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Erasmus Medical Center and Surface Oncology | Date: 2016-09-21

Disclosed herein are anti-CD47 antibody molecules, their manufacture and use in treating disorders associated with CD47 expression, for example, certain hematological cancers and solid tumors.

PARIS & EDEN PRAIRIE, Minn.--(BUSINESS WIRE)--Revealing a potential new role for fractional flow reserve (FFR) in cath labs, investigators from the Erasmus Medical Center unveiled early results from the independent, physician-sponsored FFR-Search Registry, which revealed an association between post-percutaneous coronary intervention (PCI) FFR measurements with the ACIST Navvus® Rapid Exchange FFR MicroCatheter and clinical outcomes. The investigators found that microcatheter-based FFR was feasible in various clinical settings, including acute coronary syndromes and ST elevation myocardial infarction, and almost half of patients had an FFR lower than 0.90 after PCI. As anticipated, these early results did not have a meaningful impact on 30-day clinical outcomes; patients will now be followed out to the two-year primary endpoint to shed more definitive light on the value of post-PCI FFR in clinical practice. These early findings were presented during a late-breaking trial session at EuroPCR 2017 in Paris, France. The registry enrolled over 1,000 consecutive patients with stable angina or acute coronary syndromes that had undergone percutaneous coronary intervention at Erasmus Medical Center in Rotterdam to determine the association of post-PCI FFR values on clinical outcomes, as measured at 30-days, one-year, two-years and five-years follow-up. In an attempt to replicate real world clinical practice, the protocol precluded operators from additional optimization techniques after the initial stent placement. Using the ACIST Navvus Rapid Exchange FFR MicroCatheter — an ultra-thin monorail microcatheter with fiber-optic technology — the average post-PCI FFR value was 0.96 in a resting state and 0.91 under hyperemic conditions in the 959 patients who were able to undergo FFR measurement. Utilizing the microcatheter technology allowed the investigators the unique benefit of delivering the pressure sensor diagnostic directly over any 0.014” workhorse guidewire post-PCI and only added approximately 5 minutes to the overall procedural time. Interestingly, 22 percent of patients whose lesions were stented still had at least one post-PCI FFR measurement less than or equal to 0.85. The primary clinical endpoint is MACE defined as all-cause mortality, myocardial infarction (MI) and any revascularization. The initial 30-day data found that FFR measurements greater than 0.9 resulted in a MACE rate of 1.5 percent, while measurements less than 0.9 resulted in a MACE rate of 2.3 percent (p=ns). Furthermore, as the FFR measurements decreased in patients, the MACE rates numerically increased. While the patient cohorts with FFR measurements below 0.90 were underpowered to show statistical differences between groups, FFR measurements in the 0.86-0.90, 0.81-0.85 and less than or equal to 0.80 ranges resulted in MACE rates of 2.0 percent, 2.6 percent, and 2.8 percent, respectively. “As FFR becomes more and more the standard to determine treatment approaches in patients with coronary artery disease, we are excited to see that this technology is safe, fast and easy to apply — as well as may be used to optimize longer-term outcomes after interventional procedures,” said FFR-Search investigator Dr. Nicolas M. Van Mieghem, MD, PhD, FESC, co-principal investigator and Director of Interventional Cardiology at Thoraxcenter, Erasmus Medical Center in Rotterdam, Netherlands. “The preliminary data from FFR-Search has the potential to significantly expand this technology’s role in the cath lab in the future, which is why we’re eager to see the important results of the primary endpoint at two years.” In 60 of the patients having an FFR value equal to or less than 0.85, an intravascular high definition ultrasound analysis was performed to identify potential causes for the low post procedural FFR measurement. Stent under-expansion was the most frequently identified cause for low FFR, found in 84 percent of the cases, followed by focal lesions distal to the stent (52 percent), focal lesions proximal to the stent (43 percent) and stent malapposition (22 percent). “Based on these results, we look forward to continuing to build the evidence supporting this new role of FFR,” said FFR-Search co-investigator and presenter Dr. Roberto Diletti, MD, Interventional Cardiology at Thoraxcenter, Erasmus Medical Center in Rotterdam, Netherlands. “We are eager to see how the outcomes will unfold at one, two and five years, and how we may be able to best optimize these findings through further intervention after the post-treatment FFR measurement.” Unlike traditional pressure wires, the ACIST RXi® Rapid Exchange FFR System and Navvus® Rapid Exchange FFR MicroCatheter, allows physicians to use their 0.014” guidewire of choice throughout the procedure, addressing challenges of pressure wires, including, accessibility in challenging anatomies, maintaining wire position, pressure‐measurement drift and ease of obtaining post‐intervention FFR. “Given that our differentiated microcatheter technology allows physicians the ability to perform rapid FFR measurements before, during and after intervention, all while maintaining their guidewire position, we feel that we are uniquely suited to address this new role of FFR compared to other FFR measurement modalities, including pressure wire-based FFR,” said Tom Morizio, President and CEO, ACIST Medical Systems, Inc. “We look forward to partnering with physicians to develop this new approach and are optimistic about the possibility of our technology playing a new role in improving outcomes.” About FFR FFR measurement is a technique used in cardiology to determine the effect of narrowing, or stenosis, in the coronary arteries on blood flow. It allows for a more effective assessment of coronary lesions than when only using angiography, the gold-standard imaging technique. By identifying which stenoses are causing ischemia by significantly restricting the blood flow to the heart muscle and causing the patient’s symptoms, FFR can help avoid unnecessary stenting to reopen the blood vessels, leading to improved patient outcomes.1,2 About ACIST ACIST Medical Systems, Inc. is a pioneering interventional and diagnostic technology company with a portfolio of advanced products, including the world’s first Rapid Exchange FFR and High Definition IVUS systems. It is also a global market leader in advanced contrast imaging systems for cardiovascular angiography and radiology imaging. Through these products, ACIST is demonstrating its commitment to bringing unique and innovative technologies that simplify cardiovascular procedures and empower clinicians to treat patients with superior care. As part of the Bracco Group, ACIST benefits from the resources of a multinational conglomerate with broad expertise in cath lab technology and a dedication to continuous advancement. Headquartered in Eden Prairie, Minnesota, USA, ACIST has worldwide presence with over 300 direct employees and facilities in Silicon Valley, Heerlen, and Tokyo. To learn more about ACIST, visit Bracco Group Bracco has headquarters in Milan, Italy, and was founded in 1927. It is active in the healthcare sector through Bracco Imaging (diagnostic imaging), ACIST Medical Systems and HLT (cardiology) and the Centro Diagnostico Italiano diagnostic clinic. It has around 3,400 employees and annual total consolidated revenues of over 1.3 billion Euro. Bracco operates in more than 100 countries worldwide. To learn more about Bracco Group, visit 1 Tonino PA et al. New Engl J Med 2009;360:213-24 2 De Bruyne B et al. New Engl J Med 2012;367:991-1001

