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Pancreatic Neoplasms: HELP
Articles by Laura D. Wood
Based on 61 articles published since 2010
(Why 61 articles?)
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Between 2010 and 2020, Laura Wood wrote the following 61 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Very long-term survival in pancreatic cancer. 2015

Molin, Marco Dal / Wood, Laura D. ·Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, MD, USA. ·Aging (Albany NY) · Pubmed #26143583.

ABSTRACT: -- No abstract --

2 Review Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine. 2019

Luchini, Claudio / Veronese, Nicola / Nottegar, Alessia / Cappelletti, Vera / Daidone, Maria G / Smith, Lee / Parris, Christopher / Brosens, Lodewijk A A / Caruso, Maria G / Cheng, Liang / Wolfgang, Christopher L / Wood, Laura D / Milella, Michele / Salvia, Roberto / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Castellana Grotte, 70013 Bari, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Applied Research and Technological Development Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy. · Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK. · Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands. · Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6526GA Nijmegen, The Netherlands. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of General and Visceral Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. ·Cancers (Basel) · Pubmed #31405192.

ABSTRACT: Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

3 Review Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition. 2019

Lawlor, Rita T / Veronese, Nicola / Nottegar, Alessia / Malleo, Giuseppe / Smith, Lee / Demurtas, Jacopo / Cheng, Liang / Wood, Laura D / Silvestris, Nicola / Salvia, Roberto / Scarpa, Aldo / Luchini, Claudio. ·ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. ritateresa.lawlor@univr.it. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", 70013 Castellana Grotte, Italy. ilmannato@gmail.com. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. alessia.nottegar@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. giuseppe.malleo@univr.it. · Cambridge Centre for Sport and Excercise Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK. Lee.Smith@anglia.ac.uk. · Primary Care Department, Azienda USL Toscana Sud Est, 58100 Grosseto, Italy. eritrox7@gmail.com. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. liang_cheng@yahoo.com. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ldelong1@jhmi.edu. · Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, 70124 Bari, Italy. silvestrisnicola@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. roberto.salvia@univr.it. · ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. claudio.luchini@univr.it. ·Cancers (Basel) · Pubmed #30669452.

ABSTRACT: This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13⁻1.88,

4 Review Genetics of Familial and Sporadic Pancreatic Cancer. 2019

Wood, Laura D / Yurgelun, Matthew B / Goggins, Michael G. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: Matthew_Yurgelun@dfci.harvard.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: mgoggins@jhmi.edu. ·Gastroenterology · Pubmed #30660730.

ABSTRACT: In the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatic tumorigenesis. Whole-exome and whole-genome sequencing of pancreatic ductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreatic susceptibility gene alterations are often identified in patients with pancreatic cancer without family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancer precursor lesions have begun to elucidate the evolutionary history of pancreatic tumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic ductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.

5 Review A "Clearer" View of Pancreatic Pathology: A Review of Tissue Clearing and Advanced Microscopy Techniques. 2019

Hong, Seung-Mo / Noë, Michaël / Hruban, Carolyn A / Thompson, Elizabeth D / Wood, Laura D / Hruban, Ralph H. ·Departments of Pathology. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD. ·Adv Anat Pathol · Pubmed #30256228.

