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8:00AM 11/13/2014 – Welcome from Gary Gottlieb, M.D., Partners HealthCare @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Posted in Academic Publishing, Conference Coverage with Social Media, Personalized and Precision Medicine & Genomic Research, Scientific & Biotech Conferences: Press Coverage, tagged Bioinformatics, Brigham and Women's Hospital, Children's Hospital of Philadelphia, computational genomics, curated database, Emory University School of Medicine, exons, Genomic Health, Health Information Technology, healthcare, healthIT, HIPAA, Information technology, laboratory medicine, Massachusetts General Hospital, Medical laboratory, Molecular Medicine, personalised medicine, Population Health Management, Public–private partnership, Whole genome sequencing on November 13, 2014| Leave a Comment »

8:00AM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

8:00 A.M. Welcome from Gary Gottlieb, M.D.

Opening Remarks:

Partners HealthCare is the largest healthcare organization in Massachusetts and whose founding members are Brigham and Women’s Hospital and Massachusetts General Hospital. Dr. Gottlieb has long been a supporter of personalized medicine and he will provide his vision on the role of genetics and genomics in healthcare across the many hospitals that are part of Partners HealthCare.

Opening Remarks and Introduction

Scott Weiss, M.D., M.S. @PartnersNews
Scientific Director, Partners HealthCare Personalized Medicine;
Associate Director, Channing Laboratory/
Professor of Medicine, Harvard Medical School @harvardmed

Welcome

Engine of innovations

lower cost – Accountable care
robust IT infrastructure on the Unified Medical Records
Lab Molecular Medicine and Biobanks
1. Lab Molecular medicine
2. Biobank
3. Translations Genomics: RNA Sequencing
4. Medical Records integration of coded diagnosis linked to Genomics

BIOBANKS – Samples and contact patients, return actionable procedures

LIFE STYLE SURVEY – supplements the medical record

GENOTYPING and SEQUENCING – less $50 per sequence available to researcher / investigators

RECRUITMENT – subject to biobank, own Consents – e-mail patient – consent online consenting — collects 16,000 patients per month – very successful Online Consent

LAB Molecular Medicine – CLIA — genomics test and clinical care – EGFR identified as a bio-marker to cancer in 3 month a test was available. Best curated medical exon databases Emory Genetics Lab (EMVClass) and CHOP (BioCreative and MitoMAP and MitoMASTER). Labs are renowned in pharmacogenomics and interpretability.

IT – GeneInsight – IT goal Clinicians empowered by a workflow geneticist assign cases, data entered into knowledge base, case history, GENEINSIGHT Lab — geneticists enter info in a codified way will trigger a report for the Geneticist – adding specific knowledge standardized report enters Medical Record. Available in many Clinics of Partners members.

Example: Management of Patient genetic profiles – Relationships built between the lab and the Clinician

Variety of Tools are in development

GenInsight Team –>> Pathology –>> Sunquest Relationship

Mass General (MGH) & Brigham Women’s (BWH) — Chart in EM will have the Genetic Profile of a Patients checking in

The Future

Genetic testing –>> other info (Pathology, Exams, Life Style Survey, Meds, Imaging) — Integrated Medical Record

Clinic of the Future-– >> Diagnostics – Genomics data and Variants integrated at the Clinician desk

Gary Gottlieb, M.D. @PartnersNews
President and CEO, Partners HealthCare

Translational Science

Partners 6,000 MDs, MGH – 200 years as Teaching Hospital of HMS, BWH – magnets in HealthCare

2001 – Center for Genomics was started at Partners, 2008 Genomics and Other Omis, Population Health, PM – Innovations at Partners.

Please Click on Link Video on 20 years of PartnersHealthcare

Video of Dr. Gottlieb at ECRI conference 2012

Why is personalized medicine important to Partners?

From Healthcare system to the Specific Human Conditions

Lab translate results to therapy
Biobank +50,000 specimens links to Medical Records of patients – relevant to Clinician, Genomics to Clinical Applications

Questions from the Podium

test results are not yet available online for patients
clinicians and liability – delays from Lab to decide a variant needs to be reclassified – alert is triggered. Lab needs time to accumulated knowledge before reporting a change in state.
Training Clinicians in above type of IT infrastructure: Labs around the Nations deal with VARIANT RECLASSIFICATION- physician education is a must, Clinicians have access to REFERENCE links.
All clinicians accessing this IT infrastructure — are trained. Most are not yet trained
Coordination within Countries and Across Nations — Platforms are Group specific – PARTNERS vs the US IT Infrastructure — Genomics access to EMR — from 20% to 70% Nationwide during the Years of the Obama Adm.
Shakeout in SW linking Genetic Labs to reach Gold Standard

Click to see Advanced Medical Education Partners Offers

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

@PartnersNews

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Drug Delivery Platform Technology, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Devices R&D Investment, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged American Heart Association, Aviva Lev-Ari, Calcium-Channel Blocker, Cardiac Gene, gene therapy, Hajjar, Harvard Medical School, Heart Failure, Johns Hopkins University, Larry H. Bernstein, Massachusetts General Hospital, Mount Sinai, Pulmonary hypertension, Roger J. Hajjar, Vascular smooth muscle on August 1, 2013| 27 Comments »

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Curator: Aviva Lev-Ari, PhD, RN

Image created by Adina Hazan 06/30/2021

This article is Part VI in a Series of articles on Calcium Release Mechanism, the series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD  and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

This article has THREE parts:

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

The following two discoveries in Cardiac Gene Therapies represent the FRONTIER IN CARDIOLOGY for 2012 – 2013: Solution Advancement for Improving Myocardial Contractility

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Roger J. Hajjar, MD, a pioneering Mount Sinai researcher who has published cutting-edge studies on heart failure, has been named the recipient of the 2013 BCVS Distinguished Achievement Award by theAmerican Heart Association and the Council on Basic Cardiovascular Sciences. Dr. Hajjar, who is The Arthur and Janet C. Ross Professor of Medicine and Director of The Helmsley Trust Translational Research Center, will be honored at the American Heart Association’s Scientific Sessions Annual Conference later this year.

“Dr. Hajjar will receive the award for his groundbreaking contributions to developing gene therapy treatments for cardiac disease,” says Joshua Hare, MD, who is President-elect of the Council on Basic Cardiovascular Sciences. He will also be recognized for his work on behalf of the Council.

Over the years, Dr. Hajjar’s laboratory has made important basic science discoveries that were translated into clinical trials. Most recently, Dr. Hajjar and his researchers identified a possible new drug target for treating or preventing heart failure. Says Mark A. Sussman, PhD, a former president of the Council, “Dr. Hajjar was among the first, and certainly the most successful, in combining gene therapy and treatment of heart failure. He shows a relentless pursuit of translating basic science into real-world treatment of heart disease.”

This article was first published in Inside Mount Sinai.

http://blog.mountsinai.org/blog/roger-j-hajjar-md-to-be-honored-for-research/

John Hopkins, Distinguished Alumnus Award 2011

Roger J. Hajjar, Engr ’86
Dr. Roger Hajjar received his bachelor’s degree in biomedical engineering from Johns Hopkins University in 1986. A cardiologist and translational scientist, he is a leader in gene therapy techniques and model testing for cardiovascular diseases. Dr. Hajjar is professor of medicine and cardiology, and professor of gene and cell medicine at Mount Sinai Medical Center in New York, as well as research director of Mount Sinai’s Wiener Family Cardiovascular Research Laboratories. Dr. Hajjar was recruited to Mt. Sinai from Harvard Medical School where he was assistant professor of medicine and staff cardiologist in the Heart Failure & Cardiac Transplantation Center. He received his medical degree from Harvard Medical School and trained in internal medicine and cardiology at Massachusetts General Hospital in Boston. Dr. Hajjar has concentrated his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques in the heart to improve contractility. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis. Dr. Hajjar has significant expertise in gene therapy. In 1996, he won the Young Investigator Award of the American Heart Association (Council on Circulation). In 1999, Dr. Hajjar was awarded the prestigious Doris Duke Clinical Scientist award and won first prize at the Astra Zeneca Young Investigator Forum. Dr. Hajjar holds a number of NIH grants.

http://alumni.jhu.edu/distinguishedalumni2011

Dr Hajjar is the Director of the Cardiovascular Research Center, and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai School of Medicine, New York, NY. He received his BS in Biomedical Engineering from Johns Hopkins University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences & Technology. He completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Dr. Hajjar is an internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr Hajjar’s research has been recognized with the initiation and recent successful completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance.

Prior to joining Mount Sinai, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital.

Dr. Hajjar has won numerous awards and distinctions, including the Young Investigator Award of the American Heart Association. He was awarded a Doris Duke Clinical Scientist award and has won first prize at the Astra Zeneca Young Investigator Forum. He is a member of the American Society for Clinical Investigation. He was recently awarded the Distinguished Alumnus Award from Johns Hopkins University and the Mount Sinai Dean’s award for Excellence in Translational Science. He has authored over 260 peer-reviewed publications.

http://heart.sdsu.edu/~website/IRRI/Pages/faculty/roger-hajjar-md.html

Meet the Director of Mount Sinai’s Cardiovascular Research Center

“Cardiovascular diseases are the number one cause of death globally. In order to tackle them in all aspects, we must unite improved diagnostic techniques with more refined therapies.”

Roger J. Hajjar, MD, Director of the Cardiovascular Research Center, the Arthur & Janet C. Ross Professor of Medicine, Professor of Gene & Cell Medicine, Director of the Cardiology Fellowship Program, and Co-Director of the Transatlantic Cardiovascular Research Center, which combines Mount Sinai Cardiology Laboratories with those of the Universite de Paris – Madame Curie.

In the late 1990s, the possibility that discoveries in genetics and genomics could have a positive impact on the diagnosis, treatment, and prevention of cardiovascular diseases seemed to be just a distant promise. Today, a little more than a decade later, the promise is beginning to take shape. Roger J. Hajjar, MD and his multidisciplinary team of investigators are beginning to translate scientific findings into real therapies for cardiovascular diseases. As Director of the Cardiovascular Research Institute and a cardiologist by training, Dr. Hajjar guides the growth of a cutting-edge translational research laboratory, which is positioning Mount Sinai as the leader in cardiovascular genomics.

An internationally recognized scientific leader in the field of cardiac gene therapy for heart failure, Dr. Hajjar is expanding studies of the basic mechanisms of cardiac diseases and identification of high-risk groups and genomic predictors so that they can be part of the daily clinical care of patients. Unique biorepositories combined with cardiovascular areas of excellence across Mount Sinai make possible crucial genetic studies.

First Gene Therapy for Heart Failure

Under Dr. Hajjar’s leadership, the Cardiovascular Research Center has already developed the world’s first potential gene therapy for heart failure. Known as AAV1.SERCA2a, this therapy actually revives heart tissue that has stopped working properly. It has led to new treatment possibilities for patients with advanced heart failure, whose options used to be severely limited. The significance of this research has been recognized with the initiation and successful completion Phase 1 and Phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure. Phase 3 validation begins in 2011.

The Cardiovascular Research Center’s next research projects, already underway, focus on using novel gene therapy vectors to target diastolic heart failure, ventricular arrhythmias, pulmonary hypertension, and myocardial infarctions.

In addition to targeting signaling pathways to aid failing heart cells, ongoing work at the Cardiovascular Research Center involves studying how to block signaling pathways in cardiac hypertrophy as well as apoptosis. The laboratory team is also targeting a number of signaling pathways in the aging heart to improve dystolic function.

Prior to joining Mount Sinai in 2007, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital. After earning a bachelors of science degree in Biomedical Engineering from Johns Hopkins University and a medical degree from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology, he completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

http://icahn.mssm.edu/research/centers/cardiovascular-research-center/meet-the-director

Scientific Advisors

Roger J. Hajjar, MD, Co-Founder and a Scientific Advisor of Celladon Co, plans to commercialize AAV1.SERCA2a for the treatment of heart failure.
Dr. Roger J. Hajjar is the Director of the Cardiovascular Research Center at the Mt. Sinai School of Medicine. Previously, he was the Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has an active basic science laboratory and concentrates his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques targeting the heart as a therapeutic modality to improve contractility in heart failure. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis.

http://www.celladon.net/about-us/scientific-advisors

Gene Therapy: Volume 19, Issue 6 (June 2012)

Special Issue: Cardiovascular Gene Therapy

Guest Editor

Roger J Hajjar MD, Mount Sinai School of Medicine, New York, NY Director, Cardiovascular Research Institute, Arthur & Janet C Ross Professor of Medicine

REVIEWS

SDF-1 in myocardial repair

M S Penn, J Pastore, T Miller and R Aras

Gene Ther 19: 583-587; doi:10.1038/gt.2012.32

Abstract | Full Text | PDF

Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?

R A Li

Gene Ther 19: 588-595; doi:10.1038/gt.2012.33

Abstract | Full Text | PDF

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

J-S Hulot, G Senyei and R J Hajjar

Gene Ther 19: 596-599; advance online publication, May 17, 2012; doi:10.1038/gt.2012.34

Abstract | Full Text | PDF

Gene therapy for ventricular tachyarrhythmias

J K Donahue

Gene Ther 19: 600-605; advance online publication, April 26, 2012; doi:10.1038/gt.2012.35

Abstract | Full Text | PDF

Prospects for gene transfer for clinical heart failure

T Tang, M H Gao and H Kirk Hammond

Gene Ther 19: 606-612; advance online publication, April 26, 2012; doi:10.1038/gt.2012.36

Abstract | Full Text | PDF

Targeting S100A1 in heart failure

J Ritterhoff and P Most

Gene Ther 19: 613-621; advance online publication, February 16, 2012; doi:10.1038/gt.2012.8

Abstract | Full Text | PDF

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

M Giacca and S Zacchigna

Gene Ther 19: 622-629; advance online publication, March 1, 2012; doi:10.1038/gt.2012.17

Abstract | Full Text | PDF

Vein graft failure: current clinical practice and potential for gene therapeutics

S Wan, S J George, C Berry and A H Baker

Gene Ther 19: 630-636; advance online publication, March 29, 2012; doi:10.1038/gt.2012.29

Abstract | Full Text | PDF

Percutaneous methods of vector delivery in preclinical models

D Ladage, K Ishikawa, L Tilemann, J Müller-Ehmsen and Y Kawase

Gene Ther 19: 637-641; advance online publication, March 15, 2012; doi:10.1038/gt.2012.14

Abstract | Full Text | PDF

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function

E Di Pasquale, M V G Latronico, G S Jotti and G Condorelli

Gene Ther 19: 642-648; advance online publication, March 1, 2012; doi:10.1038/gt.2012.19

Abstract | Full Text | PDF

Intracellular transport of recombinant adeno-associated virus vectors

M Nonnenmacher and T Weber

Gene Ther 19: 649-658; advance online publication, February 23, 2012; doi:10.1038/gt.2012.6

Abstract | Full Text | PDF

Gene delivery technologies for cardiac applications

M G Katz, A S Fargnoli, L A Pritchette and C R Bridges

Gene Ther 19: 659-669; advance online publication, March 15, 2012; doi:10.1038/gt.2012.11

Abstract | Full Text | PDF

Cardiac gene therapy in large animals: bridge from bench to bedside

K Ishikawa, L Tilemann, D Ladage, J Aguero, L Leonardson, K Fish and Y Kawase

Gene Ther 19: 670-677; advance online publication, February 2, 2012; doi:10.1038/gt.2012.3

Abstract | Full Text | PDF

Progress in gene therapy of dystrophic heart disease

Y Lai and D Duan

Gene Ther 19: 678-685; advance online publication, February 9, 2012; doi:10.1038/gt.2012.10

Abstract | Full Text | PDF

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

J Reinkober, H Tscheschner, S T Pleger, P Most, H A Katus, W J Koch and P W J Raake

Gene Ther 19: 686-693; advance online publication, February 16, 2012; doi:10.1038/gt.2012.9

Abstract | Full Text | PDF

Directed evolution of novel adeno-associated viruses for therapeutic gene delivery

M A Bartel, J R Weinstein and D V Schaffer

Gene Ther 19: 694-700; advance online publication, March 8, 2012; doi:10.1038/gt.2012.20

Abstract | Full Text | PDF

http://www.nature.com/gt/journal/v19/n6/index.html

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Public release date: 30-Jul-2013

Contact: Lauren Woods
lauren.woods@mountsinai.org
212-241-2836
The Mount Sinai Hospital / Mount Sinai School of Medicine

Inhalable gene therapy may help pulmonary arterial hypertension patients

Gene therapy when inhaled may restore function of a crucial enzyme in the lungs to reverse deadly PAH

The deadly condition known as pulmonary arterial hypertension (PAH), which afflicts up to 150,000 Americans each year, may be reversible by using an inhalable gene therapy, report an international team of researchers led by investigators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

In their new study, reported in the July 30 issue of the journal Circulation, scientists demonstrated that gene therapy administered through a nebulizer-like inhalation device can completely reverse PAH in rat models of the disease. In the lab, researchers also showed in pulmonary artery PAH patient tissue samples reduced expression of the SERCA2a, an enzyme critical for proper pumping of calcium in calcium compartments within the cells. SERCA2a gene therapy could be sought as a promising therapeutic intervention in PAH.

