May 20 2014

Oncologist Honored for Neuroblastoma Research

neuroblastomaThe Advances in Neuroblastoma Research Association (ANRA) recently presented its highest honor to pediatric oncologist Garrett M. Brodeur, MD, of the Cancer Center at The Children’s Hospital of Philadelphia (CHOP). Dr. Brodeur received the ANRA Lifetime Achievement Award at the association’s international meeting. The award singles out a researcher who has achieved worldwide scientific prominence in investigating neuroblastoma over the course of an exceptional career.

The most common solid tumor of childhood, neuroblastoma attacks the peripheral nervous system, typically appearing as a tumor in a child’s abdomen or chest. Neuroblastoma varies greatly in severity, ranging from forms that spontaneously disappear to high-risk subtypes that are difficult to cure. Because of this variability, researchers have sought ways to predict the course of disease to better select the most appropriate treatment for each patient.

Over his career, Dr. Brodeur has focused on identifying the genes, proteins, and biological pathways that give rise to neuroblastoma and drive its clinical behavior. He has also built on this knowledge to help develop more effective and less toxic treatments for children.

In the 1980s, Dr. Brodeur showed some neuroblastoma cells developed multiple copies of the MYCN gene, which identified a high-risk subtype of neuroblastoma, necessitating more aggressive treatment. This discovery ushered in the current era of genomic analysis of tumors, both in adult and pediatric oncology. Profiling specific molecular alterations in a specific patient’s tumor helps guide oncologists toward the most appropriate treatment.

Dr. Brodeur and his fellow colleagues also discovered important neuroblastoma-related genetic changes. He collaborated with other CHOP researchers who identified the ALK gene as the gene responsible for most cases of hereditary neuroblastoma.

Another major focus of his research regards the role of TRK receptor tyrosine kinases, which control the clinical behavior of neuroblastomas. His work led to a clinical trial with a novel drug that selectively blocks these signals. He is now working on the second generation of such drugs, as well as on nanoparticle delivery systems to treat patients with less abrasive treatments.

Dr. Brodeur has been a member of the CHOP medical staff since 1993 and holds the Audrey E. Evans Endowed Chair in Pediatric Oncology at the Hospital. He is also a professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, where he is an associate director of the Abramson Cancer Center. Last year, Dr. Brodeur received the prestigious Pediatric Oncology Award from the American Society of Clinical Oncology.

To read more about Dr. Brodeur’s award, see the full press release.

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May 19 2014

Study Probes Long-term Seizure Freedom on Ketogenic Diet

seizure freedom

The diet consists of 90 percent fats, 7 percent protein, and 3 percent carbohydrates.

Most children with epilepsy can have active and fulfilling lives, with the help of modern therapies. Yet 20 percent to 30 percent of children with epilepsy do not respond to medications, which physicians call medication-resistant or intractable epilepsy.

Researchers at The Children’s Hospital of Philadelphia continually are looking at ways to lower the frequency of seizures that children with medication-resistant epilepsy experience on a sometimes daily basis. Alternative treatment options may include the ketogenic diet, vagal nerve stimulator, or epilepsy surgery.

The ketogenic diet, which is low in carbohydrates and high in fat, achieves seizure freedom in 15 percent to 20 percent of patients and greater than 90 percent seizure reduction in one-third of children with medication-resistant epilepsy; however, few studies have considered its long-term outcomes. Katherine S. Taub, MD, an epileptologist at CHOP and assistant professor of neurology at the Perelman School of Medicine, published a study in the journal Epilepsia that provides evidence to support the continued use of the ketogenic diet in patients with initial seizure freedom even after breakthrough seizures.

“For children who are seizing daily, it has a big impact on their lives,” Dr. Taub said. “Physicians should encourage patients to continue the diet as treatment even if they have seizure recurrence because they can still have a meaningful reduction in their total number of seizures.”

Epilepsy is a brain disorder that affects 1 percent of children in the U.S.  Many types of epilepsy exist, each with its own seizure types and frequent neurological comorbidity. Children are diagnosed with epilepsy if they have had more than two unprovoked (no precipitating cause) seizures. Seizures occur when clusters of nerve cells, or neurons, in the brain have a burst of abnormal electrical signals that temporarily interrupts normal electrical brain function.

Researchers are unsure of exactly how the ketogenic diet inhibits epileptic seizures. The diet consists of 90 percent fats, 7 percent protein, and 3 percent carbohydrates, and it requires precise measuring and steadfast adherence.

