Bench to Bedside

September 2015

eMERGE Network Looks at How to Provide DNA Test Results, Improve Care


Sometimes the tiniest shift inherited in your DNA code can have tremendous ripple effects on your health and treatment choices. A new $3.6 million grant from the National Institutes of Health’s Electronic Medical Records and Genomics (eMERGE) program will allow scientists at The Children’s Hospital of Philadelphia to not only uncover the genetic causes of autism and other pediatric conditions, but also to see how this information extends beyond the lab into patients’ electronic health records and improves care.

“We have established the largest pediatric biobank in the world, and by coupling the genotyping and sequencing data we have produced from these samples with medical information from the electronic health records from CHOP and other eMERGE sites, we have the ability to identify the most effective therapies for our patients as we move forward in the era of precision medicine,” said principal investigator Hakon Hakonarson, MD, PhD, director of CHOP’s Center for Applied Genomics.

The National Human Genome Research Institute (NHGRI) announced the awards to CHOP and 11 other research centers in the eMERGE network in a press release. CHOP is one of only two pediatric sites in the network and has led and published numerous studies from earlier stages of the program. Now entering its third phase, eMERGE will concentrate on moving genomics research closer to clinical application.

For example, the CHOP investigators will use DNA sequencing data stored in the Hospital’s biorepository to characterize rare variants in 2,500 children with autism, intellectual disability, attention deficit-hyperactivity disorder, epilepsy and obesity. They will return information to about 160 patients and their families and evaluate how knowledge of their genetic makeup affects their testing and treatment decisions. The research team also will consider the potential financial, ethical and social reverberations of these genotyping activities.

“The newly funded projects are focused on discovering genes and gene variants with clinical implications by using the latest sequencing technologies to examine rare and common variants suspected to relate to disease risk and treatment effects,” said Rongling Li, MD, PhD, program director for eMERGE in the Division of Genomic Medicine at NHGRI. “The other important component of these grants is implementing what researchers learn about these gene variants into medical settings to improve patient care.”

To see the NIH announcement of these awards, click here.

Direct link:

New Research Consortium Aims to Identify Drugs for Pediatric Cancers


The Children’s Hospital of Philadelphia and four other high-profile oncology research programs plus a coordinating center joined the new Pediatric Preclinical Testing Consortium (PPTC) launched by the National Cancer Institute (NCI) to help researchers identify drug candidates for pediatric clinical trials. The centers will focus on neuroblastoma, leukemia, brain tumors, osteosarcoma, and sarcoma and kidney tumors.

“The primary rationale for this consortium is the fact that there are very few new drugs for pediatric cancer, and many of those drugs that have been introduced have been dependent on the results of clinical trials in adults,” said pediatric oncologist John M. Maris, MD, who leads CHOP’s research program within the PPTC. Maris will collaborate on this project with CHOP co-investigators Edward Attiyeh, MD, Lori Hart, and Matthew Tang.

“Before testing a drug in children, we need a scientific basis for using it, based on deep understanding of the biology involved, and supported by promising results in cell and animal models,” Dr. Maris added. “These preclinical findings will provide stronger evidence for us to engage proactively with drug companies who could partner in developing these drugs.”

By supporting a more reliable agent prioritization process, the PPTC can contribute to the goal of identifying more effective treatments for children with cancer. The PPTC builds upon 10 years of experience with the Pediatric Preclinical Testing Program, which collaborated with more than 50 pharmaceutical companies to test novel agents against the program’s pediatric preclinical models.

Maris’ laboratory at CHOP has created animal models of neuroblastoma that incorporate genetic material from patient tumor cells. These models allow scientists to design drug tests highly tailored to specific, well characterized subtypes of human neuroblastoma tumors. Because neuroblastoma is particularly complex and variable, this approach will bring oncologists closer to personalized medicine: using knowledge of the genetics of a patient’s tumor to directly attack a cancer’s vulnerabilities while sparing healthy cells.

In order to keep pace with genomic medicine, Dr. Maris and colleagues discussed in a recent editorial published in JAMA that academic, federal, and industry leaders must develop new models of drug development, as “rare diseases become even more rare” once genetically defined subsets are revealed.

