Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Christine A. Iacobuzio-Donahue
Based on 91 articles published since 2009
(Why 91 articles?)
||||

Between 2009 and 2019, C. Iacobuzio-Donahue wrote the following 91 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Keys to personalized care in pancreatic oncology. 2012

Crane, Christopher H / Iacobuzio-Donahue, Christine A. · ·J Clin Oncol · Pubmed #23045599.

ABSTRACT: -- No abstract --

2 Review Pancreatic cancer biology and genetics from an evolutionary perspective. 2016

Makohon-Moore, Alvin / Iacobuzio-Donahue, Christine A. ·Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ·Nat Rev Cancer · Pubmed #27444064.

ABSTRACT: Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease. In this Review we gather the wide-ranging aspects of pancreatic cancer research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for study.

3 Review Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches. 2016

Sahin, Ibrahim H / Lowery, Maeve A / Stadler, Zsofia K / Salo-Mullen, Erin / Iacobuzio-Donahue, Christine A / Kelsen, David P / O'Reilly, Eileen M. ·a Department of Medicine , Icahn School of Medicine at Mount Sinai St Luke's Roosevelt Hospital Center , New York , NY , USA. · b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA. · c Department of Medicine , Weill Cornell Medical College , New York , NY , USA. ·Expert Rev Gastroenterol Hepatol · Pubmed #26881472.

ABSTRACT: Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach.

4 Review Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy. 2016

Sahin, Ibrahim H / Iacobuzio-Donahue, Christine A / O'Reilly, Eileen M. ·a 1 Icahn School of Medicine at Mount Sinai St Luke's Roosevelt Hospital Center , NY, USA. · b 2 Memorial Sloan Kettering Cancer Center , NY, USA. · c 3 Weill Medical College of Cornell University, David M. Rubenstein Center for Pancreatic Cancer Research , 300 East 66th street, office 1021, NY 10065, USA ; oreillye@mskcc.org. ·Expert Opin Ther Targets · Pubmed #26439702.

ABSTRACT: INTRODUCTION: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. AREAS COVERED: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. EXPERT OPINION: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a 'precision medicine' approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.

5 Review CNS involvement in pancreatic adenocarcinoma: a report of eight cases from the Johns Hopkins Hospital and review of literature. 2015

Kumar, Abhijeet / Dagar, Meenakshi / Herman, Joseph / Iacobuzio-Donahue, Christine / Laheru, Dan. ·Department of Hematology/Oncology, University of Arizona Medical Center, 1501, N Campbell Ave, Tucson, AZ, USA, dr.abhijeetkumar@gmail.com. ·J Gastrointest Cancer · Pubmed #25451139.

ABSTRACT: PURPOSE: CNS metastasis of pancreatic cancer is extremely rare, although systemic metastasis is very common. We present eight such cases with various forms of nervous system involvement. METHODS: Data was gathered from chart review of 800 patients with pancreatic cancer treated between 2004 and 2012 of which eight patients are described with CNS metastases. RESULTS: The median age of patients was 61.5 years and the median time to develop CNS metastasis was 29 months. Interestingly, two patients had no other sites of metastasis. The treatment modalities tried included resection followed by radiation, resection alone, or whole brain radiation.

6 Review Evolution and dynamics of pancreatic cancer progression. 2013

Yachida, S / Iacobuzio-Donahue, C A. ·1] Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA [2] Division of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo, Japan. ·Oncogene · Pubmed #23416985.

ABSTRACT: Efficient metastasis is believed as the result of multiple genetic, epigenetic and/or post-translational events in the lifetime of a carcinoma. At the genetic level, these events may be categorized into those that occur during carcinogenesis, and those that occur during subclonal evolution. This review summarizes current knowledge of the genetics of pancreatic cancer from its initiation within a normal cell until the time that is has disseminated to distant organs, many features of which can be extrapolated to other solid tumor types. The implications of these findings to personalize genome analyses of an individual patient's tumor are also discussed.

7 Review Considerations for sequencing analyses of pancreatic cancer progression and metastasis. 2013

Makohon-Moore, Alvin / Iacobuzio-Donahue, Christine A. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ·Methods Mol Biol · Pubmed #23359151.

