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Eugene Hwang in an exam room

Clinical Trial Spotlight: Creating a super army to target CNS tumors

Eugene Hwang in an exam room

Following the noted success of CAR-T cells in treating leukemia, Eugene Hwang, M.D., and a team of physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors.

Following the noted success of CAR-T cells in treating leukemia, physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors. Employing a strategy of “supertraining” the cells to target and attack three tumor targets as opposed to just one, Eugene Hwang, M.D., and the team at Children’s are optimistic about using this immunotherapy technique on a patient population that hasn’t previously seen much promise for treatment or cure. The therapy is built on the backbone of T cell technology championed by Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research, which is only available at Children’s National. Hwang sees this trial as an exciting start to using T cells to recognize resistant brain cancer. “We have never before been able to pick out markers on brain cancer and use the immune system to help us attack the cancer cells. This strategy promises to help us find treatments that are better at killing cancer and lessening side effects,” he says.

This Phase 1 dose-escalation is designed to determine the safety and feasibility of rapidly generated tumor multiantigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) or recurrent, progressive or refractory non-brainstem CNS malignancies. Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or surviving) will be enrolled in one of two groups: Group A includes patients with newly diagnosed DIPGs who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from a patient’s peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase 1 dose-escalation study. Group A patients: TAA-T will be infused any time >2 weeks after completion of radiotherapy. Group B patients: TAA-T will be infused any time >2 after completing the most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

For more information about this trial, contact:

Eugene Hwang, M.D.
202-476-5046
ehwang@childrensnational.org

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Karun-Sharma-and-kids-MR-HIFU

Clinical Trial Spotlight: Treating tumors with ThermoDox® and MR-HIFU

Karun Sharma, M.D., is working with AeRang Kim, M.D., Ph.D., to evaluate the use of ThermoDox®, a heat-activated chemotherapy drug, in combination with noninvasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) to treat refractory or relapsed solid tumors in children and young adults.

A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults.

This study is looking to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lyso-thermosensitive liposomal doxorubicin (LTLD), a heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, administered in combination with magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) in children with relapsed/refractory solid tumors.

MR-HIFU is an innovative device that provides precise and controlled delivery of heat inside a tumor using an external applicator. Unlike other heating systems used in local therapy, MR-HIFU is entirely non-invasive and does not use any radiation. Integration of MR imaging allows for real-time temperature monitoring for accurate and precise targeting of tumors. LTLD is a novel formulation of doxorubicin with the unique property of heat-activated release. This selective drug delivery mechanism allows for local and rapid release of doxorubicin in high concentrations in tumors when heated. This novel combination may potentiate known effective therapy to improve local control and drug delivery without increasing toxicity.

Children’s National Health System and Celsion Corp, a leading oncology drug-development company, were the first to launch a clinical study in the U.S. that evaluates the use of ThermoDox® with MR-HIFU. Learn more about the clinical trial.

For more information about this trial or other trials available at Children’s National, contact:

Melissa Salerno
Clinical Research Program Manager
202-476-2142
msalerno@childrensnational.org

View more open phase 1 and phase 2 cancer clinical trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Eugene Hwang

Unexpected heterogeneity in CNS-PNET patients treated as a single entity

Eugene Hwang

“We found that some patients diagnosed with standard tools underwent much more treatment than necessary or intended,” said Eugene Hwang, M.D.

Eugene I. Hwang, M.D., a neuro-oncologist in the Center for Cancer and Blood Disorders, and other researchers at Children’s National Health System, Seattle Children’s Hospital and Research Institute, the Fred Hutchinson Cancer Research Center and the Hopp-Children’s Cancer Center at the NCT Heidelberg recently published the results of a clinical trial focusing on children with histologically diagnosed supratentorial primitive neuroectodermal tumors (CNS-PNET) and pineblastomas (PBLs).

The clinical trial, published online October 17, 2018 in the Journal of Clinical Oncology, included children and adolescents aged 3-22 with these brain cancers who were randomly assigned to receive carboplatin during radiation and/or isotretinoin after the standard intensive therapy (high-dose craniospinal radiation and months of inpatient chemotherapy).  Importantly, because each patient was treated prospectively according to the clinical trial design, the conclusions related to tumor biology were felt to be less affected by varied treatment plans.