ABSTRACT: Although pathologic lesions in the pancreas are 3-dimensional (3D) complex structures, we currently use thin 2D hematoxylin and eosin stained slides to study and diagnose pancreatic pathology. Two technologies, tissue clearing and advanced microscopy, have recently converged, and when used together they open the remarkable world of 3D anatomy and pathology to pathologists. Advances in tissue clearing and antibody penetration now make even dense fibrotic tissues amenable to clearing, and light sheet and confocal microscopies allow labeled cells deep within these cleared tissues to be visualized. Clearing techniques can be categorized as solvent-based or aqueous-based techniques, but both clearing methods consist of 4 fundamental steps, including pretreatment of specimens, permeabilization and/or removal of lipid, immunolabeling with antibody penetration, and clearing by refractive index matching. Specialized microscopes, including the light sheet microscope, the 2-photon microscope, and the confocal microscope, can then be used to visualize and evaluate the 3D histology. Both endocrine and exocrine pancreas pathology can then be visualized. The application of labeling and clearing to surgically resected human pancreatic parenchyma can provide detailed visualization of the complexities of normal pancreatic anatomy. It also can be used to characterize the 3D architecture of disease processes ranging from precursor lesions, such as pancreatic intraepithelial neoplasia lesions and intraductal papillary mucinous neoplasms, to infiltrating pancreatic ductal adenocarcinomas. The evaluation of 3D histopathology, including pathology of the pancreatic lesions, will provide new insights into lesions that previously were seen, and thought of, only in 2 dimensions.

6 Review From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions. 2018

Fischer, Catherine G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #30105857.

ABSTRACT: Pancreatic cancer arises from noninvasive precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression. Perhaps more importantly, they also provide a rational foundation for early detection approaches that could allow clinical intervention prior to malignant transformation. In this review, we summarize the results of comprehensive molecular characterization of PanINs, IPMNs, and MCNs and discuss the implications for cancer biology as well as early detection. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

7 Review New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis. 2018

Felsenstein, Matthäus / Hruban, Ralph H / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Adv Anat Pathol · Pubmed #28914620.

ABSTRACT: Pancreatic cancer is an aggressive disease with a dismal prognosis in dire need of novel diagnostic and therapeutic approaches. The past decade has witnessed an explosion of data on the genetic alterations that occur in pancreatic cancer, as comprehensive next-generation sequencing analyses have been performed on samples from large cohorts of patients. These studies have defined the genomic landscape of this disease and identified novel candidates whose mutations contribute to pancreatic tumorigenesis. They have also clarified the genetic alterations that underlie multistep tumorigenesis in precursor lesions and provided insights into clonal evolution in pancreatic neoplasia. In addition to these important insights into pancreatic cancer biology, these large scale genomic studies have also provided a foundation for the development of novel early detection strategies and targeted therapies. In this review, we discuss the results of these comprehensive sequencing studies of pancreatic neoplasms, with a particular focus on how their results will impact the clinical care of patients with pancreatic cancer.

8 Review Genetic Syndromes with Pancreatic Manifestations. 2016

Pittman, Meredith E / Brosens, Lodewijk A A / Wood, Laura D. ·Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Starr 1031A, 525 East 68th Street, New York, NY 10065, USA. · Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, CRB2 Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Surg Pathol Clin · Pubmed #27926368.

ABSTRACT: Although the pancreas is affected by only a small fraction of known inherited disorders, several of these syndromes predispose patients to pancreatic adenocarcinoma, a cancer that has a consistently dismal prognosis. Still other syndromes are associated with neuroendocrine tumors, benign cysts, or recurrent pancreatitis. Because of the variability of pancreatic manifestations and outcomes, it is important for clinicians to be familiar with several well-described genetic disorders to ensure that patients are followed appropriately. The purpose of this review was to briefly describe the hereditary syndromes that are associated with pancreatic disorders and neoplasia.

9 Review Molecular Genetics of Pancreatic Neoplasms. 2016

Hosoda, Waki / Wood, Laura D. ·Department of Pathology, Johns Hopkins University, CRB-II 362, 1550 Orleans Street, Baltimore, MD 21231, USA. · Department of Pathology, Johns Hopkins University, CRB-II 345, 1550 Orleans Street, Baltimore, MD 21231, USA. Electronic address: ldelong1@jhmi.edu. ·Surg Pathol Clin · Pubmed #27926367.

