center, Ramat Gan, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Oncology, Sheba Medical Center, Ramat Gan, Israel. · Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. · Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-6345, USA. · Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA. · Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA. · Howard Hughes Medical Institute (HHMI), Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA. · Division of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA. · Ludwig Center for Molecular Oncology, MIT, Cambridge, MA 02139, USA. · Marble Center for Cancer Nanomedicine, MIT, Cambridge, MA 02139, USA. · HHMI, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. · Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Harvard Medical School, Boston, MA 02115, USA. · Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ravidst@weizmann.ac.il. ·Science · Pubmed #28912244.

ABSTRACT: Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD

23 Article Diabetes mellitus in intraductal papillary mucinous neoplasm of the pancreas is associated with high-grade dysplasia and invasive carcinoma. 2017

Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Ferrone, Cristina R / Sahani, Dushyant V / Pergolini, Ilaria / Negreros-Osuna, Adrián A / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Electronic address: cfernandez@partners.org. ·Pancreatology · Pubmed #28890154.

ABSTRACT: BACKGROUND: While the association between Diabetes Mellitus (DM) and pancreatic ductal adenocarcinoma is well recognized, its importance in intraductal papillary mucinous neoplasm of the pancreas (IPMN) is not well-defined. We sought to examine the associations of DM with degree of dysplasia and morphological subtypes in IPMN. METHODS: In 454 patients with resected IPMN, we evaluated associations of DM with high-grade dysplasia (HGD), invasive carcinoma, precursor epithelial subtype (gastric, intestinal, oncocytic, pancreatobiliary), and histological type of invasive carcinomas (tubular, colloid, oncocytic) using logistic regression. We performed multivariate analyses adjusting for worrisome features and high-risk stigmata of malignancy in a subset of 289 patients with annotated radiological characteristics. RESULTS: The prevalence of DM in our study was 34%. DM was significantly associated with HGD (OR 2.02, 95% CI 1.02-4.01, P = 0.045) and invasive carcinoma (OR 2.05, 95% CI 1.08-3.87, P = 0.027) after adjusting for worrisome features. Compared to patients without DM, those with recent-onset DM (≤5 years before surgery) had 6.9-fold (95% CI 2.38-19.92, P < 0.001) higher risk of invasive carcinoma. DM was associated with increased likelihood of intestinal-type precursor epithelium (OR 1.63, 95% CI 1.07-2.47, P = 0.022) and colloid carcinomas (OR 2.46, 95% CI 1.01-5.99, P = 0.047) CONCLUSION: Preoperative DM was associated with significantly higher risk of HGD and invasive carcinoma in resected IPMN, and risk of invasive carcinoma was highest in patients with recent-onset DM. Patients with DM were more likely to harbor intestinal-type IPMN and colloid carcinomas. Our findings suggest that a diagnosis of DM in patients with IPMN may warrant more aggressive surveillance.

24 Article A novel chemoradiation targeting stem and nonstem pancreatic cancer cells by repurposing disulfiram. 2017

Cong, Juan / Wang, Yangyang / Zhang, Xiao / Zhang, Nan / Liu, Ling / Soukup, Klara / Michelakos, Theodoros / Hong, Theodore / DeLeo, Albert / Cai, Lei / Sabbatino, Francesco / Ferrone, Soldano / Lee, Hang / Levina, Vera / Fuchs, Bryan / Tanabe, Kenneth / Lillemoe, Keith / Ferrone, Cristina / Wang, Xinhui. ·Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. · Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: xwang30@mgh.harvard.edu. ·Cancer Lett · Pubmed #28864067.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF-κB-stemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDH

25 Article Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. 2017

Pergolini, Ilaria / Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Honselmann, Kim C / Rosenbaum, Matthew W / Nahar, Sabikun / Kem, Marina / Ferrone, Cristina R / Lillemoe, Keith D / Bardeesy, Nabeel / Ryan, David P / Thayer, Sarah P / Warshaw, Andrew L / Fernández-Del Castillo, Carlos / Liss, Andrew S. ·Department of Surgery and the Andrew L. Warshaw, MD Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Surgery, Universita' Politecnica delle Marche, Ancona, Italy. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #28854237.

ABSTRACT: Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.

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