“This trial really highlighted the importance of new molecular testing methods in accurately diagnosing some of the brain cancers included in the trial. We found that some patients diagnosed with standard tools underwent much more treatment than necessary or intended.” says Dr. Hwang. “Kids who aren’t receiving the right form of cancer treatment may not get better despite months and months of intensive treatment.”

During this clinical trial, 85 participants with institutionally-diagnosed CNS-PNETs/PBLs were enrolled. Out of the 60 patients with sufficient tissue, 31 were non-pineal in location, 22 of which represented tumors that did not fit in the diagnoses intended for trial inclusion.

The researchers discovered that patient outcomes across each molecularly-diagnosed tumor type were strikingly different. Patients with molecularly-confirmed supratentorial embryonal tumors/PBLs exhibited a five-year event free survival (EFS) and an overall survival rate of 62 percent and 78.5 percent, respectively. However, patients with molecularly-classified high-grade gliomas (HGGs) had a five-year EFS of 5.6 percent and OS of 12 percent, showing no benefit even with the chemotherapy and craniospinal radiation.

Researchers determined that for patients with CNS-PNETs/PBLs, prognosis is considerably better than previously assumed when molecularly-confirmed HGG are removed. Dr. Hwang and co-authors concluded that molecular diagnosis can greatly aid standard pathological diagnostic tools, preventing unnecessary intensive therapy for some patients while enabling more rational treatment for others.

“The findings from our clinical trial have highlighted the immense challenges of histology-based diagnosis for some types of pediatric brain tumors, and the enormous importance this has for children with brain cancer,” Dr. Hwang says. “We hope that ultimately our study will pave the way for molecular profiling to become a standard component of initial diagnosis.”

Javad Nazarian

Meeting of the minds: Children’s National hosts first DIPG Round Table Discussion

Javad Nazarian at DIPG Round Table Discussion

Spearheaded by Javad Nazarian, Ph.D., MSC, Scientific Director of the Children’s National Brain Tumor Institute, the focused DIPG Round Table Discussion brought investigators, neurosurgeons and clinicians from North America, Europe and Australia to Children’s National in Washington, D.C.

Over 40 experts involved in the study and treatment of diffuse intrinsic pontine gliomas (DIPG) convened at the inaugural DIPG Round Table Discussion at Children’s National Health System Sept. 30-Oct. 2.

Spearheaded by Javad Nazarian, Ph.D., MSC, Scientific Director of the Children’s National Brain Tumor Institute, the focused DIPG Round Table Discussion brought investigators, neurosurgeons and clinicians from North America, Europe and Australia to Children’s National in Washington, D.C., to engage in dialogue and learn about the changing landscape of DIPG tumor biology and therapeutics. Attendees discussed the recent discoveries in DIPG research, precision medicine, preclinical modeling, immunotherapy, data sharing and the design of next generation clinical trials.

Families affected by DIPG also had an opportunity to participate in day 2 of the event. Many voiced the necessity of data sharing to ensure progress in the field. Dr. Nazarian seconded that point of view: “It is critical to get raw data and have it harmonized and integrated so that the end users (researchers) can utilize and do cross-data analysis…We need to break down the silos.” The highlight of the data sharing session was the Open DIPG Initiative that is spearheaded by Dr. Nazarian and the Children’s Brian Tumor Tissue Consortium (CBTTC).

Nazarian Lab at DIPG Roundtable Meeting

Eshini Panditharatna, Ph.D., Madhuri Kambhampati, Sridevi Yadavilli, M.D., Ph.D., and Erin Bonner of Children’s National at the DIPG Round Table.

As recent technological and molecular advances in DIPG biology have pushed the field forward, focus groups have become essential to share data, ideas and resources with the overarching goal of expediting effective treatments for children diagnosed with DIPG. An extremely aggressive form of pediatric brain cancer, DIPG accounts for roughly 10 to 15 percent of all brain tumors in children. Between 300 and 400 children in the United States are diagnosed with DIPG each year, but the 5-year survival for the brain tumor is less than 5 percent, a strikingly low number in comparison with other types of childhood cancer. DIPG research and clinical initiatives have changed in the past years mainly due to the generous support of families for basic research. The DIPG Open Table meeting was designed to coalesce a team of experts to expedite the first crack at curing this devastating childhood cancer.

boy on a treadmil

Therapeutic targets in African-American youth with type 2 diabetes

boy on a treadmil

Ongoing research is helping to define the broad spectrum and multi-faceted nature of type 2 diabetes in terms of its presentation, its rapidity of progression and its underlying genetic susceptibilities. In a recent study of 8,980 adults published in The Lancet, diabetes was further classified into five clusters, ranging from insulin-deficient, typically referred to as type 1, to groups of patients with primary insulin-resistance, traditionally classified as type 2 diabetes, with the caveat that each cluster had a distinct risk profile for disease progression and risk for diabetes complications.

