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graphic abstract for brain tumor paper

First large-scale proteogenomic analysis offers insights into pediatric brain tumor biology

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graphic abstract for brain tumor paper

In the first large-scale, multicenter study of its kind, researchers conducted comprehensive analysis yielding a more complete understanding of pediatric brain tumors (PBT), which are the leading cause of cancer-related deaths in children. Researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Children’s Brian Tumor Network (CBTN) generated and analyzed proteomic data, which identifies common biological characteristics among different tumor types. The consortia consist of collaborators from the Icahn School of Medicine at Mount Sinai, National Cancer Institute, Fred Hutchinson Cancer Research Center, Children’s National Hospital and Children’s Hospital of Philadelphia. The study, published in Cell on November 25, 2020, provides a clearer understanding of the molecular basis of pediatric brain tumors and proposes new therapeutic avenues.

The molecular characterization of brain tumors has largely hinged upon the presence of unique alterations in the tumor genome ignoring the many layers of regulation that exist between DNA and the functional biology of the tumor cell that is actuated by proteins. The integration of proteomic data identifies common biological themes that span histologic boundaries, suggesting that treatments used for one histologic type may be applied effectively to other tumors sharing similar proteomic features.

Brian Rood, M.D., medical director of the Brain Tumor Institute and associate professor of pediatrics in the Center for Cancer and Blood Disorders at Children’s National Hospital, participated in this study and explains the importance of what the team discovered.

Q: Why was it important that researchers came together to do this work?

A: Comprehensive characterization of the fundamental biology of pediatric brain tumors, including the proteogenomic analysis done in this study, is essential to better understand and treat pediatric brain tumors.

Our study is based on the recognition that proteomics and phosphoproteomics needs to be integrated with other omics data to gain an improved systems biology view of the molecular features of brain tumors. In addition, characterizing biological themes that cross histologic boundaries and cells of origin can suggest extending treatments shown to be effective in one type of tumor to other histologically disparate tumors sharing the same proteomic features.

Proteomic data further reveal the functional impacts of somatic mutations and copy number variations (CNVs) not evident in transcriptomic data alone. Further, kinase-substrate network analyses identify activated biological mechanisms of tumor biology.

This work was only possible because of a unique collaboration between the CPTAC program of the NCI and the CBTN, of which Children’s National is a member.

Q: How will this work advance understanding and treatment of pediatric brain tumors?

A: Pediatric brain tumors have not benefitted from molecularly targeted drugs as much as other tumor types largely because they harbor relatively few gene mutations. Therefore, identifying key pathways to target in these patients’ tumors has been a challenge. The integration of proteomic and phosphoproteomic data with genomic data allows for the construction of a more comprehensive model of brain tumor biology and nominates specific key pathways to be targeted.

Q: What did you find that excites you?

A: Proteomic data revealed a number of findings that were not present in the genomic data. We found evidence to support a molecularly targeted approach to treating craniopharyngioma, a tumor that has previously been unresponsive to chemotherapy. We also found a prognostic marker for high grade gliomas that do not have a mutation in the H3 histone. We were able to identify specific kinases that may dictate the aggressive nature of certain ependymoma tumors. Importantly, we demonstrated the potential of proteomic studies to uncover unique tumor biology, paving the way for more extensive investigations using this approach.

You can find the full study published in Cell. Learn more about the Brain Tumor Institute at Children’s National.

pile of plastic bottles

The linkage between chemicals used in plastics and cardiovascular disease

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pile of plastic bottles

For people across the globe, plastics are synonymous with modern life and it’s impossible to avoid exposure to them, including clinical environments where a variety of frequently used materials, such as tubing and blood storage bags, are made from plastics.

For people across the globe, plastics are synonymous with modern life and it’s impossible to avoid exposure to them, including clinical environments where a variety of frequently used materials, such as tubing and blood storage bags, are made from plastics. Led by Nikki Posnack, Ph.D, principal investigator at The Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital, a team of Children’s National researchers has been studying the potential effects of chemicals found in plastics, such as BPA and DEHP, as possible contributors to cardiovascular disease.

Along with conducting proprietary studies of the potential effects, Posnack and her team recently reviewed available scientific studies to further identify and illuminate the potential links between exposure to the synthetic additives contained in plastics and cardiovascular mortality. The article was published this month in Nature Reviews Cardiology.

In the article Posnack cites a 10-year longitudinal study with the finding that high exposure to BPA was associated with a 46-49% higher hazard ratio for cardiovascular and all-cause mortality, compared with low exposure to BPA.

“Plastics may be indispensable materials, but their ubiquity does raise concerns about the effects of our continuous exposure to plasticizer additives like di(2-ethylhexyl) phthalate (DEHP) and synthetic chemicals used to create polymers like BPA,” said Posnack. “Although disease causation can be difficult to pinpoint in population and epidemiological studies, experimental work has clearly demonstrated a direct link to plastic chemicals and cardiac dysfunction. It is clear that future collaborative endeavors are necessary to bridge the gap between experimental, epidemiological and clinical investigations to resolve the impact of plastics on cardiovascular health.”

Nikki Gillum Posnack

Nikki Posnack, Ph.D, principal investigator at The Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital.

Posnack added that, given the omnipresence of plastics and their related chemicals, biomonitoring studies have reported detectable levels of DEHP and BPA in 75-90% of the population. Occupational or clinical environments can also result in elevated exposures to these dangerous chemicals. Previous epidemiological studies have reported links between elevated urinary levels of phthalate or bisphenol, common additives in plastic, and an increased risk of coronary and peripheral artery disease, chronic inflammation, myocardial infarction, angina, suppressed heart rate variability and hypertension.

Additionally, available research has shown that incomplete polymerization or degradation of BPA-based plastic products can result in unsafe human exposure to BPA. Despite these links, the article points out, both BPA and DEHP are still manufactured in high volumes and are used to produce a wide variety of consumer and commercial products.

Further exploring implications for pediatrics, a June 2020 article published by Posnack in Birth Defects Research looks at the potential effects of plastic chemicals on the cardiovascular health of fetal, infant and pediatric groups. The article highlighted experimental work that suggests plasticizer chemicals such as bisphenols and phthalates may exert negative influence on pediatric cardiovascular health. The article systematically called out areas of concern supported by research findings. Also addressing current gaps in knowledge, Posnack outlined future research endeavors that would be needed to resolve the relationship between chemical exposures and the impact on pediatric cardiovascular physiology.

In related work, Posnack and her team are expanding their work on plastics used in blood bags to also investigate the role of blood storage duration on health outcomes. A recently published first study demonstrates that “older” blood products (stored 35 or more days) directly impact cardiac electrophysiology, using experimental models. Published October 22, 2020 in the Journal of the American Heart Association, the study concludes that the cardiac effects are likely caused by biochemical alterations in the supernatant from red blood cell units that occur over time, including but not limited to, hyperkalemia (elevated potassium levels).

newborn in ICU

Cardiac technology advances show promise for kids but only if right-sized

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newborn in ICU

“Smaller patients, and those with congenital heart disease, can benefit from minimally-invasive methods of delivering pacemakers and defibrillators without the need for open-chest surgery,” says Charles Berul, M.D.

How to address the growing need for child-sized pacemakers and defibrillators, and finding better surgical techniques to place them, is the topic of an invited session called The Future is Now (or Coming Soon): Updates on New Technologies in Congenital Heart Care at the 2020 American Heart Association Scientific Sessions.

“Smaller patients, and those with congenital heart disease, can benefit from minimally-invasive methods of delivering pacemakers and defibrillators without the need for open-chest surgery,” says Charles Berul, M.D., co-director of the Children’s National Heart Institute and chief of Cardiology at Children’s National Hospital, who presented at the session.

