Cancer

Catherine Bollard

Engineering TGFB receptor to enhance NK cells and fight neuroblastoma

Catherine Bollard

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Catherine Bollard, M.B.Ch.B., M.D.

Catherine Bollard, M.B.Ch.B., M.D., and her research team published results showing potential efficacy of a novel cell therapeutic for treatment of pediatric patients with relapsed/refractory neuroblastoma.

The research paper, entitled, “Engineering the TGFβ receptor to Enhance the Therapeutic Potential of Natural Killer Cell as an Immunotherapy for Neuroblastoma,” was published on April 29, 2019 by Clinical Cancer Research and is being recognized for the potential efficacy of the “off the shelf” treatment for patients with relapsed/refractory neuroblastoma.

The researcher’s approach allows them to manipulate Natural Killer (NK) cells, expand and reinfuse them within a patient so they can fight cancer and disease.

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Dr. Bollard, who is the senior corresponding author of the study and director of the Center for Cancer and Immunology Research at the Children’s Research Institute. “In other words, turning the negative effects of TGFb into positive effects enhances the persistence and anti-tumor activity of these tumor-killing NK cells in vivo.”

NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of human leukocyte antigen (HLA) expression on interacting target cells, as in the case for a majority of solid tumors, including neuroblastoma. With neuroblastoma being a leading cause of pediatric cancer-related deaths, it presents as an ideal candidate for NK cell therapy.

“This manuscript encompasses a significant portion of work, in which we generated genetically-modified NK cells as an enhanced form of immunotherapy for neuroblastoma,” said Rachel Burga, Ph.D., lead author and graduate of the Institute for Biomedical Sciences at George Washington and Children’s National Health System.  “We’re very excited to share our pre-clinical findings which demonstrate the efficacy of approaches to “hijack” the TGFb receptor and target TGFb in the tumor microenvironment.”

She added that the approach will allow for the NK cells to simultaneously resist the immune suppression in the microenvironment and initiate activation to increase their ability to target tumor cells.

Pre-clinical testing and research for this trial began in 2016 and ended in 2019. “The idea came from a Department of Defense award given to Dr. Bollard and Dr. Cruz and they took the idea and reduced it to practice and showed feasibility for pre-clinical trial,” said Rohan Fernandes, Ph.D., assistant professor in the Department of Medicine at George Washington University and senior author on the manuscript.

Fernandes added that the timeframe to start the clinical trial is within the next two to four years at Children’s National.

Additional authors include Rachel A. Burga, Ph.D., Eric Yvon, Rohan Fernandes, Conrad Russell Cruz, and Catherine M. Bollard, M.B.Ch.B., M.D.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents:
Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students:
Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty:
Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students:
Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents:
Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students:
Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty:
Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff:
Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents:
Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students:
Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty:
Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff:
Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents:
Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students:
Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Beth Tarini

Getting to know SPR’s future President, Beth Tarini, M.D., MS

Beth Tarini

Quick. Name four pillar pediatric organizations on the vanguard of advancing pediatric research.

Most researchers and clinicians can rattle off the names of the Academic Pediatric Association, the American Academy of Pediatrics and the American Pediatric Society. But that fourth one, the Society for Pediatric Research (SPR), is a little trickier. While many know SPR, a lot of research-clinicians simply do not.

Over the next few years, Beth A. Tarini, M.D., MS, will make it her personal mission to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members. In May 2019 Dr. Tarini becomes Vice President of the society that aims to stitch together an international network of interdisciplinary researchers to improve kids’ health. Four-year SPR leadership terms begin with Vice President before transitioning to President-Elect, President and Past-President, each for one year.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini, associate director for Children’s Center for Translational Research.

“I’m delighted that Dr. Tarini was elected to this leadership position, and I am impressed by her vision of improving SPR’s outreach efforts,” says Mark Batshaw, M.D., Executive Vice President, Chief Academic Officer and Physician-in-Chief at Children’s National. “Her goal of engaging potential members in networking through a variety of ways – face-to-face as well as leveraging digital platforms like Twitter, Facebook and LinkedIn – and her focus on engaging junior faculty will help strengthen SPR membership in the near term and long term.”

Dr. Tarini adds: “Success to me would be leaving after four years with more faculty – especially junior faculty – approaching membership in SPR with the knowledge and enthusiasm that they bring to membership in other pediatric societies.”

SPR requires that its members not simply conduct research, but move the needle in their chosen discipline. In her research, Dr. Tarini has focused on ensuring that population-based newborn screening programs function efficiently and effectively with fewer hiccups at any place along the process.

Thanks to a heel stick to draw blood, an oxygen measurement, and a hearing test, U.S. babies are screened for select inherited health conditions, expediting treatment for infants and reducing the chances they’ll experience long-term health consequences.