In this retrospective cohort study, participants were patients at CHOP between 1991 and 2009 who had been unsuccessfully treated with four or more antiepileptic drugs prior to ketogenic diet initiation. The majority had daily seizures. Sixty-five participants achieved seizure freedom for a minimum of one month during ketogenic diet treatment. When Dr. Taub examined the probability of their sustained seizure freedom, the average time to seizure recurrence was three months or less, and the likelihood of remaining seizure-free at 18 months was 3 percent.

“A high number of patients on the diet did have breakthrough seizures, but none of our patients returned to their baseline seizure frequency,” Dr. Taub said.

Another significant finding that Dr. Taub discovered while comparing this data to previous studies is that a consistent definition of sustained seizure freedom is lacking in the medical literature. Such a consensus would facilitate future studies, such as a head-to-head study comparing the ketogenic diet versus other antiepileptic medications.

“If we’re going to be sharing comparative data between centers, then we should establish an agreed upon definition for seizure freedom, so we can evaluate institutions’ success of the diet,” Dr. Taub said.

The study’s co-authors included Sudha Kilaru Kessler, MD, an attending physician at CHOP, and Christina Bergqvist, MD, an attending physician and director of CHOP’s Ketogenic Diet Program, which is one of the largest of its kind in the country providing resources and training for families.

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May 16 2014

Targeting Youth Violence With Advocacy, Research

youth violence

Firearms remain the second leading cause of trauma death in the pediatric population.

Healthcare practitioners at children’s hospitals have a unique and powerful perspective about firearms violence because they witness the devastation that it causes families on a daily basis.

Michael L. Nance, MD, director of the pediatric trauma program and an investigator for the Center for Injury Research and Prevention at The Children’s Hospital of Philadelphia, recently updated the American Pediatric Surgical Association’s (APSA) position statement on firearms injury and children, in response to the 2012 tragedy at Sandy Hook Elementary School. Dr. Nance is still haunted by pictures of the mass shooting in Newport, Conn., that killed 20 children and six adults.

“I find that I can’t turn away from it because I’m worried that I’ll somehow lose sight of the fact that we still have a huge problem and a lot of work ahead of us,” said Dr. Nance, who has been involved in the care of firearms injuries for more than 25 years. “It’s not just these mass shootings that are causing trouble … it is this daily drip, drip, drip of firearm injuries that is the real problem, and by the end of the year, another 30,000 Americans have died.”

Firearms remain the second leading cause of trauma death in the pediatric population. Since 1999, more than 35,000 children under age 19 have died as a result of a firearms injury. In 2010, 2,711 children died by gunshot, with another 15,576 injured.

The Sandy Hook shooting is especially disturbing to Dr. Nance as a surgeon because not a single child survived long enough to receive medical attention that day. The shooter used an assault-style rifle with a high-capacity magazine, and 18 of the 20 children had multiple gunshot wounds.

“So all the systems that we put in place, all this advanced medical care, couldn’t have helped save one of those kids,” Dr. Nance said. “Something has to change, and I think that what has to change in part is advocacy.”

At the time of Sandy Hook, Dr. Nance was chairman of the trauma committee for the APSA, a professional organization of more than 1,200 surgeons who care for young victims of gun violence. In a perspectives article published in the March issue of Pediatrics, he noted that the APSA membership took an unprecedented step by voting to endorse, as an association, the revised position statement to strengthen its message: Firearms-related injury and death must be addressed as a public health issue.

Among its nine position points, the APSA called on Congress to restore funding for firearms-related research. In 1997, an appropriations bill stated: “None of the funds made available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.”

Congress expanded this language in 2003 and later broadly applied it to the National Institutes of Health, effectively shutting down any federally funded firearms-related research. Research dollars have trickled in from a few nonprofits, but the intellectual pool of investigators willing to pursue careers in gun violence research has dried up.

“The moratorium has effectively killed off generations of researchers,” Dr. Nance said. “We’ve had very little funding to do the research, and so we have very little data to go on except body counts — we know how many children are dead.”

President Obama ended the 17-year ban on gun violence research at the CDC when he signed a series of gun safety executive orders in January 2013. One of those orders issued a Presidential Memorandum directing the CDC to research the causes and prevention of gun violence.

It is too soon to tell if the executive order will make a difference in firearms research funding, Dr. Nance said, but he emphasized that data are crucial in trying to understand a problem as complex as firearms injury and desperately needed to accurately inform policy decisions.

“We don’t even have a simple understanding from a pediatric perspective of where the guns are, how they’re accessed, and how that access impacts injury,” Dr. Nance said.

The Institute of Medicine of the National Academies proposed a public health research agenda to reduce the threat of firearms-related violence. Several priorities focus specifically on children, such as determining the effectiveness of childhood education and prevention programs.

