Breakthrough Treatment With Prometric’s IV Plasminogen Treats Rare Disabling Disorder

MedicalResearch.com Interview with:
Dr. Charles T. Nakar, MD

Indiana Hemophilia and Thrombosis Center Pediatrics
Indianapolis, IN  

MedicalResearch.com: What is the background for this study?

Response: Congenital plasminogen deficiency is a rare genetic disorder that is caused by mutations in the PLG gene. Mutations in this gene lead to clinical manifestations such as fibrinous deposits on mucous membranes leading to disruption of tissue or organ function. These symptoms, when untreated, lead to significant morbidity and decreased quality of life. Life-threatening episodes may occur especially when the respiratory system is affected. There is currently no established approach to treatment of type 1 plasminogen deficiency and the available topical and systemic therapies (e.g. FFP, corticosteroids, immunomodulatory drugs, anticoagulants, amongst others) lack consistent efficacy. Patients may undergo multiple surgeries to remove lesions, but this approach typically leads to regrowth of lesions. Prometic’s intravenous plasminogen replacement therapy represents the first direct treatment for this serious disorder.

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Multiple Myeloma: Phase 3 Study of DARZALEX + VMP Reduced Risk of Disease Progression and Mortality

MedicalResearch.com Interview with:

Dr. Meletios A. Dimopoulos MD Professor and Chairman Department of Clinical Therapeutics University Athens School of Medicine Athens, Greece

Dr. Dimopoulos

DrMeletios A. Dimopoulos MD
Professor and Chairman
Department of Clinical Therapeutics
University Athens School of Medicine
Athens, Greece

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Updated data from the Phase 3 POLLUX trials showed DARZALEX, in combination with lenalidomide and dexamethasone, reduced the risk of disease progression or death by 56 percent, compared to lenalidomide and dexamethasone alone (Hazard Ratio [HR]=0.44; 95 percent CI [0.34-0.55], p<0.0001). After a median follow-up of 32.9 months, the median progression-free survival (PFS) in the DARZALEX arm has not been reached, compared with a median PFS of 17.5 months for patients who received lenalidomide and dexamethasone alone.

DARZALEX in combination with lenalidomide and dexamethasone also significantly increased the overall response rate (ORR) compared to lenalidomide and dexamethasone alone (93 percent vs. 76 percent, p<0.0001), including rates of complete response (CR) or better (55 percent vs. 23 percent, p<0.0001). DARZALEX also showed significantly higher (>3-fold) MRD-negative rates compared to lenalidomide and dexamethasone alone. These data were featured as an oral presentation (Abstract #739) at the 59th American Society of Hematology (ASH) Annual Meeting in early December.

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Daratumumab Monotherapy for Patients with Intermediate or High-Risk Smoldering Multiple Myeloma

MedicalResearch.com Interview with:

Craig C. Hofmeister, MD, MPH The Ohio State University 

Dr. Hofmeister

Craig CHofmeisterMD, MPH
The Ohio State University 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Preliminary data presented from the randomized, open-label, Phase 2 CENTAURUS (SMM2001) study evaluated three dosing schedules for DARZALEX monotherapy in patients with intermediate or high-risk smoldering multiple myeloma. A total of 123 patients were enrolled, with a median time since initial smoldering multiple myeloma diagnosis of 6.83 months (0.4-56). Patients were randomized to one of three treatment arms receiving DARZALEX 16 mg/kg intravenously in 8-week cycles: 1.) a long-intense dosing schedule (LONG) where DARZALEX was administered weekly in Cycle 1, every other week in Cycle 2-3, every 4 weeks in Cycle 4-7, and every 8 weeks up to Cycle 20; 2.) an intermediate dosing schedule (INT), where DARZALEX was given weekly for 1 cycle, and every 8 weeks up to Cycle 20 and; 3.) a short intense dosing schedule (SHORT), where DARZALEX was given weekly for 1 cycle. Results from the study showed DARZALEX monotherapy had a tolerable safety profile in patients with intermediate or high-risk smoldering multiple myeloma, with the most common treatment-emergent adverse events (TEAEs) being fatigue, cough, headache and insomnia. The efficacy endpoints included overall response rate, progression free survival, time to next treatment, and overall survival rate at 4 years. These study results serve as the basis for a Phase 3 study for DARZALEX in smoldering multiple myeloma, which is actively enrolling. These findings demonstrated DARZALEX had a manageable safety profile in patients with intermediate or high-risk smoldering multiple myeloma.

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Cost and Side Effects Influence Patients’ Preferences for Leukemia Medications

MedicalResearch.com Interview with:

Carol Mansfield, PhD, Senior Research Economist Health Preference Assessment RTI Health Solutions www.rtihs.org

Dr. Mansfield

Carol Mansfield, PhD,
Senior Research Economist

Health Preference Assessment
RTI Health Solutions
www.rtihs.org 

MedicalResearch.com: What is the background for this study?

Response: As the most prevalent form of leukemia, chronic lymphocytic leukemia (CLL) affects approximately 130,000 people in the United States. More than 20,000 new cases are diagnosed each year. In recent years, more treatment options–each with its own associated benefits, side effects, and price tag–have been approved. This leaves patients and physicians with a variety of factors they must consider when choosing a treatment plan.

While every patient wants the most effective drug with the fewest side effects, most people don’t have that option available. By asking patients to make tradeoffs and rank their preferences, we can form an understanding of how patients approach their treatment.

This study showed that patients with CLL value medicines that provide the longest progression-free survival, but are willing to trade some benefits for a lower risk of serious adverse events. Additionally, we found that cost clearly has an impact on which treatment a patient would choose. When patients get prescribed something they can’t afford, they are forced to make very difficult choices.

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Transfusions From Previously Pregnant Donors Add Risk To Younger Male Recipients

MedicalResearch.com Interview with:

Rutger Middelburg, PhD Assistant Professor in clinical epidemiology Sanquin Research and LUMC

Dr. Middelburg

Rutger Middelburg, PhD
Assistant Professor in clinical epidemiology
Sanquin Research and LUMC 

MedicalResearch.com: What is the background for this study?

Response: Six years ago we found transfusions from female donor to be associated with increased mortality among male recipients, especially under 50 years of age. This was an unexpected observation and we considered the probability of a false positive finding (i.e. a chance association) to be relatively high. We therefore immediately started a follow-up study with two main objectives. First, we wanted to confirm our findings in an independent and much larger cohort. Second, since some complications of blood transfusion are known to be related to pregnancy history of the donor, we wanted to study a possible relationship with previous pregnancy of the blood donors.

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Emergency Transfusion of Patients with Unknown Blood Type with Blood Group O Rhesus D Positive Blood

MedicalResearch.com Interview with:
Dr. med. Kathleen Selleng, OÄ, QB Hämotherapie

Universitätsmedizin Greifswald
Institut für Immunologie und Transfusionsmedizin,
Abt. Transfusionsmedizin
Sauerbruchstraße
Greifswald Deutschland

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Red blood cell concentrates (RBCs) of blood group O RhD negative are frequently used as universal blood for emergency transfusions in patients with unknown blood type. This leads to an over-proportional use of these red blood cell concentrates and regular shortages of O RhD negative RBCs.

Due to these shortages, patients with known RhD negative blood type sometimes have to be transfused with RhD positive RBCs.

The present study shows that the overall risk to induce an anti-D by transfusing all emergency patients with unknown blood type with O RhD positive RBCs is in the range of 3 to 6%, while this risk is much higher (20-30%) in RhD negative patients which have to be transfused with RhD positive RBCs due to RhD negative RBC shortages.