“The complexity of this program that is able to test nearly all 4 million babies in the U.S. each year is nothing short of astounding. You have to know the child is born – anywhere in the state – and then between 24 and 48 hours of birth you have to do testing onsite, obtain a specific type of blood sample, send the blood sample to an off-site lab quickly, test the sample, find the child if the test is out of range, get the child evaluated and tested for the condition, then send them for treatment. Given the time pressures as well as the coordination of numerous people and organizations, the fact that this happens routinely is amazing. And like any complex process, there is always room for improvement,” she says.

Dr. Tarini’s research efforts have focused on those process improvements.

As just one example, the Advisory Committee on Heritable Disorders in Newborns and Children, a federal advisory committee on which she serves, was discussing how to eliminate delays in specimen processing to provide speedier results to families. One possible solution floated was to open labs all seven days, rather than just five days a week. Dr. Tarini advocated for partnering with health care engineers who could help model ways to make the specimen transport process more efficient, just like airlines and mail delivery services. A more efficient and effective solution was to match the specimen pick-up and delivery times more closely with the lab’s operational times – which maximizes lab resources and shortens wait times for parents.

Conceptual modeling comes so easily for her that she often leaps out of her seat mid-sentence, underscoring a point by jotting thoughts on a white board, doing it so often that her pens have run dry.

“It’s like a bus schedule: You want to find a bus that not only takes you to your destination but gets you there on time,” she says.

Dr. Tarini’s current observational study looks for opportunities to improve how parents in Minnesota and Iowa are given out-of-range newborn screening test results – especially false positives – and how that experience might shake their confidence in their child’s health as well as heighten their own stress level.

“After a false positive test result, are there parents who walk away from newborn screening with lingering stress about their child’s health? Can we predict who those parents might be and help them?” she asks.

Among the challenges is the newborn screening occurs so quickly after delivery that some emotionally and physically exhausted parents may not remember it was done. Then they get a call from the state with ominous results. Another challenge is standardizing communication approaches across dozens of birthing centers and hospitals.

“We know parents are concerned after receiving a false positive result, and some worry their infant remains vulnerable,” she says. “Can we change how we communicate – not just what we say, but how we say it – to alleviate those concerns?”

Meghan Delaney

Pathology chief appointed to board of pathology advisory committee

Meghan Delaney

The American Board of Pathology (ABPath) has appointed the chief of Pathology and Laboratory Medicine at Children’s National Health System, Meghan Delaney, D.O., M.P.H., to its Test Development and Advisory Committee (TDAC) for blood banking and transfusion medicine. As a member of the committee, Dr. Delaney will play a role in the development and review of the American Board of Pathology certification exam questions. Physicians selected to serve on the TDAC are established subject matter experts in their subspecialty, with knowledge on the latest advances in the field of pathology and patient care.

“As TDAC members, these physicians play a critical role in the development of the exams and are entrusted with maintaining the integrity of the board-certified designation. The appointment to a TDAC indicates the physician is highly regarded in the field of pathology and exemplifies the utmost standards of care,” states Rebecca L. Johnson, M.D., CEO of the American Board of Pathology.

Dr. Delaney joined Children’s National as Chief of Pathology and Laboratory Medicine in 2017. A diplomate of the American Board of Pathology, with certification in transfusion medicine/blood banking and clinical pathology, she is an active member of several professional societies. She serves as chair of the AABB Transfusion Medicine Subsection Pediatric Subcommittee and as chair of the American Society of Apheresis Applications Committee Pediatric Subcommittee.  Dr. Delaney is also a scientific member of the BEST Collaborative, an associate editor for the journal Transfusion Medicine and a member of the editorial board of Transfusion.

The mission of the American Board of Pathology, as a member of the American Board of Medical Specialties, is to serve the public and advance the profession of pathology, by setting certification standards and promoting lifelong competency of pathologists. Founded in 1936, the ABPath accomplishes this mission by establishing certification and continuing certification standards, as well as, assessing the qualifications of those seeking to obtain voluntary certification in the specialty of pathology.  Since 1971, the ABPath has appointed test committees for each specialty area of pathology. The committee consists of ABPath trustees and other pathologists, or specialty physicians, who are recognized experts in their respective disciplines.

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.

ACC19 attendees from Children's National

ACC.19: A focus on pediatric cardiology

ACC19 attendees from Children's National

Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.

“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.

Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypolastic left heart syndrome.

A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:

Personalized guidelines:

  • Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
  • Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.

Early detection:

  • Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
  • Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
  • Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.

Coordinated care:

  • Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
  • Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
  • Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.

