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Pancreatic Neoplasms: HELP
Articles by David T. Ting
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, David T. Ting wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. 2019

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Clark, Jeffrey W / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Ly, Leilana / Baglini, Christian V / Blaszkowsky, Lawrence S / Ferrone, Cristina R / Parikh, Aparna R / Weekes, Colin D / Nipp, Ryan D / Kwak, Eunice L / Allen, Jill N / Corcoran, Ryan B / Ting, David T / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Berger, David L / Qadan, Motaz / Lillemoe, Keith D / Talele, Nilesh / Jain, Rakesh K / DeLaney, Thomas F / Duda, Dan G / Boucher, Yves / Fernández-Del Castillo, Carlos / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·JAMA Oncol · Pubmed #31145418.

ABSTRACT: Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. Main Outcomes and Measures: R0 resection rate. Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. Trial Registration: ClinicalTrials.gov identifier: NCT01821729.

2 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.

3 Article Quasimesenchymal phenotype predicts systemic metastasis in pancreatic ductal adenocarcinoma. 2019

Mahadevan, Krishnan K / Arora, Kshitij S / Amzallag, Arnaud / Williams, Erik / Kulkarni, Anupriya S / Fernandez-Del Castillo, Carlos / Lillemoe, Keith D / Bardeesy, Nabeel / Hong, Theodore S / Ferrone, Cristina R / Ting, David T / Deshpande, Vikram. ·Department of Pathology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Medicine, Division of Oncology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. vikramdirdeshpande@gmail.com. ·Mod Pathol · Pubmed #30683911.

ABSTRACT: Metastasis following surgical resection is a leading cause of mortality in pancreatic ductal adenocarcinoma. Epithelial-mesenchymal transition is thought to play an important role in metastasis, although its clinical relevance in metastasis remains uncertain. We evaluated a panel of RNA in-situ hybridization probes for epithelial-mesenchymal transition-related genes expressed in circulating tumor cells. We assessed the predictive value of this panel for metastasis in pancreatic ductal adenocarcinoma and, to determine if the phenotype is generalizable between cancers, in colonic adenocarcinoma. One hundred fifty-eight pancreatic ductal adenocarcinomas and 205 colonic adenocarcinomas were classified as epithelial or quasimesenchymal phenotype using dual colorimetric RNA-in-situ hybridization. SMAD4 expression on pancreatic ductal adenocarcinomas was assessed by immunohistochemistry. Pancreatic ductal adenocarcinomas with quasimesenchymal phenotype had a significantly shorter disease-specific survival (P = 0.031) and metastasis-free survival (P = 0.0001) than those with an epithelial phenotype. Pancreatic ductal adenocarcinomas with SMAD4 loss also had lower disease-specific survival (P = 0.041) and metastasis-free survival (P = 0.001) than those with intact SMAD4. However, the quasimesenchymal phenotype proved a more robust predictor of metastases-area under the curve for quasimesenchymal = 0.8; SMAD4 = 0.6. The quasimesenchymal phenotype also predicted metastasis-free survival (P = 0.004) in colonic adenocarcinoma. Epithelial-mesenchymal transition defined two phenotypes with distinct metastatic capabilities-epithelial phenotype tumors with predominantly organ-confined disease and quasimesenchymal phenotype with high risk of metastatic disease in two epithelial malignancies. Collectively, this work validates the relevance of epithelial-mesenchymal transition in human gastrointestinal tumors.

4 Article No Cell Left Unturned: Intraductal Papillary Mucinous Neoplasm Heterogeneity. 2019

Hernandez-Barco, Yasmin G / Bardeesy, Nabeel / Ting, David T. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. · Massachusetts General Hospital Division of Gastroenterology, Harvard Medical School, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. dting1@mgh.harvard.edu. ·Clin Cancer Res · Pubmed #30642914.

ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic cancer precursor lesion with established genetic features, but the cellular ecosystem of these tumors remains to be fully characterized. This study utilizes single-cell RNA sequencing to describe the dynamic landscape of epithelial, immune, and stromal cells during IPMN progression to invasive cancer.