The commentary addressed results from a study conducted by researchers from the University of Michigan, Ann Arbor, appearing in the same issue that included 91 children and young adults with relapsed, refractory, or rare cancer who underwent genetic sequencing and genetic counseling. A troubling concern highlighted by the study was “the number of children with currently incurable refractory cancer and a potentially actionable finding in which the investigators simply could not find a drug that might have provided some measure of antitumor benefit,” the editorial stated.

The PPTC is supported through NCI cooperative agreement research grants to the PPTC Coordinating Center at Research Triangle Institute International. In addition to CHOP, the other research programs participating in the consortium include Greehey Children’s Cancer Institute, San Antonio (sarcoma and renal tumors); Children’s Cancer Institute, Sydney, Australia (leukemia); Texas Children’s Hospital, Houston (brain tumors), and Albert Einstein College of Medicine, New York (osteosarcoma).


Direct link:

Focus on Vision and Balance Deficits Following Youth Concussion


Recognizing a concussion oftentimes is not crystal clear for clinicians. A young patient with a head injury may report experiencing common concussion symptoms, and yet results from a standard physical exam seem normal. Findings from two new research studies suggest that additional assessments of a patient’s visual oculomotor system and balance system may help to bring a concussion diagnosis into better focus.

About 250,000 children were treated in U.S. emergency departments for sports and recreation-related injuries that included a diagnosis of concussion or traumatic brain injury (TBI), according to 2009 estimates from the Centers for Disease Control and Prevention. A concussion is a mild TBI from a blow or jolt that causes the brain to bounce around or twist in the skull. The shaking can disrupt brain functions, which can result in headaches, dizziness, nausea, balance problems, fatigue, blurred vision, motion sickness, and light and noise sensitivity.

A research study published in the journal Clinical Pediatrics showed that vision diagnoses are common after concussion and that visual oculomotor deficits likely are contributing to those symptoms. The research team examined 100 study participants 11 to 17 years old who received clinical care as part of the Concussion Care for Kids: Minds Matter program at The Children’s Hospital of Philadelphia. Overall, 69 percent had at least one vision diagnosis after concussion.

“It appears that what your brain does in terms of integrating all your visual function can be affected by concussion,” said Christina Master, MD, CAQSM, a sports medicine pediatrician in the divisions of orthopedics and general pediatrics at CHOP, who led the study. “That finely tuned coordination seems to be injured in concussion.”

For example, half the study participants had convergence insufficiency, which is when the eyes are not able to work together to keep an object in focus as a single image at near distance. In the general population, the prevalence of convergence insufficiency is between 2 and 8 percent, but among the study participants, almost 50 percent had convergence insufficiency. Other visual oculomotor function disturbances that the study participants often had were related to eye-tracking which is important for reading.

Typical visual acuity tests may not identify the eye coordination, eye tracking, and eye focusing problems that the researchers associated with concussions. “If you don’t do particular visual assessments, you may miss these visual deficits,” Dr. Master said. “These are not part of the standard visual evaluation, so I think they have been missed for a long time.”

Dr. Master also explained that young patients with concussions often do not realize that they are having vision problems, which can make diagnosis even more challenging. Clinicians often use the Post Concussion Symptom Scale as a screening tool to identify concussion symptoms, but Dr. Master pointed out that it has only one broad, generic question about vision problems. A more specific visual symptom questionnaire called the Convergence Insufficiency Symptom Survey that the research team used in the study could be an additional way to pinpoint vision diagnoses after injury.

Recognizing and treating vision problems after concussion is increasingly important, the investigators emphasized, because children are living in a highly connected electronic environment at home and school with a heavy visual workload. Looking closely at computer monitors, tablets, and smart phones is visually demanding, and children with concussions may find it difficult to read and interact with those electronic interfaces during recovery.

“All that ‘near work’ adds to the visual workload and somewhat amplifies the symptoms of the disrupted physiology after concussion,” Dr. Master said.

The vestibular system, which controls body balance, also is not usually part of a standard physical or neurological exam. Yet Dr. Master and her colleagues showed in another study published in The Journal of Pediatrics that a high prevalence of vestibular deficits appear after concussion. Eight-one percent of 247 study participants ages 5 to 18 with a history of concussion showed a vestibular abnormality, which was associated with extended recovery times and poorer performance on neurocognitive testing.

“Again, we need to make sure our vestibular assessments are challenging enough,” Dr. Master said. “Balance deficits following a mild traumatic brain injury may be subtle and require us to be more astute as clinicians in terms of picking them up.”