Lowenberg B.,Erasmus Medical Center
Blood | Year: 2013

High-dose cytarabine applied during remission induction or as consolidation after attainment of a complete remission has become an established element in the treatment of adults with acute myeloid leukemia. Recent evidence has challenged the need for these exceptionally high-dose levels of cytarabine. In this review, we present a reappraisal of the usefulness of high-dose cytarabine for acute myeloid leukemia treatment. © 2013 by The American Society of Hematology.

Giglia-Mari G.,Erasmus Medical Center
Cold Spring Harbor perspectives in biology | Year: 2011

Structural changes to DNA severely affect its functions, such as replication and transcription, and play a major role in age-related diseases and cancer. A complicated and entangled network of DNA damage response (DDR) mechanisms, including multiple DNA repair pathways, damage tolerance processes, and cell-cycle checkpoints safeguard genomic integrity. Like transcription and replication, DDR is a chromatin-associated process that is generally tightly controlled in time and space. As DNA damage can occur at any time on any genomic location, a specialized spatio-temporal orchestration of this defense apparatus is required.

Lubberts E.,Erasmus Medical Center
Nature Reviews Rheumatology | Year: 2015

The discovery that the IL-23-IL-17 immune pathway is involved in many models of autoimmune disease has changed the concept of the role of T-helper cell subsets in the development of autoimmunity. In addition to T H 17 cells, IL-17 is also produced by other T cell subsets and innate immune cells; which of these IL-17-producing cells have a role in tissue inflammation, and the timing, location and nature of their role(s), is incompletely understood. The current view is that innate and adaptive immune cells expressing the IL-23 receptor become pathogenic after exposure to IL-23, but further investigation into the role of IL-23 and IL-17 at different stages in the development and progression of chronic (destructive) inflammatory diseases is needed. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common forms of chronic immune-mediated inflammatory arthritis, and the IL-23-IL-17 axis is thought to have a critical role in both. This Review discusses the basic mechanisms of these cytokines in RA and SpA on the basis of findings from disease-specific animal models as well as human ex vivo studies. Promising therapeutic applications to modulate this immune pathway are in development or have already been approved. Blockade of IL-17 and/or T H 17-cell activity in combination with anti-TNF therapy might be a successful approach to achieving stable remission or even prevention of chronic immune-mediated inflammatory diseases. © 2015 Macmillan Publishers Limited.

Tilanus-Linthorst M.M.A.,Erasmus Medical Center
Journal of the National Cancer Institute | Year: 2013

Background To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear. Methods We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided. Results Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (σ93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (σ102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (σ41 390) per LYG with mammography only. Conclusions Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories. © The Author 2013. Published by Oxford University Press. All rights reserved.

Spits H.,Tytgat Institute for Liver and Intestinal Research | Cupedo T.,Erasmus Medical Center
Annual Review of Immunology | Year: 2012

Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy. © 2012 by Annual Reviews. All rights reserved.

Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre-alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities.

Kappetein A.P.,Erasmus Medical Center
Journal of Thoracic and Cardiovascular Surgery | Year: 2013

Objectives: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. Background: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. Methods and Results: Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. Conclusions: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). Copyright © 2013 by The American Association for Thoracic Surgery.

BACKGROUND: Fragmentation of stacked cisterns of the Golgi apparatus into dispersed smaller elements is a feature associated with degeneration of neurons in amyotrophic lateral sclerosis (ALS) and some other neurodegenerative disorders. However, the role of Golgi fragmentation in motor neuron degeneration is not well understood.RESULTS: Here we use a SOD1-ALS mouse model (low-copy Gurney G93A-SOD1 mouse) to show that motor neurons with Golgi fragmentation are retrogradely labeled by intramuscularly injected CTB (beta subunit of cholera toxin), indicating that Golgi fragmentation precedes neuromuscular denervation and axon retraction. We further show that Golgi fragmentation may occur in the absence of and precede two other pathological markers, i.e. somatodendritic SOD1 inclusions, and the induction of ATF3 expression. In addition, we show that Golgi fragmentation is associated with an altered dendritic organization of the Golgi apparatus, does not depend on intact apoptotic machinery, and is facilitated in transgenic mice with impaired retrograde dynein-dependent transport (BICD2-N mice). A connection to altered dynein-dependent transport also is suggested by reduced expression of endosomal markers in neurons with Golgi fragmentation, which also occurs in neurons with impaired dynein function.CONCLUSIONS: Together the data indicate that Golgi fragmentation is a very early event in the pathological cascade in ALS that is associated with altered organization of intracellular trafficking.

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