“This unmet need can only be met by innovative pediatric research, geared towards miniaturization technologies for use in the smallest of children,” he says.

His presentation focused on the devices and approaches that have caught the attention of pediatric cardiology, such as pacemakers and subcutaneous defibrillators designed without lead wires, as well as less-invasive surgical approaches that may reduce recovery time for children with congenital heart disease who require these assist devices.

Using them in kids comes with added challenges, however. Often pediatric cardiologists have to be creative in how to make them work for smaller patients, Dr. Berul notes. This reiterates the important point that simply applying an adult technology to a child isn’t the right approach. The subcutaneous defibrillator, for example, is still pretty large for a child’s body. Some studies also show these devices may not be as accurate in children as in adults.

Investigators in the Sheikh Zayed Institute working together with the cardiologists at Children’s National Hospital are focused on product development and commercialization of tools and techniques to allow percutaneous minimally-invasive placement of devices, taking advantage of the newest devices and surgical techniques as they develop.

In his presentation, Dr. Berul stressed that as the technology for adults advances, it creates an opportunity for pediatric cardiology, but only if the devices, and the techniques to place them, are specifically redesigned for pediatric application.

American Heart Association Scientific Sessions 2020
The Future is Now (or Coming Soon): Updates on New Technologies in Congenital Heart Care – On Demand Session
CH.CVS.715
9:00am – 10:00am
Fri, Nov 13  (CST)

illustration of the brain

New research provides glimpse into landscape of the developing brain

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illustration of the brain

Stem and progenitor cells exhibit diversity in early brain development that likely contributes to later neural complexity in the adult cerebral cortex, this according to a new study in Science Advances. This research expands on existing ideas about brain development, and could significantly impact the clinical care of neurodevelopmental diseases in the future.

Stem and progenitor cells exhibit diversity in early brain development that likely contributes to later neural complexity in the adult cerebral cortex, this according to a study published Nov. 6, 2020, in Science Advances. Researchers from the Center for Neuroscience Research (CNR) at Children’s National Hospital say this research expands on existing ideas about brain development, and could significantly impact the clinical care of neurodevelopmental diseases in the future. The study was done in collaboration with a research team at Yale University led by Nenad Sestan, M.D, Ph.D.

“Our study provides a new glimpse into the landscape of the developing brain. What we are seeing are new complex families of cells very early in development,” says Tarik Haydar, Ph.D., director of CNR at Children’s National, who led this study. “Understanding the role of these cells in forming the cerebral cortex is now possible in a way that wasn’t possible before.”

The cerebral cortex emerges early in development and is the seat of higher-order cognition, social behavior and motor control. While the rich neural diversity of the cerebral cortex and the brain in general is well-documented, how this variation arises is relatively poorly understood.

“We’ve shown in our previous work that neurons generated from different classes of cortical stem and progenitor cells have different functional properties,” says William Tyler, Ph.D., CNR research faculty member and co-first author of the study. “Part of the reason for doing this study was to go back and try to classify all the different progenitors that exist so that eventually we can figure out how each contributes to the diversity of neurons in the adult brain.”

Using a preclinical model, the researchers were able to identify numerous groups of cortical stem and precursor cells with distinct gene expression profiles. The team also found that these cells showed early signs of lineage diversification likely driven by transcriptional priming, a process by which a mother cell produces RNA for the sole purpose of passing it on to its daughter cells for later protein production.

Tarik Haydar

“Our study provides a new glimpse into the landscape of the developing brain. What we are seeing are new complex families of cells very early in development,” says Tarik Haydar, Ph.D., director of CNR at Children’s National, who led this study. “Understanding the role of these cells in forming the cerebral cortex is now possible in a way that wasn’t possible before.”

Using novel trajectory reconstruction methods, the team observed distinct developmental streams linking precursor cell types to particular excitatory neurons. After comparing the dataset of the preclinical model to a human cell database, notable similarities were found, such as the surprising cross-species presence of basal radial glial cells (bRGCs), an important type of progenitor cell previously thought to be found mainly in the primate brain.

“At a very high level, the study is important because we are directly testing a fundamental theory of brain development,” says Zhen Li, Ph.D., CNR research postdoctoral fellow and co-first author of the study. The results add support to the protomap theory, which posits that early stem and progenitor diversity paves the way for later neuronal diversity and cortical complexity. Furthermore, the results also hold exciting translational potential.

“There is evidence showing that neurodevelopmental diseases affect different populations of the neural stem cells differently,” says Dr. Li. “If we can have a better understanding of the complexity of these neural stem cells there is huge implication of disease prevention and treatment in the future.”

“If we can understand how this early landscape is affected in disorders, we can predict the resulting changes to the cortical architecture and then very narrowly define ways that groups of cells behave in these disorders,” adds Dr. Haydar. “If we can understand how the cortex normally achieves its complex architecture, then we have key entry points into improving the clinical course of a given disorder and improving quality of life.”

Future topics the researchers hope to study include the effects of developmental changes on brain function, the origin and operational importance of bRGCs, and the activity, connections and cognitive features enabled by different families of neurons.

Catherine Bollard

Catherine Bollard, M.D., M.B.Ch.B., named next editor-in-chief of Blood Advances

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Catherine Bollard

“As editor-in-chief, I will aim to capture new developments in the hematology field, including immunology, immunotherapy, cell therapy, gene and cell therapy and transplant,” said Dr. Bollard.

The American Society of Hematology (ASH) has selected Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at the Children’s National Research Institute as the next editor-in-chief of its journal Blood Advances.

Blood Advances is a peer-reviewed online open access journal published by ASH that covers the latest developments in basic, translational and clinical hematology. Dr. Bollard’s term as editor-in-chief will begin in September 2021. She was selected by the ASH Executive Committee after a competitive international search.

“Blood Advances has a broad presence, a large and growing number of manuscript submissions, and an engaged readership,” said Dr. Bollard. “I am so looking forward to continuing to build and strengthen the journal as its editor-in-chief.”

Since its launch in 2016, Blood Advances has taken advantage of its digital, open-access publication model to emphasize multimedia and a rapid, continuous publication format. Under the leadership of founding editor-in-chief Robert Negrin, M.D., of Stanford University, the peer-reviewed journal has pioneered new means of interactive, collaborative discussion and achieved an impact factor of 4.910.

“As editor-in-chief, I will aim to capture new developments in the hematology field, including immunology, immunotherapy, cell therapy, gene and cell therapy and transplant,” said Dr. Bollard. Her vision for the future of Blood Advances also includes further expansion of the journal’s global reach as well as continued efforts to recruit an editorial team representing geographic, ethnic and gender diversity.

“We have tremendous opportunities for growth, and I think in order to grow we must consider what readers want, how we can provide quality service for authors and reviewers, and how we can establish our own identity as a journal,” she said.

Dr. Bollard is a hematologist whose research interests include developing cell and gene therapies for patients with cancer and underlying immune deficiencies. Recognized as a national and international leader in the bone marrow transplant, immunology and immunotherapy space, Dr. Bollard has an expansive understanding of cancer, immune deficiencies and viral infections in pediatric and adult patients.

In her role as director of the Center for Cancer and Immunology Research at Children’s National Hospital, she works to establish clinical and research programs focused on developing and bringing novel cell therapies from bench to bedside.

“Blood Advances is an important hub for hypothesis-generating papers, pilot studies and case reports, commentaries and other educational materials of interest to hematologists everywhere,” said ASH President Stephanie Lee, M.D., of Fred Hutchinson Cancer Research Center. “I am confident that Dr. Bollard will continue leveraging the journal’s unique digital platform to maintain its tradition of excellence as she executes her vision as editor-in-chief. I look forward to seeing how the journal evolves under her leadership.”

