Bench to Bedside

April 2015

New Research Center to Tackle Pediatric Health Disparities


Though clinicians are tasked with doing their very best to extend the same level of care to all patients, the fact remains that disparities exist in care and health outcomes, especially in pediatric patients. A new center at The Children’s Hospital of Philadelphia Research Institute will seek to support these most vulnerable patients by conducting research to better understand the root of disparities — be they racial, gender-based, or caused by geography.

The Center for Perinatal and Pediatric Health Disparities Research (CPHD) will work, according to its mission, to “identify, describe, and understand disparities in care and care practices among perinatal and pediatric patients.”

The new Center will be led by Scott Lorch, MD, MSCE, the Harriet and Ronald Lassin Endowed Chair in Pediatric Neonatology. Dr. Lorch is also director of the Neonatal-Perinatal Medicine Fellowship Program in the Division of Neonatology and Deputy Director of the Center for Outcomes Research at CHOP, as well as an associate professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

“Research in adult patients has shown that there are extensive disparities in the care received by minority patients, particularly Hispanic and African-American patients,” said Dr. Lorch. “CPHD, through multidisciplinary academic and clinical research, aims to understand how these same disparities apply to the perinatal population, where the mother-fetal interaction is of primary importance, and the pediatric population, where family/mother-child interaction is of primary importance.”

Dr. Lorch is an ideal choice to lead the new Center, because his years of work — focused on health disparities, the economics and geography of healthcare, and perinatal epidemiology — dovetails nicely with the Center’s mission. In addition to currently overseeing several federally funded investigations, Dr. Lorch has contributed to recent papers in the American Journal of Obstetrics and Gynecology, Pediatrics, JAMA Pediatrics, and The American Journal of Public Health.

Other faculty associated with the new Center include Nadia Dowshen, MD; Kristin Feemster, MD, MPH, MSHP; Chén Kenyon, MD, MSHP; and Saba Khan, MD. The Center’s Associate Director is Ashley E. Martin, MPH, while Molly Passarella, MS, will perform statistical programming for the CPHD. Both Martin and Passarella, as well several other CPHD faculty and staff, also play roles in the Center for Outcomes Research and PolicyLab, among other CHOP centers.

Hitting the Ground Running

13 faculty members and four CHOP fellows — experts in a number of topics including but not limited to emergency care, food insecurity, HIV/AIDS, and pediatric injuries — have committed to working with the Center and moving health disparities research forward.

And though it was only recently established, the CPHD has already announced its first round of pilot project funding. Designed to support pediatric and perinatal health disparities projects for a year, the CPHD Pilot Grant Program “aims to engage fellows and junior faculty in HD research and to assist established faculty in developing new lines of research in this area,” said Martin.

Geared toward junior faculty, the pilot program is open to all regardless of rank or discipline, so long as one member of the team is from Children’s Hospital. Grant proposals should be submitted by May 30, and awards will be announced in June, Martin noted.

The CPHD has also partnered with a number of community organizations and outside partners to advance its goals of identifying and addressing pediatric and perinatal disparities. They range from the governmental — in the case of the Philadelphia Department of Public Health — to those in higher education, such as the University of Pennsylvania’s Netter Center for Community Partnerships, and nonprofit organizations like Public Citizens for Children and Youth. The CPHD will also work with Children’s Hospital’s Family Relations Department and Family Advisory Council on a variety of projects.

Indeed, one of Dr. Lorch’s current investigations, on obstetric (OB) unit closures in Philadelphia, has involved working with obstetric department chairs, leaders of private obstetric groups, obstetricians, nurses, nurse managers, and midwives to understand the impact OB unit closures can have on patients and hospital. Funded by the Agency for Healthcare Research and Quality, in late 2014 Dr. Lorch and colleagues published a paper in Health Affairs that showed better planning and communication are needed to reduce stress on health systems and the patients they serve.

All of the CPHD’s work — be it research conducted by Center faculty, or that supported by Center grants — seeks to better understand and confront disparities. Ultimately, Dr. Lorch said, with its work the Center hopes to inspire the next generation of pediatric medical researchers to conduct health disparities research, and to start a dialogue about pediatric and perinatal health disparities, with the ultimate goal of improving outcomes for patients.