ABSTRACT: Sequencing analyses have been invaluable in identifying the genes associated with pancreatic -carcinogenesis. However, whereas gene discovery related to carcinogenesis can be fairly straightforward, there are several additional aspects of experimental design that need to be considered when performing genetic analyses of metastatic disease. This chapter aims to review these issues and provide examples of the types of data generated.

8 Review Molecular pathways in pancreatic carcinogenesis. 2013

Macgregor-Das, Anne M / Iacobuzio-Donahue, Christine A. ·Pathobiology Program, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. ·J Surg Oncol · Pubmed #22806689.

ABSTRACT: Pancreatic cancer is a genetic disease. Pancreatic cancers develop from one of three precursor lesions, pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs), and each arises in association with distinct genetic alterations. These alterations not only provide insight into the fundamental origins of pancreatic cancer but provide ample opportunity for improving early diagnosis and management of cystic precursors.

9 Review Genetic basis of pancreas cancer development and progression: insights from whole-exome and whole-genome sequencing. 2012

Iacobuzio-Donahue, Christine A / Velculescu, Victor E / Wolfgang, Christopher L / Hruban, Ralph H. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Clin Cancer Res · Pubmed #22896692.

ABSTRACT: Pancreatic cancer is caused by inherited and acquired mutations in specific cancer-associated genes. The discovery of the most common genetic alterations in pancreatic cancer has provided insight into the fundamental pathways that drive the progression from a normal cell to noninvasive precursor lesions and finally to widely metastatic disease. In addition, recent genetic discoveries have created new opportunities to develop gene-based approaches for early detection, personalized treatment, and molecular classification of pancreatic neoplasms.

10 Review The pathology and genetics of metastatic pancreatic cancer. 2009

Yachida, Shinichi / Iacobuzio-Donahue, Christine A. ·The Johns Hopkins Medical Institutions, The Sol Goldman Pancreatic Cancer Research Center, Baltimore, Maryland 21231, USA. ·Arch Pathol Lab Med · Pubmed #19260747.

ABSTRACT: CONTEXT: Metastatic disease is the most critical determinant of resectability of pancreatic cancer and accounts for the poor outcome of patients with this disease. Thus, a better understanding of metastatic pancreatic cancer will afford new opportunities for therapeutic intervention. OBJECTIVE: To summarize and discuss the current understanding of the clinical and molecular features of metastatic pancreatic cancer. DATA SOURCES: Published literature on advanced stage pancreatic cancer, pancreatic cancer metastasis, and autopsy findings in patients with pancreatic cancer. CONCLUSIONS: In the clinical setting, it can be difficult to distinguish a metastatic pancreatic carcinoma from primary neoplasms in the liver, lung, or ovary. However, immunolabeling for DPC4 protein as part of a diagnostic panel is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression of EphA2, loss of DPC4 and MKK4, and aberrant activation of the Hedgehog signaling pathway are associated with metastatic propensity of pancreatic cancers, providing novel therapeutic targets for the most lethal stage of this disease.

11 Clinical Trial Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer. 2016

Rao, Avani D / Sugar, Elizabeth A / Chang, Daniel T / Goodman, Karyn A / Hacker-Prietz, Amy / Rosati, Lauren M / Columbo, Laurie / O'Reilly, Eileen / Fisher, George A / Zheng, Lei / Pai, Jonathan S / Griffith, Mary E / Laheru, Daniel A / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Koong, Albert / Herman, Joseph M. ·Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Biostatistics and Epidemiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Stanford University School of Medicine, Stanford, California. · Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · University of California at San Francisco School of Medicine, San Francisco, California. · Department of Surgical Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: joe@jhmi.edu. ·Pract Radiat Oncol · Pubmed #27552809.

ABSTRACT: PURPOSE: We previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL). METHODS AND MATERIALS: Forty-nine LAPC patients received 33 Gy SBRT (6.6 Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000 mg/m RESULTS: Forty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP. CONCLUSIONS: Global QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.