Artificial Intelligence concept image

Thrombectomy can be efficient and safe in childhood stroke, new study finds

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Artificial Intelligence concept image

A recent study adds to the growing evidence that mechanical thrombectomy can be effective and safe not only in adults, but also in childhood stroke.

Previous randomized trials proved the effectiveness of thrombectomy for large intracranial vessel occlusions in adults only. However, a recent retrospective study led by Monica S. Pearl, M.D., Neurointerventional Radiology Program director at Children’s National Hospital, finds that thrombectomy can be safely performed in carefully selected cases of childhood stroke. The study further shows that treated children have good neurological outcomes.

In the findings, Dr. Pearl and other leading experts discussed specific circumstances and important considerations to take into account when managing a child with acute ischemic stroke due to a large vessel occlusion.

“We are raising the bar for the expected level of care for children with acute ischemic stroke,” said Dr. Pearl. “Care should be multidisciplinary and involve stroke neurology, neuroradiology, neurointerventional radiology, neurosurgery, cardiology, hematology and ICU teams.”

Prior to the study, clear guidelines for patient selection, thrombectomy technique and periprocedural care did not exist for the pediatric population despite the proven success of mechanical thrombectomy in adults.

Through a case-based approach encompassing a broad range of ages and clinical presentations, Dr. Pearl and other leading experts presented select cases of acute ischemic stroke in children and discussed the nuances, risks, benefits and management plan for each child.

Many of the clinical scenarios highlighted unanswered questions in the management and treatment of children with acute ischemic stroke due to large vessel occlusion. The study adds to the growing evidence that mechanical thrombectomy can be effective and safe not only in adults, but also in childhood stroke.

“It’s exciting to be shaping management for children with acute ischemic stroke,” said Dr. Pearl. “We are serving as the model for individualized, patient-centered care with multidisciplinary specialists and institutional collaboration caring for children with acute ischemic stroke.”

However, Dr. Pearl and experts encourage caution because etiology in childhood stroke differs substantially from that in acute ischemic stroke in adults, with potentially major impact on procedure success and safety.

The mission of the Neurointerventional Radiology Program, a new effort at Children’s National, is to provide exceptional family-centered care and cutting-edge diagnostic and endovascular treatment options for children with neurovascular disorders. Dr. Pearl serves as the program’s full time, dedicated neurointerventional radiologist, a specialized expertise found only in a handful of other pediatric hospitals in the country.

You can find the full study published in JAHA. Learn more about the Children’s National Research Institute Center for Neuroscience Research.

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Children’s National joins international AI COVID-19 initiative

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communication network concept image

Children’s National Hospital is the first pediatric partner to join an international initiative led by leading technology firm NVIDIA and Massachusetts General Brigham Hospital, focused on creating solutions through machine and deep learning to benefit COVID-19 healthcare outcomes.

Children’s National Hospital is the first pediatric partner to join an international initiative led by leading technology firm NVIDIA and Massachusetts General Brigham Hospital, focused on creating solutions through machine and deep learning to benefit COVID-19 healthcare outcomes. The initiative, known as EXAM (EMR CXR AI Model) is the largest and most diverse federated learning enterprise, comprised of 20 leading hospitals from around the globe.

Marius George Linguraru, D.Phil., M.A., M.Sc., principal investigator at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital, noted that one of the core goals of the initiative is to create a platform which brings resources together, from a variety of leading institutions, to advance the care of COVID-19 patients across the board, including children.

“Children’s National Hospital is proud to be the first pediatric partner joining the world’s leading healthcare institutions in this collaboration to advance global health,” says Linguraru. “We are currently living in a time where rapid access to this kind of global data has never been more important — we need solutions that work fast and are effective. That is not possible without this degree of collaboration and we look forward to continuing this important work with our partners to address one of the most significant healthcare challenges in our lifetime.”

A recent systematic review and meta-analysis from Children’s National Hospital became another core contribution to understanding how children are impacted by COVID-19. Led by Linguraru and accepted to be published in Pediatric Pulmonology, it offers the first comprehensive summary of the findings of various studies published thus far that describe COVID-19 lung imaging data across the pediatric population.

The review examined articles based on chest CT imaging in 1,026 pediatric patients diagnosed with COVID-19, and concluded that chest CT manifestations in those patients could potentially be used to prompt intervention across the pediatric population.

Marius George Linguraru

“Children’s National Hospital is proud to be the first pediatric partner joining the world’s leading healthcare institutions in this collaboration to advance global health,” says Marius George Linguraru, D.Phil., M.A., M.Sc.

“Until this point, pediatric COVID-19 studies have largely been restricted to case reports and small case series, which have prevented the identification of any specific pediatric lung disease patterns in COVID-19 patients,” says Linguraru. “Not only did this review help identify the common patterns in the lungs of pediatric patients presenting COVID-19 symptoms, which are distinct from the signs of other viral respiratory infections in children, it also provided insight into the differences between children and adults with COVID-19.”

Earlier this month, NVIDIA announced the EXAM initiative had – in just 20 days – developed an artificial intelligence (AI) model to determine whether a patient demonstrating COVID-19 symptoms in an emergency room would require supplemental oxygen hours – even days – after the initial exam. This data ultimately aids physicians in determining the proper level of care for patients, including potential ICU placement.

The EXAM initiative achieved a machine learning model offering precise prediction for the level of oxygen incoming patients would require.

In addition to Children’s National Hospital, other participants included Mass Gen Brigham and its affiliated hospitals in Boston; NIHR Cambridge Biomedical Research Centre; The Self-Defense Forces Central Hospital in Tokyo; National Taiwan University MeDA Lab and MAHC and Taiwan National Health Insurance Administration; Tri-Service General Hospital in Taiwan; Kyungpook National University Hospital in South Korea; Faculty of Medicine, Chulalongkorn University in Thailand; Diagnosticos da America SA in Brazil; University of California, San Francisco; VA San Diego; University of Toronto; National Institutes of Health in Bethesda, Maryland; University of Wisconsin-Madison School of Medicine and Public Health; Memorial Sloan Kettering Cancer Center in New York; and Mount Sinai Health System in New York.

illustration of cancer cells attacking kidneys

Renal cell carcinoma study shows excellent short-term outcomes without adjuvant therapy

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illustration of cancer cells attacking kidneys

Researchers found that patients with localized pediatric renal cell carcinoma have excellent short-term outcomes without adjuvant therapy.

Although renal cell carcinoma (RCC) is the second most common kidney cancer diagnosed in children and adolescents, guidance regarding its clinical management has been confined to retrospective case series, which were limited by reporting bias, varied treatment approaches and a lack of central pathology review to confirm the diagnosis.

Research conducted by the Children’s Oncology Group (COG) and led by Jeffrey Dome, M.D., Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, found that patients with localized pediatric RCC have excellent short-term outcomes without adjuvant therapy with 4-year overall survival estimates of 96% for patients with stage I disease, 100% for patients with stage II disease and 88% for patients with stage III disease.

“The results of this study provide important practical insights into the management of pediatric RCC,” said Dr. Dome. “Oncologists now have validation that a surgery-only approach is appropriate management for the majority of children and adolescents with RCC.”

Jeffrey Dome

“The results of this study provide important practical insights into the management of pediatric RCC,” said Jeffrey Dome, M.D., Ph.D.