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Effects of Delayed Vs Early Umbilical Cord Clamping on Infant Anemia

Ola Andersson, MD, PhD Department of Women’s and Children’s Health Uppsala University, Uppsala, Sweden

MedicalResearch.com Interview with:
Dr. Ola Andersson MD, PhD
Uppsala University,
Uppsala, Sweden

MedicalResearch.com: What is the background for this study?

Response: Anemia affects over 40% of all children under 5 years of age in the world. Anemia can impinge mental and physical performance, and is associated with long-term deterioration in growth and development. Iron deficiency is the reason for anemia in approximately 50% of the children.is. When clamping of the umbilical cord is delayed, ie after 3 minutes, iron deficiency up to 6 months of age can be prevented, but it has not been shown to prevent iron deficiency or anemia in older infants.

At birth, approximately 1/3 of the child’s blood is in the placenta. If clamping of the umbilical cord is done immediately (early cord clamping), the blood will remain in the placenta and go to waste (or can be stored in stem cell banks). If instead clamping is postponed for 3 minutes, most of the blood can flow back to the child as an extra blood transfusion, consisting of about one deciliter (1/2 cup) of blood, equivalent to about 2 liters (half a US gallon) of an adult. A blood donor leaves 0.4-0.5 liters of blood.

Blood contains red blood cells that contain hemoglobin. Hemoglobin carries oxygen to the tissues of the body. Hemoglobin contains a lot of iron, and the extra deciliter of blood may contain iron that corresponds to 3-4 months of the need for an infant.

The World Health Organization (WHO) recommends umbilical cord clamping at 1 minute or later, American College of Obstetricians and Gynecologists (ACOG) recommends umbilical cord clamping at 30-60 seconds or later.

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Novel Oral Iron Formulation Can Correct Anemia in Non-Dialysis CKD

MedicalResearch.com Interview with:

Dr. Glenn M. Chertow, MD Professor Medicine, Nephrology Stanford University School of Medicine

Dr. Glenn M. Chertow

Dr. Glenn M. Chertow, MD
Professor Medicine, Nephrology
Stanford University School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Iron deficiency is common in persons with moderate to advanced (non-dialysis-dependent) chronic kidney disease (CKD), for a variety of reasons. Conventional iron supplements tend to be poorly tolerated and of limited effectiveness. In earlier studies of patients treated with ferric citrate for its effect as a phosphate binder, we saw increases in transferrin saturation and ferritin (markers of iron stores) and hemoglobin and hematocrit (the “blood count”). Therefore, we thought we should test the safety and efficacy of ferric citrate specifically for the treatment of iron deficiency anemia (IDA).

With respect to the key findings, more than half (52%) of patients treated with ferric citrate experienced a sizeable (>=1 g/dL) increase in hemoglobin over the 16-week study period compared to fewer than one in five (19%) patients treated with placebo. Rates of adverse events (“side effects”) were similar to placebo; diarrhea in some patients and constipation in others were the most common. There were also favorable effects of ferric citrate on laboratory metrics of bone and mineral metabolism.

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Iron Deficiency Anemia Linked to Hearing Loss

MedicalResearch.com Interview with:
Kathleen Schieffer, BS, PhD Candidate
Biomedical Sciences and Clinical and Translational Science
Clinical and Translational Science Fellow
Hershey, PA 17033

MedicalResearch.com: What is the background for this study?

Response: Hearing loss is common in the United States, with its prevalence increasing with each decade of life. Iron deficiency anemia is a common, reversible condition, associated with negative health outcomes. The inner ear is highly sensitive to ischemic damage and previous animal studies have shown that iron deficiency anemia alters the inner ear physiology. Understanding the association between iron deficiency anemia and hearing loss may open new possibilities for treatment.

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No Association Between Length of Red Blood Cell Storage and Mortality

MedicalResearch.com Interview with:
Märit Halmin, MD, PhD student

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,  Stockholm, Sweden

MedicalResearch.com: What is the background for this study?

Response: During recent years the possible negative effects among recipients of stored red blood cells have been investigated.  Despite a large number of studies, including four randomized trials, no consensus exists.

We therefore performed the hitherto largest register based cohort study of transfused patients, assessing the association between length of storage of red blood cells and mortality. Our design allowed for detection of small but still clinically significant effect, if such exists.

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Bleeding Risk Reduction in Relation to Predicted Factor IX Levels in Hemophilia B Patients Receiving Idelvion (rIX-FP)

MedicalResearch.com Interview with:

Jerry Powell MD Medical Director North America Commercial Operations CSL Behring

Dr. Jerry Powell

Jerry Powell MD
Medical Director
North America Commercial Operations
CSL Behring

MedicalResearch.com: What is the background for this study?

Response: The new IDELVION results presented at the American Society of Hematology (ASH) are from a pooled analysis of clinical studies from the global PROLONG-9FP clinical development program. The analysis assessed the relationship between estimated factor IX activity levels and clinical bleeding risk in adult hemophilia B patients treated with IDELVION using prophylaxis or on-demand (episodic) treatment.

The PROLONG-9FP clinical development program included five Phase I through Phase III open-label, multicenter studies evaluating the pharmacokinetics, safety and efficacy of IDELVION in children and adults with hemophilia B.

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Computerized Working Memory Training in Pediatric Sickle Cell Disease

MedicalResearch.com Interview with:

Steven J. Hardy, PhD Licensed Clinical Psychologist Divisions of Hematology and Oncology Children’s National Health System Assistant Professor of Pediatrics and Psychiatry & Behavioral Sciences George Washington School of Medicine and Health Sciences Washington, DC

Dr. Steven J. Hardy

Steven J. Hardy, Phd
Licensed Clinical Psychologist
Divisions of Hematology and Oncology
Children’s National Health System
Assistant Professor of Pediatrics and Psychiatry & Behavioral Sciences
George Washington School of Medicine and Health Sciences Washington, DC

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Children with sickle cell disease exhibit neurocognitive deficits as a consequence of either silent or overt cerebral infarction or disease-related non-infarct central nervous system effects (likely resulting from chronic anemia and hypoxic events). These complications often lead to impairment in executive functioning (e.g., working memory, attention, inhibition, cognitive flexibility), which can make it difficult to focus in class, plan for long-term school projects, remember and carry out multi-step tasks or assignments, and stay organized. The literature on interventions to reduce neurocognitive sequelae of sickle cell disease is extremely limited.

Our research team investigated a promising home-based, computerized cognitive training program (Cogmed) involving repeated practice on performance-adapted exercises targeting working memory with a sample of youth (ages 7 – 16) with sickle cell disease. Of the participants who have enrolled in the study (n = 70), 49% exhibited working memory deficits (<25% in the general population have a working memory deficit) and were randomized to an eight-week waitlist or to begin Cogmed immediately. Participants who used Cogmed demonstrated significant improvements on multiple measures of working memory, while those randomized to the waitlist group only exhibited such improvements after receiving Cogmed. Approximately 25% of participants completed the recommended number of Cogmed sessions (20 – 25 sessions). However, analyses revealed that participants who completed at least 10 sessions (about 50% of the participants) showed comparable levels of working memory improvement.

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Monoclonal Antibody Crizanlizumab Reduces Sickle Cell Pain Crisis

MedicalResearch.com Interview with:

Kenneth I. Ataga, MD Division of Hematology/Oncology University of North Carolina at Chapel Hill Chapel Hill, NC

Dr. Kenneth I. Ataga

Kenneth I. Ataga, MD
Division of Hematology/Oncology
University of North Carolina at Chapel Hill
Chapel Hill, NC

MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The available treatments for acute painful episodes (also referred to as vaso-occlusive crises), the most common complication of sickle cell disease, are limited.

Findings from the Phase II SUSTAIN study showed that crizanlizumab (formerly SelG1) at 5 mg/kg reduced the median rate of sickle cell disease-related pain crises per year by 45.3% vs. placebo in patients with or without concomitant hydroxyurea therapy. In addition, clinically meaningful reductions in the frequency of painful crises were observed regardless of sickle cell disease genotype. 