Clinicians throughout The Children’s Hospital of Philadelphia system — from Minds Matter concussion experts to emergency room physicians to primary care pediatricians — received training to perform dynamic assessments to find potential disturbances in patients’ vestibular system, including the vestibulo-ocular reflex (VOR), after concussion. The VOR is like a “steady cam” feature in the brain that allows you to look at a fixed object and keep the picture stable, even when your head is moving up and down or side to side.

Each part of the vestibular balance assessment becomes a little more demanding for patients who may be concussed. First, they walk forward in a tandem gait, as if on a balance beam, with their eyes open and then with their eyes closed. Next, they walk in tandem backwards with eyes open and closed, which can be tough to do if your vestibular system is damaged.

“When your brain balance function is disrupted by a concussion, you need to rely more heavily on your visual input to compensate in order to maintain your balance,” Dr. Master said. “It is like a pilot flying with just the instruments as opposed to being able to see the horizon, as well.”

As more clinicians learn how to identify balance and vision problems that are common after concussions, they will be able to refer patients to specialists who can provide oculomotor interventions and vestibular rehabilitative therapies. These approaches especially may be useful for patients who have prolonged symptoms and are not bouncing back after a few days of rest, and getting back to their full activities in a few weeks, Dr. Master said.

“I think active rehab is important to look at as a therapeutic, and it needs further study, but it appears to have a huge impact in terms of helping kids with prolonged concussion symptoms have better function and improved symptoms in both of these systems,” Dr. Master said.

Direct link:

MOMS Study Suggests Candidates, Timing for Fetal Spina Bifida Surgery


Fetal spina bifida surgery to repair myelomeningocele is a remarkable and intricate procedure performed before birth. If untreated, spinal cord damage from amniotic fluid exposure is progressive during gestation. Highly skilled surgeons close a gap in the fetus’ spine that allows a portion of the spinal cord and nerves to protrude precariously. In each complex case, clinicians from the Center for Fetal Diagnosis and Treatment at The Children’s Hospital of Philadelphia and expectant families must weigh the potential benefits of fetal surgery with the risks, which include preterm birth.

A major reason for performing fetal spina bifida surgery is to avoid placing a shunt later on to avoid a life-threatening buildup of cerebrospinal fluid (CSF) and pressure in the brain called hydrocephalus. If untreated, hydrocephalus can cause irreversible brain damage.

A research article published in the Journal of Neurosurgery: Pediatrics and co-authored by CHOP investigators reported on updated data from the 2011 Management of Myelomeningocele Study (MOMS), a landmark trial that showed corrective spinal surgery in the womb led to decreased rates of shunting at 12 months and was associated with higher scores on tests of mental development and motor function at 30 months. CHOP was one of three fetal surgery programs that participated in the original MOMS trial.

The current analysis took a closer look at magnetic resonance imaging (MRI) scans of the fetuses’ ventricles, the fluid-filled cavities inside their brains, which were performed in both the prenatal (91 women) and postnatal (92 women) surgery groups as part of the MOMS trial. The researchers found that larger ventricles at initial screening are associated with an increased risk for shunting in both groups.

In the prenatal surgery group, 20 percent of those with ventricle size smaller than 10 mm, 45.2 percent with ventricle size of 10 mm up to 15 mm, and 79.0 percent with ventricle size bigger than 15 mm eventually received a shunt; whereas, in the postnatal group, 79.4 percent, 86.0 percent, and 87.5 percent, respectively, required a shunt.

“During prenatal counseling, care should be exercised in recommending prenatal surgery when the ventricles are 15 mm or larger because prenatal surgery does not appear to decrease the shunt rate in this group,” the authors concluded.

They determined that the ideal candidate for in utero intervention is a fetus with ventricles smaller than 10 mm. For cases with ventricles 15 mm or greater, they suggested a cautious approach during prenatal counseling when predicting the need for shunting. These findings also have theoretical implications for the timing of prenatal surgery, the authors pointed out, because fetuses younger than 20 weeks have even tinier ventricles. Ventricles in a fetus with spina bifida tend to enlarge during gestation.