12 Clinical Trial Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. 2015

Herman, Joseph M / Chang, Daniel T / Goodman, Karyn A / Dholakia, Avani S / Raman, Siva P / Hacker-Prietz, Amy / Iacobuzio-Donahue, Christine A / Griffith, Mary E / Pawlik, Timothy M / Pai, Jonathan S / O'Reilly, Eileen / Fisher, George A / Wild, Aaron T / Rosati, Lauren M / Zheng, Lei / Wolfgang, Christopher L / Laheru, Daniel A / Columbo, Laurie A / Sugar, Elizabeth A / Koong, Albert C. ·Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. ·Cancer · Pubmed #25538019.

ABSTRACT: BACKGROUND: This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). METHODS: A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. RESULTS: The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥ 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections. CONCLUSIONS: Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy.

13 Article Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. 2019

Blando, Jorge / Sharma, Anu / Higa, Maria Gisela / Zhao, Hao / Vence, Luis / Yadav, Shalini S / Kim, Jiseong / Sepulveda, Alejandro M / Sharp, Michael / Maitra, Anirban / Wargo, Jennifer / Tetzlaff, Michael / Broaddus, Russell / Katz, Matthew H G / Varadhachary, Gauri R / Overman, Michael / Wang, Huamin / Yee, Cassian / Bernatchez, Chantale / Iacobuzio-Donahue, Christine / Basu, Sreyashi / Allison, James P / Sharma, Padmanee. ·The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065. · The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; jallison@mdanderson.org padsharma@mdanderson.org. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. ·Proc Natl Acad Sci U S A · Pubmed #30635425.

ABSTRACT: Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma,

14 Article Precancerous neoplastic cells can move through the pancreatic ductal system. 2018

Makohon-Moore, Alvin P / Matsukuma, Karen / Zhang, Ming / Reiter, Johannes G / Gerold, Jeffrey M / Jiao, Yuchen / Sikkema, Lisa / Attiyeh, Marc A / Yachida, Shinichi / Sandone, Corinne / Hruban, Ralph H / Klimstra, David S / Papadopoulos, Nickolas / Nowak, Martin A / Kinzler, Kenneth W / Vogelstein, Bert / Iacobuzio-Donahue, Christine A. ·The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, University of California, Davis, Sacramento, CA, USA. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA. · Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA. · The Ludwig Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · VU University Amsterdam, Master's Oncology Program, VU University Medical Center, Amsterdam, The Netherlands. · Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. · Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. · Howard Hughes Medical Institute, The Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. · The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. iacobuzc@mskcc.org. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. iacobuzc@mskcc.org. ·Nature · Pubmed #30177826.

ABSTRACT: Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

15 Article Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. 2018

Pommier, Arnaud / Anaparthy, Naishitha / Memos, Nicoletta / Kelley, Z Larkin / Gouronnec, Alizée / Yan, Ran / Auffray, Cédric / Albrengues, Jean / Egeblad, Mikala / Iacobuzio-Donahue, Christine A / Lyons, Scott K / Fearon, Douglas T. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Department of Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA. · Weill Cornell Medicine, New York, NY 10065, USA. · Institut Cochin, Paris Descartes Université, CNRS UMR8104, INSERM U1016, 75014 Paris, France. · Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. dfearon@cshl.edu. · Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. ·Science · Pubmed #29773669.

ABSTRACT: The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19

16 Article Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. 2018

Lowery, Maeve A / Wong, Winston / Jordan, Emmet J / Lee, Jonathan W / Kemel, Yelena / Vijai, Joseph / Mandelker, Diana / Zehir, Ahmet / Capanu, Marinela / Salo-Mullen, Erin / Arnold, Angela G / Yu, Kenneth H / Varghese, Anna M / Kelsen, David P / Brenner, Robin / Kaufmann, Erica / Ravichandran, Vignesh / Mukherjee, Semanti / Berger, Michael F / Hyman, David M / Klimstra, David S / Abou-Alfa, Ghassan K / Tjan, Catherine / Covington, Christina / Maynard, Hannah / Allen, Peter J / Askan, Gokce / Leach, Steven D / Iacobuzio-Donahue, Christine A / Robson, Mark E / Offit, Kenneth / Stadler, Zsofia K / O'Reilly, Eileen M. ·Department of Medicine. · David M. Rubenstein Center for Pancreatic Cancer Research. · Department of Medicine, Weill Cornell. · Robert and Kate Niehaus Center for Inherited Genomics. · Center for Molecular Oncology. · Department of Pathology. · Department of Epidemiology and Biostatistics. · Department of Surgery. ·J Natl Cancer Inst · Pubmed #29506128.

