Oct 06 2015

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.

Permanent link to this article: http://blog.research.chop.edu/focus-on-vision-and-balance-deficits-following-youth-concussion/

Oct 01 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.

Permanent link to this article: http://blog.research.chop.edu/emerge-network-looks-at-how-to-provide-dna-test-results-improve-care/

Sep 29 2015

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.

Permanent link to this article: http://blog.research.chop.edu/moms-study-suggests-candidates-timing-for-fetal-spina-bifida-surgery/

Sep 24 2015

Why Injury Prevention Cannot Be ‘One-Size-Fits-All’

Flaura Winston, MD, PhD, scientific director and founder of the Hospital’s Center for Injury Research and Prevention, weighs in on why injury prevention cannot use a “one-size-fits-all” approach.

Dr. Winston is a primary care pediatrician and, as such, has been on the front lines of clinical care. With that experience comes the understanding that effective clinical care means tailoring treatments to the unique needs of each child. This is the hallmark of “Precision Medicine,” which aims to get the right treatment to the right patient for the right medical condition at the right time.

But it isn’t just in treatment that an individual approach is warranted. In CIRP’s latest blog post, Dr. Winston noted, “Just like we need ‘Precision Medicine’ to tailor care to the unique patient, so, too, do we need ‘Precision Prevention’ to tailor our preventive care and anticipatory guidance.”

Read more about the importance of this approach on CIRP’s blog.

Permanent link to this article: http://blog.research.chop.edu/why-injury-prevention-cannot-be-one-size-fits-all/

Sep 23 2015

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.

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).

More information about the PPTC is available at its website. Read a press release here.

Permanent link to this article: http://blog.research.chop.edu/new-research-consortium-aims-to-identify-drugs-for-pediatric-cancers/

Sep 22 2015

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

Young Boy Playing Baseball

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.

Permanent link to this article: http://blog.research.chop.edu/vs-cancer-and-cbttc-a-winning-team-for-childhood-brain-tumor-research/

Sep 17 2015

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

A CHOP cancer patient adding her colorful symbols of hope to a white car that is covered with children’s handprints from all over the country.

A CHOP cancer patient adding her colorful symbols of hope to a white car that is covered with children’s handprints from all over the country.

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.

Dr. Seif received a research grant at a Handprint Ceremony to support her innovative scientific investigations.

Dr. Seif received a research grant at a Handprint Ceremony to support her innovative scientific investigations.

“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.”

Permanent link to this article: http://blog.research.chop.edu/teaching-the-immune-system-to-have-long-term-memory-for-leukemia/

Sep 15 2015

Pediatric Imaging Techniques Shifting Away From Computerized Tomography

Nurse Using Digital Notepad Whilst Visiting Child Patient

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 on Aug. 24, and in the journal’s September print issue.

Permanent link to this article: http://blog.research.chop.edu/pediatric-imaging-techniques-shifting-away-from-computerized-tomography/

Sep 10 2015

New Gene Variants Found in Very Early Onset Inflammatory Bowel Disease

inflammatory bowel diseaseMelding together genomics technology, disease patterns, immunology, and microbiology, physician-scientists at The Children’s Hospital of Philadelphia are finding new and individualized therapies for patients with very early onset inflammatory bowel disease (VEO-IBD), IBD that presents before age 5.

IBD is a chronic inflammatory disease of the gastrointestinal (GI) tract that can result in ongoing inflammation, leading to a variety of symptoms including diarrhea, abdominal pain and cramping, fatigue, and weight loss. Children with VEO-IBD are a unique population who frequently present with more severe symptoms and greater extent of GI tract involvement than older children and adults with IBD. In addition, these patients tend to respond poorly to conventional IBD therapies used for older patients. These factors suggest that VEO-IBD is a distinct, more aggressive process with a strong genetic contribution to the disease.

“We currently have a cohort of about 250 patients with VEO-IBD, many of whom have significant symptoms that affect their overall quality of life,” said Judith Kelsen, MD, who is a pediatric gastroenterologist and researcher in the Center for Pediatric Inflammatory Bowel Disease at CHOP. “These children were the impetus for the initiation of our research, as we worked to identify therapies to improve their symptoms and treat their disease. We started to realize that VEO-IBD is a different disease with a different etiology, meaning the reasons for having the disease were different than older patients.”

Dr. Kelsen and her colleagues hypothesized that there are strong genetic drivers to the disease involving rare or novel genes. They are using next generation sequencing technology to allow them to detect genetic variants that they believe are enriched in patients with VEO-IBD.

In an article published online in the journal Gastroenterology, the study team reported the results from performing exome sequencing analysis of 125 patients ages 3 weeks to 4 years with VEO-IBD. They identified several novel and rare gene defects in genes associated with primary immunodeficiencies. Some of these pathways are involved in regulation of the immune response, which protects the body from potentially harmful microbes, such as viruses and bacteria.

These gene variants appear to influence both arms of the immune system, the innate response — our body’s first line of defense — and adaptive response — a more sophisticated response that is not immediately activated. The adaptive immune system includes two types of cells, known as B-cells and T-cells. Their jobs are to alert your body to intruders, fight the infection, and then remember the invaders to protect against future attacks. If B- and T-cells are not functioning correctly, they may result in a defective or inappropriate response that contributes to the development of VEO-IBD.

“As we begin to identify the different components of the immune system involved, including B- and T-cell pathways, we can begin to individualize our therapy to the specific patient,” the study authors wrote.