“The gene therapy could be delivered very easily to patients through simple inhalation — just like the way nebulizers work to treat asthma,” says study co-senior investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine and Professor of Gene & Cell at Icahn School of Medicine at Mount Sinai. “We are excited about testing this therapy in PAH patients who are in critical need of intervention.”

This same SERCA2a dysfunction also occurs in heart failure. This new study utilizes the same gene therapy currently being tested in patients to reverse congestive heart failure in a large phase III clinical trial in the United States and Europe.

“What we have shown is that gene therapy restores function of this crucial enzyme in diseased lungs,” says Dr. Hajjar. “We are delighted with these new findings because it suggests that a gene therapy that is already showing great benefit in congestive heart failure patients may be able to help PAH patients who currently have no good treatment options — and are in critical need of a life sustaining therapy.”

When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. According to researchers, the delivery of the SERCA2a gene produces SERCA2a enzymes, which helps both heart and lung cells restore their proper use of calcium.

“We are now on a path toward PAH patient clinical trials in the near future,” says Dr. Hajjar, who developed the gene therapy approach. Studies in large animal models are now underway. SERCA2a gene therapy has already been approved by the National Institutes of Health for human study.

A Simple Inhalation Corrects Deadly Dysfunction

PAH most commonly results from heart failure in the left side of the heart or from a pulmonary embolism, when clots in the legs travel to the lungs and cause blockages. When the lung is damaged from these conditions, the tissue starts to quickly produce new and enlarged cells, which narrows pulmonary arteries. This increases the pressure inside them. The high pressure in these arteries resists the heart’s effort to pump through them and the blood flow between the heart and lungs is reduced. The right side of the heart then must overcome the resistance and work harder to push the blood through the pulmonary arteries into the lungs. Over time, the right ventricle becomes thickened and enlarged and heart failure develops.

The gene therapy that Dr. Hajjar developed uses a modified adeno-associated viral-vector that is derived from a parvovirus. It works by introducing a healthy SERCA2a gene into cells, but this gene does not incorporate into a patient’s chromosome, according to the study’s lead author, Lahouaria Hadri, PhD, an Instructor of Medicine in Cardiology at Icahn School of Medicine at Mount Sinai.

“The clinical trials in congestive heart failure have shown already that the gene therapy is very safe,” says Dr. Hadri. Between 40-50 percent of individuals have antecedent antibodies to the adeno-associated vectors, so potential patients need to be screened before gene therapy to make sure they are eligible to receive the vectors. In patients without antibodies, the restorative enzyme gene therapy does not cause an immune response, according to Dr. Hadri.

The clinical application of the gene therapy for patients with PAH will most likely differ from those with heart failure. The replacement gene needs to be injected through the coronary arteries of heart failure patients using catheters, while in PAH patients, the gene will need to be administered through inhalation.

This study was supported by National Institutes of Health grants (K01HL103176, K08111207, R01 HL078691, HL057263, HL071763, HL080498, HL083156, and R01 HL105301).

Other study co-authors include Razmig G. Kratlian, MD, Ludovic Benard, PhD, Kiyotake Ishikawa, MD, Jaume Aguero, MD, Dennis Ladage, MD, Irene C.Turnbull, MD, Erik Kohlbrenner, BA, Lifan Liang, MD, Jean-Sébastien Hulot, MD, PhD, and Yoshiaki Kawase, MD, from Icahn School of Medicine at Mount Sinai; Bradley A. Maron, MD and the study’s co-senior author Jane A. Leopold, MD, from Brigham and Women’s Hospital and Harvard Medical School in Boston, MA; Christophe Guignabert, PhD, from Hôpital Antoine-Béclère, Clamart, France; Peter Dorfmüller, MD, PhD, and Marc Humbert, MD, PhD, both of the Hôpital Antoine-Béclère and INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; Borja Ibanez, MD, from Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain; and Krisztina Zsebo, PhD, of Celladon Corporation, San Diego, CA.

Dr. Hajjar and co-author Dr. Zsebo, have ownership interest in Celladon Corporation, which is developing AAV1.SERCA2a for the treatment of heart failure. Also,
Dr. Hajjar and co-authors Dr. Kawase and Dr. Ladage hold intellectual property around SERCA2a gene transfer as a treatment modality for PAH. In addition,
co-author Dr. Maron receives funding from Gilead Sciences, Inc. to study experimental pulmonary hypertension.
Other study co-authors have no financial interests to declare.

Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension

+Author Affiliations

From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.H., R.G.K., L.B., D.L., K.I., J.A., I.C.T., E.K., L.L., J.-S.H., Y.K., R.J.H.); Cardiovascular Medicine Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (B.A.M., J.A.L.); Hôpital Antoine-Béclère, Clamart, France (P.D., C.G., M.H.); INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France (P.D., M.H.); Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain (B.I.); and Celladon Corporation, San Diego, CA (K.Z.).

Correspondence to Lahouaria Hadri, PhD, Cardiovascular Research Center, Box 1030, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York, NY 10029. E-mail lahouaria.hadri@mssm.edu

Abstract

Background—Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) and alterations in Ca²⁺homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.

Methods and Results—SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline.

Conclusions—Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.

Key Words:

Received January 24, 2013.
Accepted June 13, 2013.

http://circ.ahajournals.org/content/128/5/512.abstract?sid=9b3b4fcc-e158-4e5d-bb8b-125586e2ec12

Circulation.2013; 128: 512-523 Published online before print June 26, 2013,doi: 10.1161/CIRCULATIONAHA.113.001585

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

Etiology of Heart Failure

Alcoholic
Hypertensive
Idiopathic
Inflammatory
Ischemic
Pregnancy-related
Toxic
Valvular Heart DIsease

Administration of Cardiac Gene Therapy for Heart Failure: via Percutaneous Intra-coronary Artery Infusion

Gene delivery to viable myocardium

dominance and coronary artery anatomy from angiography determines infusion scenario

Antegrade epicardial coronary artery infusion over 10 minutes

60 mL divided into 1,2,3 infusions depending on anatomy

Delivered via commercially available angiographic injection system & guide or diagnostic catheters

Dr. Roger J. Hajjar of the Mount Sinai School of Medicine will present at the ASGCT 15th Annual Meeting during a Scientific Symposium entitled: Cell and Gene Therapy in Cardiovascular Disease on Wednesday, May 16, 2012 at 8:00 am. Below is a brief preview of his presentation.

Roger J. Hajjar, MD

Mount Sinai School of Medicine

New York, NY

Novel Developments in Gene Therapy for Cardiovascular Diseases

Chronic heart failure is a leading cause of hospitalization affecting nearly 6 million people in the U.S. with 670,000 new cases diagnosed every year. Heart failure leads to about 280,000 deaths annually.

Congestive heart failure remains a progressive disease with a desperate need for innovative therapies to reverse the course of ventricular dysfunction. The most common symptoms of heart failure are shortness of breath, feeling tired and swelling in the ankles, feet, legs and sometimes the abdomen. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies.

One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which controls Ca2+ handling in cardiac myocytes on a beat to beat basis. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a).

Over the last ten years we have undertaken a program of targeting important calcium cycling proteins in experimental models of heart by somatic gene transfer. This has led to the completion of a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated vector (AAV) type 1 carrying SERCA2a. In this Phase I trial, there was evidence of clinically meaningful improvements in functional status and/or cardiac function which were observed in the majority of patients at various time points. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation and recent completion of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients. In the phase 2 trial, gene transfer of SERCA2a was found to be safe and associated with benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure.

The 12 month data presented showed that heart failure, which is a progressive disease, became stabilized in high dose AAV1.SERCA2a-treated patients: heart failure symptoms, exercise tolerance, serum biomarkers and cardiac function essentially improved or remained the same while these parameters deteriorated substantially in patients treated with placebo and concurrent optimal drug and device therapy. More recently, the 2-year CUPID data from long-term follow-up demonstrate a durable benefit in preventing major cardiovascular events.

The recent successful and safe completion of the CUPID trial along with the start of more recent phase 1 trials usher a new era for gene therapy for the treatment of heart failure. Furthermore, novel AAV derivatives with high cardiotropism and resistant to neutralizing antibodies are being developed to target a large number of cardiovascular diseases.

http://www.execinc.com/hosted/emails/asgct/file/Hajjar2(1).pdf

Power Point Presentation on Cardiac Gene Therapy –

VIEW SLIDE SHOW

http://my.americanheart.org/idc/groups/heart-public/@wcm/@global/documents/downloadable/ucm_311680.pdf

Gene Therapy for Heart Failure

+Author Affiliations

From the Cardiovascular Research Center, Mount Sinai Medical Center, New York, NY.

Correspondence to Roger J. Hajjar, MD, Mount Sinai Medical Center, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail roger.hajjar@mssm.edu

Abstract

Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today’s science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.

http://circres.ahajournals.org/content/110/5/777.abstract

Circulation Research.2012; 110: 777-793 doi: 10.1161/CIRCRESAHA.111.252981

Key Words:

Received December 8, 2011.
Revision received January 29, 2012.
Accepted January 30, 2012.

Conclusions

With a better understanding of the molecular mechanisms associated with heart failure and improved vectors with cardiotropic properties, gene therapy can now be considered as a viable adjunctive treatment to mechanical and pharmacological therapies for heart failure. In the coming years, more targets will emerge that are amenable to genetic manipulations, along with more advanced vector systems, which will undoubtedly lead to safer and more effective clinical trials in gene therapy for heart failure.

http://circres.ahajournals.org/content/110/5/777.full.pdf+html

Figure 1.

AAV entry. 1 indicates receptor binding and endocytosis; 2, escape into cytoplasm; 3, nuclear import; 4, capsid disassembly; 5, double-strand synthesis; and 6, transcription.

Figure 2.

Generation of mutant AAV library and directed evolution to identify cardiotropic AAVs. A, Creation of a library of AAVs through DNA shuffling.B, Selection of cardiotropic AAVs through directed evolution.

Figure 3.

Antegrade coronary artery infusion. A, Coronary artery infusion. The vector is injected through a catheter without interruption of the coronary flow. B, Coronary artery infusion with occlusion of a coronary artery: The vector is injected through the lumen of an inflated angioplasty catheter. C, Coronary artery infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected through an inflated angioplasty catheter and resides in the coronary circulation until both balloons are deflated.

Figure 4.

V-Focus system and retrograde coronary venous infusion. A, Recirculating antegrade coronary artery infusion: The vector is injected into a coronary artery, collected from the coronary sinus and after oxygenation readministered into the coronary artery. B, Retrograde coronary venous infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected into a coronary vein and resides in the coronary circulation until both balloons are deflated.

Figure 5.

Direct myocardial injection and pericardial injection. A, Percutaneous myocardial injection: The vector is injected with an injection catheter via an endocardial approach.B, Surgical myocardial injection: The vector is injected via an epicardial approach. C, Percutaneous pericardial injection: The vector is injected via a substernal approach.

Figure 6.

Excitation-contraction coupling in cardiac myocytes provides multiple targets for gene therapy.

SOURCE

http://circres.ahajournals.org/content/110/5/777.figures-only

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Improved Results for Treatment of Persistent type 2 Endoleak after Endovascular Aneurysm Repair: Onyx Glue Embolization

Posted in Cardiac & Vascular Repair Tools Subsegment, Carotid Artery, Cerebrovascular and Neurodegenerative Diseases, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Adhesive, Aneurysm, Boston, Coronary artery disease, Dimethyl sulfoxide, Drug-eluting stent, Endovascular aneurysm repair, EVOH, Harvard Medical School, Massachusetts General Hospital, onyx on June 28, 2013| 4 Comments »

Improved Results for Treatment of Persistent type 2 Endoleak after Endovascular Aneurysm Repair: Onyx Glue Embolization

Writer, Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This report is an evaluation of onyx glue use in endovascular aneurysm repair. Onyx® is a non-adhesive liquid embolic agent used for the pre-surgical embolization of brain Arteriovenous malformations (bAVM).

Onyx is comprised of EVOH (ethylene vinyl alcohol) copolymer dissolved in DMSO (dimethyl sulfoxide), and suspended micronized tantalum powder to provide contrast for visualization under fluoroscopy.

A DMSO compatible delivery micro catheter that is indicated for use in the neuro vasculature (e.g. Marathon™, Rebar® or UltraFlow™ HPC catheters) is used to access the embolization site.

Onyx is available in two product formulations, Onyx 18 (6% EVOH) and Onyx 34 (8% EVOH).

http://www.ev3.net/assets/002/5231_w600h.jpg

Improved results using Onyx glue for the treatment of persistent type 2 endoleak after endovascular aneurysm repair.

Abularrage CJ, Patel VI, Conrad MF, Schneider EB, Cambria RP, Kwolek CJ

Division of Vascular and Endovascular Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA.

J Vasc Surg. 2012 Sep;56(3):630-6. http://dx.doi.org/10.1016/j.jvs.2012.02.038. Epub 2012 May 8.

Persistent type 2 (PT2) endoleaks (present ≥ 6 months) after endovascular aneurysm repair are associated with adverse outcomes, and

selective secondary intervention is indicated in those patients with an expanding aneurysm sac.

This study evaluated the outcomes of secondary intervention for PT2.

From 1999 to 2007, 136 patients who underwent endovascular aneurysm repair developed PT2 and comprised the study cohort. Primary end points included

PT2 resolution (secondary interventional success) and
survival

both were evaluated using multiple logistic regression and Kaplan-Meier analyses

Fifty-one patients underwent a total of 68 secondary interventions for PT2 with expanding aneurysm sacs

with a median postsecondary interventional follow-up of 13.7 months.

Secondary interventions included

20 inferior mesenteric artery coil embolizations,
17 Onyx glue embolizations,
11 aneurysm sac coil embolizations,
10 non-Onyx glue embolizations,
7 lumbar artery coil embolizations,
2 open lumbar ligations, and 1 graft explant.

The overall secondary interventional success rate was 43% (29 of 68). Onyx glue embolization was associated with

a greater success rate when used as the initial secondary intervention (odds ratio, 59.61; 95% confidence interval, 4.78-742.73; P < .001).