For its part, the Children’s Hospital of Philadelphia launched the Violence Prevention Initiative (VPI) in January, which is taking a hospital-wide, multidisciplinary approach to curb youth violence in all forms and keep children safe. The VPI’s Signature Programs will use research protocols to develop proof-of-concept ways that address different aspects of violence and then incorporate these evidence-based interventions into daily practices that interrupt the cycle of violence.

No other institution is “better prepared to lead this very important work, which has the potential to make a difference for children in communities across the United States,” said Children’s Hospital CEO Steven M. Altschuler, MD.

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May 14 2014

Three Peanut Immunotherapy Studies Under Way

peanut immunotherapyStrict avoidance of peanuts and the constant fear of accidental exposure cause tremendous stress for children with peanut allergy and their families. As little as 1/44,000 of a peanut kernel can trigger a reaction for severely allergic individuals.

Three studies under way at The Children’s Hospital of Philadelphia are looking at potential ways to desensitize children so that they can develop a level of tolerance to peanut protein that would provide some clinical protection against accidental exposure.

“Accidental ingestions are unfortunately common, with up to 50 percent of food-allergic patients having at least one allergic reaction over a two-year period,” said Jonathan Spergel, MD, PhD, chief of CHOP’s allergy section and co-director of the Center of Pediatric Eosinophilic Disorders.

About 6 percent to 8 percent of children under the age of 3 years have food allergies. Although most children “outgrow” their sensitivity, allergy to peanuts and tree nuts may be lifelong and carry a risk of fatal food-induced anaphylaxis.

A peanut-free diet is the only treatment for children with peanut allergy, so CHOP researchers have been investigating alternative approaches such as oral immunotherapy (OIT), which is a gradual increase in peanut ingestion.

Various proof-of-concept clinical trials have shown that OIT is a slow and safe way to increase tolerance to peanuts, but OIT has not yet been approved by the U.S. Food and Drug Administration. Dr. Spergel’s research team recently received an award from Allergen Research Corp. to conduct a phase 2 study that will put OIT on the licensure pathway.

If the investigators can demonstrate that peanut OIT is effective and safe in desensitizing peanut allergic study participants, “you’ll have evidence supporting a method that may effectively treat 70 to 80 percent of people with peanut allergies,” Dr. Spergel said. “This will be a major therapy.”

Enrollment for the randomized, double-blinded, placebo-controlled study has begun and will include 55 participants from ages 4 to 26 with a history of allergy to peanuts or peanut-containing foods at eight sites in the United States. They initially will receive extremely low doses of characterized peanut allergen, a pharmaceutical-grade formulated peanut protein, followed by an up-dosing regimen every two weeks for six to nine months. The aim is for study participants to build up their tolerance to at least 250 mg of peanut protein, which would afford protection to one peanut.

Dr. Spergel is also principal investigator for CHOP’s arm of the PRROTECT study, a phase 2, randomized, double-blind, placebo-controlled trial that will determine if pretreatment with anti-IgE mAb (omalizumab/Xolair) will allow for faster and safer OIT desensitization. Anti-IgE mAb is an injectable prescription medicine used for patients with moderate to severe persistent allergic asthma. It works by blocking IgE which binds to allergens causing allergic reactions.

While OIT has been shown to be effective for about 80 percent of children with peanut allergy, most experience some type of reaction, such as itchy mouth or hives, and one in five children will require epinephrine, according to Dr. Spergel.

“Using Xolair as pretreatment with oral immunotherapy, we hope to see very little reaction,” he said.

CHOP and Food Allergy Research Education (FARE) are funding the PRROTECT study, which is a joint project with Boston Children’s Hospital, Stanford University, and Lurie Children’s Hospital.

A third study is taking a different approach to peanut immunotherapy that uses a patch to deliver precise quantities of peanut proteins on the upper layers of skin.

“The method of epicutaneous (EPIT) delivery has some potential advantages including fewer side effects seen in earlier human study and possible increased tolerance, which has been seen in murine models,” Dr. Spergel said. “EPIT also may be more palatable to patients due to the method of delivery.”

The VIPES (Viaskin® Peanut’s Efficacy and Safety) study, funded by DBV Technologies, is a 12-month randomized, double-blind, placebo-controlled study of participants ages 6 to 55 with a history of immediate hypersensitive reaction to peanuts. Initiated in 2012, VIPES is the first and only global trial ever in desensitization of peanut-allergic children and adults, and it is by far the largest involving 22 investigators and 221 participants in Europe and North America. This study is finished recruiting and will have preliminary results in late 2014.