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Key Barriers To Development of Artificial Red Blood Cells Overcome

MedicalResearch.com Interview with:

Allan Doctor, MD Pediatric Critical Care Medicine Professor of Pediatrics and (Associate) Biochemistry Washington University School of Medicine & Saint Louis Children’s Hospital St. Louis, Missouri

Dr. Allan Doctor

Allan Doctor, MD
Pediatric Critical Care Medicine
Professor of Pediatrics and (Associate) Biochemistry
Washington University School of Medicine &
Saint Louis Children’s Hospital
St. Louis, Missouri

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our research team has developed the first nanoscale artificial cells designed to emulate vital functions of natural red blood cells. If ultimately confirmed safe for use in humans, this nanotechnology-based product, called ‘ErythroMer’, could represent a new and innovative alternative to blood transfusions that would be especially valuable in situations where stored blood is needed, but difficult to obtain or use, such as in pre-hospital or battlefield settings. The artificial cells are designed to be freeze-dried, stored for extended periods at ambient temperatures, and simply reconstituted with water for immediate use.

This year, the National Academy of Sciences estimated that 30,000 civilian trauma deaths/year are preventable and of these, two-thirds arise from hemorrhage in the pre-hospital phase of care. One key goal for our team is to advance treatment for trauma victims or soldiers in austere environments by initiating resuscitation in the field, particularly when transport is prolonged. ErythroMer could be a blood substitute that medics carry in their pack and literally take it out, add water, and inject. There are currently no simple, practical means to bring transfusion to most trauma victims outside of hospitals. Delays in resuscitation significantly impact outcomes; it is our goal to push timely, effective care to field settings.

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Two Different European Strategies Achieve KDIGO Renal Anemia Targets

MedicalResearch.com Interview with:

Dorota Drozdz M.D., Ph.D Jagiellonian University Kraków

Dr. Dorota Drozdz

Dorota Drozdz M.D., Ph.D
Jagiellonian University
Kraków

Response: In Poland and Portugal we use EPO beta for anemia treatment. Our interest was to find differences in clinical patterns taking in consideration that both countries are adherent to KDIGO recommendations an guidelines.

We found that in both countries the mean hemoglobin (Hb) level and percentage of patients in target Hb level (10-12 g/dl on ESA treatment) are the same, but the approaches were different – in Poland the ESA dose was statistically lower than in Portugal and iron dose was statistically higher than in Portugal. Most other lab tests results were similar. Future secondary outcomes analysis should answer the question, which method is safer.

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Peripheral IV Lines Linked To Lower Risk of Blood Clots After Transfusion

MedicalResearch.com Interview with:
Mary A.M. Rogers, PhD, MS

Research Associate Professor
Research Director, Patient Safety Enhancement Program
Department of Internal Medicine
University of Michigan
Ann Arbor, MI

MedicalResearch.com: What is the background for this study?

Response: Peripherally inserted central catheters (PICCs) are commonly used for vascular access in hospitalized patients. Previous studies have shown that PICCs of larger gauge (diameter) increase the risk of developing venous thromboembolism (blood clots in the deep veins that sometimes travel to the lung). Red blood cell transfusion is also known to increase the risk of venous thromboembolism. Because PICCs are often used to transfuse blood, we designed a study to investigate whether the method of transfusion delivery influences the risk of developing venous thromboembolism.

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No Iron Benefit To Mother From Eating Placenta

MedicalResearch.com Interview with:

Daniel C Benyshek, PhD Professor, Department of Anthropology Adjunct Professor, UNLV School of Medicine Co-Director, Metabolism, Anthropometry and Nutrition Lab UNLV

Dr. Daniel C Benyshek

Daniel C Benyshek, PhD
Professor, Department of Anthropology
Adjunct Professor, UNLV School of Medicine
Co-Director, Metabolism, Anthropometry and Nutrition Lab
University of Nevada, Las Vegas

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Maternal placentophagy is ubiquitous among nearly all terrestrial mammals, but is rare to non-existent among humans in the historic and cross-cultural records. Recently, however, human maternal placentophagy has emerged as a popular trend among a small but growing number of women in many industrialized countries. Most women engaging in the practice today consume their processed placenta in capsule form, taken daily, over several weeks postpartum. While human maternal placentophagy advocates claim many maternal health benefits from the practice, including improved postpartum mood, increased breast-milk production, and improved energy, among others, no carefully designed, placebo-controlled studies have evaluated these claims.

Our randomized, double-blind, placebo-controlled pilot study (N=23) investigated some of these claims. Our study found that the postpartum iron status of participants who consumed their own encapsulated placenta (based on the three week daily intake recommendation of one prominent placenta encapsulation service), was no different from those women who consumed the same amount of beef placebo.

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Minimally Invasive Gene Editing Cured Thalassemia in Mice

MedicalResearch.com Interview with:

Peter M. Glazer, MD, PhD Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology Yale University

Dr. Peter M. Glazer

Peter M. Glazer, MD, PhD
Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology
Yale University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It is generally recognized that gene editing in blood stem cells could provide a strategy for treatment of inherited disorders such as sickle cell disease and thalassaemia. Recent excitement has focused on CRISPR/Cas9 technology because of it is so easy to use. However, the CRISPR approach introduces an active DNA cutting enzyme into cells, which can lead to off-target cuts in the genome. As an alternative, we have pursued triplex-forming peptide nucleic acids (PNAs) designed to bind site-specifically to genomic DNA via strand invasion and formation of PNA/DNA/PNA triplexes. PNAs consist of a charge-neutral peptide-like backbone and nucleobases enabling hybridization with DNA with high affinity. PNA/DNA/PNA triplexes recruit the cell’s own DNA repair machinery to initiate site-specific editing of the genome when single-stranded ‘donor DNAs’ are co-delivered as templates containing the desired sequence modification.

We found that triplex-forming PNAs substituted at the gamma position yielded high levels of gene editing in blood stem cells in a mouse model of human β-thalassaemia. Injection of thalassemic mice with nanoparticles containing gamma PNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood hemoglobin levels into the normal range and up to 7% β-globin gene correction in stem cells, with extremely low off-target effects. We conclude that the combination of nanoparticle delivery and next generation PNAs may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration.

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PAD: MarrowStim PAD Kit Uses Patient’s Bone Marrow Cells To Improve Critical Critical Limb Ischemia

MedicalResearch.com Interview with:

Michael P. Murphy, MD

Dr. Michael Murphy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease whereby a severe obstruction of the arteries markedly reduces blood flow to the extremities (hands, feet and legs) causing severe pain, skin ulcers, sores, or gangrene.  Up to 30% of patients with CLI do not qualify for conventional interventions, such as a bypass or angioplasty, putting them at risk for amputation.

The MOBILE trial (MarrOwStim™ PAD Kit for the Treatment of Critical LimB IschemIa in Subjects with Severe Peripheral ArteriaL DiseasE) was designed to assess the safety and efficacy of using autologous concentrated bone marrow aspirate (cBMA), cells derived from the patient’s own bone marrow, to restore blood flow and prevent amputations in patients with CLI.

MOBILE is a Phase 3, double-blind, randomized, placebo-controlled trial that evaluated 152 patients with CLI at 24 centers in the U.S. Patients were randomized to receive cBMA or placebo via injection at 40 sites on the symptomatic leg.  The cBMA was obtained from each patient using the MarrowStim PAD kit.  The placebo group underwent a sham bone marrow aspiration and received needle punctures in the index leg.