Investigators interested in working with the Center for Perinatal and Pediatric Health Disparities Research should contact Ashley E. Martin directly at or 215-590-0902, or via the Center’s email,

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Genomic Sequencing Helps Scientists Trace Leukemia Relapse


The ability to sequence all the genetic abnormalities in a tumor cell was unimaginable when Stephen Hunger, MD, was a pediatric oncology fellow. Twenty-five years later, he and a team of researchers from throughout the country used highly sensitive deep sequencing techniques to see how genetic changes in acute lymphoblastic leukemia (ALL) cells evolve from diagnosis to remission and relapse.

ALL, a fast-growing form of cancer that affects immature white blood cells, accounts for 30 percent of all pediatric cancers. While most patients respond well to current chemotherapy, 15 percent will relapse, and ALL remains a leading cause of pediatric cancer death. Once relapse occurs, it is much, much harder to cure patients.

In order to better understand high-risk pediatric ALL, Dr. Hunger, chief of the Division of Oncology and the director of the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia, and his co-investigators wanted to trace the founder mutations that appear in every leukemia cell and see how other mutations persist, expand, or are eradicated between the time of initial diagnosis and relapse. They focused on 20 trios of samples from patients: ALL cells from the time of initial diagnosis, blood samples obtained while patients were in remission, and leukemia samples obtained at the time of relapse.

The researchers performed whole exome sequencing, which identifies all the coding regions of genes, and they also performed whole genome sequencing, which identifies the noncoding regions as well. They also performed “deep sequencing” to confirm the presence of mutations and determine their frequency in samples. This sophisticated analysis gave the researchers high coverage of every piece of the leukemia cells’ genetic material.

“In many cases, we were reading the same sequences 500 to 1,000 times,” Dr. Hunger said. “It is very useful because it allows us to get exact fractions of how often specific changes are present in the whole population of leukemia cells.”

The study’s results published in Nature Communications will help scientists to decipher the process of how ALL and other cancers relapse. These insights are only “the tip of the iceberg” of what is to come from the Therapeutically Applicable Research to Generate Effective Therapies (TARGET) study, said Dr. Hunger, who is the principal investigator of the TARGET ALL Project. TARGET is collaborative effort of a large, diverse consortium of investigators devoted to determining the genetic changes that drive the initiation and progression of hard-to-treat childhood cancers.

When the study team looked at leukemia cells from the time of initial diagnosis, they recognized the founder cells that all have specific abnormalities that kick-start the ALL disease process. The researchers also identified two to five subclones, which are descendants of the founder clone that have additional mutations present. Typically, one subclone was dominant in 90 to 95 percent of cells.

“One of the most striking things we found is that in almost every case, the clone that was most dominant at diagnosis was not present at relapse,” Dr. Hunger said, which suggests that those cells were effectively extinguished with current chemotherapy.

However, some rare subclones were able to survive, populate, and create the relapse. At the time of initial diagnosis, these subclones were often detected in only 1 or 2 percent of cells.

“One of the key points is that in every case, it was clearly the same leukemia that persisted because these founder mutations were present both at diagnosis and relapse,” Dr. Hunger said. “So it’s not like you developed a new leukemia. It also tells us that we have to look at the rare changes that are present at diagnosis because those are the cells that are likely to come back and acquire more changes.”

When the researchers examined blood samples taken at the end of the first month of treatment, in some cases they identified a low frequency of mutations that also appeared at the relapse stage. These findings raise the question of whether it would be valuable for scientists to perform highly sensitive genomic analysis following the first few weeks of chemotherapy to provide early detection of mutations that might drive relapse.

To help shed light on this answer, the study team already is performing deep sequencing of hundreds of pediatric ALL cases that relapsed and comparing them to those that never relapsed. They will search for any differences in the genetic basis of the leukemia cells from the two groups.

“Those sorts of studies will help us learn whether there are particular mutations that help to predict who will and won’t be cured,” Dr. Hunger said.

Another interesting finding from the current study, Dr. Hunger pointed out, is that certain mutations emerged at relapse and caused resistance to common chemotherapy drugs, yet those mutations were never found at any level when the patient was first diagnosed.

“Could we test patients during treatment to see if those mutations are starting to be detected, and if they were, could we change treatment to use different drugs that these mutations don’t cause resistance to?” Dr. Hunger suggested as a future research question.