Participants who completed the VIPES study were invited to participate in a follow-up extension study (OLFUS-VIPES) to address the crucial question of tolerance post treatment. Subjects enrolled in this study will receive an additional 24 months of Viaskin® Peanut treatment followed by a two-month period without treatment. Before launching VIPES, a study of 100 children and adults with peanut allergy (including anaphylaxis) showed very good safety.

A true partnership among researchers, physicians, nurses, and families allows CHOP’s study teams to work on these peanut immunotherapy studies simultaneously, according to Dr. Spergel.

“There is no approved treatment of peanut allergy, and by doing these three studies, we are looking at which approach is the safest and most effective,” he said. “We will understand which one will be best.”

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May 12 2014

PCORI-Funded Study to Compare Broad, Narrow-Spectrum Antibiotics

antibioticsThe Children’s Hospital of Philadelphia’s Jeffrey S. Gerber, MD, PhD, recently received an approximately $1.8 million contract from the Patient-Centered Outcomes Research Institute (PCORI) to compare the effectiveness of broad and narrow-spectrum antibiotics in treating acute respiratory infections. An infectious diseases specialist and a Center for Pediatric Clinical Effectiveness (CPCE) faculty member, Dr. Gerber investigates the epidemiology and outcomes of antibiotic use in children.

Last year PCORI awarded the CPCE’s Ron Keren, MD, MPH, more than $2 million to study the effectiveness of oral and intravenous antibiotics. Since PCORI began funding research projects in 2012, the organization has awarded a staggering $464 million to support 279 projects. Dr. Gerber’s award was one of 71 announced during the fourth quarter of 2013.

Dr. Gerber’s three-year investigation will be focused on the use of antibiotics to treat acute respiratory tract infections (ARTI), such as ear and sinus infections. Despite the fact that guidelines frequently recommend using narrow-spectrum antibiotics to treat ARTI, many doctors often prescribe broad-spectrum antibiotics.

According to a 2011 Pediatrics study, between 2006 and 2008 there were approximately 65.6 million doctor’s visits for respiratory conditions. During those visits, there were 31.7 million antibiotic prescriptions made, including 5.8 million prescriptions to treat ARTI for which antibiotics are not indicated. Overall, broad-spectrum antibiotics were prescribed more than half the time.

While prescribing antibiotics can be challenging, “guidelines for antibiotic prescribing for the most common conditions that affect kids are relatively straightforward,” Dr. Gerber said, pointing out that roughly 80 percent of outpatient pediatric antibiotic prescriptions are intended to treat four conditions: ear infections, strep throat, sinus infections, and pneumonia.

Because pediatric antibiotic prescription rates have been documented, with this project Dr. Gerber and his team will seek to learn more about the safety and efficacy of those drugs. “Using parent- and patient-centered outcomes, this study is designed to identity which antibiotic choices best optimize clinical outcomes while minimizing side effects,” he said.

Using Qualitative Research to Inform Quantitative Research

This PCORI-funded project will be conducted in two parts: first the researchers will conduct in-person interviews with parents and children who visit the pediatrician’s office with ARTI symptoms. The goal of study’s first half is to allow parents and children to express, in their own words, the outcomes related to antibiotics that are most important to them. The investigators will then use the data gleaned from these interviews to generate outcomes that will be assessed the study’s second arm.

To oversee the interviews, Dr. Gerber has been working with a medical sociologist, Julia Szymczak, PhD. A postdoctoral fellow in the Division of Infectious Diseases, Dr. Szymczak designed the interviews to “help generate outcomes that can then be tested quantitatively,” she said. The strength of qualitative research “lies in its open-endedness and ability to generate insights that you hadn’t previously considered.” This first arm of the study is already underway, and the researchers are looking to recruit 100 parents and children across the CHOP network.

In the second half of the project, the researchers will conduct phone interviews with a much larger patient population, approximately 3000 families. They will follow the patients prospectively, calling 10 and 30 days following an antibiotic prescription.

In addition to assessing traditional medical outcomes, the investigators are seeking to gauge “outcomes that aren’t typically on a medical chart” — like diarrhea, sleeplessness, and absence from school, which may not require a visit to the hospital but can be disruptive for patients and families, Dr. Gerber said.

The study is “a very comprehensive effort to be patient-centered,” Dr. Szymczak said, adding that it is “exciting because it makes our science more relevant to people in the real world.”

Possible Implications

The possible implications of the project are wide-ranging, as antibiotic prescribing and ARTI are so widespread. There are a number of adverse events associated with antibiotic use. Side effects associated with penicillin, for instance, include upset stomach and diarrhea, and in serious cases rash, fever, and facial swelling. Additionally, there is a concern that overuse of antibiotics can lead to drug-resistant infections.

Dr. Gerber’s hope is that his project helps to empower families to ask the correct questions about their children’s care, and that it helps clinicians design better interventions.