Innovation:

  • Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.
  • Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”

“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”

Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.

“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”

Dr. Kurt Newman in front of the capitol building

Kurt Newman, M.D., shares journey as a pediatric surgeon in TEDx Talk

Kurt Newman, M.D., president and chief executive officer of Children’s National, shares his poignant journey as a pediatric surgeon, offering a new perspective for approaching the most chronic and debilitating health conditions. In this independently-organized TEDx event, Dr. Newman also shares his passion for Children’s National and the need to increase pediatric innovations in medicine.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Maureen E Lyon

Maureen E. Lyon receives American Cancer Society grant

Maureen E Lyon

Children’s Clinical Health Psychologist Maureen E. Lyon, Ph.D., has received the “Judy White Memorial Clinical Research Pilot Exploratory Projects in Palliative Care of Cancer Patients and their Families” grant from the American Cancer Society (ACS).

Over two years, Lyon will be allotted $144,000 to translate Children’s evidence-based Family-Centered (FACE) pediatric advance care planning (ACP) protocol into Spanish through a process of community-based participatory research for teens with cancer.

Lyon’s research focuses on enabling families to understand their adolescents’ treatment preferences and describing patient-reported palliative care needs for teens with cancer. Ultimately, the research will help identify the wants, values, goals and beliefs of teens with cancer.

Along with the ACS research grant, Lyon and Jessica Thompkins, BSN, R.N., CPN, research nurse coordinator at Children’s National, will present at the Annual Assembly of Hospice & Palliative Medicine conference, March 13-16, 2019 in Orlando, Fla. on data from the current multi-site, five-year randomized clinical trial funded by National Institute of Health/ National Institute of Nursing Research for English-speaking teens with cancer.

During the presentation, they will speak about the effect of FACE ACP on families’ appraisals of caregiving for their teens with cancer and describing advance care planning communication approaches.

Lyon and other researchers at Children’s National look forward to making significant contributions to the science of advance care planning aimed to minimize suffering and enhancing quality of life for young adults. Their contributions give teens a voice in their future medical care and help families “break the ice,” by providing an extra level of support to treating clinicians.

tubes filled with pink liquid

Manufacturing technologies lag behind breakthroughs in CAR-T cancer treatment

tubes filled with pink liquid

Drug companies around the country are banking on the cutting-edge cancer treatments known as CAR-T, but many manufacturing processes are holding back the treatment from reaching the market. With the success of CAR-T, which essentially re-trains T Cells to identify and target the cancer-causing cells, many manufacturers still need to catch up in the development process.

Currently, there are nearly 700 CAR-T studies in the database ClinicalTrials.gov, including 152 industry-sponsored trials that are active, recruiting or enrolling by invitation. According to market research firm, Coherent Market Insights, they predict the CAR-T market will grow to $8 billion worldwide by 2028 from $168 million in 2018.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National Health System, was featured in a recent Bloomberg Law article stating that academics, industry participants and medical product regulators are trying to catch up with the technology and determine the best standards for developing these products. Although this is an exciting and positive time in the field of oncology, it also presents a big learning curve.

Making these cells requires extracting patients T cells. They are then genetically engineered in a laboratory to produce proteins that allow them to identify cancer-causing cells. The new cells are then multiplied and then reintroduced into the body to kill off the cancer cells. The entire process can take a few weeks to complete.

“This is not a drug,” Bollard said. “This is a living biologic, and it comes from the patient and individuals. There’s so much variability.”

Along with manufacturing challenges, the outlook on creating more therapies is looking good. The FDA predicts that it will be approving 10 to 20 gene therapy products a year by 2025. Other companies are working to develop a manufacturing platform that can help reduce the complexity of the current system and ultimately make CAR-T manufacturing easier to scale.

schistosome blood fluke

Therapy derived from parasitic worms downregulates proinflammatory pathways

schistosome blood fluke

A therapy derived from the eggs of the parasitic Schistosoma helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways, reducing inflammation.

A therapy derived from the eggs of parasitic worms helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways and reducing inflammation, indicates the first transcriptome-wide profiling of the bladder during ifosfamide-induced hemorrhagic cystitis.

The experimental model study findings were published online Feb. 7, 2019, in Scientific Reports.

With hemorrhagic cystitis, a condition that can be triggered by anti-cancer therapies like the chemotherapy drug ifosfamide and other oxazaphosphorines, the lining of the bladder becomes inflamed and begins to bleed. Existing treatments on the market carry their own side effects, and the leading therapy does not treat established hemorrhagic cystitis.