There was no difference in success between the different techniques when multiple secondary interventions were required. Five-year survival was 72% ± 0.08% and

was unrelated to any of the secondary interventional techniques.

Secondary intervention for PT2 is associated with success in less than half of all cases. Onyx glue embolization was associated with greater long-term success

when used as the initial secondary intervention.

The EVAR I trial: Endovascular vs. open abdominal aortic aneurysm repair [Classics Series] (2minutemedicine.com)
Brain aneurysm treatments now have fewer complications, better outcomes (miamiherald.com)
Super Glue Used to Seal Aneurysm in Baby’s Brain (ktla.com)
The EVAR II trial: Endovascular approach when unfit for open aortic aneurysm repair [Classics Series] (2minutemedicine.com)
Red Vascular Branch Endograft System: Aortic Aneursysm (proteinbreak.wordpress.com)
ArterioVenous Malformation of the brain (pathologycloud.wordpress.com)

http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

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Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD) (larryhbern)

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Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve (larryhbern)

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Endovascular repair of cerebral aneurysm. (Photo credit: Wikipedia)

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Effect of Hospital Characteristics on Outcomes of Endovascular Repair of Descending Aortic Aneurysms in US Medicare Population

Posted in Cardiac & Vascular Repair Tools Subsegment, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, Thoracic Aorta, tagged Aneurysm, Endovascular aneurysm repair, Harvard Medical School, Invasiveness of surgical procedures, Massachusetts General Hospital, University of Pittsburgh Medical Center, Vascular surgery on June 27, 2013| 5 Comments »

Effect of Hospital Characteristics on Outcomes of Endovascular Repair of Descending Aortic Aneurysms in US Medicare Population

Writer and Curator: Larry H. Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Impact of hospital volume and type on outcomes of open and endovascular repair of descending thoracic aneurysms in the United States Medicare population.

Patel VI, Mukhopadhyay S, Ergul E, Aranson N, …., Cambria RP.

Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Journal of vascular surgery 2013; http://dx.doi.org/10.1016/j.jvs.2013.01.035

Open surgery for thoracic aortic aneurysm has had success, but it carries complication risks. In 2004, a much less invasive procedure, thoracic endovascular repair (TEVAR) was introduced. It eliminated a need for open surgery in many patients, but not all were suitable candidtes . The advances in endovascular technology and procedural breakthroughs since it was introduced has contributed to a dramatic transformation of the specialty of thoracic aortic surgery. The decision of which patients require open surgery is necessarily determined by the limitations of the procedure and the condition of the patient.

Thoracic endovascular aortic repair (TEVAR) is a minimally invasive alternative to conventional open surgical reconstruction for the treatment of thoracic aortic aneurysm. TEVAR procedures can be challenging and, at times, extraordinarily difficult. Meticulous assessment of anatomy and preoperative procedure planning are absolutely paramount to produce optimal outcomes. The rapidly Increased use of TEVAR has produced favorable outcomes of TEVAR compared with open abdominal repair for descending thoracic aortic aneurysms (DTAs). But the success of these procedure depends on requisite skills, and following guidelines intended for use in quality-improvement programs that assess the standard of care expected from all physicians who perform TEVAR procedures.

Currently, there is a diverse array of endografts that are commercially available to treat the thoracic aorta. Multiple studies have demonstrated excellent outcomes of thoracic endovascular aortic repair for the treatment of thoracic aortic aneurysms, with less reported perioperative morbidity and mortality in comparison with conventional open repair. Additionally, similar outcomes have been demonstrated for the treatment of type B dissections. However, the technology remains relatively novel, and larger studies with longer term outcomes are necessary to more fully evaluate the role of endovascular therapy for the treatment of thoracic aortic disease.

The MGH/Partners vascular surgeons evaluated the effect of case volume and hospital teaching status on clinical outcomes of intact DTA repair to gain an insight into whether there was a variability in DTAs outcomes based on hospital size, patient mix, number of procedures, staff characteristics, and teaching status. This study was needed for establishing the type of procedure most suited to the type of patient, and to obtain the most accurate analysis of cost requirements based on resource allocation for reimbursement purposes.

The Medicare Provider Analysis and Review (MEDPAR) data set (2004 to 2007) was queried to identify open repair or TEVAR for DTA. Hospitals were stratified by DTA volume into high volume (HV; ≥8 cases/y) or low volume (LV; <8 cases/y) and teaching or nonteaching. The effect of hospital variables on the primary study end point of 30-day mortality and secondary end points of 30-day complications and long-term survival after open repair and TEVAR DTA repair were studied using univariate testing, multivariable regression modeling, Kaplan-Meier survival analysis, and Cox proportional hazards regression modeling.

They identified 763 hospitals performing 3554 open repairs and 3517 TEVARs. Overall DTA repair increased (P < .01) from 1375 in 2004 to 1987 in 2007. The proportion of hospitals performing open repair significantly decreased from 95% in 2004 to 57% in 2007 (P < .01), whereas

those performing TEVAR increased (P < .01) from 24% to 76%.

Overall repair type shifted from open (74% in 2004, the year before initial commercial availability of TEVAR) to TEVAR (39% open in 2007; P < .01). The fraction of open repairs at LV hospitals

decreased from 56% in 2004 to 44% in 2007 (P < .01), whereas
TEVAR increased from 24% in 2004 to 51% in 2007 (P < .01).

Overall mortality during the study interval for

open repair was 15% at LV hospitals vs 11% at HV hospitals (P < .01), whereas
TEVAR mortality was similar, at 3.9% in LV vs 5.5% in HV hospitals (P = .43).

LV was independently associated with increased mortality after open repair (odds ratio, 1.4; 95% confidence interval, 1.1-1.8; P < .01) but not after TEVAR. There was no independent effect of hospital teaching status on mortality or complications after open repair or TEVAR repair.

The total number of DTA repairs significantly increased after the introduction of TEVAR for DTA. Operative mortality for TEVAR is independent of hospital volume and type, whereas

mortality after open surgery is lower at HV hospitals.

While the TEVAR mortality is significantly less than that of open surgery, the mortality in open surgery is higher for LV hospitals. The data suggests that TEVAR can be safely performed across a spectrum of hospitals, whereas open surgery should be performed only at HV hospitals.

Standard of Practice for the Endovascular Treatment of Thoracic Aortic Aneurysms and Type B Dissections. Fanelli F, and Dake MD. Cardiovasc Intervent Radiol. 2009 September; 32(5): 849–860. http://dx.doi.org/10.1007/s00270-009-9668-6 PMCID: PMC2744786
Thoracic aortic aneurysms and dissections: endovascular treatment. Baril DT, Cho JS, Chaer RA, Makaroun MS. Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. Mt Sinai J Med. 2010 May-Jun;77(3):256-69. http://dx.doi.org/10.1002/msj.20178.

No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it? (pharmaceuticalintelligence.com)
Elective Open Suprarenal Aneurysm Repair in England from 2000 to 2010 an Observational Study of Hospital Episode Statistics (plosone.org)
Abdominal Aortic Aneurysms (AAA): Albert Einstein’s Operation by Dr. Nissen (pharmaceuticalintelligence.com)
Abdominal Aortic Aneurysm Genetic Risk (23andme.com)
The EVAR I trial: Endovascular vs. open abdominal aortic aneurysm repair [Classics Series] (2minutemedicine.com)
Revascularization Procedures Saving Limbs Of More Peripheral Arterial Disease Patients (medicalnewstoday.com)
Brain aneurysm treatments now have fewer complications, better outcomes (miamiherald.com)
The EVAR II trial: Endovascular approach when unfit for open aortic aneurysm repair [Classics Series] (2minutemedicine.com)
SNPwatch: Three New Genetic Variants Associated with Brain Aneurysm Identified (23andme.com)

Abdominal Aortic Aneurysms (AAA): Albert Einstein’s Operation by Dr. Nissen

Posted in Abdominal Aorta, Cardiac and Cardiovascular Surgical Procedures, tagged Abdominal aortic aneurysm, Albert Einstein, Einstein, Massachusetts General Hospital, Nissen, Sunao Tawara on June 11, 2013| 2 Comments »

Abdominal Aortic Aneurysms (AAA): Albert Einstein’s Operation by Dr. Nissen

Reporter: Aviva Lev-Ari, PhD, RN

On June 11, 2013, I received the following comment by Dr. Miranda, to my article, an Interview with Dr. Richard Cambria, Chief Vascular Surgery, MGH, Boston

No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it?

Efrain Miranda, Ph.D. • It is true that abdominal aortic aneurysms (AAA) are mostly asymptomatic, until they rupture. By luck, some are identified. An example was a AAA found in Albert Einstein by Dr. Nissen when Einstein went for abdominal surgery for something completely unrelated! In my experience, I have found many AAA’s in individuals who had a totally different cause of death.
http://clinanat.com/mtd/153-aneurysm

I am presenting here the the CASE of an AAA found in Albert Einstein by Dr. Nissen when Einstein went for abdominal surgery for something completely unrelated!

A Moment in History

Dr. Rudolf Nissen
(1896 – 1981)

Dr Nissen’s life is extraordinary. Born in the city of Neisse, Germany in 1896, he was the son of a local surgeon. He studied medicine in the Universities of Munich, Marburg, and Breslau. He was the pupil of the famous pathologist Albert Aschoff (discoverer of the heart’s AV node, along with Sunao Tawara).

Nissen became a professor of surgery in Berlin, and in 1933 moved to Turkey where he was placed in charge of the Department of Surgery of the University of Istanbul. In 1939 he moved to the US, first to the Massachusetts General Hospital and later to the Jewish Hospital in Brooklyn, New York. After becoming a US citizen, he moved again in 1952 to Basel, Switzerland as Chief of the Department of Surgery, where he retired in 1967. He died in 1981.

His contributions to surgery are innumerable. He wrote over 30 books and 450 journal articles. Known for the development in 1956 of what is today known as the “Nissen fundoplication” for esophageal hiatus hernia surgery, Nissen also worked with his assistant, Dr. Mario Rossetti to develop the “floppy Nissen fundoplication”, also known as the “Nissen-Rossetti procedure”. This would be enough to honor this man, still, he (with Sauerbruch) performed the first lung lobectomy and the first pneumonectomy (called then a total pneumonectomy). In 1949 he performed the first esophagectomy with a gastroesophagostomy.

His personal life is even more interesting. Drafted at 20, he fought in WWI and was wounded several times. In 1933, under the Nazi regime, he was ordered to fire all the Jewish-German assistants under his care. Being Jewish himself, he was told that he would keep his job, Nissen could not take this. He resigned his position and moved out of Germany.

Another little known fact is that he operated on Albert Einstein in 1948. He operated on Einstein because of intestinal cysts. Having found a developing abdominal aortic aneurysm, he reinforced it with cellophane, undoubtedly giving his patient a few extra years to live. Einstein died in 1955.

As a personal side note, our good friend Dr. Aaron Ruhalter scrubbed in with Dr. Nissen while serving as a surgical resident at the Brooklyn Jewish Hospital!

Sources:
1. “Rudolf Nissen: The man behind the fundoplication” Schein et al. Surgery 1999;125:347-53
2. “Rudolf Nissen (1896–1981)-Perspective” Liebermann-Meffert, D. J Gastrointest Surg (2010) 14 (Suppl 1):S58–S61
3. “The Life of Rudolf Nissen: Advancing Surgery Through Science and Principle” Fults, DW; Taussky, P. World J Surg (2011) 35:1402–1408
4. “Total Pneumonectomy” Nissen, R. Ann Thorac Surg 1980; 29:390-394
5. “Historical Development of Pulmonary Surgery” Nissen, R. Am J Surg 80: Jan 1955 9- 15 áclav Treitz (1819-1872): Czechoslovakian Pathoanatomist and Patriot” Fox, RS; Fox, CG; Graham, WP. World J. Surg. 9, 361-366, 1985
Original image courtesy of Universität Basel.

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No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it?

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Atherogenic Processes & Pathology, Cardiac & Vascular Repair Tools Subsegment, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Origins of Cardiovascular Disease, Stents & Tools, Valves & Tools, tagged AAA, Abdominal aortic aneurysm, Albert Einstein, Aneurysm, Aortic aneurysm, Aortic valve replacement, Cambria, Carotid endarterectomy, Columbia University, Harvard Medical School, Massachusetts General Hospital, Operating theater, Vascular surgery, X-ray computed tomography on June 10, 2013| 7 Comments »

No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it?

Curator: Aviva Lev-Ari, PhD, RN

I shadowed Dr. Cambria in the Operating Room at MGH in January 2005 while he performed Carotid Endarterectomy following Aortic Valve Replacement performed by Dr. Jennifer D. Walker in a sequence, first the Valve replacement, then the Endarterectomy.

Aneurysm

Published on Thursday, 15 November 2012 |

This word has a Greek origin from the terms [aneurusma], composed of [ana] meaning “complete or throughout”, and [eurus] meaning “wide”, a “complete widening or dilation”. It is used to refer to the dilation of an artery. Aneurysms can be formed in any artery, although they have some preferred sites. The most common aneurysms are found in the aorta, arterial circle of Willis, the root of the cerebral arteries, and internal carotid arteries.Biomechanical studies suggest that once an aneurysm forms it will generally progress in its dilation until aneurysmal rupture. Because of turbulent flow within the aneurysm large clots are usually formed, which in turn can cause emboli.The image shows an excised infrarenal aortic abdominal aneurysm (AAA). The two common iliac arteries can be seen. If you click on the image you will be able to see the same aneurysm opened through its posterior wall and the clot that was contained inside.Photography by D.M.Klein

http://clinanat.com/mtd/153-aneurysm

On 6/11/2013, Efrain Miranda, Ph.D. commented on this article, as follows:

It is true that abdominal aortic aneurysms (AAA) are mostly asymptomatic, until they rupture. By luck, some are identified. An example was a AAA found in Albert Einstein by Dr. Nissen when Einstein went for abdominal surgery for something completely unrelated! In my experience, I have found many AAA’s in individuals who had a totally different cause of death.

Dr. Richard Cambria describes an Aortic Aneurysm and recalls the numerous risk factors associated with the condition.

VIEW VIDEO

http://www.empowher.com/aortic-aneurysm/content/there-are-no-early-symptoms-there-way-know-if-i-have-aortic-aneurysm-it-rupt

By Dr. Richard Cambria Expert April 12, 2011 – 10:08am

Dr. Cambria:
An aortic aneurysm can be most simply thoughts of as a weakening or ballooning of the aorta which is the body’s major and largest blood vessel. That’s important because this ballooning or weakening can eventually lead to the aneurysm bursting, which is usually a fatal event.

Aneurysms have been referred to as the ‘silent killer’ because in most cases these aortic aneurysms cause no symptoms or problems prior to bursting. Most aortic aneurysms occur in older patients, but there are a clearly defined set of risk factors which makes certain patients at higher risk of developing aortic aneurysms. These include, most importantly, a family history of aortic aneurysm disease, and by family history I mean, if your mother or father or a brother or sister had an aortic aneurysm, you are clearly at increased risk of developing an aneurysm.

20% of the patients that we treat for aortic aneurysms have a positive family history of aneurysm disease. You are also at higher risk for developing an aortic aneurysm if you are female, if you have a history of high blood pressure, if you have been a cigarette smoker, and if you have chronic obstructive pulmonary disease or emphysema, which is in turn related to long-term cigarette smoking.

If you are at risk for developing an aortic aneurysm there are simple diagnostic x-ray studies such as ultrasounds and CAT scans to accurately diagnose number one, whether or not an aneurysm is present, and more importantly, if it is present, to measure just how large it is because that’s the single most important factor in determining whether or not your aneurysm needs to be treated.