The excellent survival in patients with stage III disease held up even in those with tumor involvement of regional lymph nodes, a finding that differs from adult RCC. However, patients with metastatic disease (stage IV), had a 4-year overall survival estimate of only 29%, demonstrating the need to find active treatments for this group. Outcomes varied according to tumor histological subtype. Nearly all recurrences occurred in patients with the translocation histology and renal medullary carcinoma; recurrences were rare in other subtypes.

A follow-up study called AREN1721 is now open in the Children’s Oncology Group and adult cancer cooperative groups that participate in the National Clinical Trials Network. This study involves a comparison of two treatment regimens for metastatic or unresectable “translocation” renal cell carcinoma, the most common subtype of renal cell carcinoma in children, adolescents and young adults. The treatment regimens will include nivolumab, a PD1 immune checkpoint inhibitor, with or without axitinib, a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR).

illustration of lungs surrounded by virus

COVID-19: First comprehensive review of pediatric lung imaging features

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illustration of lungs surrounded by virus

A systematic review and meta-analysis by Children’s National Hospital researchers, published in Pediatric Pulmonology, provides the first comprehensive review of the findings of published studies describing COVID-19 lung imaging data in children.

The number COVID-19 studies focused on children have been small and with limited data. This has prevented the identification of specific pediatric lung disease patterns in COVID-19. Although children make up around 9.5% of COVID-19 infections, less than 2% of the literature on the virus, its symptoms and effects, have focused on kids.

A systematic review and meta-analysis by Children’s National Hospital researchers, published in Pediatric Pulmonology, provides the first comprehensive review of the findings of published studies describing COVID-19 lung imaging data in children. The analysis concludes that chest CT manifestations in children with COVID‐19 could potentially prompt intervention in the pediatric population.

Marius George Linguraru, D.Phil., M.A., M.Sc., principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, discusses the importance of this work.

Q: What findings stand out to you?

A: We found that more than a third of children with COVID-19 had normal imaging. The lung imaging findings in these children were overall less frequent and less severe than in adult patients, but they were also more heterogeneous than in adults. Importantly, children with COVID-19 were three times more likely to have a normal exam than adults.

Several common lung imaging findings reported in adults were extremely rare or not found in the pediatric studies. These discoveries, and other recent reports in this space, support the fact that children’s symptoms may be less obvious than adults or even absent, but they still carry the virus and may be at risk for serious and life-threatening illness.

Marius George Linguraru

Marius George Linguraru, D.Phil., M.A., M.Sc., principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National.

Q: How will the findings of this study benefit pediatric care?

A: In our study, we showed how the health of the lungs of these children is impacted. Our results from data from 1,026 children (from newborns to 18 year old) with COVID-19 present chest manifestations that could potentially prompt informed intervention and better recovery.

Another conclusion of our study is that the abnormalities reported on the chest scans of children infected with COVID-19 are distinct from the typical lung images seen during other viral respiratory infections in the pediatric population. This is important for preparing for the cold and flu season.

Q: Why was this review important to our understanding of how COVID-19 impacts children?

A: This is the first systematic review and meta-analysis focused on the manifestation of the COVID-19 infection in the lungs of children. Our study, and others from colleagues at Children’s National, helps lead the efforts on elucidating how the pandemic affects the health of children.

Though children were initially thought to be less susceptible to infection, the data has made it clear that many children are at high risk for hospitalization and severe health complications. Although there are similarities between how children and adults are affected by the pandemic, there are also critical differences.

Given the limited knowledge in the manifestation of COVID-19 in children, with children susceptible to infection and hospitalization, and with children returning to school, continued efforts to understand the impact of COVID-19 on young patients is critically important. Understanding how children fare through the pandemic is the foundation of discovering better ways to take care of young patients and their health.

You can find the full study published in Pediatric Pulmonology. Learn more about the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National.

Annual Pediatric Device Innovation Symposium panelists

Accelerating pediatric device innovation through legislative processes and industry changes

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Annual Pediatric Device Innovation Symposium panelists
While the way we deliver healthcare is changing rapidly, far too often the tools we use to treat children are stuck in the past.

Over the last decade, pediatric medical device innovation, particularly for the youngest, most fragile children, has made dismal progress. Of the Class 3 (high risk/high benefit) medical devices approved by FDA for pediatrics in the last 10 years, less than 4% are for ages 0-2 years old; and even less for neo-natal patients. Simply put, as medical devices advance, children are not seeing the benefit of innovation.

The 8th Annual Pediatric Device Innovation Symposium presented by Children’s National Hospital in conjunction with the National Capital Consortium for Pediatric Medical Devices (NCC-PDI) featured a keynote panel, “Pediatric Device Innovation: What’s Next?”, to examine the legislative and industry changes needed to speed up device innovation for kids.

One of the keynote panelists, and leading voices on this issue, is Children’s National Hospital president and CEO Kurt Newman, M.D. Dr. Newman, a former pediatric surgeon, knows firsthand that every day in our nation’s pediatric hospitals, surgeons are manipulating adult medical devices to create creative solutions for children’s bodies because it’s the only available option.

“Children need and deserve devices that are conceived and designed with their biology and future in mind,” says Dr. Newman. “While children may only make up a small percentage of our population – maybe 20 or 25% – they are 100% of our future.”

Dr. Kurt Newman in front of the capitol building

“Children need and deserve devices that are conceived and designed with their biology and future in mind,” says Children’s National Hospital president and CEO Kurt Newman, M.D. “While children may only make up a small percentage of our population – maybe 20 or 25% – they are 100% of our future.”

Dr. Newman also addressed the current barriers to pediatric device innovation, which ranges from limited pediatric clinical trials to a market size that’s not financially appealing.

“The truth is, the frontiers of pediatric medicine are really in the innovative treatments, devices, therapies, and cures awaiting us on the other side of research and development.,” says Dr. Newman.

Former CNN correspondent, Jeanne Meserve, moderated the 45-minute keynote panel discussion, asking questions about the challenges to pediatric innovation, what policy changes need to take place to see improvement in the field of pediatric device innovation, and how federal funding can assist in creating change.

Michelle McMurry-Heath, new CEO of DC-based Biotechnology Innovation Organization (BIO), who joined Dr. Newman on this keynote panel, agreed that more needs to be done in the pediatric space. Dr. McMurry-Heath believes the Food and Drug Administration (FDA) is a public health advocate at heart and that the Pediatric Device Consortia (PDC), which Children’s National Hospital is part of, is starting to make new advancements in pediatric innovation by giving FDA clearance to more start-up companies than we’ve seen in the past.

“The FDA is interested in is what improves the health outcomes for the people and innovation is a huge piece. This is an important part of their mission and it is starting to yield benefits,” says Dr. Michelle McMurry-Heath. “Innovation is a team sport – it’s not easy. It takes a village of expertise and collaboration to progress and projects like the Pediatric Device Consortia is an important piece in this puzzle.”

NCC-PDI is one of five consortia in the FDA’s Pediatric Device Consortia (PDC) Grant Program created to support the development and commercialization of medical devices for children and is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital and the A. James Clark School of Engineering at the University of Maryland, with support from partners MedTech Innovator, BioHealth Innovation and design firm Archimedic.

To date, NCC-PDI has mentored over 100 medical device sponsors to help advance their pediatric innovations, with seven devices having received either their FDA market clearance or CE marking.

Dr. McMurry-Heath also addressed the challenge of diseases that don’t exist in adults and posed the question, “How do you create a device for kids if it doesn’t exist in adults?” She cited the lack of market in pediatrics and the difficulty in bringing a device to market as problems that hinder innovation, which is why advocating for these devices is crucial to children’s healthcare everywhere.