Moreover, investigators have recently demonstrated, through the Restoring Insulin Secretion (RISE) Consortium, that youth compared to adults with early type 2 diabetes have greater insulin resistance relative to insulin secretion. Understanding variances on the diabetes spectrum, especially as it relates to risk for disease progression in youth, helps researchers develop targeted therapies that may help reduce complications and the burden of this chronic disease.

Ongoing research

Stephanie Chung, M.B.B.S., a pediatric endocrinologist at the National Institutes of Health and an adjunct assistant professor of pediatrics at Children’s National, is one researcher who hopes to use this knowledge to transform public health outcomes. Dr. Chung is studying how teens and young adults with severe insulin-resistant diabetes (SIRD) respond to new treatment, paired with lifestyle-based interventions.

Here is a Q&A with Dr. Chung about her latest research:

Tell Innovation District readers more about your diabetes research. How has your previous research influenced this study?

My research and publications are focused on understanding how genes, environment and lifestyle factors contribute to the pathology of diabetes, obesity and insulin resistance in populations of African descent and on identifying more effective screening and treatment options.

We know that African-American youth with type 2 diabetes have the highest complication and treatment failure rates among minority youth. However, the reasons underlying this health disparity are still not fully understood. Metformin, the only approved oral diabetes treatment for youth with type 2 diabetes, works less than half of the time in African-American youth. Although new evidence suggests that gut bacteria and genetics may influence the efficacy of metformin, this data is insufficient in African-American youth.

What is your goal with this diabetes clinical study?

The primary objective of this new study, entitled Therapeutic Targets in African-American Youth with Type 2 Diabetes, is to compare the combination of metformin and liraglutide versus metformin alone to reduce excess glucose produced by the liver in African-American youth with type 2 diabetes.

Additional objectives will evaluate the mechanism of action in the liver of these two agents and the influence of genetics and gut bacteria. This project brings together the research expertise of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Human Genome Research Institute and the Children’s National Medical Center.

Do you envision this type of dual therapy, a combination of drugs and lifestyle interventions, will serve as a bridge to optimal insulin function?

While metformin, diet and lifestyle changes remain the mainstay of diabetes treatment, our study will evaluate whether this combination regimen could help to slow the progression of type 2 diabetes in African American youth. Our ultimate goal is the development of new precision medicine treatment options that can address the disparities in outcomes for African-American youth with type 2 diabetes.

What lessons do you see participants learning as they progress through the trial?

Our patients and their families are equal partners in care. Our comprehensive team of doctors, nurses, dietitians and counselors work closely with the patients and their families to help empower them to take charge of managing their diabetes. We teach them skills that include regularly monitoring their blood glucose levels and understanding how their activity and foods affect these levels. They are coached on making healthy food choices and incorporating exercise into their daily lives.

How do you teach children and teens about how their body responds to different foods?

This education starts as soon as participants enter the study. While patients are at the NIH for the inpatient study, we provide them with meals containing different ratios of carbohydrates, proteins, and fats and help them to analyze how their blood sugar responds to these levels, both before and after they take the medication. This type of education is important since participants will also have to monitor their blood sugar twice a day at home during the study. Most of the time, we use real-life situations as teaching moments. For example, if a participant had pizza for dinner, we will discuss with them why their blood sugar spiked and suggest alternative food choices. We provide this type of coaching every week. I often joke that after three months they become tired of hearing from us. But one of the strengths of this study is that participants receive personalized feedback that enables them to make healthy food choices for the rest of their life.

Can you tell us more about targeted food choices for teens?

A very enlightening procedure that we conduct on all of our study participants is measuring their basal metabolic rate (energy expenditure at rest). We show them how many calories they need to consume each day to maintain their body’s normal functions and compare that number with an estimate of how many calories they usually consume in a day. For many participants this is the first time that they have insight into the reasons for their weight gain.

How does this lab work help with meal planning?

After we create a participant’s metabolic chart we make food plans that support their lifestyle and caloric needs and are realistic to follow. For example, a 2,000 calorie per day diet can be separated into 400 calories for breakfast, 600 calories for lunch, 200 calories for snack and 800 calories for dinner.