It’s important to detect and monitor aortic aneurysms before they reach the stage of bursting because treatment is then usually successful with an expected excellent recovery. Treatment of aortic aneurysms today is very effective and involves replacing the aneurysm with an artificial blood vessel.

There are a variety of different surgical treatments, some of them including minimally invasive operations known as stent grafts, which are applied today in many patients.

Mass General has been a leader in the northeast in the successful management of aortic aneurysms. More than a decade ago, we formed the Mass General Thoracic Aortic Center, which is a team-approach of vascular surgeons, cardiac or heart surgeons, and cardiologists to effectively manage thoracic aneurysms which are often the most challenging and clinically complex to treat.

About Dr. Richard Paul Cambria, M.D.:
Richard P. Cambria, M.D. is Professor of Surgery at Harvard Medical School and Chief, Division of Vascular/Endovascular Surgery at Massachusetts General Hospital. Dr. Cambria received his medical degree from the College of Physicians and Surgeons, Columbia University, in 1977. He trained in general and vascular surgery at Massachusetts General Hospital.

http://www.empowher.com/aortic-aneurysm/content/there-are-no-early-symptoms-there-way-know-if-i-have-aortic-aneurysm-it-rupt

Education & Awards

Dr. Cambria graduated from Columbia University, New York. He has 15 awards.

Awards

	One of America’s Leading Experts on:
	Abdominal Aortic Aneurysm
	Aortic Aneurysm
	Aortic Diseases
	Aortic Rupture
	Arterial Occlusive Diseases
	Blood Vessel Prosthesis Implantation
	Carotid Endarterectomy
	Carotid Stenosis
	Kidney Failure
	Mesenteric Vascular Occlusion
	Spinal Cord Ischemia
	Thoracic Aortic Aneurysm
	Vascular Surgical Procedures

Castle Connolly America’s Top Doctors® (2002 – 2012)

	Top Ten Doctors (2012)
	Vascular Surgery, Downtown, Boston, MA

http://www.vitals.com/doctors/Dr_Richard_Cambria.html#ixzz2VqxwIwMK

Publications & Research

Dr. Cambria has contributed to 164 publications.

Title	Giant Cell Aortitis of the Ascending Aorta Without Signs or Symptoms of Systemic Vasculitis is Associated with Elevated Risk of Distal Aortic Events.
Date	February 2012
Journal	Arthritis and Rheumatism

Title	Long-term Outcomes of Patients Undergoing Endovascular Infrainguinal Interventions with Single-vessel Peroneal Artery Runoff.
Date	May 2011
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Management of Diseases of the Descending Thoracic Aorta in the Endovascular Era: a Medicare Population Study.
Date	October 2010
Journal	Annals of Surgery
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Title	The Effects of Systemic Hypothermia on a Murine Model of Thoracic Aortic Ischemia Reperfusion.
Date	August 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
Excerpt	Read excerpt

Title	Long-term Outcomes of Diabetic Patients Undergoing Endovascular Infrainguinal Interventions.
Date	August 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Preoperative Variables Predict Persistent Type 2 Endoleak After Endovascular Aneurysm Repair.
Date	August 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Surgical Management of Descending Thoracic Aortic Disease: Open and Endovascular Approaches: a Scientific Statement from the American Heart Association.
Date	August 2010
Journal	Circulation

Title	Balloon Expandable Stents Facilitate Right Renal Artery Reconstruction During Complex Open Aortic Aneurysm Repair.
Date	March 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Preoperative Functional Status Predicts Perioperative Outcomes After Infrainguinal Bypass Surgery.
Date	March 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Intermediate-term Outcomes of Endovascular Treatment for Symptomatic Chronic Mesenteric Ischemia.
Date	February 2010
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	A Multicenter Clinical Trial of Endovascular Stent Graft Repair of Acute Catastrophes of the Descending Thoracic Aorta.
Date	December 2009
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Effect of Pj34 on Spinal Cord Tissue Viability and Gene Expression in a Murine Model of Thoracic Aortic Reperfusion Injury.
Date	December 2009
Journal	Vascular and Endovascular Surgery
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Title	Secondary Intervention After Endovascular Abdominal Aortic Aneurysm Repair.
Date	October 2009
Journal	Annals of Surgery
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Title	Aortic Remodeling After Endovascular Repair of Acute Complicated Type B Aortic Dissection.
Date	September 2009
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Significant Perioperative Morbidity Accompanies Contemporary Infrainguinal Bypass Surgery: an Nsqip Report.
Date	September 2009
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Pj34, a Poly-adp-ribose Polymerase Inhibitor, Modulates Visceral Mitochondrial Activity and Cd14 Expression Following Thoracic Aortic Ischemia-reperfusion.
Date	August 2009
Journal	American Journal of Surgery
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Title	Thoracoabdominal Aneurysm Repair: Hybrid Versus Open Repair.
Date	July 2009
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Successful Use of Bivalirudin for Combined Carotid Endarterectomy and Coronary Revascularization with the Use of Cardiopulmonary Bypass in a Patient with an Elevated Heparin-platelet Factor 4 Antibody Titer.
Date	April 2009
Journal	Anesthesia and Analgesia
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Title	Atherosclerotic Peripheral Vascular Disease Symposium Ii: Controversies in Carotid Artery Revascularization.
Date	January 2009
Journal	Circulation

Title	Functional Outcome After Thoracoabdominal Aneurysm Repair.
Date	December 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Outcomes Following Endovascular Abdominal Aortic Aneurysm Repair (evar): an Anatomic and Device-specific Analysis.
Date	August 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Zenith Abdominal Aortic Aneurysm Endovascular Graft.
Date	August 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Spinal Cord Complications After Thoracic Aortic Surgery: Long-term Survival and Functional Status Varies with Deficit Severity.
Date	August 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Five-year Results of Endovascular Treatment with the Gore Tag Device Compared with Open Repair of Thoracic Aortic Aneurysms.
Date	June 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Aortic Aneurysms.
Date	May 2008
Journal	Journal of the American College of Radiology : Jacr

Title	International Controlled Clinical Trial of Thoracic Endovascular Aneurysm Repair with the Zenith Tx2 Endovascular Graft: 1-year Results.
Date	March 2008
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Contemporary Management of Descending Thoracic and Thoracoabdominal Aortic Aneurysms: Endovascular Versus Open.
Date	February 2008
Journal	Circulation

Title	Contemporary Management of Carotid Stenosis: Carotid Endarterectomy is Here to Stay.
Date	January 2008
Journal	Perspectives in Vascular Surgery and Endovascular Therapy
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Title	Long-term Durability of Open Abdominal Aortic Aneurysm Repair.
Date	November 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Commentary On: Mas Jl, Chatellier G, Beyssen B, Et Al. Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis. N Engl J Med. 2006;355:1660-1671.
Date	November 2007
Journal	Perspectives in Vascular Surgery and Endovascular Therapy
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Title	Defining the High-risk Patient for Carotid Endarterectomy: an Analysis of the Prospective National Surgical Quality Improvement Program Database.
Date	October 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Persistent Type 2 Endoleak After Endovascular Repair of Abdominal Aortic Aneurysm is Associated with Adverse Late Outcomes.
Date	July 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Restenosis After Eversion Vs Patch Closure Carotid Endarterectomy.
Date	July 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Surgical Revascularization Versus Endovascular Therapy for Chronic Mesenteric Ischemia: a Comparative Experience.
Date	July 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Comparison of Risk-adjusted 30-day Postoperative Mortality and Morbidity in Department of Veterans Affairs Hospitals and Selected University Medical Centers: Vascular Surgical Operations in Men.
Date	July 2007
Journal	Journal of the American College of Surgeons
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Title	Thoracoabdominal Aneurysm Repair: a 20-year Perspective.
Date	March 2007
Journal	The Annals of Thoracic Surgery
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Title	Stent-graft Versus Open-surgical Repair of the Thoracic Aorta: Mid-term Results.
Date	January 2007
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Intermediate Results of Percutaneous Endovascular Therapy of Femoropopliteal Occlusive Disease: a Contemporary Series.
Date	October 2006
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Long-term Outcomes After Endovascular Abdominal Aortic Aneurysm Repair: the First Decade.
Date	October 2006
Journal	Annals of Surgery
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Title	Poly Adenosine Diphosphate-ribose Polymerase Inhibitor Pj34 Abolishes Systemic Proinflammatory Responses to Thoracic Aortic Ischemia and Reperfusion.
Date	August 2006
Journal	Journal of the American College of Surgeons
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Title	Contemporary Results of Open Surgical Repair of Descending Thoracic Aortic Aneurysms.
Date	August 2006
Journal	Seminars in Vascular Surgery
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Title	Commentary on “extra-anatomic Visceral Revascularization and Endovascular Stent-grafting for Complex Thoracoabdominal Aortic Lesions”.
Date	May 2006
Journal	Perspectives in Vascular Surgery and Endovascular Therapy

Title	Multi-institutional Pivotal Trial of the Zenith Tx2 Thoracic Aortic Stent-graft for Treatment of Descending Thoracic Aortic Aneurysms: Clinical Study Design.
Date	May 2006
Journal	Perspectives in Vascular Surgery and Endovascular Therapy
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Title	Aortic Dissection: Perspectives in the Era of Stent-graft Repair.
Date	March 2006
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter

Title	Current Results of Open Surgical Repair of Descending Thoracic Aortic Aneurysms.
Date	March 2006
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter

Title	Late Results of Combined Carotid and Coronary Surgery Using Actual Versus Actuarial Methodology.
Date	December 2005
Journal	The Annals of Thoracic Surgery
Excerpt	Read excerpt

Title	Contemporary Results of Angioplasty-based Infrainguinal Percutaneous Interventions.
Date	November 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Pj34, a Poly-adp-ribose Polymerase Inhibitor, Modulates Renal Injury After Thoracic Aortic Ischemia/reperfusion.
Date	October 2005
Journal	Surgery
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Title	Safety and Efficacy of Reoperative Carotid Endarterectomy: a 14-year Experience.
Date	July 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Determinants of Carotid Endarterectomy Anatomic Durability: Effects of Serum Lipids and Lipid-lowering Drugs.
Date	May 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Early Outcomes of Endovascular Versus Open Abdominal Aortic Aneurysm Repair in the National Surgical Quality Improvement Program-private Sector (nsqip-ps).
Date	May 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
Excerpt	Read excerpt

Title	Thoracoabdominal Aneurysm Repair: Anesthetic Management.
Date	March 2005
Journal	International Anesthesiology Clinics

Title	Endovascular Treatment of Thoracic Aortic Aneurysms: Results of the Phase Ii Multicenter Trial of the Gore Tag Thoracic Endoprosthesis.
Date	March 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Poly(adenosine Diphosphate Ribose) Polymerase Inhibition Modulates Spinal Cord Dysfunction After Thoracoabdominal Aortic Ischemia-reperfusion.
Date	March 2005
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Current Status of Thoracoabdominal Aneurysm Repair.
Date	November 2004
Journal	Advances in Surgery

Title	Stenting for Carotid-artery Stenosis.
Date	October 2004
Journal	The New England Journal of Medicine

Title	Carotid Endarterectomy at the Millennium: What Interventional Therapy Must Match.
Date	September 2004
Journal	Annals of Surgery
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Title	Surgical Management of Popliteal Artery Embolism at the Turn of the Millennium.
Date	June 2004
Journal	Annals of Vascular Surgery
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Title	Regional Hypothermia with Epidural Cooling for Prevention of Spinal Cord Ischemic Complications After Thoracoabdominal Aortic Surgery.
Date	April 2004
Journal	Seminars in Thoracic and Cardiovascular Surgery
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Title	Preservation of Renal Function with Surgical Revascularization in Patients with Atherosclerotic Renovascular Disease.
Date	February 2004
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Durability of Aortouniiliac Endografting with Femorofemoral Crossover: 4-year Experience in the Evt/guidant Trials.
Date	June 2003
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Late Aortic and Graft-related Events After Thoracoabdominal Aneurysm Repair.
Date	February 2003
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Surgical Treatment of Complicated Distal Aortic Dissection.
Date	October 2002
Journal	Seminars in Vascular Surgery
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Title	Thoracoabdominal Aneurysm Repair: Results with 337 Operations Performed over a 15-year Interval.
Date	October 2002
Journal	Annals of Surgery
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Title	Clinical Outcome of Internal Iliac Artery Occlusions During Endovascular Treatment of Aortoiliac Aneurysmal Diseases.
Date	October 2002
Journal	Journal of Vascular and Interventional Radiology : Jvir
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Title	Evolving Experience with Thoracic Aortic Stent Graft Repair.
Date	July 2002
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Clinical Failures of Endovascular Abdominal Aortic Aneurysm Repair: Incidence, Causes, and Management.
Date	July 2002
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Regarding “analysis of Predictive Factors for Progression of Type B Aortic Intramural Hematoma with Computed Tomography”.
Date	July 2002
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter

Title	Contemporary Management of Aortic Branch Compromise Resulting from Acute Aortic Dissection.
Date	July 2001
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Endovascular Stent-graft in Abdominal Aortic Aneurysms: the Relationship Between Patent Vessels That Arise from the Aneurysmal Sac and Early Endoleak.
Date	June 2001
Journal	Radiology
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Title	Regional Hypothermia with Epidural Cooling for Spinal Cord Protection During Thoracoabdominal Aneurysm Repair.
Date	April 2001
Journal	Seminars in Vascular Surgery
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Title	Endovascular Repair of Abdominal Aortic Aneurysms: Current Status and Future Directions.
Date	August 2000
Journal	Ajr. American Journal of Roentgenology

Title	Epidural Cooling for Spinal Cord Protection During Thoracoabdominal Aneurysm Repair: A Five-year Experience.
Date	July 2000
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Utility and Reliability of Endovascular Aortouniiliac with Femorofemoral Crossover Graft for Aortoiliac Aneurysmal Disease.
Date	July 2000
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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Title	Surgical Renal Artery Reconstruction Without Contrast Arteriography: the Role of Clinical Profiling and Magnetic Resonance Angiography.
Date	January 2000
Journal	Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
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http://www.vitals.com/doctors/Dr_Richard_Cambria/credentials
http://www.vitals.com/doctors/Dr_Richard_Cambria/credentials#ixzz2VqyhFZVd

Cambria RP, Brewster DC, Lauterbach SR, Kaufman JA, Geller SC, Fan CM, Greenfield A, Hilgenberg A, Clouse WD. Evolving experience with thoracic aortic stent-graft repair. J Vasc Surg 2002:35:1129-36.

Cambria, RP, Clouse WD, Davison JK, Dunn PF, Corey M, Dorer D. Thoracoabdominal aneurysm repair: Results with 337 operations performed over a 15 year interval. Ann Surg 2002;236-471-79.

Cambria RP, Lauterbach SR, Brewster DC, Gertler JP, LaMuraglia GM, Isselbacher EM, Hilgenberg AD, Moncure AC. Contemporary management of aortic branch compromise secondary to acute aortic dissections. J Vasc Surg 2001;331185-92.

Cambria RP and Black JH. Aortic dissection perspectives for the vascular/endovascular surgeon. In Rutherford (ed) Comprehensive Vascular and Endovascular Surgery 6 th , W. B. Saunders, Inc. (in press, 2004).