ABSTRACT: Background: Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Methods: Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. Results: PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. Conclusions: PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.

17 Article Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. 2018

Hu, Zishuo I / Shia, Jinru / Stadler, Zsofia K / Varghese, Anna M / Capanu, Marinela / Salo-Mullen, Erin / Lowery, Maeve A / Diaz, Luis A / Mandelker, Diana / Yu, Kenneth H / Zervoudakis, Alice / Kelsen, David P / Iacobuzio-Donahue, Christine A / Klimstra, David S / Saltz, Leonard B / Sahin, Ibrahim H / O'Reilly, Eileen M. ·Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Weill Cornell Medical College, New York, New York. · Department of Medicine, Weill Cornell Medical College, New York, New York. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Trinity College, Dublin, Ireland. · Emory University School of Medicine, Atlanta, Georgia. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. oreillye@mskcc.org. ·Clin Cancer Res · Pubmed #29367431.

ABSTRACT:

18 Article Smad4 Loss Correlates With Higher Rates of Local and Distant Failure in Pancreatic Adenocarcinoma Patients Receiving Adjuvant Chemoradiation. 2018

Herman, Joseph M / Jabbour, Salma K / Lin, Steven H / Deek, Matthew P / Hsu, Charles C / Fishman, Elliot K / Kim, Sinae / Cameron, John L / Chekmareva, Marina / Laheru, Daniel A / Narang, Amol K / Pawlik, Timothy M / Hruban, Ralph H / Wolfgang, Christopher L / Iacobuzio-Donahue, Christine A. · ·Pancreas · Pubmed #29329157.

ABSTRACT: OBJECTIVES: The tumor suppressor gene SMAD4 (DPC4) is genetically inactivated in approximately half of pancreatic ductal adenocarcinomas (PDAs). We examined whether Smad4 tumor status was associated with outcomes after adjuvant chemoradiation (CRT) for resected PDAs. METHODS: Patients treated with adjuvant CRT were identified (N = 145). Smad4 status was determined by immunolabeling and graded as intact or lost. Kaplan-Meier method and multivariable competing risk analyses were performed. RESULTS: On multivariate competing risk analysis, Smad4 loss was associated with increased risk of local recurrence (LR) (hazard ratio, 2.37; 95% confidence interval, 1.10-5.11; P = 0.027), distant failure (DF) (hazard ratio, 1.71; 95% confidence interval, 1.03-2.83; P = 0.037), and synchronous LR and DF at first recurrence (14.9 % vs 5.3%, P = 0.07) compared with Smad4 intact cancers. Smad4 loss was not associated with median overall survival (22 vs 22 months; P = 0.63) or disease-free survival (lost [13.6 months] vs intact [13.5 months], P = 0.79). CONCLUSIONS: After PDA resection and adjuvant CRT, Smad4 loss correlated with higher risk of LR and DF, but not with survival. Smad4 loss may help predict which surgical patients are at higher risk for failure after definitive management and may benefit from intensified adjuvant therapy.