ABSTRACT: Pancreatic neoplasms have a wide range of histologic types with distinct clinical outcomes. Recent advances in high-throughput sequencing technologies have greatly deepened our understanding of pancreatic neoplasms. Now, the exomes of major histologic types of pancreatic neoplasms have been sequenced, and their genetic landscapes have been revealed. This article reviews the molecular changes underlying pancreatic neoplasms, with a special focus on the genetic changes that characterize the histologic types of pancreatic neoplasms. Emphasis is also made on the molecular features of key genes that have the potential for therapeutic targets.

10 Review Pancreatic cancer. 2016

Kamisawa, Terumi / Wood, Laura D / Itoi, Takao / Takaori, Kyoichi. ·Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan. Electronic address: kamisawa@cick.jp. · The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, USA. · Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan. · Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. ·Lancet · Pubmed #26830752.

ABSTRACT: Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

11 Review Genetics of pancreatic neuroendocrine tumors: implications for the clinic. 2015

Pea, Antonio / Hruban, Ralph H / Wood, Laura D. ·a 1 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Expert Rev Gastroenterol Hepatol · Pubmed #26413978.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated.

12 Review Pancreatic adenocarcinoma pathology: changing "landscape". 2015

Brosens, Lodewijk A A / Hackeng, Wenzel M / Offerhaus, G Johan / Hruban, Ralph H / Wood, Laura D. ·1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·J Gastrointest Oncol · Pubmed #26261723.

ABSTRACT: Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.

13 Review Genomic landscapes of pancreatic neoplasia. 2015

Wood, Laura D / Hruban, Ralph H. ·The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol Transl Med · Pubmed #25812653.

ABSTRACT: Pancreatic cancer is a deadly disease with a dismal prognosis. However, recent advances in sequencing and bioinformatic technology have led to the systematic characterization of the genomes of all major tumor types in the pancreas. This characterization has revealed the unique genomic landscape of each tumor type. This knowledge will pave the way for improved diagnostic and therapeutic approaches to pancreatic tumors that take advantage of the genetic alterations in these neoplasms.

14 Review Pathological and molecular evaluation of pancreatic neoplasms. 2015

Rishi, Arvind / Goggins, Michael / Wood, Laura D / Hruban, Ralph H. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: rhruban@jhmi.edu. ·Semin Oncol · Pubmed #25726050.

ABSTRACT: Pancreatic neoplasms are morphologically and genetically heterogeneous and include a wide variety of tumors ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from the molecular and genetic perspectives.

15 Review Pancreatic cancer genomes: toward molecular subtyping and novel approaches to diagnosis and therapy. 2013

Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Weinberg 2242, 401 North Broadway, Baltimore, MD, 21231, USA, ldwood@jhmi.edu. ·Mol Diagn Ther · Pubmed #23757204.

ABSTRACT: Pancreatic neoplasms represent a broad range of clinical entities, many of which have drastic effects on the lives of patients. Recently, high-throughput sequencing analyses have been performed in many pancreatic neoplasms, providing deep insights into the underlying biology of these neoplasms as well as novel approaches to diagnosis and treatment. This review discusses the molecular alterations underlying pancreatic neoplasms as well as the clinical impact of these alterations for diagnosis and treatment.

16 Review Pathology and molecular genetics of pancreatic neoplasms. 2012

Wood, Laura D / Hruban, Ralph H. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Cancer J · Pubmed #23187835.

ABSTRACT: Cancer is fundamentally a genetic disease caused by the accumulation of somatic mutations in oncogenes and tumor suppressor genes. In the last decade, rapid advances in sequencing and bioinformatic technology led to an explosion in sequencing studies of cancer genomes, greatly expanding our knowledge of the genetic changes underlying a variety of tumor types. Several of these studies of cancer genomes have focused on pancreatic neoplasms, and cancers from the pancreas are some of the best characterized tumors at the genetic level. Pancreatic neoplasms encompass a wide array of clinical diseases, from benign cysts to deadly cancers, and the genetic alterations underlying neoplasms of the pancreas are similarly diverse. This new knowledge of pancreatic cancer genomes has deepened our understanding of tumorigenesis in the pancreas and has opened several promising new avenues for novel diagnostics and therapeutics.