Cambria RP, Marone LK, Cloud WD, Dorer, DJ, Brewster, DC, LaMuraglia, GM, Watkins, MT, Kwolek, CJ. Preservation of renal functions with surgical revascularization in patients with atherosclerotic renovascular disease. J Vasc Surg 2004; 10.023.

http://www2.massgeneral.org/vascularsurgery/doctors/cambria.htm

Abdominal Aortic Aneurysm – Case Study

Angela Rodriguez-Wong, MD, RVT, RPVI

Lois Eliassi, BS, RVT

http://www.navixdiagnostix.com/downloads/Navix%20-%20Q1%20’13%20Ultrasound%20Solutions.pdf

An aneurysm is defined as a focally dilated segment of an artery that is 1.5 times its normal diameter and involves all three arterial walls (intima, media and adventitia). Aneurysms can be found in the common femoral and popliteal arteries in the lower extremities, the splenic, mesenteric, and renal arteries in the abdomen, and also in the intracranial vessels. However, the most common is an abdominal aortic aneurysm (AAA) involving the aorta and iliac arteries.

Abdominal aortic aneurysms are generally asymptomatic and are discovered accidentally either by physician palpation or by a radiologic examination such as a chest or abdominal X-ray. The risk factors that increase the probability of developing a AAA are primarily smoking and family history. An abdominal aortic aneurysm can rupture and, according to the Centers for Disease Control and Prevention, ruptured AAA was the 10th leading cause of death in males between the ages of 65-74 in the United States in 2000.

The preferred method of screening for AAA is diagnostic ultrasound. According to the Journal of Vascular Surgery, diagnostic ultrasound performed by a registered vascular technologist has a sensitivity of 100 percent and a specificity of 96 percent for the detection of an infrarenal AAA. The abdominal aorta is considered aneurysmal when it measures >3.0 cm.

Because of its accuracy, diagnostic ultrasound not only has become an integral part in diagnosing AAA but is also an integral part in the evaluation of disease progression, the preoperative AAA evaluation, and the follow-up of AAA surgical repair. It is important to note that a rupture of an AAA is a surgical emergency and is difficult to evaluate with ultrasound due to the inability to easily demonstrate abdominal free fluid. If a rupture is suspected, it is recommended that other imaging modalities such as CT be employed to better demonstrate the ruptured aneurysm and any intra-abdominal free fluid.

Case Study –

Abdominal Aortic Aneurysm – A 77 year-old male

Angela Rodriguez-Wong, MD, RVT, RPVI

Lois Eliassi, BS, RVT

Figure 1 Distal abdominal aortic aneurysm with mural thrombus.

Figure 2 Bifurcation of the aorta.

Case Study: A 77 year-old male with a past medical history of diabetes, hypertension, arthritis, aortic valve disease and heavy smoking was referred to Eastern Vascular Diagnostic Center with a 4.2 centimeter aneurysm. The patient denied any family history of aneurysm and is allergic to intravenous contrast. A physical exam found the patient alert with a blood pressure of 100/60 mmHg, a pulse of 58 and respiration of 16. Auscultation found a bruit in the left carotid artery, clear lungs, and a regular heart rhythm with an aortic systolic murmur. The patient had a well healed sub-costal incision on his abdomen. The physician was unable to palpate the aneurysms. The patient had an aortic valve replacement in 2007 and also a cholecystectomy. On May 12, 2012, a magnetic resonance imaging (MRI) scan without contrast was performed on the patient’s abdomen. The MRI found an AAA measuring greater than 3 cm with extensive plaque near the bifurcation. The aneurysm extended into the right common iliac artery (CIA) measuring 4.2 cm and into the left CIA measuring 3.1 cm. The MRI exam did not include the pelvis, so the extent of the iliac aneurysms was not clear. On July 31, 2012, the ultrasound was performed, demonstrating normal ankle brachial index (right-1.2, left-1.1) and a AAA measuring 3.9 cm which extended into the right and left CIA. The maximum diameter of the right CIA measures 4.1 cm with mural thrombus creating a residual lumen of 2.0 cm. The maximum diameter of the left CIA measures 4.3 cm, there is also mural thrombus noted but without significant appreciable diameter reduction within the vessel. A computed tomography (CT) scan of the abdomen and pelvis without contrast was performed on July 18th confirming the infrarenal AAA with extension into the iliac arteries bilaterally.

Surgery is recommended when an AAA reaches 5.0-5.5 cm in a male and 4.5-5.0 cm in females. Surgery, depending on the aneurysm, can be an open repair or an endovascular repair. In this patient, despite the size of the AAA being 4.1 cm, the disease also involved the bilateral common iliacs prompting the need for surgical intervention. The patient was cleared by cardiology and on July 31st had an AAA and bilateral Iliac aneurysm resection with a re-implantation of the inferior mesenteric artery and an Aorta to right Hypogastric bypass to maintain pelvic perfusion.

The U.S. Preventive Services Task Force has released a statement summarizing recommendations for screening for AAA. It states that screening benefits patients who have a relatively high risk for dying from an aneurysm; major risk factors are age 65 years or older, male sex, and smoking at least 100 cigarettes in a lifetime. The guideline recommends one-time screening with ultrasound for AAA in men 65 to 75 years of age who have ever smoked. No recommendation was made for or against screening in men 65 to 75 years of age who have never smoked, and it recommended against screening women. Men with a strong family history of AAA should be counseled about the risks and benefits of screening as they approach 65 years of age.

Angela Rodriguez-Wong, MD, RVT, RPVI

awong@navixdiagnostix.com

Lois Eliassi, BS, RVT

leliassi@navixdiagnostix.com

Figure 3 Sagittal image of the right common iliac artery demonstrating the measurement of the aneurysm and the true lumen.

Figure 4 Coronal view of the left common iliac artery.

REFERENCES

1. Anderson RN. Deaths: Leading causes for 2000. Natl Vital Stat Rep. 2002;50:1–85.

2. Kent KC, Zwolak RM, Jaff MR, et al. Screening for abdominal aortic aneurysm. J Vasc Surg. 2004;39:267–9.

3. Upchurch G Jr, Schaub T. Abdominal aortic aneurysm. American Family Physician. 2006;73(7), 1198-1204. http://www.aafp.org/afp/2006/0401/p1198.html

http://www.navixdiagnostix.com/downloads/Navix%20-%20Q1%20’13%20Ultrasound%20Solutions.pdf

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Immunomodulatory Therapeutic Antibodies for Cancer, August 13-15, 2013 – Boston, MA – Final Agenda

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Interviews with Scientific Leaders, tagged Cancer - General, Harvard MedicalSchool, Immunotherapy, Management of cancer, Massachusetts General Hospital, Memorial Sloan–Kettering Cancer Center on May 16, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Immunomodulatory Therapeutic Antibodies for Cancer

http://www.immunotherapiescongress.com/Conferences_Overview.aspx?id=124174

ImmunotherapiesCongress.com

August 13-15, 2013 • Hilton Boston Back Bay Hotel • Boston, MA Final Agenda

Register by May 17 and Save up to $300!

Organized by:

Cambridge Healthtech Institute

Inaugural Immunomodulator Antibodies for Cancer

August 14-15

Inaugural Emerging Cancer Immunotherapies and Vaccines

August 13-14

Sessions Include:

• Cancer Biology and Biomarkers

• Emerging Cancer

Immunotherapies & Vaccines

• Clinical Development of

Immunomodulatory Antibodies

• Bispecific Immunomodulatory

Antibodies

Keynote Presentations:

The Promise of T-Cell Engineering

Michel Sadelain, M.D., Ph.D., Director, Center

for Cell Engineering & Gene Transfer and

Gene Expression Laboratory, Memorial Sloan-

Kettering Cancer Center

Immune Monitoring on

Pre-Surgical Clinical Trials with

a Novel Checkpoint Blockade

Agent, Anti-CTLA-4

Padmanee Sharma, M.D., Associate Professor,

Genitourinary Medical Oncology, University of

Texas MD Anderson Cancer Center

Co-Located Event

Eighth Annual

Novel Vaccines:

Innovations & Adjuvants

To Advance the Science of Vaccines

Immuno The

Congress

herapies Immune System Modulation

for Novel Cancer Treatments

ImmunotherapiesCongress.com

Short Courses:

Melanoma Biology and Immunotherapies

Monday, August 12

Manufacturing Vaccines:

New Approaches, New Technologies

Wednesday, August 14

ImmunotherapiesCongress.com 2

Pre-Conference Short Course *

Monday, August 12 • 2:00-5:00PM

Melanoma Biology and

Immunotherapies

Significant advances have been made in the understanding of the molecular

underpinnings of melanoma development and progression and in elucidating

the mechanisms by which these tumors escape immune surveillance. This

session will address the current understanding of somatic genetic alterations

that serve as the fundamental building blocks for malignant transformation

in melanoma and as the basis for the first generation of molecular targeted

therapies. Immune recognition of melanoma has been long recognized and

underlies melanoma’s relatively unique responsiveness to cytokine-based

immunotherapy. However, understanding of the negative immunomodulatory

regulators that prevent elimination of melanoma has led to novel therapeutic

approaches that manipulate effector antitumor T cell function.

Instructors:

Keith T. Flaherty, M.D., Associate Professor, Department of Medicine, Harvard Medical

School; Director, Termeer Center for Targeted Therapy, Cancer Center, Massachusetts

General Hospital

Jennifer Wargo, M.D., Surgical Oncologist, Massachusetts General Hospital; Instructor,

Harvard Medical School

Dinner Short Course*

Wednesday, August 14 • 6:30-9:30pm

Manufacturing Vaccines:

New Approaches, New Technologies

Novel vaccine production platforms are changing vaccines, affecting efficacy,

and steering manufacturing away from egg-based production. This course will

look at how vaccine production is being innovated, and how these innovations

are affecting the way vaccines work. New technologies, such as cell culturebased

production and using the BEVS (Baculovirus Expression Vector System),

are opening the door to improved vaccines. Join us for this intimate discussion

of how vaccine production is being revolutionized.

Instructors:

Sue Behrens, Ph.D., Consultant, Biologic, Vaccine & Sterile Products Manufacturing

Technology, SB Executive Consulting, LLC (former Senior Director of Biological Sciences

& Strategy, Vaccine & Sterile Operations at Merck)

Todd Talarico, Ph.D., Vice President, Manufacturing, Medicago-USA

*Separate registration required

Conference Hotel:

Hilton Boston Back Bay Hotel

40 Dalton Street

Boston, MA 02115

Phone: 617-236-1100

Discounted Room Rate: $195 s/d

Discounted Room Rate Cut-off Date: July 15, 2013

Please visit our conference website to make your

reservations online or call the hotel directly to

reserve your sleeping accommodations. Identify

yourself as a Cambridge Healthtech Institute

conference attendee to receive the reduced room

rate. Reservations made after the cut-off date

or after the group room block has been filled

(whichever comes first) will be accepted on a

space- and rate-availability basis. Rooms are

limited, so please book early.

HOTEL & TRAVEL INFORMATION

Flight Discounts:

To receive a 5% or greater discount on all American Airline flights please use one of the following

methods:

• Call 1-800-433-1790 use Conference code (8283BJ)

• Go online http://www.aa.com enter Conference code (8283BJ) in promotion

discount box

• Contact Rona Meizler, Great International Travel 1-617-559-3735

Car Rental Discounts:

Special discount rentals have been established with Hertz for this conference. Please use one of the

following methods:

• Call HERTZ, 800-654-3131 use our Hertz Convention Number (CV): 04KL0002

• Go online http://www.hertz.com use our Hertz Convention Number (CV): 04KL0002

3 ImmunotherapiesCongress.com

Inaugural

Emerging Cancer Immunotherapies and Vaccines

Next-Generation Targets and Strategies

August 13-14

Using lessons learned from early cancer vaccines and immunotherapeutics, a new wave of programs are underway that promise improved efficacy and

safety over a wider range of cancers. Emerging Cancer Immunotherapies and Vaccines will examine new targets and strategies in this space, along with

important studies in preclinical development associated with developing these programs into successful drug products. Speakers will offer approaches to

resolve the most challenging steps in the transition of these programs from research into clinical development.

TUESDAY , AUGUST 13, 2013

7:30 am Main Conference Registration and Morning Coffee

8:05 Chairperson’s Opening Remarks

T Cell Immunotherapy Strategies

»»8:15 Op ening Keynote Presentation

The Promise of T Cell Engineering

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering & Gene Transfer and

Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center

T cell engineering offers a unique means to overcome the immune escape

stratagems used by tumors to elude immune rejection. The genetic

reprogramming of patient T cells can thus be used to enforce tumor

recognition, improve T cell survival, augment T cell expansion, generate

memory lymphocytes and offset T cell anergy and immune suppression.

Using “second-generation chimeric antigen receptors” (CARs), recent clinical

studies support the merit of this novel immunotherapy.

9:00 It Takes Two to Tango: Fine Tuning of Tumor Cells and T

Lymphocytes for Maximized Anti-Tumor Activity

Daniel J. Powell, Jr., M.D., Assistant Professor, Pathology and Laboratory Medicine, Perelman

School of Medicine, University of Pennsylvania

Genetic engineering with chimeric immune receptors now allows for rapid

de novo generation of autologous T cells with potent anti-tumor activity for

adoptive cell transfer therapy for cancer. Still, low target antigen expression

by tumor cells and antigen expression on normal tissues may render therapy

ineffective or potentially toxic. We have identified agents that sensitize tumor

cells to immune attack and made advances in T cell engineering strategies to

better direct T cells to tumor antigen and confine T cell activity to tumor.

9:30 Improved Cancer Immunotherapy through CD134 plus

CD137 Dual Co-Stimulation

Adam J. Adler, Ph.D., Associate Professor of Immunology, University of Connecticut

T cell-mediated anti-tumor immunity is dampened by tolerance mechanisms

that evolved to prevent autoimmunity. Since tolerance largely results as

a consequence of insufficient co-stimulation during antigenic priming, costimulatory

receptor agonists can program tumor-specific T cell expansion and

effector differentiation. In particular, dual administration of agonists to CD134 plus

CD137 activates multiple immune cells with tumoricidal potential including NK

cells, cytotoxic CD8+ T cells, and surprisingly, cytotoxic CD4+ T cells.

10:00 Refreshment Break

Cancer Biology and Biomarkers

10:30 Vascular Normalization as an Emerging Strategy to

Enhance Cancer Immunotherapy

Rakesh K. Jain, Ph.D., Andrew Werk Cook Professor of Tumor Biology, Harvard Medical

School; Director, E.L. Steele Laboratory of Tumor Biology, Department of Radiation Oncology,

Massachusetts General Hospital

The immunosuppressive tumor microenvironment remains a limiting factor

for anti-cancer vaccine therapies. In addition, tumors systemically alter

immune cells’ function via secretion of cytokines such as VEGF, a major proangiogenic

cytokine. Hence, anti-angiogenic treatment may be an effective

modality to potentiate immunotherapy. I will discuss the effects of VEGF

on anti-tumor immune responses, and propose a potentially translatable

strategy to re-engineer the tumor immune microenvironment and improve

cancer immunotherapy.

11:00 Advances in Biomarker Validation and Trial Design for

Antitumor Immunotherapy

Susan R. Slovin, M.D., Ph.D., Genitourinary Oncology Service, Sidney Kimmel Center for Prostate

and Urologic Cancers, Memorial Sloan–Kettering Cancer Center

Conventional imaging modalities have been the mainstay of assessing

treatment response. Recent data suggests that evaluating circulating tumor

cells may provide insight regarding changes in the tumor cells’ overall

behavior. Immunologic treatments often do not impact the cancer with

immediacy; a means of determining whether an immunologic target is hit

and whether it impacts the tumor’s biology remains a challenge. Changes in

T cell populations or myeloid suppressor cells may reflect potential impact on

the intra- and extra-tumoral milieu.