The primary efficacy endpoint was amputation-free survival, defined as freedom from all causes of death and/or major amputation, at 52 weeks after treatment. Other endpoints included changes in blood flow in the leg, wound healing, measures of pain and quality of life, and distance walked in 6 minutes. The trial completed in June 2016, and a preliminary analysis found that cBMA demonstrated a meaningful improvement in amputation-free survival and a comparable safety profile to placebo.

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IV Iron Postoperatively May Reduce Infections, Transfusions and Length of Hospital Stay

MedicalResearch.com Interview with:
Alhossain A. Khalafallah, Clinical Professor
Menzies Institute for Medical Research,
University of Tasmania, Australia
Consultant Haematologist
Launceston General Hospital
Australia

MedicalResearch.com: What is the background for this study?

Response: There are limited data regarding the effect of postoperative anemia on patient’s outcomes. The issue of postoperative anemia was noticeably to affect a large cohort of patients world-wide.

This study was aiming at comparing the new approach with a single ferric carboxymaltose infusion versus standard or routine usual care for management of postoperative anemia.

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Anemia Increases Mortality From Stroke

MedicalResearch.com Interview with:
Raphae Barlas M.A
3rd year MBChB student
The Institute of Applied Health Sciences
Aberdeen

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Anemia and stroke are both common conditions. While previous studies have found an association between anemia on admission and increased mortality in stroke patients, this was not consistent throughout the literature. We aimed to comprehensively assess this association by conducting our own observational study, consisting of 8000 patients from UK regional stroke registry data. We then aggregated our findings into a systematic review and meta-analysis of the existing literature for a total study population of approximately 30,000 patients.

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ALPROLIX – Recombinant Factor IX Fc Fusion Protein – Resolved Joint Bleeds in Hemophilia B

MedicalResearch.com:
Nisha Jain, Director
Global Medical at Biogen

Regarding: Post Hoc Analysis to Evaluate the Effect of Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis in Adults and Adolescents with Target Joints and Hemophilia B being presented at the World Federation of Hemophilia (WFH) 2016 World Congress

MedicalResearch.com: What is the background for this study?

Response: People with hemophilia B experience prolonged bleeding episodes that can cause pain, irreversible joint damage and life-threatening hemorrhages. For people with severe hemophilia, most bleeding events occur in joints, with joint damage being the most common complication of the condition.(1) Over time, joints can become severely damaged and an individual can suffer from acute pain as well as restricted range of motion in those joints.(1)

MedicalResearch.com: What are the main findings?

Response: The B-LONG and B-YOND trials evaluated ALPROLIX® [Coagulation Factor IX (Recombinant), Fc Fusion Protein] in hemophilia B patients. In this post-hoc analysis of 37 patients with target joints in B-LONG and B-YOND, most (98.9%) target joints were considered resolved using the International Society on Thrombosis and Haemostasis (ISTH) definition of resolution as ≤ 2 bleeds into the joint within a consecutive 12-month period.

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Sickle Cell Trait Not Associated With Increased Mortality in Military Population

MedicalResearch.com Interview with:
D. Alan Nelson, MPAS, PhD
Postdoctoral research fellow
Stanford Medicine

MedicalResearch.com: What is the background for this study?

Response: The study was inspired by the uncertainty surrounding sickle cell trait (SCT) and its association with serious exertional collapse events and mortality in active populations. I conducted initial, exploratory analyses on these topics in 2014-15 while examining a range of military readiness predictors and outcomes. The early work indicated that the risk of mortality, rhabdomyolysis and other exertional events arising from SCT might be substantially lower than that suggested by prior work in the research literature.

Dr. Lianne Kurina and I decided to conduct further, focused study at the Stanford University School of Medicine to confirm or refute these findings. In considering best approaches, we noted that there was an absence of prior research in which the  sickle cell trait status of an entire, large, physically-active study population was known. This limitation could introduce bias to inflate the apparent impact of a theorized predictive factor.

Aside from the challenges in studying the impact of SCT on exertional outcomes, with respect to prevention, a further concern is that  sickle cell trait is a non-modifiable trait. If it were a serious risk factor for rhabdomyolysis and/or mortality, despite careful exertional injury precautions such as those employed by the Army, this might present great challenges for prevention efforts. To maximize the potential for new research to provide actionable prevention information, our interests included examining a range of modifiable risk factors for rhabdomyolysis.

Dr. Kurina and I have employed large, longitudinal military datasets for about five years to examine critical military health outcomes, making this study a natural progression of our joint work. The research proceeded with the support of the Uniformed Services University of the Health Sciences, and in cooperation with a distinguished group of experts who co-authored the paper and advised the project. The study was conducted using de-identified records of all SCT-tested African American US Army soldiers on active duty during 2011 – 2014 (N = 47,944).

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IV Iron Administered Post-Op May Improve Surgical Outcomes

MedicalResearch.com Interview with:
Clinical Professor Alhossain A.Khalafallah
Menzies Institute for Medical Research,
University of Tasmania, Australia
Consultant Haematologist
Senior Staff Specialist
Launceston General Hospital,
Australia

MedicalResearch.com: What is the background for this study?

Response:
1. Iron deficiency is one of the most common nutritional deficiencies worldwide, affecting up to one third of the population worldwide.
2. Prevalence of anaemia in orthopaedic surgery ranges between 10-20% with the main cause of anaemia identified as nutritional deficiency.
3. New intravenous iron preparations have been developed at a higher purchase price than oral iron. Iron carboxymaltose, as one example, remains underutilised in the treatment of perioperative anaemia.
4. To our knowledge, this study is the first to compare the efficacy, safety and long term effect on iron stores and length of hospital stay in the postoperative anaemia setting.

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Iron Levels Should Be Checked During Pregnancy

MedicalResearch.com Interview with:
Kris Poppe, MD, PhD
Co-Head Endocrine Unit
CHU St-Pierre UMC
Université libre de Bruxelles

MedicalResearch.com: What is the background for this study? 

Response: Pregnant women are often referred by gynecologists to my endocrine practice, for altered thyroid function. At that occasion, I often noticed that the women also had low iron/ferritin levels (ferritin is the iron reserve). Searching in literature did not reveal many publications on the association between iron (deficiency) and thyroid function during pregnancy and so that was the background/aim to perform this study.

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Iron Deficiency Common In Heart Failure Patients and Linked To Worse Outcomes

MedicalResearch.com Interview with:

John G. F. Cleland, MD, FRCP, FESC Department of Cardiology Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston-Upon-Hull National Heart and Lung Institute Royal Brompton and Harefield Hospitals Imperial College London, United Kingdom

Dr. John Cleland

John G. F. Cleland, MD, FRCP, FESC
Department of Cardiology
Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston-Upon-Hull
National Heart and Lung Institute
Royal Brompton and Harefield Hospitals Imperial College
London, United Kingdom

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This analysis shows that iron deficiency is very common in patients with heart failure and often leads to anaemia and that the prevalence of both iron deficiency and anaemia are highly sensitivity to the criteria used to define them. The World Health Organization defines anaemia as a haemoglobin concentration of <13g/dL in men and <12g/dL in women but doctors should realise this is the lower limit of normal and haemoglobin concentrations should ideally be about 2g/dL higher than this. A man with a haemoglobin of 12g/dL is quite severely anaemic. This study suggest that iron deficiency is common when haemoglobin drops below 14g/dL for men and 13g/dL for women.

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HIV Lymphoma Patients Now Candidates For Stem Cell Transplants

MedicalResearch.com Interview with:

Joseph Alvarnas, MD Associate clinical professor Department of hematology and Director of value-based analytics City of Hope National Medical Center Duarte, CA

Dr. Joseph Alvarnas

Joseph Alvarnas, MD
Associate clinical professor
Department of hematology and Director of value-based analytics
City of Hope National Medical Center
Duarte, CA

MedicalResearch.com: What is the background for this study?