Around the world, people can become exposed to parasitic Schistosoma eggs through contaminated freshwater. Once inside the body, the parasitic worms mate and produce eggs; these eggs are the trigger for symptoms like inflammation. To keep their human hosts alive, the parasitic worms tamp down excess inflammation by secreting a binding protein with anti-inflammatory properties.

With that biological knowledge in mind, a research team led by Michael H. Hsieh, M.D., Ph.D., tested a single dose of IPSE, an Interleukin-4 inducing, Schistosoma parasite-derived anti-inflammatory molecule and found that it reduced inflammation, bleeding and urothelial sloughing that occurs with ifosfamide-related hemorrhagic cystitis.

In this follow-up project, experimental models were treated with ifosfamide to learn more about IPSE’s protective powers.

The preclinical models were given either saline or IPSE before the ifosfamide challenge. The bladders of the experimental models treated with ifosfamide had classic symptoms, including marked swelling (edema), dysregulated contraction, bleeding and urothelial sloughing. In contrast, experimental models “pre-treated” with IPSE were shielded from urothelial sloughing and inflammation, the study team found.

Transcriptional profiling of the experimental models’ bladders found the IL-1-B TNFa-IL-6 proinflammatory cascade via NFkB and STAT3 pathways serving as the key driver of inflammation. Pretreatment with IPSE slashed the overexpression of Il-1b, Tnfa and Il6 by 50 percent. IPSE drove significant downregulation of major proinflammatory pathways, including the IL-1-B TNFa-IL-6 pathways, interferon signaling and reduced (but did not eliminate) oxidative stress.

“Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE,” says Dr. Hsieh, a urologist at Children’s National Health System and the study’s senior author. “These preliminary findings reveal several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis in humans.”

When certain chemotherapy drugs are metabolized by the body, the toxin acrolein is produced and builds up in urine. 2-mercaptoethane sulfonate Na (MESNA) binds to acrolein to prevent urotoxicity. By contrast, IPSE targets inflammation at the source, reversing inflammatory changes that damage the bladder.

“Our work demonstrates that there may be therapeutic potential for naturally occurring anti-inflammatory molecules, including pathogen-derived factors, as alternative or complementary therapies for ifosfamide-induced hemorrhagic cystitis,” Dr. Hsieh adds.

In addition to Dr. Hsieh, study co-authors include Lead Author Evaristus C. Mbanefo and Rebecca Zee, Children’s National; Loc Le, Nirad Banskota and Kenji Ishida, Biomedical Research Institute; Luke F. Pennington and Theodore S. Jardetzky, Stanford University; Justin I. Odegaard, Guardant Health; Abdulaziz Alouffi, King Abdulaziz City for Science & Technology; and Franco H. Falcone, University of Nottingham.

Financial support for the research described in this report was provided by the Margaret A. Stirewalt Endowment, the National Institute of Diabetes and Digestive and Kidney Diseases under award R01DK113504, the National Institute of Allergy and Infectious Diseases under award R56AI119168 and a Urology Care Foundation Research Scholar Award.

Roger Packer

Roger J. Packer, M.D. presents keynote address for BRAIN 2019

Roger Packer

2019 Otto Lien Da Wong visiting professor in neuro-oncology at BRAIN 2019, Roger J. Packer, M.D. presented the keynote address.

 

More than 400 neurologists, neurosurgeons, pathologists, pediatricians, clinical and basic scientists gathered in Hong Kong for Brain 2019, a conjoint congress of the 3rd Asian Central Nervous System Germ Cell Tumour Conference (CNSGCT), the 9th Interim Meeting of the International Chinese Federation of Neurosurgical Sciences (ICFNS) and the 16th Asia Pacific Multidisciplinary Meeting for Nervous System Diseases (BRAIN) which is also jointly organized by The Chinese University of Hong Kong. This three-day convention discussed advances in pediatric neuro-oncology and neuro-rehabilitation.

Invited as the 2019 Otto Lien Da Wong (OLDW) visiting professor in neuro-oncology, Roger J. Packer, M.D., senior vice president for the Center of Neuroscience and Behavioral Medicine and director at the Gilbert Neurofibromatosis and Brain Tumor Institutes, presented a keynote address titled “Advances in Pediatric Brain Tumors.” Established in 2009, the purpose of the visiting professorship is to advance surgical knowledge and techniques in neuro-oncology between Hong Kong and major medical centers around the world. Dr. Packer was selected from an international field of acclaimed academic surgeons and scholars in the field of neuro-oncology. Two additional presentations included “Pediatric Brain Tumors in Molecular Era: Germ Cell Tumors” as an invited guest of the BRAIN conference and a presentation on “Treatment of Medulloblastoma and PNET” as a session presented by the ICFNS.