11:30 Exploring Synergy between Targeted Therapy and

Immunotherapy

Zachary Cooper, Ph.D., Postdoctoral Research Associate, Surgical Oncology, Massachusetts

General Hospital

Recent advances in the treatment of melanoma include the use of BRAFtargeted

therapy and immune checkpoint inhibitors, though each of

these treatments alone has its limitation. There is increasing evidence

for synergy between these modalities. Treatment with a BRAF inhibitor

results in enhanced melanoma antigen expression and a more favorable

microenvironment. Exploring the potential synergy using mouse models is

necessary in overcoming monotherapy limitations.

12:00pm Sponsored Presentations (Opportunities Available:

Contact Suzanne Carroll at 781-972-5452 or scarroll@healthtech.com

for more information)

12:30 Luncheon Presentation (Opportunity Available)

or Lunch on Your Own

Emerging Cancer Immunotherapies

1:55 Chairperson’s Opening Remarks

2:00 Synergism Between Anti-Tumor Antibodies and PKExtended

IL-2

K. Dane Wittrup, Ph.D., Dubbs Professor, Chemical Engineering and Biological Engineering, Koch

Institute for Integrative Cancer Research, Massachusetts Institute of Technology

We have found that combination treatment with anti-tumor antibody and an

IL-2 Fc fusion exerts a significantly stronger suppression of tumor growth

than either agent alone. This effect depends on the presence of both CD8+

T cells and neutrophils, indicating a close cooperation between innate and

cellular immunity. Strong potential exists for further synergy between antitumor

antibodies and the new generation of T cell-directed immunotherapies.

ImmunotherapiesCongress.com 4

2:30 Identifying New Cancer Immunotherapy Targets for T Cells

Robert Holt, Ph.D., Senior Scientist and Head of Sequencing, British Columbia Cancer Agency,

Canada

Effective cancer immunotherapy relies on effective tumor antigens. However,

most variations that distinguish tumor cells from normal cells are sporadic,

and their immunogenicity is undetermined. High throughput genomic

analysis is a useful approach for evaluating the potential immunogenicity

of individual tumors and identifying new candidate antigens for follow-on

validation. We are using two methods for T cell antigen discovery that will be

described, including tumor genome sequencing and computational epitope

prediction, plus deep TCR sequencing of tumor-associated T cells.

3:00 Immunomodulatory Antibody-Fusion Proteins for Cancer

Immunotherapy

Dafne Müller, Ph.D., Researcher, Institute of Cell Biology and Immunology, University of Stuttgart,

Germany

Cytokines of the common cytokine receptor γ-chain family and costimulatory

members of the B7- and TNF-family have shown great potential

to support the generation and development of an antitumor immune

response. In order to improve the efficacy of such molecules at the tumor

site we designed antibody fusion proteins for therapeutic approaches,

focusing either on optimized presentation or a combined mode of action.

3:30 Refreshment Break

4:00 TIM (T Cell Immunoglobulin and Mucin)-3 as a Potential

Target for Cancer Immunotherapy

Ana Carrizosa Anderson, Ph.D., Assistant Professor, Neurology, Harvard Medical School

TIM-3 marks both “exhausted” CD8+ T cells and regulatory T cells (Treg) present

in solid tumors. TIM-3/PD-1 co-blockade down-modulates Treg suppressor

function in Tim-3+ Treg, restores function to exhausted CD8+ T cells, and is highly

effective in controlling tumor growth. Thus, TIM-3/PD-1 blockade down-modulates

two major mechanisms of immune suppression that are active in tumor-bearing

hosts, namely exhausted CD8+ T cells and Treg.

4:30 Allovectin: In vivo Studies and Potential Synergy with

other Advanced Melanoma Immunotherapeutics

John Doukas, Ph.D., Senior Director, Preclinical Safety and Efficacy, Vical, Inc.

Allovectin® is a cancer immunotherapeutic currently completing

evaluation in a pivotal Phase 3 metastatic melanoma study. Designed

for direct intratumoral administration, it is intended to induce antitumor

immune responses against both treated and distal lesions by stimulating

innate and adaptive immune responses. This presentation will review

Allovectin’s proposed mechanisms of action and potential synergy with

other immunotherapies, drawing supporting data from preclinical and

clinical studies.

5:00 Clinical Update of IL2 Adjunctive Co-Therapy for

Suppression of Solid Tumors with Designer T Cells

Richard P. Junghans, M.D., Professor, Department of Medicine, Boston University School of

Medicine; Roger Williams Medical Center

IL2, an essential adjunct in therapies with tumor-infiltrating lymphocytes, has

not been widely applied in designer T cell interventions, although rationales

for supplementation would seem to bridge both settings. This discrepancy

may reflect the restricted set of investigators with IL2 experience rather than

a biologically motivated choice. Preclinical data establishesthe need for IL2

to eliminate established tumors with dTc, and early clinical data in prostate

cancer targeting may be interpreted similarly.

5:30-6:30 Reception in Exhibit Hall with Poster Viewing

WEDNESDAY , AUGUST 14, 2013

8:55am Chairperson’s Opening Remarks

Emerging Cancer Vaccines

9:00 Challenges in Vaccine Therapy for Hematological

Malignancies

David E. Avigan, M.D., Associate Professor, Medicine, Harvard Medical School; Director,

Hematologic Malignancy/Bone Marrow Transplant Program, Beth Israel Deaconess Medical

Center

We have developed a tumor vaccine in which patient-derived tumor cells

are fused with autologous dendritic cells. We have demonstrated that

vaccination during post-transplant lymphopoietic reconstitution results in the

significant expansion of myeloma-specific T cells. We are now integrating

vaccination with reversing critical elements of tumor-mediated immune

suppression. This includes vaccination in the context of blockade of the

PD-1/PDL-1 pathway.

9:30 Biomarkers Correlative of Clinical Response to Sipuleucel-T

James Trager, Ph.D., Vice President, Research, Dendreon

Sipuleucel-T is an autologous cellular immunotherapy approved in the

United States for the treatment of asymptomatic or minimally symptomatic

metastatic castrate resistant prostate cancer. A variety of biomarkers,

both baseline and pharmacodynamic, are correlative of clinical response to

sipuleucel-T. We will discuss the biological interpretations of these markers

and in particular their implications in understanding the mechanism of action

for sipuleucel-T.

10:00 Partnering Therapeutic Vaccines with Large Pharma

Kevin Heller, Global Lead Oncology; Search, Evaluation and Diligence, Bristol-Myers Squibb

10:30 Refreshment Break in Exhibit Hall with Poster Viewing

11:15 Clinical Results of Pexa-Vec (JX-594): Multi-Mechanistic

Oncolytic Viruses as a Strategy for Cancer Immunotherapy

Anne Moon, Ph.D., Vice President, Product Development, Jennerex

Oncolytic immunotherapy is an emerging therapeutic approach designed

to induce acute tumor debulking as well as chronic suppression of tumor

outgrowth. Pexa-Vec (JX-594) is an oncolytic vaccinia virus engineered for

enhanced cancer targeting and immune stimulation. Recent preclinical and

clinical results demonstrate a multi-pronged MOA, including induction of

tumor-specific immunity, demonstrating the potential for Pexa-Vec to serve

as an active immunotherapy that is “personalized” yet “off-the-shelf.”

11:45 Clinical Update on PROSTVAC, a Therapeutic Vaccine

Candidate for Advanced Prostate Cancer

Alain Delcayre, Ph.D., Vice President, R&D, BN Immunotherapeutics

PROSTVAC® is a candidate cancer vaccine that demonstrated a statistically

significant overall survival benefit while displaying a favorable side effect

profile in patients with asymptomatic-to-minimally-symptomatic metastatic

castrate-resistant prostate cancer in a randomized, placebo-controlled Phase

II trial. A Phase III clinical trial is underway to confirm clinical benefit, as well

as expand our understanding of immune responses to cancer vaccines.

12:15 pm Close of Conference

Sponsoring Pubs

5 ImmunotherapiesCongress.com

The recent approval of BMS’s Yervoy (ipilumumab) and a succession of related programs advancing through clinical trials has generated increased interest

in the development of antibody-based immunomodulators for cancer. Immunomodulatory Therapeutic Antibodies for Cancer will provide updates of

clinical stage programs, and examine how these novel therapeutics influence trial design and the selection of clinical endpoints. Strategies for immune

modulation that are most appropriate for targeting with antibodies will be considered, along with where combination regimens and new therapeutic formats

can be effectively applied.

Inaugural

Immunomodulatory Antibodies for Cancer

Clinical Progress and Challenges in Drug Product Development

August 14-15

WEDNESDAY , AUGUST 14, 2013

1:40 pm Chairperson’s Opening Remarks

»»1:45 Keynote Presentation:

Immune Monitoring on Pre-Surgical Clinical Trials with a Novel

Checkpoint Blockade Agent, Anti-CTLA-4

Padmanee Sharma, M.D., Associate Professor, Genitourinary Medical Oncology, The University

of Texas MD Anderson Cancer Center

Biomarker studies for immunotherapies have typically involved monitoring

immunologic changes within the systemic circulation; however, recent

data indicates that immunological changes within tumor tissues are more

likely to predict clinical responses. We conducted a pre-surgical clinical trial

with anti-CTLA-4 (ipilimumab) in patients with localized bladder cancer, and

identified ICOS as the marker of a subset of effector T cells that is increased

in frequency after anti-CTLA-4 therapy. ICOS+ T cells are being explored

as pharmacodynamic markers for treatment with anti-CTLA-4 and as novel

targets to improve the efficacy of anti-CTLA-4 therapy.

Immune Checkpoint Blockades

2:30 Preliminary Clinical Efficacy and Safety of MK-3475

(Anti-PD-1 Monoclonal Antibody) in Patients with Advanced

Melanoma

Omid Hamid, M.D., Director, Melanoma Center, Angeles Clinic and Research Institute

The programmed death-1 (PD-1) pathway has emerged as an important

tumor-evasion mechanism. When PD-1 and PDL-1 join together, the T cell’s

ability to target the tumor cell is disarmed. Targeting either PD-1 or PDL-1

can stimulate the immune system and enhance T cells’ ability to lyse tumor

cells. Similar to, but distinct from cytotoxic T lymphocyte antigen 4 (CTLA-4)

this pathway hold promise for many solid tumors.

3:00 Sponsored Presentations (Opportunities Available: Contact

Suzanne Carroll at 781-972-5452 or scarroll@healthtech.com for

more information)

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Development of Immunomodulatory PD-1 Antibodies in

Renal Cell Carcinoma

Lauren Harshman, M.D., Assistant Professor, Dana-Farber Cancer Institute

Targeting the immunosuppressive PD-1 pathway is an area of intense

investigation. RCC tumor cells may innately express the ligand of PD-1 or

they may acquire it from adaptive immunity. Expression has been associated

with worse outcomes. Attempts at countering this host immune system

evasion technique are underway with a variety of monoclonal antibodies

against PD-1 and its ligands.

4:45 Anti-PD-1 Antibody Therapy for B-Cell Lymphoma

Sattva S. Neelapu, M.D., Associate Professor, Department of Lymphoma and Myeloma, Division

of Cancer Medicine, The University of Texas MD Anderson Cancer Center

In a phase II trial, the combination of pidilizumab, a humanized anti-PD-1

monoclonal antibody, and rituximab was active and non-toxic in patients with

relapsed follicular lymphoma. Activation of T and NK cells was observed in

both peripheral blood and tumor microenvironment after pidilizumab therapy

and predictors of clinical outcome based on the molecular features of tumorinfiltrating

immune cells at baseline were identified.

5:15 AMP-224, A Fusion Protein with Potential to Modulate

the PD-1 Pathway

Solomon Langermann, Ph.D., CSO, Amplimmune

AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients

that binds to and modulates the PD-1 axis through a unique MOA. The

MOA hypothesis for AMP-224 is depletion of PD-1 high expressing T-cells

representing exhausted effector cells. The pharmacodynamic readouts

obtained to date demonstrate that AMP-224 is biologically active in its

target patient population. Data from the trial has been used to establish

hypotheses regarding the characteristics of patients most likely to respond

clinically to AMP-224 treatment.

5:45 Close of Sessions

THURSDAY , AUGUST 15, 2013

Emerging Targets

8:25 am Chairperson’s Opening Remarks

8:30 Immunocytokines: A Novel Potent Class of Armed Antibodies

Catherine Hutchinson, Ph.D., Research Scientist, Philochem, Switzerland

The severe toxicity of recombinant cytokines even at low doses limits

their therapeutic potential, but this can be mitigated by using monoclonal

antibodies to target their delivery. This talk will cover the latest advanced

preclinical and clinical data of the Philogen group, detailing the discovery and

development of armed antibodies against angiogenesis-specific markers,

which are attractive targets relevant to many angioproliferative diseases.

9:00 Mechanism of Action and Progress Update for MGA271:

An Fc-Enhanced mAb Targeting B7-H3 in Solid Tumors

Paul Moore, Ph.D., Vice President, Cell Biology & Immunology, Macrogenics

Characterization of murine monoclonal antibodies generated from cancer

cell and/or stem cell-based immunizations identified a panel targeting the

immunoregulatory protein B7-H3 displaying broad tumor reactivity but

limited binding to normal tissue. Preclinical evaluation of MGA271, an Fcenhanced

anti-B7H3 mAb, revealed strong ADCC activity against a broad

range of tumor cell types, potent antitumor activity in xenograft models

employing human FcR transgenic mice and a favorable safety profile in nonhuman

primate toxicology studies. A phase I/IIa clinical study of MGA271

in patients with B7-H3-positive metastatic or recurrent adenocarcinoma is

currently recruiting patients.

ImmunotherapiesCongress.com 6

9:30 Preclinical Update: Development of a Human Anti-CD27

Monoclonal Antibody as a Potential Cancer Therapy

Lawrence J. Thomas, Ph.D., DABT, CMAR, Senior Director, Preclinical Research and

Development, Celldex Therapeutics, Inc.

Agonist antibodies binding the co-stimulatory molecule CD27 have potent

antitumor activity in murine tumor models through boosting of durable T

cell antitumor immunity. Anti-CD27 antibodies have also been shown to

mediate the direct killing of CD27-expressing tumors. Such preclinical data

supports the therapeutic potential of this anti-CD27 monoclonal antibody as

a cancer immunotherapy.

10:00 Sponsored Presentation (Opportunity Available)

10:15 Refreshment Break in the Exhibit Hall with Poster Viewing

11:00 Targeting CD47-SIRPα Interactions for Potentiating

Antibody Therapy in Cancer

Timo van den Berg, Ph.D., Head, Blood Cell Research, Sanquin Blood Supply Foundation,

The Netherlands

We will present findings demonstrating that interactions between CD47

expressed on cancer cells and the myeloid inhibitory immunoreceptor SIRPα

form a barrier for the antibody-mediated destruction of cancer cells. These

findings identify the CD47-SIRPα interaction as a potential generic target for

improving the efficacy of cancer antibody therapeutics.

11:30 Presentation to be Announced

12:00 Sponsored Presentations (Opportunities Available)

12:30 Luncheon Presentation (Opportunity Available)

or Lunch on Your Own

Clinical Development of

Immunomodulatory Antibodies

1:55 Chairperson’s Opening Remarks

2:00 Clinical Trials Design for Cancer Immune Therapies

Harriet Kluger M.D., Associate Professor, Yale Cancer Center

Clinical development of immune therapies is challenging; standard drug

development paradigms are often not applicable. Modifications are

necessary in regard to dose escalation, management and definition of

toxicities, within-patient dose reduction, and radiographic assessment of

response to therapy. In later stage trials new definitions of study endpoints

are needed. Correlative biomarker studies are complex, and require

assessment of baseline immune function and tumor characteristics.