Dr. Alvarnas: Patients with HIV infection have a significantly increased risk of non-Hodgkin lymphoma and Hodgkin lymphoma. Prior to the availability of effective anti-retroviral therapy, HIV-infected patients with lymphoma had very poor treatment outcomes. Following the availability of effective anti-HIV therapy, patient outcomes for HIV-infected patients now parallel those of non-infected patients. Historically, however, HIV infection has been used as a criterion for not offering patients autologous blood stem cell transplantation outside of centers with unique expertise. The purpose of this trial was to evaluate outcomes, complication rates, and immunological reconstitution of HIV-infected patients following autologous blood stem cell transplantation.
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Sickle Cell Anemia: Discontinuing Blood Exchange After Transition to Adulthood Linked with Increased Mortality

MedicalResearch.com Interview with:

Samir K. Ballas MD FACP Emeritus Professor of Medicine and Pediatrics Department of Medicine/Cardeza Foundation for Hematologic Research Thomas Jefferson University Philadelphia, PA

Dr. Samir Ballas

Samir K. Ballas MD FACP
Emeritus Professor of Medicine and Pediatrics
Department of Medicine/Cardeza Foundation for Hematologic Research
Thomas Jefferson University
Philadelphia, PA

Medicalresearch.com: What is the background for this study?

Dr. Ballas: Previous studies have shown that the incidence of overt stroke is about 11% in children with sickle cell anemia by ages 2 – 20 years. Untreated stokes recur periodically with increasing severity and mortality. Transfusion therapy has been documented to decrease the frequency and morbidity of stroke in children by 90%. Accordingly, children who develop overt stroke are treated with chronic blood exchange transfusion to prevent the recurrence of additional strokes. When children reach the age of 18-20 years their medical care is transitioned to adult programs. This transition process is associated with several issues one of which is the discontinuation of chronic blood exchange transfusion in patients with history of overt stokes partly due to logistic considerations and partly due to lack of research in strokes in adult patients and the complications of chronic blood transfusion .

Medicalresearch.com: What are the main findings?

Dr. Ballas: The major finding of the study is that the discontinuation of chronic blood exchange after transition to adult programs is associated with increased mortality. All the patients who discontinued blood transfusion died within 3-5 years after transition whereas patients who continued having blood exchange transfusion survived to a mean age of 36 years at the time of writing this study.
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Should Dose of EPO in CKD Be Individualized For Patient’s Quality of Life?

MedicalResearch.com Interview with:
Dr. Navdeep Tangri
Attending physician and Assistant Professor in the Division of Nephrology
Department of Medicine and the Department of Community Health Sciences
University of Manitoba

and Dr. David Collister 
Seven Oaks General Hospital Renal Program
Winnipeg, Manitoba Canada. 

Medical Research: What is the background for this study? What are the main findings?

Response: Anemia is common in chronic kidney disease (CKD) including dialysis and its treatment with erythopoetin stimulating agents (ESAs) reduces the need for blood transfusions and has varying effects on morbidity and mortality. The optimal hemoglobin (HGB) targets for treating anemia in CKD are controversial with safety concerns around the normalization of hemoglobin levels due to an increase in cardiovascular (CV) events. The effects of ESAs on health related quality of life (HRQOL) are unclear with individualization o fhemoglobin targets being controversial as clinicians and patients attempt to balance perceived HRQOL benefits with cardiovascular risk.

We performed an updated meta-analysis of randomized controlled trials (RCTs) that evaluated the treatment of anemia in CKD with ESAs that targeted higher versus lower hemoglobin targets using validated HRQOL metrics including SF-36 and KDQ. We included 17 studies and found that higher hemoglobin targets compared to lower HGB targets did result in a statistically significant difference in HRQOL and thus did not improve HRQOL beyond a clinically meaningful threshold. Any change in HRQOL was further attenuated in dialysis subgroups.

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Nanobody is Potentially First Targeted Therapy for TTP

MedicalResearch.com Interview with:
Dr. Filip Callewaert PhD
Senior Clinical Scientist
Clinical Development, Ablynx
Zwijnaarde, Belgium

Medical Research: What is the background for this study? What are the main findings?

Dr. Callewaert: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening coagulation disorder, in which accumulation of ultra-large von Willebrand factor (ULvWF) multimers is implicated, leading to an increased risk of thrombus formation in small blood vessels due to excessive platelet aggregation. There are no approved pharmacological therapies for acquired TTP. Despite treatment with the current standard of care (plasma exchange and immunosuppressive therapy), mortality remains at 10-20% and there is significant neurological, cardiac, and renal morbidity.

Caplacizumab is a bivalent Nanobody that binds to the A1 domain of vWF thereby preventing vWF-mediated platelet aggregation. The clinical effects of caplacizumab were demonstrated in the phase II randomised, placebo-controlled TITAN study in 75 patients with acquired TTP. Compared to placebo, there was a nearly 40% reduction in median time to platelet count normalisation in the caplacizumab group (p = 0.005). Treatment with caplacizumab reduced the use of daily plasma exchange and prevented further consumption of platelets in microthrombi and small blood vessel occlusion. In addition, there were fewer recurrences of TTP requiring re-initiation of daily plasma exchange during treatment with caplacizumab (N=3) vs. placebo (N=11). The safety profile of caplacizumab was favorable, with a slightly higher tendency of mostly mild bleeding events.  Continue reading

Hemophilia: New Fusion Protein Allows For Less Frequent Dosing To Prevent Bleeding

Dr. Elena Santagostino

Dr. Elena Santagostino

MedicalResearch.com Interview with:
Dr. Elena Santagostino, MD PhD
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Ca’ Granda Foundation
Maggiore Hospital Policlinico, Milan, Italy

Medical Research: What is the background for this study? What are the main findings?

Dr. Santagostino: Two of our abstracts presented at the 57th ASH Annual Meeting are part of the PROLONG-9FP clinical program evaluating the efficacy and safety of CSL Behring’s investigational long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).  The first is an oral presentation on results from two Phase III studies and an ongoing extension study of rIX-FP for routine prophylaxis in previously-treated people with hemophilia B.

The two Phase III studies included adolescents and adults (ages 12 to 61) treated with dosing intervals of up to 14 days for 12 to 18 months, and children (ages 1 to 11) who received seven-day prophylaxis treatment for approximately 12 months. Overall, the median annualized spontaneous bleeding rate (AsBR) was 0.00 for all treatment intervals. The extension study is examining longer treatment intervals, including 10- and 14-day intervals in patients younger than 12 and more prolonged treatment intervals in patients older than 18, and so far has reported favorable long-term tolerability with no serious adverse reactions such as the development of inhibitors to factor IX or antibodies to rIX-FP.

A second abstract reported on a surgical sub-study in these trials found that a single pre-operative dose of rIX-FP maintained hemostasis during surgery with responses rated by investigators as “excellent” or “good.” Oven a 14-day perioperative period, patients needed six or seven infusions, and none developed inhibitors to factor IX or antibodies to rIX-FP.

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Triplet Therapy Induces Durable Response In Refractory Myeloma

MedicalResearch.com Interview with:
Dr. Ajai Chari MD
Associate Professor
Medicine, Hematology and Medical Oncology
Tisch Cancer Institute
Mount Sinai School of Medicine
New York, NY

Medical Research: What is the background for this study?

Dr. Chari: This is a heavily pretreated population where the median progression free survival (PFS) of the pomalidomide dexamethasone is only 4 months and ORR is only 31%. While the anti CD38 monoclonal antibody daratumumab has single agent has activity in this setting, patients with rapidly progressive disease need combination therapy to achieve rapid and deep responses. Pomalidomide also upregulates CD38 on MM cells and like daratumumab, increases the effector cell activity against myeloma. Thus, there is a strong preclinical and clinical rationale for combining daratumumab with pomalidomide and dexamethasone.