“Given that these four conditions account for 80 percent of antibiotic prescribing, and given that outpatient antibiotic prescribing accounts for 80 percent of all antibiotic prescribing, even a small difference in efficacy can have huge implications,” Dr. Gerber said.

To read more about Dr. Gerber’s project, see the April issue of CHOP Research’s in-depth monthly research publication Bench to Bedside, or the CPCE website.

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May 08 2014

Rare Disease Study Could Broaden Tumor Development Understanding

tumor development

Dr. Kalish plans to look at the role particular genes play in BWS and tumor development. In particular, she will focus on chromosome 11, as several genes’ expression there is altered in BWS and other cancers.

A new study by The Children’s Hospital of Philadelphia’s Jennifer Kalish, MD, PhD, into a rare disease could broaden researchers’ understanding of how numerous cancers develop. Dr. Kalish recently received an award from the Alex’s Lemonade Stand Foundation to investigate tumor development associated with the rare childhood overgrowth disease Beckwith-Wiedemann Syndrome.

A genetic disorder that is often associated with overgrowth of the tongue (macroglossia), or a condition called hemihypertrophy in which one side of the body is larger than the other, Beckwith-Wiedemann Syndrome (BWS) occurs in approximately 1 out of 13,700 births. BWS is associated with an increased risk of childhood cancers, in particular the kidney cancer Wilms tumor and hepatoblastoma, a form of liver cancer.

In addition to studying the clinical characterization of BWS, a major focus of Dr. Kalish’s research has been working to understand why some children with BWS develop tumors. “Up to 25 percent of children with BWS develop tumors, but we do not have a good understanding of why they do,” she said. In late 2013 Dr. Kalish, an attending physician in the Division of Genetics, received a “Young Investigator” grant from the Alex’s Lemonade Stand Foundation to support her BWS investigation.

Patients with BWS face rigorous, frequent cancer screening tests. Until they are four years old, patients must have blood drawn every six weeks, and must undergo abdominal ultrasounds every three months until they are eight years old. Though the screening is “pretty intense,” Dr. Kalish said the testing remains necessary because doctors cannot yet tell which BWS patients will develop tumors and which ones will not.

Working to Improve Screening, Treatments

In an attempt to understand why only some children with BWS develop tumors, and to work to develop better screening markers, Dr. Kalish is currently conducting a two-part study. She is developing an animal model of the disease, as well as deriving induced pluripotent stem cells (iPSCs) from BWS patients’ fibroblasts. Mature cells that have been “reprogrammed,” iPSCs are capable of developing into many cell types. Dr. Kalish will use the iPSCs she creates to form liver cells to study how the BWS patient cells can develop into liver tumor cells.

Dr. Kalish plans to look at the role particular genes play in BWS and tumor development. In particular, she will focus on chromosome 11, as several genes’ expression there is altered in BWS and other cancers.

“This region is dysregulated in other cancers, outside of BWS cancers, so there is clearly something about this region that is leading to tumors,” Dr. Kalish said. “BWS is an example of a rare disease that allows us to study a more common mechanism of disease.”

While previous research indicates BWS patients develop normally, Dr. Kalish pointed out that her new investigation, coupled with the BWS referrals she has been receiving from all over the country and the world, could give researchers the ability to take a more comprehensive look at BWS patients’ long-term health and tumor risk.

“Ultimately, we would like to have better markers to screen for, a better understanding of why these children get tumors, but most importantly possible treatments,” Dr. Kalish said.

To learn more about Beckwith-Wiedemann Syndrome, see the Hospital’s site. For more information about the numerous investigations currently underway at The Children’s Hospital of Philadelphia Research Institute, see the Research Institute’s page.

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May 07 2014

Prophylactic Antibiotics Cut Rate of Repeat UTIs in Half

Prophylactic Antibiotics

The study included 607 children, mostly girls, between the ages of 2 and 6 who had VUR.

The use of prophylactic antibiotics to prevent urinary tract infections (UTIs) associated with vesicoureteral reflux (VUR) has been controversial, and a multisite clinical trial that The Children’s Hospital of Philadelphia participated in is adding to the debate.

Results from the RIVUR trial published in The New England Journal of Medicine were “pretty dramatic,” according to co-investigator Ron Keren, MD, MPH, vice president of quality and chief quality officer for CHOP.

About 5 percent of children will experience a UTI by the time they reach age 6, and approximately one-third of these patients have VUR. When a child with VUR urinates, some urine backs up in the ureters toward the kidneys and so the bladder does not empty completely. This increases the chance of a UTI occurring, and if it reaches the kidneys, it is often accompanied by a fever and is called pyelonephritis.