How do you envision personalizing the field of diabetes research and treatment?

A precision medicine approach to type 2 diabetes will help us to better explore if and how factors like genes, environment and lifestyle impact insulin and glucose metabolism in populations with significant treatment outcomes disparities. With this approach we hope to uncover novel targeted treatment and prevention strategies that demonstrate more efficacy and cost-efficiency than current treatment approaches for high-risk populations.

Where can people learn more about the trial?

Learn more about the study by watching this informational video. If you’re interested in joining the study, please contact the NIH Office of Clinical Trial Recruitment at 866-999-1116.

Pedbot video game

New robotic therapies for cerebral palsy

Little girl on hippobot

The hippobot is a mechanical horseback riding simulator that provides hippotherapy for children.

Cerebral palsy is the most common type of movement disorder in children, affecting 1 in 500 babies born each year. For these infants, learning to sit up, stand and walk can be a big challenge which often requires years of physical therapy to stretch and strengthen their muscles. A team led by Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sally Evans, M.D., director of Pediatric Rehabilitation Medicine at Children’s National, has created two new types of robotic therapy that they hope will make physical therapy more enjoyable and accessible for children.

Hippobot equine therapy simulator

One of the most effective types of therapy for children with cerebral palsy is hippotherapy, which uses horseback riding to rehabilitate children with neurological and musculoskeletal disabilities. The movement of horses helps riders with cerebral palsy improve endurance, balance and core strength, which in turns helps them gain the ability to sit without support. If a child with cerebral palsy does not master independent sitting early in life, he or she may never gain the ability to stand or walk. Unfortunately, many children never have the chance to experience hippotherapy due to geographical constraints and cost issues.

To increase patient access to hippotherapy, the bioengineering team (Reza Monfaredi, Ph.D.; Hadi Fooladi Talari, M.S.; Pooneh Roshani Tabrizi, Ph.D.; and Tyler Salvador, B.S.) developed the hippobot — a mechanical horseback riding simulator that provides hippotherapy for children ages 4 to 10 in the office setting. To create the hippobot, the researchers mounted a carousel horse on a six-degree of freedom commercial motion platform (the platform moves in the x, y and z directions and rotates about roll, pitch and yaw axes). They then programmed the platform to simulate a horse walking, trotting and cantering.

“Several experienced horse riders have tried the motion platform and commented that it gives a realistic feel,” says Dr. Cleary.

The team then incorporated optical tracking of the hippobot rider’s spine and pelvis to monitor their posture and created a virtual reality video display that simulates a horse moving down a pier. As other animals come towards the horse, the rider must lean right or left to avoid them.  The trackers on their back show which way they are leaning and feed that information into the gaming system.

“We wanted to see how the patient’s spine reacts as the horse moves through different patterns, and if the patients get better at maintaining their posture over several sessions,” says Dr. Cleary.

To date the system has been used with several children with cerebral palsy under an IRB-approved study. All of the participants enjoyed riding the horse and came back for multiple sessions.

The hippobot system was developed in close collaboration with the Physical Medicine and Rehabilitation Division at Children’s National, including Olga Morozova, M.D., Justin Burton, M.D., and Justine Belschner, P.T.

Pedbot ankle rehabilitation system

Pedbot video game

Patients use pedbot as an input device to pilot an airplane through a series of hoops. The level of the difficulty of the game can be easily adjusted based on the patient’s capability and physical condition.

More than half of children with cerebral palsy also have gait impairment as a result of excessive plantar flexion and foot inversion/eversion, or equinovarus/equinovalgus at their ankle and foot. To help these patients, Dr. Cleary’s team developed the pedbot — a small robot platform that enables better strengthening, motor control and range of motion in the ankle joint.

“Children with cerebral palsy have difficulty walking in part because they have trouble controlling their feet,” explains Dr. Evans. “Use of pedbot as part of therapy can help to give them increased control of their feet.”

Most ankle rehabilitation robots are limited in their movements, and have only one or two degrees of freedom, focusing on ankle dorsiflexion/plantarflexion and sometimes inversion/eversion. Pedbot is unique in that it has three degrees of freedom with a remote center of motion in the ankle joint area that allows it to move in ways other devices can’t.