19 Article Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. 2017

Balachandran, Vinod P / Łuksza, Marta / Zhao, Julia N / Makarov, Vladimir / Moral, John Alec / Remark, Romain / Herbst, Brian / Askan, Gokce / Bhanot, Umesh / Senbabaoglu, Yasin / Wells, Daniel K / Cary, Charles Ian Ormsby / Grbovic-Huezo, Olivera / Attiyeh, Marc / Medina, Benjamin / Zhang, Jennifer / Loo, Jennifer / Saglimbeni, Joseph / Abu-Akeel, Mohsen / Zappasodi, Roberta / Riaz, Nadeem / Smoragiewicz, Martin / Kelley, Z Larkin / Basturk, Olca / Anonymous7661303 / Anonymous7671303 / Anonymous7681303 / Anonymous7691303 / Anonymous7701303 / Anonymous7711303 / Anonymous7721303 / Anonymous7731303 / Anonymous7741303 / Anonymous7751303 / Anonymous7761303 / Anonymous7771303 / Anonymous7781303 / Anonymous7791303 / Anonymous7801303 / Anonymous7811303 / Anonymous7821303 / Anonymous7831303 / Anonymous7841303 / Anonymous7851303 / Anonymous7861303 / Anonymous7871303 / Gönen, Mithat / Levine, Arnold J / Allen, Peter J / Fearon, Douglas T / Merad, Miriam / Gnjatic, Sacha / Iacobuzio-Donahue, Christine A / Wolchok, Jedd D / DeMatteo, Ronald P / Chan, Timothy A / Greenbaum, Benjamin D / Merghoub, Taha / Leach, Steven D. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK. · Cold Spring Harbor Laboratory, New York, New York, USA. · Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA. · Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Weill Cornell Medical College, Cornell University, New York, New York, USA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Tisch Cancer Institute, Departments of Medicine, Hematology and Medical Oncology, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire, USA. ·Nature · Pubmed #29132146.

ABSTRACT: Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8

20 Article Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype. 2017

Lowery, Maeve A / Jordan, Emmet J / Basturk, Olca / Ptashkin, Ryan N / Zehir, Ahmet / Berger, Michael F / Leach, Tanisha / Herbst, Brian / Askan, Gokce / Maynard, Hannah / Glassman, Danielle / Covington, Christina / Schultz, Nikolaus / Abou-Alfa, Ghassan K / Harding, James J / Klimstra, David S / Hechtman, Jaclyn F / Hyman, David M / Allen, Peter J / Jarnagin, William R / Balachandran, Vinod P / Varghese, Anna M / Schattner, Mark A / Yu, Kenneth H / Saltz, Leonard B / Solit, David B / Iacobuzio-Donahue, Christine A / Leach, Steven D / O'Reilly, Eileen M. ·Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. maevelowery@gmail.com oreillye@mskcc.org. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medicine, Weill Cornell Medical College, New York, New York. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. ·Clin Cancer Res · Pubmed #28754816.

ABSTRACT:

21 Article An unusual genomic variant of pancreatic ductal adenocarcinoma with an indolent clinical course. 2017

Kohutek, Zachary A / Rosati, Lauren M / Hong, Junguei / Poling, Justin / Attiyeh, Marc A / Makohon-Moore, Alvin / Herman, Joseph M / Iacobuzio-Donahue, Christine A. ·Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA. · Sloan Kettering Institute, New York, New York 10065, USA. · Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA. · Division of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ·Cold Spring Harb Mol Case Stud · Pubmed #28679692.

ABSTRACT: We describe an 85-yr-old male of Ashkenazi Jewish descent with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA). The patient underwent a modified course of gemcitabine and stereotactic body radiation therapy and survived for 42 mo with a stable pancreatic head mass and no evidence of metastatic disease before death due to complications from a stroke. Whole-exome sequencing of his tumor revealed a simple genome landscape with no evidence of mutations, copy-number changes, or structural alterations in genes most commonly associated with PDA (i.e.,

22 Article Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling. 2017

Yamamoto, Kimiyo N / Yachida, Shinichi / Nakamura, Akira / Niida, Atsushi / Oshima, Minoru / De, Subhajyoti / Rosati, Lauren M / Herman, Joseph M / Iacobuzio-Donahue, Christine A / Haeno, Hiroshi. ·Department of Biology, Kyushu University, Fukuoka, Japan. kimiyo@jimmy.harvard.edu kyamamoto@kyushu-u.org haeno@kyushu-u.org. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan. · Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. · Division of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. · Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan. · Department of Biostatistics and Informatics, University of Colorado School of Medicine, Colorado. · Department of Radiation Oncology & Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, David M. Rubenstein Center for Pancreatic Cancer Research, and the Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. ·Cancer Res · Pubmed #28381541.