17 Clinical Trial Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. 2013

Herman, Joseph M / Fan, Katherine Y / Wild, Aaron T / Hacker-Prietz, Amy / Wood, Laura D / Blackford, Amanda L / Ellsworth, Susannah / Zheng, Lei / Le, Dung T / De Jesus-Acosta, Ana / Hidalgo, Manuel / Donehower, Ross C / Schulick, Richard D / Edil, Barish H / Choti, Michael A / Hruban, Ralph H / Pawlik, Timothy M / Cameron, John L / Laheru, Daniel A / Wolfgang, Christopher L. ·Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA. jherma15@jhmi.edu ·Int J Radiat Oncol Biol Phys · Pubmed #23773391.

ABSTRACT: PURPOSE: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

18 Article Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. 2019

Riquelme, Erick / Zhang, Yu / Zhang, Liangliang / Montiel, Maria / Zoltan, Michelle / Dong, Wenli / Quesada, Pompeyo / Sahin, Ismet / Chandra, Vidhi / San Lucas, Anthony / Scheet, Paul / Xu, Hanwen / Hanash, Samir M / Feng, Lei / Burks, Jared K / Do, Kim-Anh / Peterson, Christine B / Nejman, Deborah / Tzeng, Ching-Wei D / Kim, Michael P / Sears, Cynthia L / Ajami, Nadim / Petrosino, Joseph / Wood, Laura D / Maitra, Anirban / Straussman, Ravid / Katz, Matthew / White, James Robert / Jenq, Robert / Wargo, Jennifer / McAllister, Florencia. ·Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Engineering, Texas Southern University, Houston, TX, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Departments of Medicine, Oncology and Molecular Microbiology & Immunology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, MD, USA. · Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. · Department of Pathology and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Resphera Biosciences, Baltimore, MD, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fmcallister@mdanderson.org. ·Cell · Pubmed #31398337.

ABSTRACT: Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

19 Article Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. 2019

Fischer, Catherine G / Beleva Guthrie, Violeta / Braxton, Alicia M / Zheng, Lily / Wang, Pei / Song, Qianqian / Griffin, James F / Chianchiano, Peter E / Hosoda, Waki / Niknafs, Noushin / Springer, Simeon / Dal Molin, Marco / Masica, David / Scharpf, Robert B / Thompson, Elizabeth D / He, Jin / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Lennon, Anne Marie / Jiao, Yuchen / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: karchin@jhu.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. ·Gastroenterology · Pubmed #31175866.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

20 Article Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. 2019

Eissa, Maryam A L / Lerner, Lane / Abdelfatah, Eihab / Shankar, Nakul / Canner, Joseph K / Hasan, Nesrin M / Yaghoobi, Vesal / Huang, Barry / Kerner, Zachary / Takaesu, Felipe / Wolfgang, Christopher / Kwak, Ruby / Ruiz, Michael / Tam, Matthew / Pisanic, Thomas R / Iacobuzio-Donahue, Christine A / Hruban, Ralph H / He, Jin / Wang, Tza-Huei / Wood, Laura D / Sharma, Anup / Ahuja, Nita. ·Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, Yale-New Haven Health, Yale University, School of Medicine, P.O. Box 208062, New Haven, CT, 06520-8062, USA. · Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. nita.ahuja@yale.edu. · Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. nita.ahuja@yale.edu. · The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA. nita.ahuja@yale.edu. · Department of Surgery, Yale-New Haven Health, Yale University, School of Medicine, P.O. Box 208062, New Haven, CT, 06520-8062, USA. nita.ahuja@yale.edu. ·Clin Epigenetics · Pubmed #30953539.