The pedbot platform can move in three translational directions (x, y and z) and also rotate about three axes (the x, y and z axes). As an analogy, this is similar to the movement of a flight simulator. The system also includes motors and encoders at each axis and can be used in passive and active modes.

In both modes, the patient sits on a therapy chair with their foot strapped to the robotic device. In the passive mode, the therapist assists the patient in training motions along each axis. The robot can then repeat the motion under therapist supervision while incrementally increasing the range of motion as desired by the therapist.

For the active mode or “gaming” mode, the team developed a video game based on an airplane motif. Patients use pedbot as an input device to pilot an airplane through a series of hoops. The level of the difficulty of the game can be easily adjusted based on the patient’s capability and physical condition.

To date, four patients have participated in an IRB-approved clinical trial for the pedbot. All of the patients enjoyed the game and they were willing to continue to participate as suggested by a physiotherapist.

The pedbot team, in addition to the engineers mentioned above, includes Catherine Coley, P.T.; Stacey Kovelman, P.T.; and Sara Alyamani, B.A. In future work, they plan to expand the system to include electromyography measurements with Paola Pergami, M.D.,Ph.D. They also are planning to develop a low cost, 3D printed version for the home market so children can do Pedbot therapy every day.

Doctors-working-with-Digital-Tablet

New network will advance treatments for children

Doctors-working-with-Digital-Tablet

Three leaders from Children’s National Health System are among the investigators of a new FDA-funded program created to launch a global clinical trials network. The initial $1 million grant from the Food and Drug Administration (FDA) establishes a network among the Institute for Advanced Clinical Trials for Children (I-ACT for Children), the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) (affiliated with Children’s National), PEDSnet, the James M. Anderson Center for Health Systems Excellence and the Critical Path Institute, to address the unmet medical needs of children by improving quality and efficiency in developing innovative pediatric drugs and devices.

Along with the fiscal 2017 funds, there is a potential for $1 million in funding each year for an additional four years to I-ACT for Children, contingent on annual appropriations and the availability of funding. I-ACT for Children is a new independent, nonprofit organization that works to improve the planning and completion of pediatric clinical trials. PEDSnet and the Anderson Center will serve as the network’s data and learning core, while the Critical Path Institute will serve as the regulatory science core and NCC-PDI will serve as the medical device core.

From Children’s National, the investigators include: Peter Kim, M.D., Ph.D., vice president of the Sheikh Zayed Institute for Pediatric Surgical Innovation; Kolaleh Eskandanian, Ph.D., executive director of the Sheikh Zayed Institute and NCC-PDI and Johannes van den Anker, M.D., Ph.D., division chief of Clinical Pharmacology and vice chair of Experimental Therapeutics.

“We are pleased that this grant addresses innovative reengineering of the pediatric device trials system,” says Eskandanian. “In contrast with drug trials, device trials are generally less optimally understood in academic medical centers and clinical sites.”

She explains that children have medical device needs that are considerably different from adults. Designing devices for children requires considerations such as growth and development, anatomical and physiological differences. Often, the lack of available devices for children forces clinicians to use an adult device off-label or to improvise. Off-label use may be the only option, but such use can bring risks of serious adverse events that could be avoided if there were more FDA–approved pediatric devices.

“Thanks to partnership with I-ACT we will be able to address the pressing need to improve clinical trials and post-market monitoring of pediatric devices,” says Eskandanian.

Leading the network as principal investigator is Edward Connor, M.D., president of I-ACT for Children and an emeritus professor of Pediatrics, Microbiology, Immunology, and Tropical Medicine at George Washington University School of Medicine and Children’s National.

Work has been initiated to integrate network components and engage public and private shareholders. Next steps include selecting priority projects for implementation in 2018 and beyond, and scaling the network in North America and abroad.

Funding for this work was made possible, in part, by the Food and Drug Administration through grant 1 U18 FD 006297. Views expressed in written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Pamela Hinds

Giving children a voice in clinical trials

Pamela Hinds

“When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children’s organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience,” says Pamela S. Hinds, Ph.D., R.N.

Children as young as 8 years old with incurable cancer can reliably characterize the impact an experimental therapy has on their symptoms and quality of life – even at the earliest stages of drug development – making self-reported patient outcomes a potential new clinical trial endpoint, according to a longitudinal validity study led by Children’s National Health System researchers.

Cancer is the No. 1 disease-related cause of death in U.S. children aged 1 to 19, and roughly 25 percent of the 12,400 children newly diagnosed with cancer will die of their disease, the study authors write.