In addition to his presentations, Dr. Packer will participate in surgical teaching and scholastic exchange with local surgeons, surgical trainees and medical students.

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.

AlgometRX

Breakthrough device objectively measures pain type, intensity and drug effects

AlgometRX

Clinical Research Assistant Kevin Jackson uses AlgometRx Platform Technology on Sarah Taylor’s eyes to measure her degree of pain. Children’s National Medical Center is testing an experimental device that aims to measure pain according to how pupils react to certain stimuli. (AP Photo/Manuel Balce Ceneta)

Pediatric anesthesiologist Julia C. Finkel, M.D., of Children’s National Health System, gazed into the eyes of a newborn patient determined to find a better way to measure the effectiveness of pain treatment on one so tiny and unable to verbalize. Then she realized the answer was staring back at her.

Armed with the knowledge that pain and analgesic drugs produce an involuntary response from the pupil, Dr. Finkel developed AlgometRx, a first-of-its-kind handheld device that measures a patient’s pupillary response and, using proprietary algorithms, provides a diagnostic measurement of pain intensity, pain type and, after treatment is administered, monitors efficacy. Her initial goal was to improve the care of premature infants. She now has a device that can be used with children of any age and adults.

“Pain is very complex and it is currently the only vital sign that is not objectively measured,” says Dr. Finkel, who has more than 25 years of experience as a pain specialist. “The systematic problem we are facing today is that healthcare providers prescribe pain medicine based on subjective self-reporting, which can often be inaccurate, rather than based on an objective measure of pain type and intensity.” To illustrate her point, Dr. Finkel continues, “A clinician would never prescribe blood pressure medicine without first taking a patient’s blood pressure.”

The current standard of care for measuring pain is the 0-to-10 pain scale, which is based on subjective, observational and self-reporting techniques. Patients indicate their level of pain, with zero being no pain and ten being highest or most severe pain. This subjective system increases the likelihood of inaccuracy, with the problem being most acute with pediatric and non-verbal patients. Moreover, Dr. Finkel points out that subjective pain scores cannot be standardized, heightening the potential for misdiagnosis, over-treatment or under-treatment.

Dr. Finkel, who serves as director of Research and Development for Pain Medicine at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, says that a key step in addressing the opioid crisis is providing physicians with objective, real-time data on a patient’s pain level and type, to safely prescribe the right drug and dosage or an alternate treatment.,

She notes that opioids are prescribed for patients who report high pain scores and are sometimes prescribed in cases where they are not appropriate. Dr. Finkel points to the example of sciatica, a neuropathic pain sensation felt in the lower back, legs and buttocks. Sciatica pain is carried by touch fibers that do not have opioid receptors, which makes opioids an inappropriate choice for treating that type of pain.

A pain biomarker could rapidly advance both clinical practice and pain research, Dr. Finkel adds. For clinicians, the power to identify the type and magnitude of a patient’s nociception (detection of pain stimuli) would provide a much-needed scientific foundation for approaching pain treatment. Nociception could be monitored through the course of treatment so that dosing is targeted and personalized to ensure patients receive adequate pain relief while reducing side effects.

“A validated measure to show whether or not an opioid is indicated for a given patient could ease the health care system’s transition from overreliance on opioids to a more comprehensive and less harmful approach to pain management,” says Dr. Finkel.

She also notes that objective pain measurement can provide much needed help in validating complementary approaches to pain management, such as acupuncture, physical therapy, virtual reality and other non-pharmacological interventions.

Dr. Finkel’s technology, called AlgometRx, has been selected by the U.S. Food and Drug Administration (FDA) to participate in its “Innovation Challenge: Devices to Prevent and Treat Opioid Use Disorder.” She is also the recipient of Small Business Innovation Research (SBIR) grant from the National Institute on Drug Abuse.

SIOP logo

Children’s National physicians attend the International Society of Paediatric Oncology in Japan

SIOP logo

From November 16 to 19, medical professionals, clinicians, nurses and oncology patients and families from around the globe gathered for the International Society of Paediatric Oncology (SIOP) in Kyoto, Japan. Pediatric experts in their respective fields Jeffrey Dome, M.D., Ph.D., AeRang Kim, M.D., Ph.D., Steven Hardy, Ph.D., and Karun Sharma, M.D., attended SIOP representing Children’s National. The four-day scientific programme engaged those in pediatric oncology with educational lectures, keynote speakers, tailored sessions for survivors, families and support organizations, free paper sessions, specialist sessions and Meet the Expert talks.