2:30 Characteristics and Management of Immune-Related

Adverse Effects Associated with Ipilimumab, a New

Immunotherapy for Metastatic Melanoma

Stephanie Andrews, Oncology Nurse Practitioner, Moffitt Cancer Center

Immune-Related Adverse Effects are a new phenomenon related to

advances in the use of the first FDA approved monoclonal antibody

Ipilimumab for metastatic melanoma. These side effects are different

than side effects of traditional cytotoxic regimens. These immunemediated

side effects include enterocolitis, hepatitis, dermatitis,

neuropathy andendocrinopathy.

Bispecific Immunomodulatory Antibodies

3:00 Safety Challenges to Development of Immune System

Activating Antibodies

Rakesh Dixit, Ph.D., DABT, Vice President, Research & Development, Global Head, Biologics

Safety Assessment, Pathology & LAR, MedImmune (AstraZeneca Biologics)

Immune system activating antibodies with abilities to harness and enhance

an individual patient’s immune system and target tumors are revolutionizing

the treatment of many deadly cancers. However, many immune-activating

biologics have serious dose-limiting toxicities, including cytokine stormassociated

critical toxicities and serious autoimmune diseases in multiple

key organs that may limit their long-term use. Nonclinical and clinical safety

challenges and risk mitigation opportunities will be discussed in the context

of immune activating antibodies, including bispecific BiTE antibodies.

3:30 Refreshment Break

3:45 MCLA-117: ABiclonics – ENGAGE Bispecific IgG Product

Lead Targeting CLEC12A and CD3 in AML

Lex Bakker, Ph.D., Chief Development Officer, Merus, The Netherlands

MCLA-117, a common light chain T cell-engaging full-length human bispecific

antibody (Biclonics – ENGAGE) was discovered that targets CD3 on T cells

and CLEC12A on acute myeloid leukemia (AML) blasts and leukemic stem

cells. Co-incubation of resting patient T cells and AML cells with MCLA-

117 results in efficient tumor cell lysis. Clinical application of MCLA-117

potentially provides a therapy in AML that more efficiently eradicates the

cancer cells and prevents relapse.

4:15 Bispecific Antibody Targeting CD47 Aiming at Increasing

Phagocytosis of Cancer Cells

Krzysztof Masternak, Ph.D., Head of Biology, Novimmune SA, Switzerland

CD47 is a ubiquitously expressed transmembrane receptor with multiple

functions in cell-to-cell communication. Its interaction with SIRPα expressed

in macrophages and DCs inhibits their phagocytic function. Overexpression

of CD47 in cancer cells is often observed and it is believed to help cancer

cells escape immune surveillance. We have generated bispecific antibodies

(BsAbs) that preferentially neutralize CD47-SIRPα interaction on cancer cells.

4:45 Close of Conference

7 ImmunotherapiesCongress.com

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http://www.immunotherapiescongress.com/Conferences_Overview.aspx?id=124174

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Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation

Posted in Frontiers in Cardiology and Cardiovascular Disorders, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, tagged Coronary artery disease, Coronary circulation, Heart disease, Massachusetts General Hospital, X-ray computed tomography on April 18, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Can Coronary Artery Anomalies Be Detected on CT Calcium Scoring Studies?

Academic Radiology, 04/11/2013 Review Article

Maddux PT et al. – The purpose of this study is to determine whether coronary artery anomalies can be detected on noncontrast computed tomography (CT) coronary artery calcium scoring (CCS) studies. Benign and malignant coronary artery anomalies can be detected with relatively high accuracy on noncontrast–enhanced CCS studies. CCS studies should be reviewed for signs of coronary artery anomalies in order to identify malignant variants with possible impact on patient management.

Methods

A total of 126 patients (mean age 62 years; 35 women) underwent noncontrast CCS and contrast enhanced coronary CT angiography (cCTA).
Thirty–three patients were diagnosed with a coronary anomaly on cCTA, whereas coronary anomalies were excluded in 93.
Two observers (reader 1 [R1] and reader 2 [R2]), blinded to patient information independently evaluated each CCS study for: 1) visibility of coronary artery origins, 2) detection of coronary anomalies, and 3) benign or malignant (ie, interarterial) course.
Using cCTA as the reference standard, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CCS studies for detecting coronary anomalies were calculated.

Results

Of the 33 coronary anomalies, 16 were benign and 17 malignant.
Based on noncontrast CCS studies, R1 and R2 correctly identified the left main origin in 123/126 (97.6%) and 121/126 (96%) patients; the left anterior descending origin in 125/126 (99.2%) and 122/126 (96.8%); the circumflex origin in 120/126 (95.2%) and 105/126 (83.3%); and the right coronary artery origin in 117/126 (92.9%) and 103/126 (81.7%), respectively.
R1 and R2 identified 34 and 27 coronary anomalies and classified 19 and 15 as malignant, respectively.
Interobserver reproducibility for detection of coronary anomalies was good (k = 0.76).
Interobserver agreement for detection of malignant variants was even stronger (k = 0.80).
On average, coronary artery anomalies were diagnosed with 85.2% sensitivity, 96.4% specificity, 90.5% PPV, and 94.1% NPV on noncontrast CCS studies.

http://www.mdlinx.com/radiology/news-article.cfm/4559774/?xml

http://www.mdlinx.com/radiology/news-article.cfm/4559774/cardiac-ct-coronary-anomaly-coronary-anatomy#ixzz2QrCXwP2q

Advanced CT reconstruction improves cardiac plaque assessment

By Eric Barnes, AuntMinnie.com staff writer

April 12, 2013 — Automated plaque assessment in coronary CT angiography (CCTA) is a promising new way to evaluate a patient’s plaque burden quickly and noninvasively — but it won’t be quick or accurate without the use of advanced iterative reconstruction, according to researchers from Massachusetts General Hospital in Boston.

Automated techniques are still in their infancy, but once they become more reliable they promise to greatly improve risk assessment and management compared with, for example, calcium scoring, by precisely quantifying the amount of coronary artery plaque — fibrotic, lipid core, and calcium — that is present.

“We know the plaque volume and characteristics … are at least as important as the presence of calcium,” said Dr. Stefan Puchner in an interview with AuntMinnie.com. “If we could make plaque assessment more accurate, we could implement all this stuff in our daily practice.”

The process isn’t accurate today. Automated plaque quantification requires significant time for radiologists to fix the incorrectly drawn vessel wall boundaries, making it impractical for routine use. Manually drawing the boundaries would actually take about a day’s work for each patient, so automation is the only way forward, Puchner said. The group wanted to determine if an advanced reconstruction algorithm might produce fewer errors and make semiautomated plaque estimation practical.

In a study that reconstructed ex vivo coronary vessel segments using three different reconstruction methods, the study team found that, indeed, accuracy in plaque quantification depended on the reconstruction algorithm, as well as vessel size and the extent of calcifications. Using advanced reconstruction, fewer corrections were needed to the vessel wall segmentation, Puchner reported at the 2013 European Congress of Radiology (ECR) in Vienna. Specifically, they compared the use of automated vessel assessment using model-based iterative reconstruction (MBIR, GE Healthcare) compared with an earlier IR algorithm, advanced statistical iterative reconstruction (ASIR, GE), or conventional filtered back projection (FBP) reconstruction.

Cross section of a noncalcified plaque reconstructed with the three different algorithms (left to right: FBP, ASIR, MBIR). No significant differences can be seen between the three algorithms in terms of correct delineation of the plaque borders. All images courtesy of Dr. Stephan Puchner.

For subjects, the group examined three ex vivo human hearts imaged with CCTA and reconstructed with FBP, ASIR, and MBIR. An automated plaque quantification tool (Vitrea Cardiac Solutions, Vital) was applied to each of the three reconstruction algorithms to fit the outer and inner vessel wall boundaries in nine “triplets” constituting 27 vessels. Only the first 40 mm of the contrast-filled vessels was used for analysis.

Each coronary cross section for which the software assigned incorrect boundaries was tallied and corrected in a blinded manner. The group then compared the number of vessel wall corrections between the different reconstruction algorithms using a Chi-square test.

Cross sections reconstructed with ASIR (middle) and MBIR (right) are correctly delineated by the software

Cross ection of a calcified plaque reconstructed with the three different algorithms (left to right: FBP, ASIR, MBIR). In this case, FBP shows an incorrect delineation of the inner vessel wall boundary, including parts of the calcified plaque. In contrast, the vessel wall boundaries in the cross sections reconstructed with ASIR and MBIR are correctly delineated by the software.

“Our analysis included the percentage of corrections between the three algorithms, and a per-vessel comparison of the percentage of corrections between the three algorithms,” Puchner said in his presentation.

In all, the study comprised 2,295 cross sections in 0.5-mm increments from nine coronary vessels, combined into 765 coregistered triplets evaluated with the three algorithms. Overall, 31% of the cross sections needed boundary corrections, he said. Outer vessel wall boundary corrections were needed in 400 cross sections, and inner vessel boundaries were needed in 381 cross sections.

Only in the cross section reconstructed with MBIR (right) are the boundaries correctly delineated

Cross section of a calcified plaque reconstructed with the three different algorithms (left to right: FBPR, ASIR, MBIR). In this case, FBP and ASIR show an incorrect delineation of the inner vessel wall boundary, including the whole or parts of the calcified plaque. Only in the cross section reconstructed with MBIR are the boundaries correctly delineated by the software.

The percentage of corrected cross sections was lower for MBIR (24.1%) versus ASIR (32.4%, p = 0.0003) and FBP (36.6%, p < 0.0001) — but the differences were only marginal between ASIR and FBP, he said.

“We found that MBIR works much better than the conventional algorithms … significantly reducing the number of corrections needed compared to FBP and ASIR, whereas the difference between the two other algorithms was not significant,” Puchner said.

The use of MBIR significantly reduced the need for vessel wall boundary corrections compared with other reconstruction algorithms, particularly at the site of calcifications.

Automated segmentation is certainly faster than manual processing, Puchner said. Just on the three cases used in the study and in the analysis of the proximal 40 mm of each vessel, use of the software saved about three hours compared with what manual segmentation would have required. There is significant processing time required to create MBIR reconstructions, he acknowledged, but in those cases, it’s the technologists, not the physicians, who are spending the additional time, he said.

“The next step will be to look at it in an in vivo environment, to see this application in a beating heart,” Puchner told AuntMinnie.com. And to test other applications and other iterative reconstruction schemes, of course.

“I’m pretty sure that the other newer algorithms will have similar effects, because overall some studies have shown that the use of newer algorithms reduces blooming effects and other stuff that makes it difficult for the software to delineate it correctly,” he said. With manual segmentation, radiologists tend to overcorrect for older reconstruction algorithms and undercorrect for newer techniques, “but if the software does it, the software is much more dependent on image quality, and it makes a difference if it was reconstructed with the newer algorithms or the older algorithms.”

Automated plaque measurements will also have to be compared with assessments in other modalities such as intravascular ultrasound, and even to histology using the donor hearts, he said.

MBIR tops ASIR for ultralow-dose CT enterography, November 6, 2012

Study pinpoints optimal ASIR blend for stomach cancer, November 6, 2012

MBIR takes on ASIR in low-dose chest CT, November 6, 2012

http://www.auntminnie.com/index.aspx?sec=sup&sub=cto&pag=dis&itemid=103108&wf=5397

http://www.mdlinx.com/radiology/news-article.cfm/4559774/?xml

Coronary CT Angiography in the ED

For an analysis of the finding of ROMICAT II Trial:

Hoffmann U, et al; ROMICAT-II Investigators. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012 Jul 26;367(4):299-308.

go to:

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA, Curator: Aviva Lev-Ari, PhD, RN, 3/10/2013

http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

It is well known that taking a good history and physical, getting a non-ischemic EKG, and serial cardiac biomarkers, results in a risk of death/AMI of <5% in 30 days. Patients, in whom you still suspect have CAD, should undergo provocative testing within the next 72 hours based on the AHA/ACC guidelines. Their guidelines deem provocative testing as including:

Exercise treadmill stress test,
Myocardial perfusion scan,
Stress echocardiography, and/or
Coronary CT angiography (CCTA).

Myocardial perfusion scans and stress echos have a sensitivity of 85–90% and specificity of 75–80%. In contrast, CCTA’s have been shown to have a sensitivity of 93-97% and specificity of 80-90%.

Recently two landmark trials were published in NEJM discussing the use of CCTA in the emergency department.

ACRIN-PA Trial: Litt HI, et al. CT angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med. 2012 Apr 12;366(15):1393-403. PMID: 22449295

What they did:

Non-inferiority study
5 Pennsylvania EDs
1,370 patients, Age > 30 years
Inclusion criteria: TIMI score of 0–2, EKG without ischemic changes, and negative first set of Cardiac Biomarkers
Randomized 2 patients to CCTA arm (908 patients) for every 1 patient to Standard Stress arm (462 patients)

Primary Outcome:

MI or Death from CAD at 30 days

Secondary Outcomes:

Rate of discharge from ED
Length of stay (LOS) in ED
Rate of detection of CAD
Resource utilization

What they found:

640/908 pts (70.5%) who underwent CCTA had coronary stenosis of <50% and none had MI or death due to CAD at 30 days
Discharge from ED 49.6% with CCTA vs 22.7% with standard stress arm
ED LOS 18 hr in CCTA arm vs 24.8 hr in standard stress arm

Conclusion: CCTA allows early discharge of low to intermediate risk patients presenting to the ED with possible ACS.

http://academiclifeinem.blogspot.com/2013/04/chest-pain-part-3-of-3-coronary-ct.html

ROMICAT II Trial: Hoffmann U, et al; ROMICAT-II Investigators. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012 Jul 26;367(4):299-308.PMID: 22830462

What they did:

Randomized controlled trial
9 EDs in the US
1,000 patients with acute chest pain with ages 40–74 years
CCTA (501 patients) versus Standard Evaluation (499 patients)

Primary Outcome:

Hospital length of stay

Secondary Outcomes:

Cardiovascular events at 28 days
Rate of discharge from ED
Time to diagnosis
Cost
Utilization of resources

What they found:

Hospital LOS decreased by 7.6 hr in CCTA group
Rate of discharge from ED 47% in CCTA arm vs 12% in Standard Evaluation Arm
No difference in cardiovascular events at 28 days
Cost was similar between two groups $4,289 CCTA vs $4,060 in Standard arm

Conclusion: CCTA decreases length of stay without an increase in rate of cardiovascular events.

Some discussion points worth mentioning:

CCTA with 0 lesions is NEGATIVE: These patients can certainly be discharged home with primary care follow up with a nearly 100% NPV for ACS/AMI.
CCTA with <50% lesion is NOT NEGATIVE: This patient has CAD. It may not be clinically significant, but we can see plaques. 2/3 of AMIs occur from plaques that have <50% stenosis. Certainly we can start risk factor modification with beta blockers, ASA, and statins, but there are no studies looking at how this group of patients will do long term.
CCTAs are anatomic studies and not functional studies. Identified lesions will lead to more diagnostic tests, which is one of the big arguments against CCTA. CCTA identifies CAD more often than standard stress modalities, which leads to more heart catheterizations and PCIs.
As the number of CT slice increases, radiation dose decreases:

A 64 slice CT = 10 – 15 mSv of radiation
A 128 slice CT = 5 – 10 mSv of radiation
A 256 slice CT = 1 – 5 mSv of radiation
In contrast, a single-view CXR = 0.02 mSV of radiation

There is currently an ongoing National Heart, Lung, and Blood Institute-funded trial called the PROMISE (Prospective Multi-center Imaging Study for Evaluation of Chest Pain) Study with 10,000 patients. Patients with symptoms suggestive of CAD will be randomized to a CCTA vs usual care with a functional test. What’s interesting about this study is it is being performed in the offices of primary care physicians and cardiologists rather than EDs. The study authors hypothesize that medically optimizing patients identified, as having non-obstructive CAD will yield improved long-term outcomes.