“When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children’s organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience,” says Pamela S. Hinds, Ph.D., R.N., director of Nursing Research and Quality Outcomes at Children’s National and lead author of study published June 5, 2017 in the journal Cancer. “Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects.”

To demonstrate the feasibility of children self-reporting outcomes, Hinds and colleagues recruited children and adolescents aged 8 to 18 with incurable or refractory cancers who were enrolled in Phase 1 safety trials or Phase 2 efficacy trials at four cancer settings: Children’s National, Seattle Children’s Hospital, Children’s Hospital of Philadelphia and Boston Children’s Hospital. Using a validated instrument to measure symptoms, function and other aspects of quality of life reported by patients, as well as four open-ended interview questions, researchers were able to better understand what aspects of symptoms and quality of life were most important to patients at this point in their lives and cancer treatment.

Of the 20 study participants, most were male (60 percent), adolescents (65 percent) and white (70 percent). Thirteen (65 percent) had solid tumors. Patients could describe “a good day” as having fewer side effects from the experimental therapy and fewer interruptions to their lives. “Bad days” were marked by interruptions to their usual activities and missing out on spending time with family and friends due to being at the hospital. A few study participants suggested that researchers add questions related to being away from home, family and friends and the ripple effect of treatment on other family members.

“Only by measuring and understanding self-reported symptoms and function in children and adolescents with incurable cancer can we adequately address threats to their quality of life and improve symptom control and supportive care,” Hinds and co-authors conclude. “By giving children a voice in the process, clinicians will be able to better anticipate and manage symptoms and thereby improve life for patients and their families.”

Training developing immune systems to prevent wheezing early in life

Stephen Teach does an asthma exam

Extensively engaging stakeholders such as parents, families and local service providers in the actual study design transformed a planned research project into a more patient-centered study.

For the small number of U.S. children who grow up on working farms, activities such as feeding the cows and clearing spent hay from the barn are little changed from a thousand years ago. Through such close contact with dirt and farm animals, rural kids’ immune systems develop more normally and better distinguish common bacteria from household allergens like dust, molds, pets, and pests. Rates of allergy and asthma continue to be lower in children who grow up in those conditions.

By contrast, rates of asthma have spiked among urban and disadvantaged kids, who have far less exposure to dirt and animals early in life. Today, leading pediatric institutions, such as Children’s National Health System, are “awash in emergency department (ED) visits for asthma” with each ED visit associated with 10 to 15 missed school days annually on a population basis, says Stephen J. Teach, MD, MPH, Director and Principal Investigator of IMPACT DC , a care, research, and advocacy program focused on under-resourced and largely minority children with asthma.

A paradigm-shifting multicenter clinical trial aims to reverse that trend by going old school and safely exposing very young infants to the type of immune system training they would have experienced if they grew up closer to the earth.

The five-year study, named “Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children,” is funded by a $27 million cooperative agreement grant from the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health. Children’s National, one of eight participating sites across the nation, will enroll an estimated 150 children in the study and will receive at least $2.5 million of that grant.

“It is currently thought by many, including me, that asthma and allergic diseases are a result of disordered development of the immune system very early in life,” says Dr. Teach, who is also Chair of the Department of Pediatrics at George Washington University. The immune system development process begins to unfold in the last few months of pregnancy and continues through infancy, meaning “the die is cast, we think, at a very young age.”

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation have asthma, but in the District of Columbia, a disproportionately higher number of children suffer from the respiratory ailment. Once children experience early wheezing, changes begin to occur in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, and resulting in a heightened tendency for the airways in the lungs to become inflamed and to excrete more mucous. As a result, the children’s poorly trained immune system becomes hyper vigilant, ready to recognize a multitude of things as potentially allergenic.

“We’ve got to do something to change the course of the disease and to make it less common and less severe,” Dr. Teach says.

The study will identify 1,000 babies who range in age from 6 months to 18 months who are the highest risk for asthma, either through family history, being diagnosed with eczema, or both. The infants will receive safe doses of the inactivated bacteria, which is marketed under the name Broncho-Vaxom®. The therapy comes in capsule form, which for two years will be sprinkled into bottles or onto food. The children will be followed to gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

“The rationale if we can expose these very young children to the benefits, but not the risks, of early life bacterial exposure, they may reap the benefits of developing a more properly functioning and less allergic immune system,” Dr. Teach says.