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

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

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

6 Article STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines. 2017

Grant, Trevor J / Mehta, Anita K / Gupta, Anamika / Sharif, Ahmad A D / Arora, Kshitij S / Deshpande, Vikram / Ting, David T / Bardeesy, Nabeel / Ganem, Neil J / Hergovich, Alexander / Singh, Anurag. ·Department of Pharmacology and Experimental Therapeutics, Center for Cancer Research, Boston University Graduate School of Medicine, Boston, MA, USA. · University College London, Cancer Institute, London, United Kingdom. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA. ·Oncotarget · Pubmed #29108249.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic

7 Article A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma. 2016

Indolfi, Laura / Ligorio, Matteo / Ting, David T / Xega, Kristina / Tzafriri, Abraham R / Bersani, Francesca / Aceto, Nicola / Thapar, Vishal / Fuchs, Bryan C / Deshpande, Vikram / Baker, Aaron B / Ferrone, Cristina R / Haber, Daniel A / Langer, Robert / Clark, Jeffrey W / Edelman, Elazer R. ·Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: lindolfi@mit.edu. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Health Sciences, University of Genoa, Genoa, Italy. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: dting1@mgh.harvard.edu. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · CBSET Inc., Department of Applied Sciences, Lexington, MA, USA. · Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Biomaterials · Pubmed #27082874.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer.

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

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

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

9 Article Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. 2016

Deshpande, Vikram / Konstantinidis, Ioannis T / Castillo, Carlos Fernandez-Del / Hezel, Aram F / Haigis, Kevin M / Ting, David T / Bardeesy, Nabeel / Goyal, Lipika / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. vdeshpande@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. ·J Gastrointest Surg · Pubmed #26956004.

ABSTRACT: PURPOSE: Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS: Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS: Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS: Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials.

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

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

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

11 Article Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. 2014

Ting, David T / Wittner, Ben S / Ligorio, Matteo / Vincent Jordan, Nicole / Shah, Ajay M / Miyamoto, David T / Aceto, Nicola / Bersani, Francesca / Brannigan, Brian W / Xega, Kristina / Ciciliano, Jordan C / Zhu, Huili / MacKenzie, Olivia C / Trautwein, Julie / Arora, Kshitij S / Shahid, Mohammad / Ellis, Haley L / Qu, Na / Bardeesy, Nabeel / Rivera, Miguel N / Deshpande, Vikram / Ferrone, Cristina R / Kapur, Ravi / Ramaswamy, Sridhar / Shioda, Toshi / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Health Sciences, University of Genoa, 16126 Genoa, Italy. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Radiation Oncology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu. ·Cell Rep · Pubmed #25242334.

ABSTRACT: Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.

12 Article RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. 2012

Yu, Min / Ting, David T / Stott, Shannon L / Wittner, Ben S / Ozsolak, Fatih / Paul, Suchismita / Ciciliano, Jordan C / Smas, Malgorzata E / Winokur, Daniel / Gilman, Anna J / Ulman, Matthew J / Xega, Kristina / Contino, Gianmarco / Alagesan, Brinda / Brannigan, Brian W / Milos, Patrice M / Ryan, David P / Sequist, Lecia V / Bardeesy, Nabeel / Ramaswamy, Sridhar / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. ·Nature · Pubmed #22763454.

ABSTRACT: Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.

13 Article Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. 2011

Ting, David T / Lipson, Doron / Paul, Suchismita / Brannigan, Brian W / Akhavanfard, Sara / Coffman, Erik J / Contino, Gianmarco / Deshpande, Vikram / Iafrate, A John / Letovsky, Stan / Rivera, Miguel N / Bardeesy, Nabeel / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. ·Science · Pubmed #21233348.

ABSTRACT: Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we showed that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDACs), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over that in normal tissue. In 15 of 15 human PDACs, alpha satellite transcripts were most abundant and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of the lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the long interspersed nuclear element 1 (LINE-1) retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions. The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection.

14 Minor In Reply. 2018

Franses, Joseph W / Ting, David T. ·Cancer Center, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Oncologist · Pubmed #30305416.

ABSTRACT: -- No abstract --