At CHOP, an interdisciplinary team of physicians who specialize in gastroenterology and immunology meet once a month in a VEO-IBD clinic to better target therapies to patients’ underlying genetic defects. Dr. Kelsen and Kathleen Sullivan, MD, PhD, chief of the division of Allergy and Immunology, run the clinic. In many cases, instead of prescribing traditional IBD drugs, they are now using therapies that are directed to diseases of the immune system. Some patients may require more intensive interventions, such as a patient Dr. Kelsen described who is undergoing a stem cell transplant due to the identification of a whole gene deletion (the whole gene is missing) that is critical for the immune system to work appropriately.

Dr. Kelsen also works with Marcella Devoto, PhD, of CHOP’s Division of Human Genetics, and Noor Dawany, PhD, of the department of Biomedical and Health Informatics, to analyze and identify the genes that are responsible for the disease. It is combining the clinical data and the genetics that has proved to be the most successful in treating these children.

As the incidence of VEO-IBD is rising rapidly — accounting for about 6 to 15 percent of pediatric IBD cases — there are many different research avenues to explore, Dr. Kelsen said. In addition to genetic contributors, she and her team, including Maire Conrad, MD, a GI IBD fellow, are studying how differences in the communities of microbes made up of bacteria, viruses, parasites, and fungi that normally reside in our intestinal tract, known as the microbiome, may be partly responsible for triggering the disease. In a study published in August in the journal Inflammatory Bowel Disease, Dr. Kelsen found several bacterial lineages are potentially associated with pediatric Crohn’s disease, a type of IBD.

Families of children with VEO-IBD have been extremely supportive of Dr. Kelsen’s investigations, as she attempts to unravel this complex disease for which there currently is no standard of care for evaluation and treatment.

“I think it is hard at any age to have inflammatory bowel disease, but in many cases, patients with VEO-IBD have a particularly difficult burden due to their young age,” Dr. Kelsen said. “These children often are chronically ill and have not had the opportunity to experience feeling well and participating in every day childhood activities; therefore, their parents are very willing and generous with their time to help with the research. Without them, we would not be successful in learning more about this disease, so we are incredibly appreciative.”

Dr. Kelsen’s research is supported by a career development award from the National Institute of Diabetes and Digestive and Kidney Diseases.

Permanent link to this article: http://blog.research.chop.edu/new-gene-variants-found-in-very-early-onset-inflammatory-bowel-disease/

Sep 09 2015

Cancer Survivor Sees Big Picture of Childhood Cancer Research


Some summers are unforgettable. While her days were not always sunny during the summer of 2005, it is a time that remains close to Raine Talley’s heart as a cancer survivor. Toward the end of second grade, it seemed like Talley could not get rid of a terrible cold, but the illness dragging her down turned out to be acute lymphoblastic leukemia (ALL), a cancer of the bone marrow and blood.

Instead of heading off to camp or lounging at the pool like her friends, Talley, of West Chester, Pa., began receiving chemotherapy and then preparing her tiny body for a bone marrow transplant at The Children’s Hospital of Philadelphia in the fall. ALL is the most common form of leukemia found in children, accounting for about 30 percent of all pediatric cancer. It also has one of the highest cure rates of all childhood cancers; currently, more than 80 percent of children with ALL will survive into adulthood. Talley, now 18, remains cancer-free.

As the seasons turn this year, Talley is packing bags, buying books, and getting ready for her first semester as a college student majoring in film at Drexel University in Philadelphia. Her ultimate goal is to make a documentary film that would help others gain a better understanding of childhood cancer and these young patients’ journeys.

“I really identify myself by my history with cancer and how it has affected me,” Talley said. “Because at a young age, I saw of lot of sickness, it gave me a different insight into people.”

One of the ways Talley already has given back to the cancer survivor community is by contributing her time to research projects at CHOP that aim to help investigators learn about the late complications that can follow childhood cancer. A few years ago, she met Goli Mostoufi-Moab, MD, MSCE, an endocrinologist and pediatric oncologist for the Cancer Survivorship Program at CHOP, whose research focuses on why cancer survivors are at risk for poor bone health, given the numerous, complex endocrine abnormalities that can occur after various childhood cancer regimens. Dr. Mostoufi-Moab invited Talley to participate in research studies that involved evaluation of her bone density and body composition.


Photo courtesy of Ainsley Barry

“It was pretty interesting to see how research can help you in your daily life,” Talley said. “I found out more about why it is important for me to be conscious of my bones and really try to keep them healthy. I think it would be good for others to do research because it can help them know more about their bodies too.”

In an article published in the September issue of Journal of Bone and Mineral Research, Dr. Mostoufi-Moab and colleagues reported that long-term survivors of bone marrow transplants treated with total body irradiation had skeletal complications that included increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution. These factors could affect bone mineral density, a component of bone strength.

“Furthermore, long-term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities,” the study authors wrote. “Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood (allogeneic hematopoietic stem-cell transplantation) survivors.”

Childhood cancer survivors demonstrate increasing prevalence of chronic endocrine abnormalities, particularly as they age into young adulthood. Yet, there is a paucity of extended, long-term follow-up survivorship research studies in aging childhood cancer survivors, Dr. Mostoufi-Moab said.

“Motivated survivors such as Raine, who are invested in their health and participate in research studies, provide the foundation to elucidating the long-term effects of childhood cancer therapy,” Dr. Mostoufi-Moab said. “The ultimate goal from survivorship research is to establish better prevention and risk-based screening protocols for childhood cancer survivors. For this reason, the data from survivorship research studies are critical to ensure continued healthcare investment in the follow-up care survivors need, particularly as they transition to adulthood.”

Permanent link to this article: http://blog.research.chop.edu/cancer-survivor-sees-big-picture-of-childhood-cancer-research/

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