He says the Children’s National research team has had “remarkable success” engaging young children and their parents in such long-term studies, losing few to attrition.

“Going for five years will be breaking new ground. But all of our experience suggests that we will succeed if we show the families we care, we stay in touch with them, and we form these therapeutic partnerships by saying: ‘We want to partner with you. We can do this safely with mutual benefit.’ Families will get on board,” he says.

Related resources: Learn more about the clinical trial | Research at a Glance

Training kids developing immune systems to prevent wheezing

What’s Known
Some 6.3 million U.S. children younger than 18—or 8.6 percent of the nation’s kids—have asthma. The disease is characterized by an inflammation of the airways, and    symptoms may be triggered by breathing in such allergens as animal dander, pollen, dust, or mold.

Once children experience early wheezing, changes begin in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, which can result in a heightened tendency for the airways in the lungs to become inflamed.

What’s New
Asthma and allergic diseases are thought to result from disordered development of the immune system, a process that begins in the womb. A paradigm-shifting multicenter clinical trial will enroll patients at eight locations, including Children’s National Health System, to provide the type of “immune system training” that infants would experience if they grew up in rural settings—where most children’s immune systems develop more normally. The five-year study funded by the National Heart, Lung, and Blood Institute will identify 1,000 babies aged 6 months to 18 months who are at risk for asthma to receive safe doses of an inactivated bacteria to help them develop more properly functioning immune systems. The University of Arizona Health Sciences in Tucson will lead the national research effort. Researchers will gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

Questions for Future Research

Q: What will be the longer-term effects of preventing early wheezing? Will the children develop asthma less frequently?
Q: If intervention with young children occurs early enough to interrupt the disease cycle—preventing asthma, wheezing, and allergies—will they miss fewer days of school when they are older?
Q: Will families be willing to consistently follow the complex regimen necessary to administer the inactivated bacterial products on a long-term basis?

Source: Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children.

Enroll in this clinical trial—https://clinicaltrials.gov/ct2/show/NCT02148796

The search for precise blood biomarkers of neonatal brain injury

Bloodbiomarkers

What’s Known:
Hypoxic-ischemic encephalopathy (HIE) is characterized by reduced blood and oxygen flow to a baby’s brain around birth and may cause neurologic disability or death. It occurs most commonly after intrauterine asphyxia brought on by such difficulties as circulatory problems, placental abruption, or inflammatory processes. Newborns with HIE may suffer seizures, difficulty feeding, and disturbed control of heart rate and breathing. Cooling therapy, which is the standard of care, offers some protection to the developing brain, but up to 50 percent of HIE-affected infants still have poor outcomes.

What’s New:
Research scientists at Children’s National Health System are involved in a multi-center clinical trial to determine if erythropoietin (EPO), a hormone naturally secreted by the kidneys and commonly used to treat anemia, helps to prevent brain injury in these infants. The trial, called the HEAL Study (High Dose Erythropoietin for Asphyxia and Encephalopathy), is exploring whether EPO, given in addition to hypothermia, further lowers the risk of brain injury in HIE-affected babies. As a part of this study, researchers at Children’s National are leading the investigation to identify biomarkers of brain injury. Biomarkers are telltale chemicals in the blood and are used in tests that evaluate whether patients have suffered a heart attack. While available biomarkers warn when the heart, kidney, or liver is in trouble, there is no blood biomarker that signals ongoing brain injury. Such blood biomarkers could help to determine which infants are responding to treatment as well as to precisely identify which HIE-affected infants are still struggling and require additional treatments, such as EPO, to protect the brain and improve outcomes.

Questions for Future Research: 

  • Does EPO, in tandem with hypothermia, improve long- term neurodevelopmental outcomes in newborns with HIE?
  • Which biomarkers, or panel of biomarkers, best reflect the timing and severity of neonatal brain injury?
  • Can biomarkers direct which types of treatments are best for specific patients and when they should be used?

Source: Plasma Biomarkers of Brain Injury in Neonatal HIE (Hypoxic-Ischemic Encephalopathy).” A.N. Massaro, Y. Wu, T.K. Bammler, A. Mathur, R.C. McKinstry, T. Chang, D.E. Mayock, S. Mulkey, K. Van Meurs, L. Dong, R. Ballard, and S. Juul. Presented during the 2016 Pediatric Academic Societies Annual Meeting, Baltimore, MD. May 3, 2016.