“The problem with pyelonephritis is that it sometimes results in kidney scarring, and there is a concern that this could lead to high blood pressure and renal failure when you get older,” Dr. Keren explained.

Clinicians currently use a long-term course of daily antibiotics or antireflux surgery to treat children with VUR; however, an international clinical study conducted in the 1980s that compared the two approaches showed no difference in the rates of recurrent UTIs or renal scarring. More recent trials that looked at antibiotics’ effectiveness had conflicting results and methodological weaknesses, so researchers launched the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial to obtain more evidence to guide clinical practice.

The study included 607 children, mostly girls, between the ages of 2 and 6 who had VUR. They were recruited from 19 clinical sites across the U.S and followed for two years. Researchers analyzed the data to determine if children who received daily doses of trimethoprim-sulfamethoxazole had fewer recurrences of UTIs than children who received the placebo and if there were any differences in the occurrence of renal scarring.

“The rate of recurrent UTIs was cut in half for those in the antimicrobial prophylaxis group,” Dr. Keren said. “I was surprised that the prophylactic antibiotics worked as well as they did.”

The percentage of children getting UTIs continued to increase over time in the placebo group but not in the treatment group, Dr. Keren pointed out, which demonstrates the sustained effectiveness of antibiotic prophylaxis. Also, certain subgroups of children — those with bowel and bladder dysfunction and those who had febrile UTIs — seemed to benefit the most from the long-term antibiotics.

The occurrence of renal scarring did not differ significantly between the treatment and placebo groups. This finding likely will add fuel to an ongoing debate, Dr. Keren said. Some physicians will say it is not worth using daily antibiotics in children with VUR if they do not prevent kidney damage. Others will say it is important to continue to treat these children with antibiotics because a UTI recurrence could land them in the emergency room or hospital.

Another contentious issue among clinicians is the use of urinary tract imaging, known as a voiding cystourethrogram (VCUG), to screen for VUR. While VCUG can be a helpful diagnostic tool, it involves radiation exposure, is invasive and uncomfortable, and can be traumatic for young children. Current guidelines recommend that physicians take a watchful waiting approach until a second febrile UTI happens before suggesting that a child go through the procedure. Part of the rationale for the watchful waiting approach was the lack of strong evidence for the effectiveness of prophylaxis in children found to have VUR.

“Now that we know that prophylaxis works, this changes our calculus about the risks and benefits of getting a VCUG on every child who has a first UTI,” Dr. Keren said.

But even without prophylaxis, only one-quarter of children with VUR will experience a repeat UTI, so Dr. Keren emphasized that it is important to explain to families what the research shows and to help parents to make informed decisions about whether to proceed with VCUG imaging.

With so many ongoing discussions about the best ways to approach UTIs, it is ripe for further research. Dr. Keren is involved with another NIH supported study that follows a design similar to RIVUR, known as the Careful Urinary Tract Infection Evaluation (CUTIE) trial, but it is focusing on the rate of recurrent UTIs and kidney scarring in children who do not have VUR.

The RIVUR study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Science. In addition to CHOP, the primary clinical trial sites included Children’s Hospital of Pittsburgh; Women and Children’s Hospital of Buffalo; Wayne State University School of Medicine, Detroit; and Johns Hopkins School of Medicine, Baltimore.

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May 06 2014

Blocking Paths to Resistance to T Cell Therapy for B-ALL

B-ALLTremendous interest in immunotherapy approaches to cancer treatment is building, as researchers look for new ways to train patients’ own immune system to recognize and attack their tumors.

Andrei Thomas-Tikhonenko, PhD, and Stephan A. Grupp, MD, PhD, both investigators for CHOP’s Center for Childhood Cancer Research (CCCR), have begun a unique collaboration that will contribute to scientific understanding of how immunotherapy can improve the survival of children with B cell acute lymphoblastic leukemia (B-ALL) that resists standard therapy. As the team moves aggressively into this area of research, Dr. Thomas-Tikhonenko described their investigations as, “very fresh, new, and exciting.”

B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. Most children with B-ALL are highly responsive to treatment, but 15 percent will have high-risk relapsed or refractory disease that is not curable with chemotherapy.

The biological importance of CD19, a protein that is broadly expressed on the surface of B-cell tumors, has been a research focus for many years in the lab of Dr. Thomas-Tikhonenko, a cancer cell biologist. Yet he never anticipated that his work would be of assistance to a high profile project that used CD19 as a prime target for an innovative cell therapy with some remarkable success for patients with B-ALL who were out of therapeutic options.