ABSTRACT: Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with

23 Article Reconstructing metastatic seeding patterns of human cancers. 2017

Reiter, Johannes G / Makohon-Moore, Alvin P / Gerold, Jeffrey M / Bozic, Ivana / Chatterjee, Krishnendu / Iacobuzio-Donahue, Christine A / Vogelstein, Bert / Nowak, Martin A. ·Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA. · IST (Institute of Science and Technology) Austria, Klosterneuburg 3400, Austria. · The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · The Ludwig Center and Howard Hughes Medical Institute at The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ·Nat Commun · Pubmed #28139641.

ABSTRACT: Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications. Genome-wide sequencing data has enabled modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumour samples at unprecedented depth. However, existing methods are not designed to infer metastatic seeding patterns. Here we develop a tool, called Treeomics, to reconstruct the phylogeny of metastases and map subclones to their anatomic locations. Treeomics infers comprehensive seeding patterns for pancreatic, ovarian, and prostate cancers. Moreover, Treeomics correctly disambiguates true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumour heterogeneity among distinct samples. In silico benchmarking on simulated tumour phylogenies across a wide range of sample purities (15-95%) and sequencing depths (25-800 × ) demonstrates the accuracy of Treeomics compared with existing methods.

24 Article Alterations of type II classical cadherin, cadherin-10 (CDH10), is associated with pancreatic ductal adenocarcinomas. 2017

Jinawath, Natini / Shiao, Meng-Shin / Norris, Alexis / Murphy, Kathleen / Klein, Alison P / Yonescu, Raluca / Iacobuzio-Donahue, Christine / Meeker, Alan / Jinawath, Artit / Yeo, Charles J / Eshleman, James R / Hruban, Ralph H / Brody, Jonathan R / Griffin, Constance A / Harada, Shuko. ·Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. · Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Sidney Kimmel Cancer Center Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. · Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. ·Genes Chromosomes Cancer · Pubmed #28124395.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), either sporadic or familial, has a dismal prognosis and finding candidate genes involved in development of the cancer is crucial for the patient care. First, we identified two patients with germline alterations in or adjacent to CDH10 by chromosome studies and sequencing analyses in 41 familial pancreatic cancer (FPC) cases. One patient had a balanced translocation between chromosome 5 and 20. The breakpoint on chromosome band 5p14.2 was ∼810 Kb upstream of CDH10, while that on chromosome arm 20p was in the pericentromeric region which might result in inactivation of one copy of the gene leading to reduced expression of CDH10. This interpretation was supported by loss of heterozygosity (LOH) seen in this region as determined by short tandem repeat analyses. Another patient had a single nucleotide variant in exon 12 (p.Arg688Gln) of CDH10. This amino acid was conserved among vertebrates and the mutation was predicted to have a pathogenic effect on the protein by several prediction algorithms. Next, we analyzed LOH status in the CDH10 region in sporadic PDAC and at least 24% of tumors had evidence of LOH. Immunohistochemical stains with CDH10 antibody showed a different staining pattern between normal pancreatic ducts and PDAC. Taken together, our data supports the notion that CDH10 is involved in sporadic pancreatic carcinogenesis, and might have a role in rare cases of FPC. Further functional studies are needed to elucidate the tumor suppressive role of CDH10 in pancreatic carcinogenesis.

25 Article Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. 2017

McDonald, Oliver G / Li, Xin / Saunders, Tyler / Tryggvadottir, Rakel / Mentch, Samantha J / Warmoes, Marc O / Word, Anna E / Carrer, Alessandro / Salz, Tal H / Natsume, Sonoko / Stauffer, Kimberly M / Makohon-Moore, Alvin / Zhong, Yi / Wu, Hao / Wellen, Kathryn E / Locasale, Jason W / Iacobuzio-Donahue, Christine A / Feinberg, Andrew P. ·Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Duke Cancer Institute, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA. · Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA. · Departments of Pathology and Human Oncology and Pathogenesis Program, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Departments of Medicine, Biomedical Engineering and Mental Health, Johns Hopkins University Schools of Medicine, Engineering and Public Health, Baltimore, Maryland, USA. ·Nat Genet · Pubmed #28092686.

ABSTRACT: During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic-epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

Next