”These findings impact the counseling of families when the fetus already has very large ventricles of 15 mm or larger,” said N. Scott Adzick, MD, Surgeon-in-Chief of The Children’s Hospital of Philadelphia and the founder and director of the Center for Fetal Diagnosis and Treatment. “All of the pros and cons of fetal surgery are discussed with these families, keeping in mind the other benefits of fetal surgery including possible improved leg function and better prospects for walking. Our research in Dr. Alan Flake’s laboratory at CHOP is focused on using tissue engineering approaches for prenatal closure of myelomeningocele combined with minimally invasive fetoscopic approaches to treat the spina bifida fetus earlier in gestation (less than 20 weeks gestation). Tissue engineering would seal the myelomeningocele defect, prevent exposure of the developing spinal cord to the ravaging neurotoxic effects of amniotic fluid, and stop CSF leakage from the defect, thereby averting the development of hydrocephalus and the need for a shunt after birth.”

As the most common central nervous system birth defect, spina bifida affects approximately 1,500 babies born in the U.S. each year, and myelomeningocele is the most serious form. The Center for Fetal Diagnosis and Treatment has performed more 244 fetal surgeries on babies with myelomeningocele. PBS Television recently presented a documentary series about the carefully coordinated care that the Center offers families.

The current study’s first author is Noel B. Tulipan, MD, of Vanderbilt University, Nashville. Dr. Adzick is the senior author. The other co-authors are from George Washington University, Washington, D.C.; University of California, San Francisco; Columbia University, New York; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

Direct link:

Vs. Cancer and CBTTC a Winning Team for Childhood Brain Tumor Research


From pitchers and catchers to fast base runners and big hitters, baseball rosters need a diverse range of skills, but to achieve victory, individual players need to work together. Such dedication to collaboration also is a winning game plan when patients, clinicians, researchers, and donors team up to accelerate the study of childhood brain tumors.

This summer, the Children’s Brain Tumor Tissue Consortium (CBTTC) established in 2011 by The Children’s Hospital of Philadelphia scored a home run when they received a grant from the Vs. Cancer Foundation. The 2-year-old nonprofit organization has inspired athletes and communities across the country to raise $1 million so far to fund childhood cancer efforts at 50 children’s hospitals.

“One of our favorite things about Vs. Cancer is that, like the CBTTC, they are interested in partnering with as many people as possible toward a common goal,” said CBTTC Neurosurgery Director Adam Resnick, PhD. “By engaging young players, they give them an amazing opportunity to be impactful as human beings. Whether they become major league stars or even go on to medical school or to do research, maybe they will pay attention to pediatric brain tumors.”

Vs. Cancer Chief Executive Officer, Founder, and brain cancer survivor Chase Jones visited CHOP’s Research Institute’s facilities with a senior-year baseball player from the University of Pennsylvania’s Quakers team to meet the investigators, post-docs, and bench scientists whose innovative work will be supported by the donation. Earlier this year, Quakers players took a few good swings with their hair clippers and shaved their heads as part of a Vs. Cancer fundraising event.

On the tour, they learned firsthand how the CBTTC reaches way beyond their “home field” laboratories. The CBTTC is a collaborative, multi-institute program committed to tissue-based research that will lead to new treatments and diagnostic tools for childhood brain tumors, which are the leading cause of disease-related death in children. It has a state-of-the-art biorepository that collects and stores brain tumor biospecimens at CHOP for genomic sequencing.

Data is shared with the whole world so that scientists can begin making hypotheses about what is causing the cancer and how they can potentially target therapies. Open access to in-depth descriptions of these tumors’ biology is vital because pediatric brain cancers are rare, as compared to adult cancers, and no one pediatric institution has a large enough biospecimen collection to analyze.

Anyone can query the data and specimens that are available, and then they can submit a scientific proposal for biospecimens that is reviewed by a scientific committee. If approved, the biospecimens are provided to the investigator with the requirement that the data generated from the project be shared back with the CBTTC in real time.

“We recognize that many scientists worldwide could potentially help to cure kids’ cancer,” Dr. Resnick said. “Vs. Cancer’s support of the CBTTC’s sequencing data empowers specimens to be used not just by the data generators, but by the cancer community. Everyone can look into the repository, analyze the associated clinical data that is integrated into it, and design projects to begin making headway to understand pediatric cancer.”

The CBTTC’s member institutions currently include Seattle Children’s, Ann and Robert H. Lurie Children’s Hospital of Chicago, Children’s Hospital of Pittsburgh of UPMC, and Meyer Children’s Hospital of Florence, Italy.