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Stored Blood For Transfusions Works As Well As Fresh Blood

Dr. Walter H. Dzik MD Associate Pathologist, Massachusetts General Hospital Associate Professor of Pathology Harvard Medical Schoo

Dr. Walter Dzik

MedicalResearch.com Interview with:
Dr. Walter H. Dzik MD
Associate Pathologist, Massachusetts General Hospital
Associate Professor of Pathology
Harvard Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Dzik: Millions of Red Blood Cell transfusions are given each year.  To maintain adequate blood inventories worldwide, Red Blood Cell units are stored under refrigerated conditions.  Previous animal and laboratory research has highlighted the fact that red cells undergo biochemical, morphologic, and biophysical changes during prolonged refrigerated blood storage.    Researchers and clnicians have questioned whether the changes that occur during storage would impair the ability of transfused Red Cells to delivery oxygen to tissues.

Our study was a randomized controlled trial conducted in patients with extreme anemia and insufficient global tissue oxygenation.    We randomly assigned children with severe anemia and lactic acidosis to receive Red Blood Cells stored 1-10 days versus Red Blood Cells stored 25-35 days.   We measured the recovery from lactic acidosis in response to transfusion in the two groups.   We also measured cerebral tissue oxygenation using a non-invasive tissue oximeter.    We found that the proportion of patients who achieved reversal of lactic acidosis was the same in the two RBC storage-duration groups.   The rate of decline of lactic acidosis was also equal.   There was also no difference in cerebral oxygenation, resolution of acidosis, correction of vital signs, clinical recovery, survival and 30-day followup.   
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FDA Study Compares Anaphylactic Risk of IV Iron Products

Cunlin Wang, MD, PhD Division of Epidemiology I, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research US Food and Drug Administration

Dr. Wang

MedicalResearch.com Interview with:
Cunlin Wang, MD, PhD
Division of Epidemiology I,
Office of Surveillance and Epidemiology,
Center for Drug Evaluation and Research
US Food and Drug Administration

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Wang:  IV Iron has been known for its risk of anaphylactic reaction, but there has been little research on the comparative safety of individual IV Iron products from a large population-based study. This study included 688,183 new users of IV iron not on dialysis from the U.S. Medicare program over a ten-year span (January 2003 to December 2013). The main findings of the study are:  the risk for anaphylaxis at first exposure was higher for iron dextran than non-dextran IV iron products combined (iron sucrose, gluconate and ferumoxytol).  When individual IV Iron products were compared, the data suggested that iron dextran has the highest risk of anaphylaxis and Iron sucrose has the lowest risk, estimated both at the first time exposure and after cumulative exposures.  The low and high molecular weight dextran products could not be individually identified during most of study period. However,  from January 2006 through March 2008, during which the use of two dextran products could be distinguished, there was very low use of high molecular weight dextran (Dexferrum@). This suggested that the study results likely represent the risk of the low molecular weight dextran (Infed@).

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IV Iron in Hospitalized Hemodialysis Patients Not Linked With Worsening Infections

Dr. Julie H. Ishida MD San Francisco Veterans Affairs Medical Center Nephrology Section San Francisco, CAMedicalResearch.com Interview with:
Dr. Julie H. Ishida MD
San Francisco Veterans Affairs Medical Center
Nephrology Section
San Francisco, CA

Medical Research: What is the background for this study? What are the main findings?

Dr. Ishida: Intravenous iron is important in the treatment of anemia of end-stage renal disease, but it is biologically plausible that iron may increase infection risk. While results from epidemiologic studies evaluating the association between intravenous iron and infection in hemodialysis patients have been conflicting, guidelines for the treatment of anemia of chronic kidney disease have recommended caution in prescribing, avoidance and withholding of intravenous iron in the setting of active infection. However, no data specifically support the recommendation to withhold intravenous iron during active infection.

Our study observed that among hemodialysis patients hospitalized for bacterial infection who had been receiving intravenous iron as an outpatient, continued receipt of intravenous iron was not associated with higher all-cause mortality, readmission for infection, or longer hospital stay.

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Biomarker May Predict Cancers Grow With Anemia Drug

Anil K. Sood, M.D

Dr. Anil Sood

MedicalResearch.com Interview with:
Anil K. Sood, M.D.
Professor of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Sood: Erythropoietin is an important drug for managing anemia, but concerns have surfaced that it might promote cancer growth. The data with the conventional epo-receptor were not convincing with regard to an explanation for why tumor growth might increase. Therefore, we considered whether there could be an alternative receptor to explain these findings. We carried out a systematic search and identified EphB4 as the alternative receptor that explained the increased tumor growth in response to epo.

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Serum Phosphorus Level May Be a Biomarker For Anemia

MedicalResearch.com Interview with:
Lac Tran, MD
Division of Nephrology and Hypertension
Kaiser Permanente Los Angeles Medical Center
Los Angeles, CA

Medical Research: What is the background for this study? What are the main findings?

Dr. Tran: Abnormal serum phosphorus levels have been associated with adverse cardiovascular outcomes and progression to renal failure.  Given phosphorus’s important biological roles in cellular replication and bone mineral metabolism, we sought to investigate the association between phosphorus levels and anemia in normal kidney function and early chronic kidney disease.

Our study is a population-based study among a large racially/ethnically diverse population within the Kaiser Permanente Southern California health system.
Among 155, 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia.  We found that phosphorus levels greater than 3.5 mg/dL and less than 2.0 mg/dL showed a greater likelihood for moderate anemia.  Every 0.5 mg/dL phosphorus level increase demonstrated a 16% greater likelihood for moderate anemia.  The highest phosphorus tertile of our population had a 26% greater likelihood for anemia compared to the middle tertile.  We also found that female sex, Asian race, diabetes, low albumin, and low iron saturation were risk factors for anemia.

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Patient-Derived Stem Cells May Be Able To Reverse Hemophilia A

Dong-Wook Kim Center for Genome Engineering, Institute for Basic Science Yonsei University College of Medicine Seoul, KoreaMedicalResearch.com Interview with:
Dong-Wook Kim
Center for Genome Engineering, Institute for Basic Science
Yonsei University College of Medicine
Seoul, Korea

Medical Research: What is the background for this study?

Response: Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation.

Medical Research: What are the main findings?

Response: We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia.

Medical Research: What should clinicians and patients take away from your report?

Response: Our results provide a proof of principle for functional correction of large chromosomal inversions in Hemophilia patient-derived induced pluripotent stem cells and suggest potential therapeutic applications in the future.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: We need to prove the safety of patient-derived iPSCs before we move towards clinics.

The safety of iPSCs means to prevent teratoma formation when we do clinical trials.

For that purpose, we need to develop good differentiation protocols into EC cells and to purify the cells as well. In addition, we need much more animal study.

Citation:

Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

Chul-Yong Park Duk Hyoung Kim Jeong Sang Son Jin Jea Sung Jaehun Lee Sangsu Bae Jong-Hoon Kim Dong-Wook Kim Jin-Soo Kim

Cell Stem Cell Available online 23 July 2015

doi:10.1016/j.stem.2015.07.001

Dong-Wook Kim (2015). Patient-Derived Stem Cells May Be Able To Reverse Hemophilia

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Iron Deficiency Anemia May Complicate Diagnosis of Diabetes

MedicalResearch.com Interview with:
Emma English PhD

Lecturer in Healthcare Science and Academic Lead for Clinical Biochemistry
University of Nottingham, School of Medicine
Royal Derby Hospital, UK

MedicalResearch: What is the background for this study? What are the main findings?