ABSTRACT: BACKGROUND: Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. RESULTS: Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71-0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63-0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77-0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90-0.98) compared to 57.1% for CA 19-9 alone. CONCLUSION: The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

21 Article Why is pancreatic cancer so deadly? The pathologist's view. 2019

Hruban, Ralph H / Gaida, Matthias M / Thompson, Elizabeth / Hong, Seung-Mo / Noë, Michaël / Brosens, Lodewijk Aa / Jongepier, Martine / Offerhaus, G Johan A / Wood, Laura D. ·Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of General Pathology, The University Hospital of Heidelberg, Heidelberg, Germany. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, The University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. ·J Pathol · Pubmed #30838636.

ABSTRACT: The remarkable aggressiveness of pancreatic cancer has never been fully explained. Although clearly multifactorial, we postulate that venous invasion, a finding seen in most pancreatic cancers but not in most cancers of other organs, may be a significant, underappreciated contributor to the aggressiveness of this disease. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

22 Article Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms. 2019

Skaro, Michael / Nanda, Neha / Gauthier, Christian / Felsenstein, Matthäus / Jiang, Zhengdong / Qiu, Miaozhen / Shindo, Koji / Yu, Jun / Hutchings, Danielle / Javed, Ammar A / Beckman, Ross / He, Jin / Wolfgang, Christopher L / Thompson, Elizabeth / Hruban, Ralph H / Klein, Alison P / Goggins, Michael / Wood, Laura D / Roberts, Nicholas J. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: nrobert8@jhmi.edu. ·Gastroenterology · Pubmed #30716324.

ABSTRACT: BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.

23 Article Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis. 2019

Luchini, Claudio / Veronese, Nicola / Nottegar, Alessia / Riva, Giulio / Pilati, Camilla / Mafficini, Andrea / Stubbs, Brendon / Simbolo, Michele / Mombello, Aldo / Corbo, Vincenzo / Cheng, Liang / Yachida, Shinichi / Wood, Laura D / Lawlor, Rita T / Salvia, Roberto / Scarpa, Aldo. ·National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," Castellana Grotte, Bari. · Department of Surgery, Section of Pathology, San Bortolo Hospital, Vicenza, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, Paris, France. · ARC-Net Research Center, University of Verona, Verona, Italy. · Health Service and Population Research Department, King's College London, London, United Kingdom. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN. · Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. ·Pancreas · Pubmed #30451797.

ABSTRACT: OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior.

24 Article Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. 2019

Kuboki, Yuko / Fischer, Catherine G / Beleva Guthrie, Violeta / Huang, Wenjie / Yu, Jun / Chianchiano, Peter / Hosoda, Waki / Zhang, Hao / Zheng, Lily / Shao, Xiaoshan / Thompson, Elizabeth D / Waters, Kevin / Poling, Justin / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #30430578.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

25 Article Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas. 2019

Amato, Eliana / Mafficini, Andrea / Hirabayashi, Kenichi / Lawlor, Rita T / Fassan, Matteo / Vicentini, Caterina / Barbi, Stefano / Delfino, Pietro / Sikora, Katarzyna / Rusev, Borislav / Simbolo, Michele / Esposito, Irene / Antonello, Davide / Pea, Antonio / Sereni, Elisabetta / Ballotta, Maria / Maggino, Laura / Marchegiani, Giovanni / Ohike, Nobuyuki / Wood, Laura D / Salvia, Roberto / Klöppel, Günter / Zamboni, Giuseppe / Scarpa, Aldo / Corbo, Vincenzo. ·ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, Tokai University School of Medicine, Isehara, Japan. · Institute of Pathology, Heinrich-Heine-University and University Hospital of Düsseldorf, Düsseldorf, Germany. · Department of Surgery, General Surgery B, University of Verona, Verona, Italy. · Section of Anatomic Pathology, Azienda Ospedaliera Rovigo, Rovigo, Italy. · Department of Pathology and Laboratory Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Technical University Munich, Munich, Germany. · Division of Pathology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy. ·J Pathol · Pubmed #30306561.

ABSTRACT: Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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