Dr. Kim, an oncologist with the Center for Cancer and Blood Disorders and a member of the solid tumor faculty at Children’s National, presented with Dr. Sharma, director of Interventional Radiology at Children’s, on “Interventional Radiology: Technology and Opportunities” in Meet the Expert talks on both Saturday and Sunday of the programme. They discussed background information, preclinical studies, current, ongoing studies of high-intensity focused ultrasound (HIFU), HIFU in combination with heat sensitive formulated chemotherapy and future directions. In 2017, Children’s National was the first U.S. children’s hospital to successfully use MR-HIFU to treat osteoid osteoma, and is currently accruing on early phase studies evaluating HIFU ablation and HIFU in combination with lyso-thermosensitive liposomal doxorubicin for pediatric patients with refractory/recurrent solid tumors.

Dr. Hardy, a pediatric psychologist in the Center for Cancer and Blood Disorders at Children’s, presented on “Brief Psychosocial Screening to Identify Patients in Need of a Mental Health Treatment Referral in a Childhood Cancer Survivorship Clinic.” In his educational lecture, Dr. Hardy described findings that show a brief mental and behavioral health questionnaire given to patients in the Children’s National survivorship clinic is a sensitive screening tool that can identify patients in need of more formal psychosocial evaluation and treatment. He also presented data supporting the use of a lower threshold of psychological symptoms necessary to trigger discussions about mental health treatment compared to previous reports. The key implication of Dr. Hardy’s work is that survivorship clinics lacking embedded psychology support could adopt this questionnaire, which is publically available and translated into 86 languages, to help identify survivors with mental and behavioral health concerns and ensure appropriate referrals are made.

Dr. Dome, Vice President of the Center for Cancer and Blood Disorders, served on the SIOP Scientific Programme Advisory Committee, which selected the topics for presentation.

SIOP provides an international forum for the sharing of new research and ideas related to pediatric oncology. The annual conference furthers the efforts made towards developing new treatments and cures and opens the conversation, encouraging innovation and collaboration with experts from around the world. Children’s National has taken part in SIOP for many years, most recently hosting the meeting in Washington, D.C., in 2017.

Dr. Andrew Campbell examines a child

Children’s National physicians provide education at 46th Annual Sickle Cell Disease Association of America Convention

Dr. Andrew Campbell examines a child

Andrew Campbell, M.D., presented at the conference on the topics of hydroxyurea (HU) and blood transfusions.

More than 600 researchers, physicians, nurses, social workers and individuals living with sickle cell disease (SCD) and sickle cell trait (SCT) gathered in Baltimore for the 46th Annual National Sickle Cell Disease Association of America (SCDAA) Convention in mid-October. Children’s National physicians Andrew Campbell, M.D., director of the Comprehensive Sickle Cell Program, and Deepika Darbari, M.D., were among the speakers at the four-day convention discussing the latest scientific research and clinical information through seminars, panel discussions and symposiums.

Dr. Campbell presented at the conference on the topics of hydroxyurea (HU) and blood transfusions. He spoke to families about the benefits of HU, explaining how it lowers the percentage of sickle cells in the blood and decreases the overall inflammatory process. He stressed the importance of HU as a medication used in the prevention of SCD and emphasized the potential decrease in organ damage and increased overall survival rate of SCD patients. The importance of minor antigen blood group phenotyping was also discussed, as it can decrease the chance of patients rejecting future blood transfusions by developing new red blood cell antibodies.

“The indications for blood transfusions in the acute ‘ill’ setting can be life-saving and improve oxygen delivery and overall clinical outcomes within sickle cell complications, including acute chest syndrome, stroke and splenic sequestration. Approximately 10 to 15 percent of patients will need monthly blood transfusions for primary (i.e. stroke, patients with abnormal brain vessel TCD velocities >200cm/s) and secondary (i.e. patients with a previous stroke, multiple splenic sequestrations, recurrent priapism, recurrent acute chest syndromes) sickle cell complications,” explains Dr. Campbell.

Dr. Darbari, a hematologist at Children’s National, educated medical colleagues on chronic pain in SCD and emphasized the increase in pain from adolescence to adulthood.

“During childhood, pain in SCD is considered a consequence of discrete episodes of vaso-occlusion.  Such vaso-occlusion is a complex process in which abnormally shaped (so-called ‘sickled’) red blood cells episodically obstruct the microcirculation thereby causing distal ischemia and resultant pain. As patients get older, mechanisms such as peripheral neuropathic or centralization may play important roles in transition and maintenance of chronic pain. It is important to consider underlying mechanisms contributing to pain when managing a patient with SCD,” states Dr. Darbari. She referenced her coauthored and published Analgesic, Anesthetic and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-American Pain Society Taxonomy (AAPT) criteria for classifying chronic pain in SCD and how useful this tool can be for physicians in the treatment of patients with SCD.