Direct link:

Expanding Clinical Teams’ Communication Skills When Sharing Care Plans


It can be incredibly distressing for a family dealing with a serious or life-threatening illness to receive mixed messages from the clinical team about their child’s prognosis or care plan. The roots of this miscommunication may begin way before they must make an important treatment decision. For instance, clinical team members may have different opinions about when it is time to offer palliative care to families.

“Clinical teams caring for these complex patients often struggle to communicate effectively with each other as well as with families when they reach those branch points,” said Jennifer Walter, MD, a pediatrician and assistant professor in the department of pediatrics and the department of medical ethics at The Children’s Hospital of Philadelphia. Her research focuses on the intricacies of clinical communication.

During goals of care conversations where the team shares upsetting news and attempts to understand what is most important to families, it is essential that entire team is able to communicate with empathy and clarity. Yet, many physicians have not developed this basic skill set, Dr. Walter said, and team members may not always be in unison about the range of options that are appropriate to present to families. The end results for parents are confusion and mistrust as they contemplate the transition to supportive care.

Dr. Walter received a Sojourns Scholar Leadership Award from the Cambia Health Foundation to investigate the effectiveness of an interprofessional communication training program designed to improve clinical teams’ collaboration in creating care plans and how they prepare to share them consistently with families. Her study participants will be members of the cardiac intensive care unit at CHOP, which relies on many specialties including cardiologists, intensive care doctors, nurses, nurse practitioners, social workers, child life specialists, and surgeons. This large team must work together to effectively support parents in making decisions about significant surgeries or other risky procedures.

“My research will focus on how the team communicates with one another about the central elements of a good care plan for a patient and how they respectfully engage the different members of the team with different levels of expertise,” Dr. Walter said. “And then, how do they demonstrate that true collaboration in their communication with the family? Does the family really experience that the team is on the same page? Or, if there are differences of opinion, are they conveyed to the family clearly with the pros and cons of the different options?”

First, Dr. Walter will observe cardiac intensive care unit team meetings and audio record how they communicate with each other and families during clinical care discussions. Next, she will create a simulated family meeting and audio record how the team engages with actors playing the role of parents.

During the intervention phase of the investigation, small groups will participate in team building workshops to help them identify sources of communication breakdowns. They will supplement their communication skills by learning to how to give bad news and to elicit the values of family members. The training is based on methods created by a nonprofit organization called VitalTalk that originally taught oncologists how to communicate better with their adult patients. After the intervention, the investigators will observe and audio record another set of actual and simulated encounters with families.

The study team will use a validated, objective system that looks for behaviors associated with interprofessional collaboration to code randomized audio files from the pairs of meetings. For example, the coders will note if one voice is dominating the entire conversation or if there are opportunities for multiple team members to contribute important information. The clinical team members also will complete surveys to get their feedback about the collaborative experience before and after the intervention to see if they perceive any improvement.

“The hope would be to demonstrate that the intervention changes the clinicians’ behaviors and perception of collaboration in both simulated encounters as well as in actual encounters,” Dr. Walter said. “The next steps for these projects would be to develop a study that also would engage families. The real outcome that we care about is whether families identify their teams as more consistent and supportive in making decisions that they struggle with.”

The National Palliative Care Research Center also recognized Dr. Walter’s research with a career development award. Her mentors for the project include Bob Arnold, MD, developer of the VitalTalk system; Chris Feudtner, MD, PhD, a well-established pediatric palliative care clinician and researcher at CHOP; and Victoria Miller, PhD, a psychologist and director of research for the Craig-Dalsimer Division of Adolescent Medicine at CHOP, who has deep expertise in quantitative and qualitative coding of observational studies.

Direct link:

Missing Well Visits Results in Preventive Care Gaps for Preterm Infants


Newborns’ first big journeys into the world often are to well-baby exams at pediatricians offices. These checkups usually are scheduled within the first days or weeks after discharge from the hospital, followed by exams every few months during their first year of life. Well visits give parents important opportunities for their babies to receive routine vaccinations, to have their growth and development monitored, and to participate in health screenings.

While well visits, also known as health supervision visits, have become a mainstay of pediatric care and are recommended by the American Academy of Pediatrics’ Bright Futures: Guidelines for Health Supervision of Infants, Children, and Adolescents, until now researchers have not gathered much data to demonstrate these exams’ value.