“So much of our innovation comes from our small, innovative companies,” say Dr. McMurry-Heath. “For example, my company is working on a COVID-19 tracker now and 70% of the innovation is coming from our smallest biotech companies. It’s a race against time for these companies to bring their innovation to market in order to keep the lights on and pay their scientists; this dog-eat-dog world isn’t immediately obvious to outsiders.

Beyond advocating, Dr. Newman and Children’s National are developing the first-of-its-kind pediatric research and innovation campus, which is currently under construction at DC’s former Walter Reed Army Medical Center site.

“We secured 12 acres to create something that has never been done before and that’s a campus for innovation dedicated to children,” says Dr. Newman. “Our close proximity to federal research institutions and agencies enables the new Children’s National campus to leverage the rich ecosystem of public and private sectors to help bolster biohealth, medical device, and life science innovation.”

As Children’s National continues to champion ways to accelerate pediatric device development, one focus is the on-site incubator Johnson & Johnson Innovation – JLABS, which will help start-up companies strengthen their ideas by working with coaches, having access to mentors and learning how to interact with the FDA. This partnership also offers an audience for their device which could potentially lead to investments.

The Children’s National Research & Innovation Campus will create an ecosystem that can accelerate breakthroughs in pediatric healthcare discoveries and technologies: The new campus is currently under construction and expected to open in the first quarter of 2021.

Both panelists agreed they’d like to see more flexibility with regulators to work with innovators in order create more incentives for them to present their device, like the NCC-PDI “Make Your Medical Device Pitch for Kids!” Competition, which was recently held in September 2020. The six winners received up to $50,000 in FDA-funded grant awards in order to develop their device, eventually bring it to market in order to improve healthcare for kids.

sick child in palliative care hospital bed

Children’s National Research Institute receives NIH grant for palliative care study

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sick child in palliative care hospital bed

A new NIH grant will support the first study that examines palliative care needs in pediatric rare disease community.

The National Institute of Health (NIH) has awarded $500,875 to the Children’s National Research Institute (CNRI), the academic arm of Children’s National Hospital, to support a new study examining the palliative care needs of children living with rare genetic diseases.

This is the first study of families of children with genetic and metabolic conditions, termed collectively as rare diseases, that is designed to intervene to support the well-being of family caregivers and create advance care plans for future medical decision making. In the United States, a rare disease is defined as a particular condition affecting fewer than 200,000 people. Pediatric patients with rare diseases experience high mortality rates, with 30 percent not living to see their fifth birthday.

“Children with ultra-rare or complex rare disorders are routinely excluded from research studies because of their conditions, creating a significant health disparity. Surveys show that families of children with rare diseases are adversely impacted by lack of easy access to peer and psychological support,” says Maureen Lyon, Ph.D., Clinical Health Psychologist and Professor of Pediatrics at the CNRI and principal investigator on the project. “This study will examine the palliative care needs of family caregivers of children with rare genetic disorders and advance care planning intervention, which will ultimately help facilitate discussions about future medical care choices that families are likely to be asked to make for their child.”

Although greatly needed, there are few empirically validated interventions to address these issues Currently, there is only one intervention described for families of children with rare diseases — a Swedish residential, competence program — which focuses on active coping. However, this intervention does not address pediatric advance care planning, a critical aspect of palliative care.

Lyon adds that the major benefit of this proposed project will be filling the gap in knowledge about what family caregivers of medically fragile children with rare diseases want with respect to palliative care. In the United States, these families are expected to provide a level of care that, until a few decades ago, was reserved for hospitals.

Maureen E Lyon

Maureen Lyon, Ph.D., Clinical Health Psychologist and Professor of Pediatrics at the CNRI and principal investigator on the project.

“Our hope is that this study will provide a structured model for facilitating family decisions about end-of-life care, for those families who do not have the good fortune to have children who have the capacity to share in decision-making,” Lyon says.

In addition to bridging the knowledge gap regarding palliative care in rare disease patients, the study will also help inform current clinical, ethical and policy discussions, as well as the legal issues in a variety of areas, such as the debate surrounding advocacy, particularly for those children with impairments in physical function.

“We look forward to the results of this study,” said Marshall Summar, M.D., director of the Rare Disease Institute and division chief, Genetics and Metabolism at Children’s National Hospital. “As a leader in rare disease care, we continually examine how we can improve care and support for our patient families at our clinic and want to share our findings with others engaged in caring for rare disease patients. Because rare diseases can be life limiting in some cases, we need to learn all we can about how best to care and support a patient and family as they prepare for a potential transition to palliative care.”

All research at Children’s National Hospital is conducted through the CNRI, including translational, clinical and community studies. The CNRI also oversees the educational activities and academic affairs of the hospital and the Department of Pediatrics at the George Washington University School of Medicine and Health Sciences, frequently partnering with many other research institutions regionally and nationally. CNRI conducts and promotes translational and clinical medical research and education programs within Children’s National Hospital that lead to improved understanding, prevention, treatment and care of childhood diseases.

Pediatric Device Innovation Symposium graphic

Real-world evidence and the impact on pediatric device innovation

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Pediatric Device Innovation Symposium graphic

The 8th Annual Pediatric Device Innovation Symposium presented by @ChildrensNatl in conjunction with @Devices4kids took place Sept. 28-30.

The 8th Annual Pediatric Device Innovation Symposium presented by Children’s National Hospital in conjunction with the National Capital Consortium for Pediatric Medical Devices (NCC-PDI) kicked off on Monday, Sept. 28, 2020 with a panel featuring three fellow members of the FDA-funded Pediatric Device Consortia (PDC) Grants Program discussing real-world evidence and the vital role that innovation and technology play in advancing healthcare for the pediatric population.

As described by the FDA, real-world evidence (RWE) is the clinical evidence regarding the usage and potential benefits or risks of a medical product, derived from the analysis of patient data. RWE can be generated by different study designs or analyses, including but not limited to, randomized trials, including large simple trials, pragmatic trials and observational studies (prospective and/or retrospective).

The symposium panel, “Pediatric Device Consortia Update on the Use of Real-World Evidence (RWE) for Pediatric Device Innovation” examined real-world evidence (RWE) demonstration projects from Southwest Pediatric Device Consortium, UCSF-Stanford Pediatric Device Consortium and the West Coast Consortium for Technology and Innovation in Pediatrics (CTIP). The panel was moderated by Juan Espinoza, M.D., FAAP, director of CTIP.

“Real-world evidence projects are critical to the advancement of pediatric medical device innovation,” said Kolaleh Eskandanian, Ph.D., M.B.A., P.M.P., vice president and chief innovation officer at Children’s National Hospital, and principal investigator for NCC-PDI. “Bringing together our colleagues in pediatric healthcare through the symposium helps us together identify solutions that will bring medical device innovations to the market faster to benefit the children and families we all serve.”

Here are some of the key discussion points made by panelists regarding current RWE demonstration projects:

  • Emerging medical and consumer technologies are enabling the diabetes community to take great strides toward truly personalized, real-time, data-driven management.
  • “Connected” technologies such as smartphone apps, wearable devices and sensors create an ecosystem of data driven-tools that can link patients and care teams for precision management of conditions like diabetes, including predicting a hypoglycemic event.
  • RWE has an important future in treating rare diseases by using existing data and harnessing that to improve treatment among pediatric patients.
  • Through the rich data in academic healthcare systems, practitioners are better equipped to provide RWE to address important regulatory and research questions.
  • The creation of a pediatric device patient database, which provides real-time updates to clinical, device and patient-generated health data, offers several regulatory, safety and research advantages in advancing device innovation.
Kolaleh-Eskandanian

Kolaleh Eskandanian, PhD, MBA, PMP, vice president and chief innovation officer at Children’s National Hospital, and principal investigator for NCC-PDI.