Both Drs. Campbell and Darbari shared their expertise on different facets of SCD with families and medical professionals alike. Their impactful work is paving the way for future treatments and pain management techniques for treating patients living with SCD and their families.

ASCAT Conference Attendees

Children’s National represented at ASCAT conference in London

ASCAT Conference Attendees

From left to right: Lisa Thaniel, Ph.D., Brittany Moffitt, Deepika Darbara, M.D., Steven Hardy, Ph.D., Andrew Campbell, M.D., Barbara Speller-Brown, DNP, Stefanie Margulies and Karen Smith-Wong all represented Children’s National at the ASCAT Conference in London.

Deepika Darbari, M.D., Andrew Campbell, M.D., and Steven Hardy, Ph.D., represented Children’s National at the Annual Sickle Cell Disease and Thalassemia (ASCAT) Conference in London in late October. The theme of this year’s conference was Sickle Cell Disease and Thalassemia: Bridging the Gap in Care and Research.

Dr. Darbari, a Children’s National hematologist, was the featured Grand Rounds speaker and led a pain management symposium. Dr. Darbari studies complications of sickle cell disease with an emphasis on pain. She conducts clinical and translational studies to better understand sickle cell pain and its management. She addressed the topics of pain mechanisms and phenotypes in sickle cell disease during her symposium.

Dr. Campbell, Director of the Comprehensive Sickle Cell Disease Program at Children’s National, has served on the steering committee for this annual international conference for the past two years, working alongside colleagues from across the globe to bring together multiple experts who work with children with blood disorders. Dr. Campbell remarks, “I’m pleased to promote and be a part of [this conference] because it’s one of the best sickle cell/thalassemia conferences in the world pushing the field forward with international representation.” He spoke at the conference during Dr. Darbari’s symposium, discussing sickle cell disease pain around the globe.

Dr. Hardy, a pediatric psychologist in the divisions of Blood and Marrow Transplant, Blood Disorders (Hematology) and Oncology and the Center for Cancer and Blood Disorders at Children’s National, also presented at the conference on his abstract “Computerized Working Memory Training Improves Cognition in Youth with Sickle Cell Disease.” His abstract received the Best Oral Abstract Award at the conference and was awarded a 500 pound prize. In his work at Children’s National, Dr. Hardy provides evidence-based psychological assessments and treatments for children with cancer, sickle cell disease and other blood disorders, as well as those patients undergoing bone marrow transplants.

Poster presentations were also given by Barbara Speller Brown, NP, DNP, Lisa Thaniel, MSW, Ph.D., Brittany Moffitt, MSW, and Stefanie Margulies, senior clinical research coordinator, all representing Children’s National at the ASCAT Conference.

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.”

Maureen E Lyon

Maureen E. Lyon, Ph.D., ABPP, lauded for outstanding excellence in patient-centered advance care planning

Maureen E Lyon

Maureen E. Lyon, Ph.D., a principal investigator at Children’s Center for Translational Science, will be honored with a “Recognition Award for Excellence and Innovation in Research” by Respecting Choices for outstanding excellence in patient-centered advance care planning and shared decision-making.

Respecting Choices will present the award on Oct. 26, 2018, during its “National Share the Experience Conference” in Bloomington, Minnesota.

Lyon’s expertise is in advance care planning and shared decision-making for children and adolescents with life-threatening illnesses and their families, a field that has transformed in recent decades in order to pave better paths forward for difficult but necessary conversations.

“It came from my clinical experience,” Lyon says. “In the early days of the human immunodeficiency virus (HIV) epidemic in the U.S., everything, absolutely everything, was done to keep the kids alive in the hopes that some new drug would come around the corner, and we could bring them back from the brink. I remember one of the young boys saying to his case manager that he didn’t want all of these interventions. But he hadn’t told his family.”

That young man’s eye-opening comments – and learning that Children’s National Health System had a policy that teenagers were to be included in conversations about their own advance care planning – inspired Lyon to conduct a series of surveys involving adolescents, families and clinicians.

“I remember sitting down with friends and saying ‘There must be a better way to do this. Everyone is afraid to broach the subject,’ ” Lyon recalls. So, she conducted surveys of all healthy kids coming through Children’s adolescent clinic and kids diagnosed with HIV, cancer and sickle cell disease.

“It turned out the kids did want to talk about it. That was the first thing. Families told us they wanted help breaking the ice. Physicians felt it wasn’t their role – many doctors felt their role was to save people – or, they didn’t have the training,” she says.

Through a series of focus groups with youths living with HIV, families and community members, Lyon adapted the adult-centric Respecting Choices model to create a three-session intervention to better meet the advance care planning needs of youths and adolescents living with HIV.