Dr. English: HbA1c is widely used for monitoring glycaemic control in people with diabetes as there is clear evidence that lowering HbA1c values leads to reductions in the rates of diabetes complications. Recently the World Health Organization and the American Diabetes Association have both advocated the use of HbA1c for the diagnosis of Type 2 diabetes at a value of ≥48 mmol/mol (6.5%). Whilst there are many advantages to the use of HbA1c as a diagnostic tool there are equally some significant limitations to its use. A widely cited confounder is anaemia, however to what extent and which types of anaemia affect HbA1c results was not clearly understood. When HbA1c was introduced as a diagnostic test in England we received many queries from healthcare professionals asking questions such as ‘at what level of anaemia should I not use HbA1c?’ and ‘should I routinely screen patients for anaemia when using HbA1c? And if so, what test should I use?’. In order to answer these questions we conducted a systematic review of the literature to determine what was known on this subject.

Our findings, presented in Diabetologia, suggest that iron deficiency and iron deficiency anaemia may lead to a spuriously elevated HbA1c level, thus may lead a false positive diagnosis of diabetes. However, non-iron deficiency anaemias can lead to an artificially lower HbA1c and may lead to a false negative result where a diagnosis of diabetes would be missed. There is no clear evidence to suggest at what levels anaemia can give rise to these effects on HbA1c value and also there does not appear to be a single ideal test for identifying patients where this could be an issue.

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Major Disease States Cause Slowdown in Red Blood Cell Production and Destruction

MedicalResearch.com Interview with:
John M. Higgins, MD
MGH Center for Systems Biology
Boston, MA

Medical Research: What is the background for this study? What are the main findings?

Dr. Higgins: Hundreds of studies over the past 8 years have shown that increased variation in the size of red blood cells (RBCs) is associated with increased risk for a very wide range of common diseases, like heart disease, many types of cancer, infection, many autoimmune diseases, and lots of other conditions.  The size of red blood cells (RBCs) in the circulation of a healthy person usually varies by about 12-14%, meaning that if you took a sample of the cells, most of the bigger cells would be about 14% larger than the smaller cells.  People whose red blood cells show more variation in size have a greater risk of developing a wide range of diseases.  Also, among patients already diagnosed with many common diseases like heart disease or cancer, those with higher RBC size variation have worse outcomes.  It is unknown how all of these different diseases could be connected to variation in the size of red blood cells.  The study explains a major cause for this connection.  We find that the human body seems to slow down the production and destruction of RBCs in just about every major disease very slightly.  Since red blood cells gradually become smaller as they age, a delay in destruction will increase the fraction of small cells, and the overall variation in size increases.  The study also describes a method to estimate a patient’s RBC clearance rate.

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Low Dose Vitamin C May Improve Iron Deficiency in Dialysis Patients

MedicalResearch.com Interview with:
Dr. Tanjim Sultana MD
Department of Nephrology
Lenox Hill Hospital New York

Medical Research: What is the background for this study? What are the main findings?

Response: Almost all dialysis patients are anemic. One quarter of patients requiring High dose Epogen have functional iron deficiency, which means they have adequate iron store but unable to utilize it. Vitamin C has been shown to mobilize iron from their storage and making it available to use in red blood cell production. Prior studies showed intravenous high dose vitamin C could increase hemoglobin levels and decrease epogen requirement. In our study we used daily low dose oral vitamin C in functional iron deficient patients to achieve the same goals. Patients taking daily low dose vitamin C for 3 months had significant decrease in their epogen dose compared to the control group.

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Blood Transfusions: Stored Blood Becomes Less Functional With Time

Gabriel Popescu Associate Professor Department of Electrical and Computer Engineering & Bioengineering University of Illinois at Urbana-Champaign Beckman Institute for Advanced Science Urbana, IL 61801 MedicalResearch.com Interview with:
Gabriel Popescu
Associate Professor
Department of Electrical and Computer Engineering & Bioengineering
University of Illinois at Urbana-Champaign
Beckman Institute for Advanced Science Urbana, IL

Medical Research: What are the main findings of the study?

Prof. Popescu: We used a new imaging method, which combines microscopy and interferometry, to measure nanoscale fluctuations in the red blood cell membrane. We found that the fluctuations, known to be due to thermal or Brownian motion, decrease with blood storage time. These results indicate that the deformability of the cells degrades with time. It means that blood functionality is lower the longer the blood is stored.

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Two Forms of Polycythemia Vera: One Indolent, One Aggressive

Jerry Spivak, M.D Professor of Medicine and Oncology Director, Center for the Chronic Myeloproliferative Disorders John Hopkins MedicineMedicalResearch.com Interview with:
Jerry Spivak, M.D
Professor of Medicine and Oncology
Director, Center for the Chronic Myeloproliferative Disorders
John Hopkins Medicine

Medical Research: What are the main findings of the study?

Dr. Spivak: The main findings of this study are that polycythemia vera occurs in two clinical forms: an indolent form in which only phlebotomy may be necessary and a more aggressive form requiring myelosuppressive therapy and that these two forms of the disease can be distinguished genetically.
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More Children With SCID Are Now Transplant Candidates

MedicalResearch.com Interview with:
Richard J. O’Reilly, MD
Memorial Sloan Kettering Cancer Center

Medical Research: What are the main findings of the study?
Dr. O’Reilly:

1.       In a comparison of the results of HLA-matched sibling transplants with other established transplant approaches, including T-cell depleted half-matched parental marrow grafts, unmodified transplants from matched unrelated donors and cord blood transplants in the current era (2000-2009), transplants from donors other than HLA-matched siblings had 5 year survival outcomes similar to those of matched siblings when applied to young infants (≤ 3.5 months of age) or infants of any age that were not infected at the time of transplants. Thus any child born with SCID can now be successfully transplanted.

2.       Active infection at the time of transplant significantly reduced chances of long-term survival for all infants except those who received transplants from HLA-matched siblings. Thus, infection is a dominant determinant of transplant outcome.  Control of treatable infections prior to transplant should be a major clinical objective.

3.       Treatment with chemotherapy containing busulfan significantly enhances the likelihood of recovering a normal ability to make antibodies and fosters better recovery of T-cells that provide cell mediated immunity, and may be an acceptable risk in uninfected infants. However, use of any chemotherapy prior to transplant in an infant who is infected, greatly decreases chances of survival. In infected patients who lack a matched sibling, T-cell depleted transplants from half matched related donors had the best outcomes.
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Chronic Kidney Disease Patients Receiving Less ESA Therapy For Anemia

MedicalResearch.com Interview with:
Dennis J. Cotter
President
Medical Technology and Practice Patterns Institute, Inc.
Bethesda, MD 20816

Medical Research: What are the main findings of the study?

Answer: This is the first study to document anemia management practice patterns among predialysis CKD patients before and after publication of TREAT. Using a retrospective observational design based on a large US health plan database with over 1.2 million claims for predialysis CKD stage 3 and 4 patients, we report 4 main study findings.

1) For CKD stage 3 patients, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline) and for CKD stage 4 patients, from 34% to 27% (a 22% decline).

2) Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period.

3) ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin <10 g/dL, only 25% of stage 3 and 33% of stage 4 CKD were prescribed ESAs two years after TREAT, a notable 50% decline.

4) After adjusting for all covariates, the probability of prescribing ESAs was 35% less during a two year period after vs. before TREAT publication.
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Traumatic Brain Injury: Maintaining Hemoglobin With Transfusions or EPO Found Not Helpful

Claudia Robertson, MD Professor, Department of Neurosurgery Baylor College of Medicine One Baylor Plaza Houston, Texas 77030MedicalResearch.com Interview with:
Claudia Robertson, MD
Professor, Department of Neurosurgery
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030

Medical Research: What are the main findings of the study?

Dr. Robertson: We studied two issues related to treatment of anemia after severe traumatic brain injury.