The FDA currently supports RWE demonstration projects that are focused on understanding data quality, improving RWE tools and evaluating RWE approaches to study design and data analytics. Dr. Espinoza highlighted the importance of ongoing dialogue on the use of RWE as it pertains to innovations that advance pediatric healthcare across the board.

“Thank you to the NCC-PDI team for creating this opportunity for PDCs to talk about the impact of real-world evidence on pediatric medical device development and the projects we have to move that field forward,” said Dr. Espinoza, director of CTIP and principal investigator on the PDC’s RWE Demonstration Project. “These projects are intended to inform the FDA and the industry’s approach to RWE including study design, data standards, fitness for use and regulatory decision making and reproducibility. This is complicated work that involves research, IT infrastructure, clinical care and operations.”

NCC-PDI, which is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital and the A. James Clark School of Engineering at the University of Maryland, is one of five members of the FDA’s Pediatric Device Consortia Grant Program. To date, NCC-PDI has mentored over 100 medical device sponsors to help advance their pediatric innovations, with seven devices having received either their FDA market clearance or CE marking.

illustration of brain showing cerebellum

NIH grant supports research on locomotor dysfunction in Down Syndrome

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illustration of brain showing cerebellum

The National Institutes of Health (NIH) has granted the Children’s National Research Institute (CNRI) nearly $500,000 to better understand and identify specific alterations in the circuitry of the cerebellum that results in locomotor dysfunction in down syndrome.

Down syndrome (DS), the most commonly diagnosed chromosomal condition, affects a range of behavioral domains in children including motor and cognitive function. Cerebellar pathology has been consistently observed in DS, and is thought to contribute to dysfunction in locomotor and adaptive motor skills. However, the specific neural pathways underlying locomotor learning that are disrupted in DS remain poorly understood.

The National Institutes of Health (NIH) has granted the Children’s National Research Institute (CNRI) nearly $500,000 through their NIH-wide initiative INCLUDE – INvestigating Co-occurring conditions across the Lifespan to Understand Down syndrome – to better understand and identify specific alterations in the circuitry of the cerebellum that results in locomotor dysfunction in DS. The INCLUDE initiative aims to support the most promising high risk-high reward basic science.

“There is still a lot unknown about Down syndrome, in particular how fundamental cellular and physiological mechanisms of neural circuit function are altered in this syndrome,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director of CNRI. “Grant funding is particularly important to have the resources to develop and apply new cutting-edge methodology to study this neurodevelopmental disorder.”

The main goal of this research is to identify specific alterations in the circuitry of the cerebellum that result in locomotor dysfunction in DS. Defining specific abnormalities in motor behavior, and identifying the brain regions and neurons which are functionally involved will provide the basis for developing potential therapies for treating motor problems in individuals with DS.

“The last decade has brought rapid advances in neurotechnology to address questions at the ‘systems-level’ understanding of brain function,” says Aaron Sathyanesan, Ph.D., a Children’s National postdoctoral research fellow. “This technology has rarely been applied to preclinical models of neurodevelopmental disorders, and even more rarely to models of Down syndrome.”

An example is the use of fiber-optics to probe changes in neural circuitry during behavior. Using this technology, researchers can now directly correlate the changes in circuitry to deficits in behavior.

“Along with the other approaches in our proposal, this represents the synthesis of a new experimental paradigm that we hope will push the field forward,” says Dr. Sathyanesan.

In 1960, the average life expectancy of a baby with Down syndrome was around 10 years. Today, that life expectancy has increased to more than 47 years. That significant increase reflects critical advances in medicine, however, kids with DS still live with long-term challenges in motor and cognitive ability.

Children’s National strongly supports translation and innovation, and recently recruited internationally renowned DS researcher, Tarik Haydar, Ph.D., as its new director of the Center for Neuroscience Research.

“We’re building significant strength in this area of research. This grant helps open new avenues of investigation to define which cells and circuits are impacted by this common neurodevelopmental disorder,” says Dr. Gallo. “Our cutting-edge approach will help us answer questions that we could not answer before.”

NCC-PDI device competition

Medical device competition announces six winners to share in $250K

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Judges award grants for pediatric medical devices that address cardiovascular, NICU, and orthopaedic and spine device innovations.

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coronavirus

Higher COVID-19 rates seen in minority socioeconomically disadvantaged children

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coronavirus

Minority and socioeconomically disadvantaged children have significantly higher rates of COVID-19 infection, a new study led by Children’s National Hospital researchers shows.

Minority and socioeconomically disadvantaged children have significantly higher rates of COVID-19 infection, a new study led by Children’s National Hospital researchers shows. These findings, reported online August 5 in Pediatrics, parallel similar health disparities for the novel coronavirus that have been found in adults, the authors state.

COVID-19, an infection caused by the novel coronavirus SARS-CoV-2 that emerged in late 2019, has infected more than 4.5 million Americans, including tens of thousands of children. Early in the pandemic, studies highlighted significant disparities in the rates of infection in the U.S., with minorities and socioeconomically disadvantaged adults bearing much higher burdens of infection. However, says Monika Goyal, M.D., M.S.C.E, a pediatric emergency medicine specialist and associate division chief in the Division of Emergency Medicine at Children’s National whose research focuses on health disparities, it’s been unclear whether these disproportionate rates of infection also extend to youth.

To investigate this question, she and her colleagues looked to data collected between March 21, 2020, and April 28, 2020, from a drive-through/walk-up COVID-19 testing site affiliated with Children’s National — one of the first exclusively pediatric testing sites for the virus in the U.S. To access this free testing site, funded by philanthropic support, patients between the ages of 0 and 22 years needed to meet specific criteria: mild symptoms and either known exposure, high-risk status, family member with high-risk status or required testing for work. Physicians referred patients through an online portal that collected basic demographic information, reported symptoms and the reason for referral.

When Dr. Goyal and her colleagues analyzed the data from the first 1,000 patients tested at this site, they found that infection rates differed dramatically among different racial and ethnic groups. While about 7% of non-Hispanic white children were positive for COVID-19, about 30% of non-Hispanic Black and 46% of Hispanic children were positive.

“You’re going from about one in 10 non-Hispanic white children to one in three non-Hispanic Black children and one in two Hispanic children. It’s striking,” says Dr. Goyal.

Using data from the American Families Survey, which uses five-year census estimates derived from home address to estimate median family income, the researchers separated the group of 1,000 patients into estimated family income quartiles. They found marked disparities in COVID-19 positivity rates by income levels: while those in the highest quartile had infection rates of about 9%, about 38% of those in the lowest quartile were infected.

There were additional disparities in exposure status, Dr. Goyal adds. Of the 10% of patients who reported known exposure to COVID-19, about 11% of these were non-Hispanic white. However, non-Hispanic Black children were triple this number.

Although these numbers show clear disparities in COVID-19 infection rates, the authors are now trying to understand why these disparities occur and how they can be mitigated.

“Some possible reasons may be socioeconomic factors that increase exposure, differences in access to health care and resources, as well as structural racism,” says Dr. Goyal.

She adds that Children’s National is working to address those factors that might increase risk for COVID-19 infection and poor outcomes by helping to identify unmet needs — such as food and/or housing insecurity — and steer patients toward resources when patients receive their test results.

“As clinicians and researchers at Children’s National, we pride ourselves on not only being a top-tier research institution that provides cutting-edge care to children, but by being a hospital that cares about the community we serve,” says Denice Cora-Bramble, M.D., M.B.A., chief medical officer of Ambulatory and Community Health Services at Children’s National and the research study’s senior author. “There’s still so much work to be done to achieve health equity for children.”