It is well known that in low risk patients, doing a good H&P, having a negative EKG (no ischemic changes), and negative serial cardiac biomarkers gives us about 99% NPV & 99% sensitivity for ACS/AMI. This is even without additional testing, such as CCTAs.So are CCTAs worth the cost and potential harms in this low-risk group to add another 1% to the 99% NPV and 99% sensitivity rates? In my opinion, that answer is NO.

Additional References:

Jancin B. Comparing Technologies for Imaging Chest Pain in the ED. ACEP News 2013 Mar; 32(3): 1 – 11.
Goldstein JA. A Randomized Controlled Trial of Multi-Slice Coronary Computed Tomography for Evaluation of Acute Chest Pain. JACC 2007;49: 863 – 71. PMID: 17320744
Goldstein JA. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) Trial. JACC 2011 Sept; 58: 1414 – 22. PMID: 21939822
Hulten E. Outcomes After Coronary Computed Tomography Angiography in the Emergency Department: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. JACC 2013 Feb; 61: 880 – 92. PMID: 23395069

Posted by Salim Rezaie

http://academiclifeinem.blogspot.com/2013/04/chest-pain-part-3-of-3-coronary-ct.html

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Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Posted in Advanced Drug Manufacturing Technology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Alois Alzheimer, Alzheimer, Alzheimer Disease, Alzheimers Disease, ApoE, BCHE brain imaging, Beta amyloid, biomarkers, cellular inflammatiory response, CLU, conitive loss, Decode Genetics, dementia, Icelanders, innovative applications, Kári Stefánsson, mapping, Massachusetts General Hospital, Picalm, plaque regression, Tau protein on March 9, 2013| 1 Comment »

Alzheimer’s Genomic Diagnosis and Treatment

Curator: Larry H Bernstein, MD, FCAP

Gene Mutation Protects Against Alzheimer’s

by Greg Miller on 11 July 2012
Brain preserver. A newly discovered gene mutation appears to protect against Alzheimer’s disease. Credit: Alzheimer’s Disease Education and Referral Center/NIA/NIH
http://news.sciencemag.org/sciencenow/2012/07/gene-mutation-protects-against-a.html

A rare mutation that alters a single letter of the genetic code protects people from the

memory-robbing dementia of Alzheimer’s disease.

The DNA change may inhibit the buildup of β amyloid, the

protein fragment that forms the hallmark plaques in the brains of Alzheimer’s patients.
The mutation affects a gene called APP,
which encodes a protein that gets broken down into pieces,
including β amyloid.

Researchers previously identified more than 30 mutations to APP, none of them good. Several of these changes increase β amyloid formation and cause

• a devastating inherited form of Alzheimer’s that afflicts people in their 30s and 40s—

• much earlier than the far more common “late-onset” form of Alzheimer’s

that typically strikes people their 70s and 80s.

The new mutation, discovered from whole-genome data from 1795 Icelanders for variations in APP that protect against Alzheimer’s, appears to do the opposite. The mutation interferes with one of the enzymes that breaks down the APP protein and causes a 40% reduction in β amyloid formation

New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F.
University of Catania, Viale Andrea Doria 6, Catania, Italy.
Br J Clin Pharmacol. 2012 Apr;73(4):504-17. doi: 10.1111/j.1365-2125.2011.04134.x.

Current approved drug treatments for Alzheimer disease (AD) include

cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the
NMDA receptor antagonist memantine.

These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop ‘disease modifying drugs’ hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success,

it is crucial to have biomarkers for early detection of AD-related brain dysfunction,
- usable before clinical onset.

Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy,

with specific cut off values validated in clinical practice.

Disease modifying drugs developed so far include drugs to

reduce β amyloid (Aβ) production,
drugs to prevent Aβ aggregation,
drugs to promote Aβ clearance,
drugs targeting tau phosphorylation and assembly

None of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from

methodological flaws to
fundamental understanding of AD pathophysiology and biology.

Diagnostic criteria applicable to presymptomatic stages of AD have now been published.

These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. http://www.ncbi.nlm.nih.gov/pubmed/22035455

Gene mutation defends against Alzheimer’s disease
Rare genetic variant suggests a cause and treatment for cognitive decline.
Ewen Callaway 11 July 2012
http://www.nature.com/news/gene-mutation-defends-against-alzheimer-s-disease-1.10984

J. NIETH/CORBIS
Almost 30 million people live with Alzheimer’s disease worldwide, a staggering health-care burden that is expected to quadruple by 2050. Yet doctors can offer no effective treatment, and scientists have been unable to pin down the underlying mechanism of the disease.
Research published this week offers some hope on both counts – few people carry a genetic mutation that naturally prevents them from developing the condition – 0.5% of Icelanders have a protective gene, as are 0.2–0.5% of Finns, Swedes and Norwegians. Icelanders who carry it have a 50% better chance of reaching age 85, are more than five times more likely to reach it 85 without Alzheimer’s. The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without major cognitive decline, and perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.
The discovery not only confirms the principal suspect that is responsible for Alzheimer’s, it also suggests that the disease could be

an extreme form of the cognitive decline seen in many older people.

The mutation — the first ever found to protect against the disease — lies in a gene that produces

amyloid-β precursor protein (APP),
which has an unknown role in the brain

APP was discovered 25 years ago in patients with rare,

inherited forms of Alzheimer’s that strike in middle age.
In the brain, APP is broken down into a smaller molecule called amyloid-β.

Visible clumps, or plaques, of amyloid-β found in the autopsied brains of patients are a hallmark of Alzheimer’s.
Scientists have long debated whether the plaques are a cause of the neurodegenerative condition

or a consequence of other biochemical changes associated with the disease.

The latest finding supports other genetics studies blaming amyloid-β, according to Rudolph Tanzi, a neurologist at the Massachusetts General Hospital in Boston and a member of one of the four teams that discovered APP’s role in the 1980s.
If amyloid-β plaques were confirmed as the cause of Alzheimer’s, it would bolster efforts to develop drugs that block their formation, says Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik, Iceland, who led the latest research. He and his team first discovered the mutation by comparing the complete genome sequences of 1,795 Icelanders with their medical histories. The researchers then studied the variant in nearly 400,000 more Scandinavians.
This suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. A drug that mimics the effects of the mutation, might slow cognitive decline as well as prevent Alzheimer’s.
Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called

β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks —
and the alteration is enough to reduce the enzyme’s efficiency.

Stefánsson’s study suggests that blocking β-secretase from cleaving APP has the potential to prevent Alzheimer’s, but Philippe Amouyel, an epidemiologist at the Pasteur Institute in Lille, France, says “it is very difficult to identify the

precise time when this amyloid toxic effect could still be modified”.

“If this effect needs to be blocked as early as possible in life to protect against Alzheimer’s disease, we will need to propose a new design for clinical trials” to identify an effective treatment.

The results demonstrate that whole-genome sequencing can uncover very rare mutations that might offer insight into common diseases.

disease risk, may be determined by genetic variants that slightly tilt the odds of developing disease
In this case a rare mutant may provide very key mechanistic insights into Alzheimer’s

Jonsson, T. et al. Nature http://dx.doi.org/10.1038/nature11283 (2012).
Kang, J. et al. Nature 325, 733–736 (1987).
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Science 235, 877–880 (1987).

BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss. http://www.genengnews.com/

New Alzheimer’s Genes Found
Gigantic Scientific Effort Discovers Clues to Treatment, Diagnosis of Alzheimer’s Disease
By Daniel J. DeNoon
WebMD Health News Reviewed by Laura J. Martin, MD
http://www.webmd.com/alzheimers/news/20110403/new-alzheimers-genes-found

A massive scientific effort has found five new gene variants linked to Alzheimer’s disease. The undertaking involved analyzing the genomes of nearly 40,000 people with and without Alzheimer’s. This study was undertaken by two separate research consortiums in the U.S. and in Europe, which collaborated to confirm each other’s results.
Four genes had previously been linked to Alzheimer’s. Three of them affect only the risk of relatively rare forms of Alzheimer’s. The fourth is APOE, until now the only gene known to affect risk of the common, late-onset form of Alzheimer’s. Roughly 27% of Alzheimer’s disease can be attributed to the five new gene variants. Even though Alzheimer’s is a very complex disease, the new findings represent a large chunk of Alzheimer’s risk, according to Margaret A. Pericak-Vance, PhD, of the U.S. consortium –

20% of the causal risk of Alzheimer’s disease and
32% of the genetic risk.

Alzheimer’s Tied to Mutation Harming Immune Response
By GINA KOLATA Published: November 14, 2012 in NY Times
http://www.nytimes.com/2012/11/15/health/gene-mutation-that-hobbles-immune-response-is-linked-to-alzheimers.html?_r=0
Alzheimer’s researchers and drug companies have for years concentrated on one hallmark of Alzheimer’s disease: the production of toxic shards of a protein that accumulate in plaques on the brain.
Two groups of researchers working from entirely different starting points have converged on a mutated gene involved in another aspect of Alzheimer’s disease:

the immune system’s role in protecting against the disease.

The mutation is suspected of interfering with

the brain’s ability to prevent the buildup of plaque.

When the gene is not mutated, white blood cells in the brain spring into action,

gobbling up and eliminating the plaque-forming toxic protein, beta amyloid.

As a result, Alzheimer’s can be staved off or averted. People with the mutated gene have a threefold to fivefold increase in the likelihood of developing Alzheimer’s disease in old age.

Comparing Differences

Dr. Julie Williams’s, Cardiff, Wales (European team leader) report identified CLU and Picalm. A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1. The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke UMC, in Durham, North Carolina.
The findings “are beginning to give us insight into the biology, but I don’t think you can expect treatments overnight,” Dr. Michael Owen (Cardiff, Wales) said. Instead, the genes will show a mosaic of risk, and “the key issue is what hand of cards you’re dealt,” he said.

Promise for Early Diagnosis
BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.

Dr. Bernstein’s comments:

There has been a long history of failure of drugs to slow down the progression of Alzheimer’s. Regression of the plaques has not corresponded with retention of cognitive ability, which has been behind the arguments over beta amyloid or tau.
We now have two particularly interesting mutations –
1. ApoE gene mutation that increases risk
2. APP mutation that quite dramatically affects retention of cognition

Alzheimer’s Disease: Green Tea Extract Found To Interfere With The Formation Of Amyloid Plaques (medicalnewstoday.com)
Aging Brain – The Specific Gene That Causes It (belmarrahealth.com)
The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease (plosone.org)
Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (eurekalert.org)
Major step toward an Alzheimer’s vaccine (nextbigfuture.com)
Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (medicalxpress.com)
Top Signs You are at Risk for Alzheimer’s (belmarrahealth.com)
A Reliable Way to Detect Endogenous Murine β-Amyloid (plosone.org)

β-amyloid fibrils. (Photo credit: Wikipedia)

English: PET scan of a human brain with Alzheimer’s disease (Photo credit: Wikipedia)

Depiction of amyloid precursor protein processing, created by I. Peltan Ipeltan (Photo credit: Wikipedia)

English: Diagram of how microtubules desintegrate with Alzheimer’s disease Français : La protéine Tau dans un neurone sain et dans un neurone malade Español: Esquema que muestra cómo se desintegran los microtúbulos en la enfermedad de Alzheimer (Photo credit: Wikipedia)

English: Histopathogic image of senile plaques seen in the cerebral cortex in a patient with presenile onset of Alzheimer disease. Bowdian stain. The same case as shown in a file “Alzheimer_dementia_(1)_presenile_onset.jpg”. (Photo credit: Wikipedia)

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MGH’s Largest-ever Genetic Study of Five Psychiatric Disorders: Variation in SNPs in Two Genes involved in Calcium-Channel Signaling

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, tagged Lancet, Major depressive disorder, Massachusetts General Hospital, National Institute of Mental Health, Perelman School of Medicine, Smoller, University of Bologna on February 28, 2013| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Five Psych Disorders Have Common Genetics

By Michael Smith, North American Correspondent, MedPage Today

Published: February 27, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

share common genetic underpinnings — despite differences in symptoms and course of disease, researchers discovered.

In particular, single nucleotide polymorphisms (SNPs) in two genes involved in calcium-channel activity appear to play a role in all five, Jordan Smoller, MD, ScD, of Massachusetts General Hospital in Boston, and colleagues reported online in The Lancet.

The findings come from a genome-wide analysis of 33,332 cases and 27,888 controls in what the authors described as the largest-ever genetic study of psychiatric illness.

The results are “new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes,” Smoller said in a statement.

The findings are especially important because of revisions to the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, which have “reinvigorated debate about the validity of diagnostic boundaries,” the authors noted.

Indeed, the findings confirm previous evidence of “abundant pleiotropy in human complex disorders” – meaning the same genetic variant plays a role in several diseases, argued Alessandro Serretti, MD, PhD, and Chiara Fabbri of the University of Bologna in Italy.

For instance, they noted in an accompanying commentary, calcium signaling, a key regulator of the growth and development of neurons, was expected to be highly pleiotropic, an expectation that “has now been confirmed.”

But while some gene variants play a role in many disorders, there are almost certainly others that contribute to the “consistent diversity among disorders,” Serretti and Fabbri argued.

“Many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases,” they wrote.

Nonetheless, they concluded, one implication of the study is that genetics “can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs.”

But that is not likely to happen soon, according to Randy Ross, MD, of the University of Colorado School of Medicine in Aurora, Colo.

The study is a “beginning step to give us ideas that will eventually lead to new treatments,” he told MedPage Today.

In the long run, however, this study and subsequent research will change both diagnosis and treatment, Ross said, as psychiatric diseases are put on a biological footing.

The researchers found that SNPs (single-letter changes in the genetic code) in four regions were associated with all five disorders:

two on chromosome 10, including the L-type voltage-gated calcium-channel subunit CACNB2,
one on chromosome 3, and
another calcium-channel subunit, CACNA1C, on chromosome 12.

The statistical significance of all four surpassed the cutoff for genome-wide significance of P<5×10^-8, Smoller and colleagues reported.

The calcium-channel gene CACNA1C has been previously linked to

bipolar disorder,
schizophrenia, and
major depressive disorder, they wrote, as well as to
Timothy syndrome, a developmental disorder that can include autism.

The other calcium-channel gene has been linked to bipolar disorder in people of Han Chinese ethnicity, they added.

“Our results suggest that voltage-gated calcium signaling, and, more broadly, calcium-channel activity, could be an important biological process in psychiatric disorders,” they argued.

The region on chromosome 3 includes more than 30 genes, Smoller and colleagues noted, but previous research has linked SNPs in the area to

bipolar disorder,
schizophrenia, and
depression.

They cautioned that they compared models of cross-disorder effects with widely used goodness-of-fit measures, but different criteria might yield other results.

They also noted that diagnostic misclassification in the study cohort might produce “spurious evidence of genetic overlap between disorders,” although such errors would have to be widespread to affect the results.

Another limitation: the members of the study cohort were of European ancestry, so it’s not known if the findings apply to other populations.

The study was supported by the National Institute of Mental Health, as well as grants from the NIH, government grants from other countries, and private and foundation support.

The authors declared they had no conflicts.

The comment authors declared they had no conflicts.

Primary source: Lancet

Source reference:
Smoller JW, et al “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis” Lancet 2013; DOI: 10.1016/S0140-6736(12)62129-1.

Additional source: Lancet
Source reference:
Alessandro Serretti, Chiara Fabbri “Shared genetics among major psychiatric disorders” Lancet 2013; DOI: 10.1016/S0140-6736(13)60223-8.

SOURCE:

http://www.medpagetoday.com/Psychiatry/GeneralPsychiatry/37584

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