Dr. Grupp, who also is a CHOP attending physician and director of Translational Research for CCCR, and his colleagues from the University of Pennsylvania, demonstrated in a groundbreaking trial that they could genetically re-engineer immune cells taken from a patient’s own blood, called T cells, and return them to the body where they multiplied rapidly to seek and destroy cancer cells that expressed CD19. These chimeric antigen receptor-armed T cells (CTL019) — formerly known as CART19 — received widespread attention last year when an article in the The New England Journal of Medicine described how one of the first pediatric patients to receive the investigational treatment achieved a complete response and remained cancer-free.

However, another patient who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor CD19, essentially making them invisible to CTL019. Drs. Thomas-Tikhonenko and Dr. Grupp are blending their diverse but complementary research expertise to determine the mechanism of relapse after successful CART19 therapies and investigate the potential use of the drug dasatinib to stave off such relapses.

A Quest for Cures two-year grant announced in January by the Leukemia & Lymphoma Society will support their work. What the research team learns about resistance will help to inform how chimeric antigen receptors potentially can be designed better as personalized therapies for subsets of patients.

“It was part serendipity and part rational design that basic scientists like myself and physician-scientists like Dr. Grupp are in the same institution,” Dr. Thomas-Tikhonenko said. “We talk to each other and learn from each other. That could only happen in a place like CHOP where basic research is valued.”

Together, they will conduct comprehensive profiling of the B-ALL cells that are no longer making CD19. The investigators want to know how B-cell tumors grow without CD19. Do they have alternative mechanisms of survival, rather than CD19-based? Can production of CD19 be restarted so that the cancer cell is once again visible to the immune system?

“We are going to look at the major proteins that are activated upon CTL019 treatment and interrogate their expression patterns, to see if we can get any hints as to what would make B-ALL cells uniquely susceptible to another therapy,” Dr. Thomas-Tikhonenko said. “We need more targets.”

A central hypothesis that they are testing is that the emergence of pre-existing CD19-negative B-ALL cells can be prevented by combining CTL019 and dasatinib. Dasatinib is a drug in a class of medications that is efficient at stopping activity of another cancer-related protein called Lyn that CD19 turns on. Even when CD19 is gone, Lyn appears to remain as a second in command signaling the tumor cells to multiply. So far, preliminary research in mice performed by another CHOP collaborator, David M. Barrett, MD, shows that using CTL019 and dasatinib together is beneficial in some cases.

Another important research direction is to understand the mechanism of CD19 silencing. When tumor cells are put under pressure, whether it is chemotherapy, radiation, or immunotherapy, they often rearrange their genomes and get rid of genes that are not helpful to them. One possibility is that following CTL019 therapy the CD19 gene is forever lost. But is it also possible that it is retained in CD19-negative B-ALL cells, but simply fails to become active or function properly.

“This would be good news,” Dr. Thomas-Tikhonenko explained. “If we can find some defects in how the protein is made, then potentially we can correct the problem with drugs that restore protein production – and sensitivity to CTL019.” Elena Sotillo, PhD, a CHOP scientist, currently is pursuing this part of the Quest for the Cure study.

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May 05 2014

Patient Engagement Study Set to Inform National Policy

patient engagementClinicians tapping on computers during patient visits has become routine in the era of electronic health records (EHRs). Now families increasingly are being encouraged to spend some screen time on their own entering health-related preferences and goals.

“Incorporating these patient-generated reports systematically into the electronic data we collect can help healthcare providers to tailor treatment and respond to patients’ and families’ most important concerns,” said Alexander G.  Fiks, MD, MSCE, assistant professor of pediatrics and co-medical director of the Pediatric Research Consortium (PeRC) at CHOP.

Patients’ ability to submit health information and actively participate in their healthcare is a main focus of Meaningful Use Stage 3 (MU3) criteria. The federal government allocated $27 billion to fund a staged program to boost the meaningful use of EHRs. A phased approach to participation helps eligible providers move from creating information in Stage 1, to exchanging health information in Stage 2, to focusing on improved outcomes in Stage 3.

Yet a knowledge gap remains on the best ways to accomplish MU3’s objectives, so the Agency for Healthcare Research and Quality funded 12 research projects to provide real-world evidence to inform MU3 policy development and implementation. Dr. Fiks is the principal investigator of one of those studies under way at The Children’s Hospital of Philadelphia. It aims to help policymakers understand the feasibility of using patient portals linked to EHRs to foster patient engagement in pediatrics.

“Data is lacking on which Meaningful Use goals can be reasonably achieved in pediatric primary care settings,” Dr. Fiks said. “We are on track to potentially shape what the expectations should be about using patient portals and these types of tools to collect patient reported outcome data as Stage 3 is rolled out.”