Other Children’s National researchers who contributed to this study include Joelle N. Simpson, M.D.; Meleah D. Boyle, M.P.H, Gia M. Badolato, M.P.H; Meghan Delaney, D.O,. M.P.H.; and Robert McCarter Jr., Sc.D.

mother measuring sick child's temperature

Connections between Kawasaki disease and MIS-C

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mother measuring sick child's temperature

A new review article enumerates some key similarities and differences between MIS-C and Kawasaki disease.

Since May 2020, there has been some attention in the general public and the news media to a specific constellation of symptoms seen in children with COVID-19 or who have been exposed to COVID-19. For a time, headlines even called it a “Kawasaki-like” disease. At first glance, both the symptoms and the effective treatments are remarkably similar. However, a new review published in Trends in Cardiovascular Medicine finds that under closer scrutiny, the two conditions have some interesting differences as well.

“At the beginning of this journey, we thought we might be missing actual cases of Kawasaki disease because we identified a few patients who presented late and developed coronary artery abnormalities,” says Ashraf Harahsheh, M.D., senior author of the review article, “Multisystem inflammatory syndrome in children: Is there a linkage to Kawasaki disease?” and a cardiologist at Children’s National Hospital. “But as time passed, children exposed to COVID-19 started to present with a particular constellation of symptoms that actually had some important similarities and distinctions from Kawasaki.”

Similarities between Kawasaki disease and MIS-C

Both disease patterns seem to have a common trigger that provokes the inflammatory cascade reaction in genetically susceptible children, the authors write. However, there is also early evidence that children with each disease have different genetic markers, meaning different populations are genetically susceptible to each disease.

Additionally, the authors found that the massive activation of pro-inflammatory cytokines seen in MIS-C, also known as a “cytokine storm,” overlaps with a similar occurrence seen in Kawasaki disease, adult COVID-19 patients, toxic shock syndrome and some other viral infections.

Primary differences between Kawasaki disease and MIS-C

Overall, when compared to Kawasaki disease, children with MIS-C tend to:

  • Present at an older age
  • Have a more profound form of inflammation
  • Have more gastrointestinal manifestation
  • Show different laboratory findings
  • Have greater risk of left ventricle dysfunction and shock

Further study of both Kawasaki and MIS-C needed

Despite noted differences, the authors are also careful to credit the documented similarities between Kawasaki disease and MIS-C as a key to the quick identification of the new syndrome in children. The study of Kawasaki disease also gave clinicians a valid basis to begin developing diagnostic recommendations and treatment protocols.

The review’s first author Yue-Hin Loke, M.D., who is also a cardiologist at Children’s National, says, “The quick recognition of MIS-C is only possible because of meticulous research conducted by Dr. Tomisaku Kawasaki, who recently passed away on June 5th, 2020. Even though some aspects of both are still shrouded in mystery, the previous research and clinical advancements made in Kawasaki disease set the stage for our immediate response to MIS-C.”

“Previous research provided key information for cardiologists facing this new syndrome, including the necessity of routine echocardiograms to watch for coronary artery abnormalities (CAAs) and for use of  intravenous immunoglobulin (IVIG) to mitigate  the development of CAAs,” says Charles Berul, M.D., chief of Cardiology at Children’s National and a co-author. “Both of these factors have played a key role in reducing the mortality of MIS-C to almost zero.”

The authors note that more research is needed to understand both Kawasaki disease and the specifics of MIS-C, but that what is learned about the mechanisms of one can and should inform study and treatment of the other. And in the meantime, caution and continued surveillance of these patients, especially with respect to coronary artery and myocardial function, will continue to improve the long-term outcomes for both syndromes.

Yuan Zhu

Study suggests glioblastoma tumors originate far from resulting tumors

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Yuan Zhu

“The more we continue to learn about glioblastoma,” Yuan Zhu, Ph.D., says, “the more hope we can give to these patients who currently have few effective options.”

A pre-clinical model of glioblastoma, an aggressive type of cancer that can occur in the brain, suggests that this recalcitrant cancer originates from a pool of stem cells that can be a significant distance away from the resulting tumors. The findings of a new study, led by Children’s National Hospital researchers and published July 22 in the journal Nature Communications, suggest new ways to fight this deadly disease.

Despite decades of research, glioblastoma remains the most common and lethal primary brain tumor in adults, with a median survival of only 15 months from diagnosis, says study leader Yuan Zhu, Ph.D., the scientific director and endowed professor of the Gilbert Family Neurofibromatosis Institute at Children’s National. Unlike many cancers, which start out as low-grade tumors that are more treatable when they’re caught at an early stage, most glioblastomas are almost universally discovered as high-grade and aggressive lesions that are difficult to treat with the currently available modalities, including surgery, radiation and chemotherapy.

“Once the patient has neurological symptoms like headache, nausea, and vomiting, the tumor is already at an end state, and disease progression is very rapid,” Dr. Zhu says. “We know that the earlier you catch and treat cancers, the better the prognosis will be. But here, there’s no way to catch the disease early.”

However, some recent research in glioblastoma patients shows that the subventricular zone (SVZ) – an area that serves as the largest source of stem cells in the adult brain – contains cells with cancer-driving mutations that are shared with tumors found in other often far-distant brain regions.

To see if the SVZ might be the source for glioblastoma tumors, Dr. Zhu and his colleagues worked with pre-clinical models that carried a single genetic glitch: a mutation in a gene known as p53 that typically suppresses tumors. Mutations in p53 are known to be involved in glioblastoma and many other forms of cancer.

Using genetic tests and an approach akin to those used to study evolution, the researchers traced the cells that spurred both kinds of tumors back to the SVZ. Although both single and multiple tumors had spontaneously acquired mutations in a gene called Pten, another type of tumor suppressor, precursor cells for the single tumors appeared to acquire this mutation before they left the SVZ, while precursor cells for the multiple tumors developed this mutation after they left the stem cell niche. When the researchers genetically altered the animals to shut down the molecular pathway that loss of Pten activates, it didn’t stop cancer cells from forming. However, rather than migrate to distal areas of the brain, these malignant cells remained in the SVZ.

Dr. Zhu notes that these findings could help explain why glioblastoma is so difficult to identify the early precursor lesions and treat. This work may offer potential new options for attacking this cancer. If new glioblastoma tumors are seeded by cells from a repository in the SVZ, he explains, attacking those tumors won’t be enough to eradicate the cancer. Instead, new treatments might focus on this stem cell niche as target for treatment or even a zone for surveillance to prevent glioblastoma from developing in the first place.

Another option might be to silence the Pten-suppressed pathway through drugs, a strategy that’s currently being explored in various clinical trials. Although these agents haven’t shown yet that they can stop or reverse glioblastomas, they might be used to contain cancers in the SVZ as this strategy did in the pre-clinical model — a single location that might be easier to attack than tumors in multiple locations.

“The more we continue to learn about glioblastoma,” Dr. Zhu says, “the more hope we can give to these patients who currently have few effective options.”

Other Children’s National researchers who contributed to this study include Yinghua Li, Ph.D., Wei Li, Ph.D., Yuan Wang, Ph.D., Seckin Akgul, Ph.D., Daniel M. Treisman, Ph.D., Brianna R. Pierce, B.S., Cheng-Ying Ho, M.D. /Ph.D.