One issue was the optimal hemoglobin transfusion threshold for this subgroup of critically ill patients, and the second issue was use of erythropoietin to increase hemoglobin concentration and reduce the need for transfusion.  For the transfusion threshold, we found that there was no difference in long-term neurological outcome when patients were transfused at a hemoglobin concentration of less than 7 g/dl compared to those transfused at less than 10 g/dl.  In addition, there was an increased risk of thromboembolic events in those transfused at less than 10 g/dl.  With administration of erythropoietin, we found no improvements in neurological outcome, and no increase in hemoglobin concentration or reduction in the need for transfusion.

Medical Research: Were any of the findings unexpected?

Dr. Robertson: It has been believed that maintaining hemoglobin concentration at least 10 g/dl is an important management practice to reduce secondary injury to the brain.  This study does not support that practice.

Medical Research: What should clinicians and patients take away from your report?

Dr. Robertson: The major message is that patients with traumatic brain injury should be managed the same as other critically ill patients with a restrictive transfusion practice.  There is no advantage to maintaining hemoglobin concentration at a higher level, and there is some risk of transfusion related complications.  There is also no support from this study for use of erythropoietin in patients with traumatic brain injury.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Robertson: The findings with erythropoietin were disappointing because there have been many studies in experimental models of brain injury showing neuroprotection.  It is possible that we are not able to give high enough doses of erythropoietin in patients because of potential side effects and that derivatives of erythropoietin which do not have these side effects may still be of interest for future clinical trials.

Citation:

Sickle Cell Disease Potentially Cured with Nonmyeloablative HLA-Matched Allogeneic Stem Cell Transplantation

John F. Tisdale, MDMedicalResearch.com Interview with:
Dr. John Tisdale MD
Molecular and Clinical Hematology Branch
National Institute of Diabetes and Digestive and Kidney Diseases,
National Heart, Lung, and Blood Institute, Bethesda, Maryland


MedicalResearch: What are the main findings of the study?

Dr. Tisdale: Using a nonmyeloablative allogeneic HLA-match peripheral blood stem cell transplantation strategy aimed at tolerance induction, we were able to revert the phenotype in 26 of 30 adult patients with severe sickle cell disease ranging in age from 16 to 65 years. In contrast to standard transplantation strategies which rely on high doses of chemo and/or radiotherapy after which the entire bone marrow and blood system is replaced by that of the donor, our patients had a mixture of their own and that of their donor. This procedure was well tolerated, with no non-relapse mortality, and led to complete replacement of red blood cells by that of the donor in successfully engrafted patients. This replacement resulted in decreases in pain, pain medication usage, hospitalizations, and improvements in organ function.

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Dialysis Patients: A Standardized Transfusion Ratio to Evaluate Anemia Management

MedicalResearch.com Interview with:
David T. Gilbertson, Ph.D.
Chronic Disease Research Group
Center for Observational Research, Amgen, Inc, Thousand Oaks, CA

MedicalResearch: What were the main findings of the study?

Dr. Gilbertson: Since transfusion avoidance is important in patients receiving maintenance hemodialysis, development of a measure of red blood cell transfusion use to assess dialysis facility anemia management is reasonable. Because dialysis facility size varies widely, calculation of a standardized transfusion ratio (STfR) using standard methods is possible, but these methods result in significant instability in estimates for small dialysis facilities. Use of more advanced statistical methods results in standardized transfusion ratio estimates that are considerably more stable and more consistently precise across dialysis facilities of all sizes.
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Genetic Variants Alter Monoclonal Antibody Effects

Jun-ichi Nishimura, M.D., Ph.D. Assistant Professor Department of Hematology and Oncology Osaka University Graduate School of Medicine C9, 2-2 Yamadaoka, Suita, Osaka 565-0871, JapanMedicalResearch.com Interview with:
Jun-ichi Nishimura, M.D., Ph.D.
Assistant Professor Department of Hematology and Oncology
Osaka University Graduate School of Medicine
C9, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

MedicalResearch.com: What are the main findings of the study?

Dr. Nishimura: Our major findings are a C5 mutation (c.2654G→A) in Japanese patients with PNH prevents binding and blockade by eculizumab, a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement–mediated hemolysis associated with PNH, while retaining the functional capacity of the mutant C5 to cause hemolysis.

MedicalResearch.com: Were any of the findings unexpected?

Dr. Nishimura: Yes, one patient with a poor response to eculizumab was referred to us from Argentina. Although the known C5 polymorphism (c.2654G→A) was not identified in this patient, a new mutation (c.2653C→T) was detected in the base next to the known polymorphism, suggesting the importance of this site in C5 recognition by eculizumab.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Nishimura: Today’s take home messages are that the polymorphism in the target protein might be important to consider in patients with a poor response to the antibody-based treatments for various diseases.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Nishimura:  We will need to verify the distribution of these variants, especially among Asian, South American, Middle Eastern, and African countries.

Citation:

Genetic Variants in C5 and Poor Response to Eculizumab

Jun-ichi Nishimura, M.D., Ph.D., Masaki Yamamoto, M.D., Shin Hayashi, M.D., Ph.D., Kazuma Ohyashiki, M.D., Ph.D., Kiyoshi Ando, M.D., Ph.D., Andres L. Brodsky, M.D., Ph.D., Hideyoshi Noji, M.D., Kunio Kitamura, M.D., Ph.D., Tetsuya Eto, M.D., Toru Takahashi, M.D., Masayoshi Masuko, M.D., Ph.D., Takuro Matsumoto, M.D., Yuji Wano, M.D., Tsutomu Shichishima, M.D., Ph.D., Hirohiko Shibayama, M.D., Ph.D., Masakazu Hase, Ph.D., Lan Li, M.D., Krista Johnson, M.Sc., Alberto Lazarowski, Ph.D., Paul Tamburini, Ph.D., Johji Inazawa, M.D., Ph.D., Taroh Kinoshita, Ph.D., and Yuzuru Kanakura, M.D., Ph.D.

N Engl J Med 2014; 370:632-639
February 13, 2014DOI: 10.1056/NEJMoa1311084

 

Risk of Adverse Pregnancy Outcomes: Anemia and Prenatal Iron Use

MedicalResearch.com Interview with Batool Haider, MD, MS, DSc candidate
Departments of Epidemiology and Nutrition
School of Public Health
Harvard University

Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis

MedicalResearch.com: What are the main findings of the study?

Dr. Haider: The main findings of the study are that iron use in the prenatal period increased maternal mean haemoglobin concentration by 4.59 (95% confidence interval 3.72 to 5.46) g/L compared with controls and significantly reduced the risk of anaemia (relative risk 0.50, 0.42 to 0.59), iron deficiency (0.59, 0.46 to 0.79), iron deficiency anaemia (0.40, 0.26 to 0.60), and low birth weight (0.81, 0.71 to 0.93). The effect of iron on preterm birth was not significant (relative risk 0.84, 0.68 to 1.03). Analysis of cohort studies showed a significantly higher risk of low birth weight (adjusted odds ratio 1.29, 1.09 to 1.53) and preterm birth (1.21, 1.13 to 1.30) with anaemia in the first or second trimester.

Exposure-response analysis indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the relative risk of maternal anaemia was 0.88 (0.84 to 0.92) (P for linear trend<0.001). Birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend=0.005) and risk of low birth weight decreased by 3% (relative risk 0.97, 0.95 to 0.98) for every 10 mg increase in dose/day (P for linear trend<0.001). Duration of use was not significantly associated with the outcomes after adjustment for dose. Furthermore, for each 1 g/L increase in mean haemoglobin, birth weight increased by 14.0 (6.8 to 21.8) g (P for linear trend=0.002); however, mean haemoglobin was not associated with the risk of low birth weight and preterm birth. No evidence of a significant effect on duration of gestation, small for gestational age births, and birth length was noted.
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