Patient portals are online healthcare applications that allow patients to communicate with their healthcare providers, such as by transferring information about upcoming appointments and test results. The study will use “MyAsthma,” a patient portal created and tested at CHOP that offers advanced functionality to increase shared decision making among parents and clinicians.

MyAsthma provides asthma education, collects patient-reported outcomes, evaluates medication use and side effects, and tracks parent’s preferences and goals. The portal transmits information entered by parents to the clinician’s office, which allows the medical team to address immediate problems and adjust treatment if needed. Dr. Fiks and colleagues recently described the portal’s development in the April issue of The Journal of Ambulatory Care Management.

Asthma is well-suited to the study of patient portals because it has a high prevalence, affecting more than 7 million children in the U.S., especially in socioeconomically disadvantaged communities. It requires symptoms to be tracked over time, and it poses a significant burden on patients’ and families’ quality of life. Patients with persistent asthma regularly use controller medications, so patient portals also may help in medication management for this population.

“On a monthly basis, families check in,” Dr. Fiks said, “so their healthcare isn’t just tied to office visits. There is ongoing monitoring of how kids with this condition are doing.”

A unique aspect of the study is its approach to primary care research across two networks. The American Academy of Pediatrics electronic subnetwork of Pediatric Research in Office Settings (ePROS) is collaborating with PeRC. This is enabling the researchers to evaluate two types of patient portals used across multiple EHR vendors in varied pediatric primary care settings with at least 20 percent Medicaid patients.

“Little is known about the effectiveness of meaningful use policy, and even less is known about how it applies to pediatrics,” Dr. Fiks said. “Most meaningful use research has primarily been structured within adult health care settings. Being able to inform how the process works within pediatric settings is important because the needs of children are different. “

Dr. Fiks anticipates a rapid turnaround time for study results. The majority of data from parent surveys will be collected by the end of summer, followed by individual interviews of parents and practitioners to describe any factors that facilitated or posed barriers to patient portal adoption.  He expects to identify strategies that will directly inform national healthcare priorities for MU3, which are scheduled to take effect in 2017.

“There’s a lot of satisfaction for me as a pediatrician in thinking about ways to transform primary care using technology so that we can more effectively help kids with chronic conditions who need the most attention,” Dr. Fiks said.

CHOP’s Center for Biomedical Informatics, Center for Pediatric Clinical Effectiveness, and PolicyLab also are contributing to the study.

“It is really a great collaboration among groups that brings together CHOP’s health service research expertise, policy expertise, and technological expertise,” Dr. Fiks said.

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May 02 2014

CRISSP Alumna Finds Future Career Path Through Internship


2013 CHOP Research Institute Summer Scholars Program (CRISSP) students.

The Children’s Hospital of Philadelphia’s Research Institute is dedicated to training undergraduates by giving them hands-on exposure to sophisticated scientific and research techniques. CHOP Research Institute Summer Scholars Program (CRISSP) provides full-time mentored research experience to future leaders in the biomedical sciences, with a special emphasis on advancing laboratory, clinical, behavioral, and translational pediatric research.

CRISSP built a young scientist’s confidence to follow her investigative spirit. The 2013 CRISSP alumna blogged about how her invaluable learning experience revealed her future career focus.

Lindsay Zajac, a Bucknell University student, spent an internship last summer at the Center for Injury Research and Prevention (CIRP) assisting with research studies designed to increase understanding of how to best help children coping with pediatric injury and illness. She described the mentoring she received from Meghan Marsac, PhD, and Nancy Kassam-Adams, PhD, as, “truly one of a kind, which was illustrated by frequent meetings with my mentors and their thoughtful advice.”


Nancy Kassam-Adams, PhD mentoring Lindsay Zajac during her CRISSP internship in the summer of 2013.

CRISSP interns train within a designated research laboratory or group from June through August and complete an independent research project that they present at a commencement event. They receive formal instruction in human subject protections, care and use of animals in research, laboratory safety, and responsible conduct of research.

“This program brings undergraduates into the Research Institute and shows them how great science is,” CHOP Research Chief Scientific Officer and Executive Vice President Philip R. Johnson, MD, noted in the Research Institute’s Annual Report.

Zajac’s favorite role was approaching and enrolling families to participate in research studies while they were at the hospital. It exposed her to the rewards of conducting behavioral research for a pediatric population, and she began to develop her professional identity.

“My experience at CIRP has ignited my passion for research and solidified my strong desire to pursue a career in clinical psychology,” Zajac wrote.

With her career plan in place, Zajac was inspired to help other Bucknell students to find their professional paths. The second semester senior is in the midst of organizing an internship panel specifically for psychology students.

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