This work is supported by grants from the National Institutes of Health (2P01 CA085878-10A1, 1R01 NS053900 and R35CA197701).

screenshot of pitch competition

“COVID-19-edition” of pediatric medical device competition announces winners

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$1M grant funds research on quantitative imaging for tumors

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“For children who are at risk of losing their vision, this project will bring a window of opportunity for physicians to start treatment earlier and save their vision,” says Marius George Linguraru, DPhil, MA, MSc.

A team from Children’s National Hospital is part of a project receiving a two-year grant of nearly $1,000,000 from the National Institutes of Health (NIH) for the first pediatric project in the Quantitative Imaging Network (QIN) of the National Cancer Institute (NCI). Marius George Linguraru, DPhil, MA, MSc, principal investigator from the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital in Washington, D.C., is one of two principal investigators on the project, which focuses on developing quantitative imaging (QI) tools to improve pediatric tumor measurement, risk predictions and treatment response. Roger Packer, M.D., Senior Vice President of the Center for Neuroscience & Behavioral Health, Director of the Gilbert Neurofibromatosis Institute and Director of the Brain Tumor Institute, is co-investigator.

The project, in collaboration with Children’s Hospital of Philadelphia and Children’s Hospital Colorado, centers on the most common type of brain tumor in children, called a low-grade glioma. This project focuses on a clinically challenging group of children with neurofibromatosis type 1 (NF1), the most common inherited tumor predisposition syndrome. Nearly 20% of children with NF1 will develop a low-grade glioma called optic pathway glioma (OPG). In children with this type of brain tumor, the growth occurs around the optic nerve, chiasm and tracts, also called the optic pathway, which connects the eye to the brain. OPGs can cause vision loss and even blindness. Permanent vision loss usually occurs between one and eight years of age with doctors closely monitoring the tumor with magnetic resonance imaging (MRI) to assess the disease progression.

“Our traditional two-dimensional measures of tumor size are not appropriate to assess the changes in these amorphous tumors over time or how the tumor responds to treatment,” says Linguraru. “This means physicians have difficulty determining the size of the tumor as well as when treatment is working. Research such as this can lead to innovative medical technologies that can improve and possibly change the fate of children’s lives.”

Dr. Linguraru is leading the technical trials on this project, which take place in the first two years, or phase one, starting in June 2020. Phase one focuses on improving the often inaccurate human measurements of tumor size by developing QI tools to make precise and automated measures of tumor volume and shape using machine learning. In this phase, the project will use and homogenize MRI data from multiple centers to develop predictive models of the treatment response based on the tumor volume that are agnostic to the differences in imaging protocols. By doing this, it will allow physicians to make more informed decisions about the treatment’s success and whether the child will recover their vision.

When phase one is complete, Linguraru and the project’s other principal investigator Robert A. Avery, DO, MSCE, neuro-ophthalmologist in the Division of Ophthalmology at Children’s Hospital of Philadelphia, will initiate the second phase, which includes validating the QI application on data from the first ever phase III clinical trial comparing two treatments for NF1-OPGs. Phase two is scheduled to start in the Summer 2022 and continue through Summer 2025.

“For children who are at risk of losing their vision, this project will bring a window of opportunity for physicians to start treatment earlier and save their vision,” says Linguraru. “For those children who won’t benefit from chemotherapy because the tumor poses no threat to their sight, this project will save them from having to go through that difficult treatment unnecessarily. It will be life-changing for the children and their families, which is what excites me about this QI application.”

This project is a collaboration between Children’s Hospital of Philadelphia and Children’s National Hospital in Washington, D.C., in partnership with Children’s Hospital of Colorado and University of Pennsylvania. Upon project completion, the QI application will provide a precision-medicine approach for NF1-OPGs and improve clinical outcomes for pediatric tumors.

NCC-PDI-COVID19-Edition-Competition

“COVID-19-edition” of pediatric medical device competition announces finalists

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Sixteen finalists have been selected in the “Make Your Medical Device Pitch for Kids!” special COVID-19 edition competition presented by the National Capital Consortium for Pediatric Device Innovation (NCC-PDI). Representing innovations in COVID-19-related pediatric medical devices, the finalists will compete in a virtual pitch event held on July 20,2020 where up to $250,000 in awards will be given. Winners will receive grant funding of up to $50,000.

The competition is led by NCC-PDI co-founders the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital and the A. James Clark School of Engineering at the University of Maryland and powered by nonprofit accelerator and NCC-PDI member, MedTech Innovator.

This competition focuses on pediatric medical devices that support home health monitoring and telehealth, and improve sustainability, resiliency and readiness in diagnosing and treating children during a pandemic.

“As COVID -19 continues to threaten the health of families and children across the nation, we must continue to seek new and better ways to deliver quality care during a pandemic and offer technology solutions to reopen more safely,” says Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National Hospital and principal investigator of NCC-PDI. “Competitions like this are vital to get ahead of the healthcare challenge that COVID-19 presents in the world of pediatrics. By supporting innovation, we provide critical breakthroughs that can positively impact the lives of the children and families we serve.”

Along with grant funding, one company from the competition will be selected by Johnson & Johnson Innovation – JLABS to receive a one-year residency at JLABS @ Washington, DC, which will be located on the new Children’s National Research & Innovation Campus currently under construction. In addition to the 2021 JLABS residency, the awardee will have access to the JLABS community and expert mentoring by the Johnson & Johnson family of companies.

The 16 pediatric device innovations that judges selected for the final competition include:

  • Adipomics – simple and fast, one-step COVID-19 diagnostic kit for home or school use
  • Bloom Standard (Kaaria) – wearable, AI-driven ultrasound for infant cardiac and pulmonary screening and diagnostics
  • CereVu Medical – remote COVID-19 sensor, monitor and centralized data hub that measures blood oxygen saturation, muscle aches, temperature and trouble breathing
  • Children’s Hospital of Philadelphia – a transparent reusable DIY origami facemask that reveals facial expressions & improves communication
  • Children’s National Hospital – Lab-on-a-chip device for high-throughput combination drug screening
  • Hopscotch – gamified cognitive behavioral therapy-based computer exercises to encourage kids to stay engaged and complete treatment programs
  • Medichain – cost effective, accurate COVID-19 test with results in minutes and can detect the virus in the early stage
  • Medipines – monitor device that displays critical respiratory parameters analyzed from a patient’s breathing sample
  • OtoPhoto – a smart otoscope that quickly and accurately aids diagnosis of ear infections for home telehealth use
  • OxiWear – continuous wear oxygen-monitoring device used to reduce patient insecurity
  • REALTROMINS – real time, continuously updated predictive analytics to identify impending mortality in children
  • SurgiPals – digital assistant and urine biochemical sensor to aid in outpatient care of children with COVID-19
  • TGV-Dx – a novel, phenotype-based test system for rapid selection of effective antibiotic regimen
  • VitaScope – quick, accurate infant vital signs to facilitate high-quality virtual care
  • Vitls – wearable platform for remote patient monitoring of the vitals clinicians require to assess a patient
  • X-Biomedical – rugged, portable smart ICU ventilator for pediatric and adult patients

Funding for the competition is made possible by a grant from the Food and Drug Administration (FDA) and a philanthropic gift from Mei Xu, founder of e-commerce platform Yes She May, a site dedicated to women-owned brands.

In addition to this COVID-19 special edition event, NCC-PDI recently revealed the ten finalists in its prestigious 8th annual “Make Your Medical Device Pitch for Kids!” competition. Cardiovascular, NICU, and orthopaedic and spine device innovations are the focus of the fall competition, taking place October 7, 2020 as part of the 8th Annual Symposium on Pediatric Device Innovation, presented by Children’s National and co-located with The MedTech Conference powered by AdvaMed.

pitch competition finalists