In an article published in the journal Pediatrics, a study team at The Children’s Hospital of Philadelphia looked at outpatient data from a retrospective cohort of 1,854 preterm infants born between 2005 and 2009 who received care at CHOP’s primary care network. Adherence to a well-visit schedule especially is a priority for preterm infants because they are at increased risk for medical complications and lifelong health problems.

The study results were disconcerting to lead investigator Scott Lorch, MD, MSCE, an attending neonatologist at CHOP and an associate professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania: Only 43 percent received all expected health supervision visits during the first 18 months of life.

“All it took was one missed visit, and we saw some fairly substantial differences in their health outcomes,” Dr. Lorch said. “The most telling finding was that missing one visit meant that the likelihood that a patient received all shots on time went down fairly dramatically, with a 64 percent drop in the likelihood of being up to date by 18 months.”

Families missed the well visits for two primary reasons. Sometimes they showed up for a well visit, but baby was not feeling well that day, so it became a sick visit. Other times they came in for a sick visit and then cancelled their next well visit. In both scenarios, the well visits were never rescheduled, and families did not receive the preventive care that normally would have occurred during those sessions. In addition to not getting vaccinations, the babies were less likely to receive screening tests and developmental assessments on time.

“We found that some groups of the smallest babies were being seen on average every week by the healthcare system, so that is a lot of competition for well visits,” Dr. Lorch said. “When children are showing up for sick issues, like chronic lung disease from prematurity, the things that physicians do or focus on during well visits seemed to get crowded out.”

Some of the other risk factors that the researchers associated with missed well visits were families who had public health insurance or no health insurance. On the flip side, continuity of care was linked to families being more likely to attend well visits. Having the same provider for sick and well visits keeps everyone in the loop, Dr. Lorch suggested, which may allow more time for them to concentrate on the real purpose of each visit.

In future research, Dr. Lorch and his study team will take a closer look at some of the potential barriers to families’ attendance at well visits. They also will investigate factors that could improve continuity of care and determine ways to avoid delays in immunizations and help close gaps in health monitoring. Already, they have shared insights from the current study with staff on the logistical side of scheduling outpatient visits to figure out strategies for handling no-shows.

“This is one of the first studies to provide documented evidence that there are health consequences for missing well visits,” Dr. Lorch said. “It shows how difficult it is for providers to get caught up with the services that these visits provide to patients.”

Direct link:

Teaching the Immune System to Have Long-term Memory for Leukemia


Your immune system is designed to protect against foreign invaders such as infections, but you may not realize that it also destroys abnormal cells that your body produces. Researchers suggest that some types of cancer cells, such as acute lymphoblastic childhood leukemia (ALL) that recurs or is resistant to standard therapies, are especially adept at dampening the immune system’s radar.

Alix Seif, MD, MPH, an attending physician in both the Blood and Marrow Transplantation and the Hematologic Malignancies sections at The Children’s Hospital of Philadelphia, is interested in finding ways to teach the immune system to recognize leukemia and give it long-term immune memory to prevent disease relapse.

“Think of the immune system like a border guard,” Dr. Seif said. “These approaches give the border guard a little more power to look inside the body and detect culprits who may be starting an uprising. It makes the immune cells more suspicious of the bad cells.”

Hyundai Hope on Wheels, a national independent nonprofit organization committed to helping kids fight cancer, presented Dr. Seif a research grant at a Handprint Ceremony Sept. 9 to support her innovative scientific investigations. During the event, children receiving cancer treatments at Children’s Hospital dipped their hands in paint and added their colorful symbols of hope to a white car that is covered with children’s handprints from all over the country.

ALL is the most common childhood cancer, usually appearing between the ages of 2 and 4. It has a good track record for successful treatment; however, about 15 to 20 percent of patients with ALL will relapse. It can be extremely difficult for physicians to help this group of children stay in remission using standard chemotherapy. Novel immune therapies are alternative approaches that are generating excitement in the pediatric cancer research community because they are potentially more effective, less toxic, and longer lasting than cell poisons.

Chimeric antigen receptor-armed T cells (CTL019) — formerly known as CART19 — is an immune therapy that made international headlines over the last two years. Researchers from the University of Pennsylvania and Children’s Hospital engineered immune cells, called T cells, to recognize CD19 protein, an antigen that is expressed by a type of tumor common to ALL, and then kill the leukemia. In research studies, children with relapsed or refractory cancer had a complete response 90 percent of the time with CTL019 therapy.