Lyon’s recent work includes a single-blinded, randomized study published Oct. 19, 2018, in Pediatrics that finds the more families understand the end-of-life treatment preferences expressed by adolescents living with HIV, the less likely these youth are to suffer HIV-related symptoms, compared with youths whose families do not understand their end-of-life care goals.

She also has adapted the Respecting Choices intervention to facilitate its use with children diagnosed with cancer. More recently, she has adapted the model for use by parents of children with rare diseases who cannot communicate on their own.

“For the other life-threatening health conditions, we worked to support adolescents in expressing their advance care planning choices in their own voices. With rare diseases, we’re shifting gears,” she adds.

Published research indicates a sizable proportion of pediatric patients who die in hospitals now have confirmed or suspected rare diseases, she says. During a pilot involving seven families, many parents multitasked during the conversations, taking pauses to attend to various alarms as they sounded, to complete regular feedings and to contend with their child’s petit mal seizures.

“The level of burden of taking care of these children with terminal illnesses was pretty overwhelming,” she says. “Still, families were not too burdened to participate in advance care planning, but first wanted to identify their priority palliative care needs and to develop a support plan to meet those needs. We also had more fathers involved.”

Jeffrey Dome

The impact of surveillance imaging to detect relapse in Wilms tumor patients

Jeffrey Dome

Dr. Jeffrey Dome, M.D., Ph.D., vice president, Center for Cancer and Blood Disorders.

The Children’s Oncology Group published an article in the Journal of Clinical Oncology looking at the impact that surveillance imaging has on patients with Wilms tumor (WT), the most common kidney cancer in children.

Despite the risks and costs, the use of computed tomography (CT) for routine surveillance to detect recurrence in patients with WT has increased in recent years. The rationale for using CT scans rather than chest x-rays (CXR) and abdominal ultrasounds (US) is that CT scans are more sensitive, thereby enabling recurrences to be detected earlier.

In this study, led by Jeffrey S. Dome, M.D., Ph.D, vice president of the Center for Cancer and Blood Disorders at Children’s National Health System, researchers conducted a retrospective analysis of patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) who experienced relapse to determine if relapse detection with CT scan correlates with improved overall survival compared with relapse detection by CXR or abdominal US.

A total of 281 patients with favorable-histology WT (FHWT) were included in the analysis. The key findings of the study were that:

  • Among patients with relapse after completion of therapy, outcome was improved in patients whose relapse was detected by surveillance imaging rather after signs and symptoms developed.
  • A higher disease burden at relapse, defined by the diameter of the relapsed tumor and the number of sites of relapse, was associated with inferior survival.
  • Relapses detected by CT scan were detected earlier and were smaller on average than relapses detected by CXR or US.
  • However, there was no difference in survival between patients whose relapse was detected by CT versus CXR or US.

An analysis of radiation exposure levels showed that surveillance regimes including CT scans have about seven times the radiation exposure compared to regimens including only CXR and US. Moreover, the cost to detect each recurrence reduced by 50 percent when CXR and US are used for surveillance.

“The results of this study will be practice changing,” said Dr. Dome, one of the doctors leading the clinical trial. “The extra sensitivity that CT scans provide compared to CXR and US do not translate to improved survival and are associated with the downsides of extra radiation exposure, cost and false-positive results that can lead to unnecessary stress and medical interventions,” he added. “Although counter-intuitive, the more sensitive technology is not necessarily better for patients.”

In conclusion, the doctors found that the elimination of CT scans from surveillance programs for unilateral favorable histology Wilms tumor is unlikely to compromise survival. However, it could result in substantially less radiation exposure and lower health care costs. Overall, the risk-benefit ratio associated with imaging modalities should be considered and formally studied for all pediatric cancers.

Learn more about this research in a podcast from the Journal of Clinical Oncology.

Affiliations

Elizabeth A. Mullen, Dana-Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center, Boston, MA; Yueh-Yun Chi and Emily Hibbitts, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Katarina J. Steacy, University of Maryland Medical Center, Baltimore, MD; James I. Geller, Cincinnati Children’s Hospital Medical Centre, Cincinnati, OH; Daniel M. Green, St Jude Children’s Research Hospital, Memphis, TN; Geetika Khanna, Washington University School of Medicine, St Louis, MO; Marcio H. Malogolowkin, University of California at Davis Comprehensive Cancer Center, Sacramento, CA; Paul E. Grundy, Stollery Children’s Hospital, University of Alberta, Alberta; Conrad V. Fernandez, University, Halifax, Nova Scotia, Canada; and Jeffrey S. Dome, Children’s National Health System, George Washington University School of Medicine and Health Sciences, Washington, D.C.