“It feels miraculous to those of us who have cared for these children who otherwise would not have options,” Dr. Seif said. “Unfortunately, it’s not a perfect treatment.”

CTL019 therapy offers incredible benefits in some cases, but in others, the leukemia stops putting CD19 on its surface, taking away the engineered T cells’ target. Another problem is that the T cells may not have a long enough lifespan to completely eliminate the leukemia. Dr. Seif and her study team aim to help solve these treatment challenges by coaching the immune system as a whole to identify and remember several antigens on ALL cells.

“Our approach relies on stimulating multiple immune cells, rather than engineering one type of immune cell, which may open up this type of therapy to other tumor types,” Dr. Seif said. “I could imagine it being used in conjunction with CART19 or as an alternative for children who have tumors without CD19.”

Using a mouse model, Dr. Seif’s research team added foreign proteins from jellyfish and fireflies to leukemia cells to elicit a strong response from the mouse immune system, which cleared the leukemia spontaneously. Next, the researchers introduced leukemia cells minus the foreign proteins, and the mouse immune system again eliminated the leukemia.

“What this tells us is that it’s not just recognizing that one protein,” Dr. Seif said, “which suggests that if the CD19 went away, it could still recognize other features on the leukemia.”

While these study results show that it may be possible to evoke an internal immune response and memory against multiple antigens on the same tumor, a potential roadblock is that the immune systems of children with ALL may be too tolerant of the leukemia cells. Basically, the immune system learns how to differentiate between healthy “self” cells and harmful intruders, so that it does not attack its own body tissue. ALL cells may convince the immune system that they more closely resemble “self” than foreign by sending messages that, “I’m OK, don’t attack me.”

Dr. Seif’s study team is looking at ways to circumvent tolerance and counter ALL’s evasion tactics. They will test drugs already available that could either block the inhibitory signals that ALL gives the immune system or rev up the immune system’s surveillance to promote long-term protection.

“We’re trying to retrain the immune system to do what it should have been doing all along,” Dr. Seif said. “If a precancerous cell slips through, the immune system should be able to recognize it, remember it, and kill it.”

Direct link:

Pediatric Imaging Techniques Shifting Away From Computerized Tomography


Children’s hospitals are shifting away from imaging techniques that use ionizing radiation and moving toward alternatives that do not pose potential hazards. Accumulating evidence suggests that high dosages of ionizing radiation used in computerized tomography (CT) scans is linked to increased cancer risk.

Researchers from leading children’s hospitals, including The Children’s Hospital of Philadelphia, analyzed data from more than 150,000 children admitted to 33 U.S. pediatric hospitals from January 2004 to December 2012. They obtained the records from the Pediatric Health Information System of the Children’s Hospital Association.

Compared to 10 years ago, hospitalized children are significantly less likely to receive CT scans for common pediatric diagnoses, and more likely to receive magnetic resonance imaging (MRI) and ultrasound imaging, neither of which use ionizing radiation. The researchers assessed trends in the 10 most common diagnoses for which CT scans are performed in children’s hospitals, including seizures, concussions, upper respiratory tract infections, and abdominal pain.

“This study reinforces our commitment in the pediatric community to shift away from medical technology with potential for harm from ionizing radiation, towards alternatives that do not pose those risks,” said CHOP pediatrician and health services researcher Evan S. Fieldston, MD, a co-author of the study.

In addition to safety concerns, the study team attributed the shift in imaging tools to growing confidence in and ability to perform MRIs and ultrasounds. The increasing use of electronic health records also expedites the transference of imaging data between centers, reducing the use of duplicate scans.

“While there may still be times when a CT scan is the more appropriate imaging tool to use, parents should question whether an alternate imaging technology is available and appropriate, or what techniques the facility uses to limit radiation dose,” Dr. Fieldston said.

Dr. Fieldston added that Image Gently, for example, is a resource that can help patients, families and providers understand imaging approaches. CHOP’s radiologist-in-chief, Diego Jaramillo, MD, helped found Image Gently in 2007.

Co-authors of the study with Dr. Fieldston were from Cincinnati Children’s Hospital Medical Center; Children’s Medical Center, Dallas; and the Children’s Hospital Association. They published these findings online in Pediatrics Aug. 24 and in the journal’s September print issue.

Direct link:

Produced by The Children’s Hospital of Philadelphia Research Institute.

© 2017 by The Children’s Hospital of Philadelphia, All Rights Reserved.