Pediatric ALL was the first disease to be piloted for the TARGET initiative, which launched in 2006. The project expanded to include research efforts focused on acute myeloid leukemia, neuroblastoma, osteosarcoma, and Wilms’ Tumor. The TARGET ALL team includes investigators from the Children’s Oncology Group , the National Cancer Institute, University of New Mexico Cancer Center, and St. Jude Children’s Research Hospital.

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Shared Decision-Making Portal Shown to Improve Asthma Care


A quick search for the term “shared decision making” on PubMed shows an interesting progression. The term first appears in the title of a 1968 paper on education, and then in five papers in the 1970s. Likewise, it appears in only two papers in the 1980s. Fast forward to 2012, and “shared decision making” is included in the titles of 104 papers; in 2013 it appears in 126 studies; in 2014, 173 papers; and through March 2015, it has already been the focus of 37 studies.

Clearly then, the concept of shared decision-making (SDM) — in which patients and clinicians work together to make choices — has gained steam since it was first used. The Children’s Hospital of Philadelphia’s Alexander G. Fiks, MD, MSCE, has been on the leading edge of SDM-related research, contributing to a total of 10 SDM papers since 2010.

His latest is a Pediatrics study of an SDM Internet portal focused on asthma. Known as MyAsthma, the portal is a modification of Children’s Hospital’s MyCHOP site, which allows patients and families to request appointments, view medications, and see their child’s growth charts, among other things.

Much of Dr. Fiks’ research has been focused on using technology — such as electronic health records (EHRs) — to improve outcomes for pediatric patients. In addition to the SDM study in Pediatrics, he recently published an editorial in the same journal noting health departments and outside groups should collaborate to effectively use electronic data.

“With nearly 80 percent of pediatric practices now capturing data in EHRs, a remarkable opportunity exists to use these data to improve health outcomes,” Dr. Fiks wrote.

For the last several years, Dr. Fiks has been working with other CHOP investigators — including the Department of Biomedical and Health Informatics’ (DBHi) Robert Grundmeier, MD as well as DBHi’s Dean Karavite, MS, and PolicyLab’s Stephanie Maybe, MHS — on the MyAsthma portal.

Portal Proved Feasible, Improving Outcomes

In the current study, Dr. Fiks and colleagues studied the acceptability, feasibility, and impact of MyAsthma. The researchers conducted a six-month trial in which they enrolled 60 families, 30 of whom were randomized to an intervention group who had access to the MyAsthma portal and received training on its use, as well as periodic reminders to use it.

The portal, which is linked to patients’ EHRs, features tools to track symptoms; a timeline of asthma control assessments; asthma educational information; and details on each patient’s care plan and team. Families who used the portal were sent e-mail reminders to complete surveys.

Based on surveys of both groups of patients, the researchers found that not only was the portal feasible — with more than 77 percent of the intervention group completing more than one survey — but also that it was acceptable to the majority of families. Many reported that the portal “made it easier to care for their child’s asthma, and that they were satisfied with the portal,” the researchers write.

“It made me more aware of how serious his asthma could get if he did not maintain his medication administration,” one parent reported in the Pediatrics study. Another parent noted communication “with our providers has been much more convenient this way. I think it may have even cut out some unnecessary visits.”

In addition, families randomized to use the portal reported fewer visits to the emergency department, and saw a slight decrease in the number of school days missed for asthma.

In all, the study’s results “underscore the value of providing decision support to families at home,” the investigators write. The study’s results, they say, “demonstrate the additional value of decision support systems that engage families as well as the clinical team and justify the continued development and evaluation of decision support systems to foster shared, as opposed to simply clinician-focused, decision-making.”

For more information, see the Pediatrics study or read PolicyLab’s description of the project.

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A Tireless Advocate for Adolescent Girls’ Health


Adolescent gynecologist Aletha Y. Akers, MD, MPH, is a busy woman. Still relatively new to The Children’s Hospital of Philadelphia, Dr. Akers has already tackled her many responsibilities with aplomb: launching Children’s Hospital’s new adolescent gynecological consult service; seeing patients in the clinic; and leading two studies: a clinical trial, and an analysis of data from two large datasets of adolescent health in the U.S.

Dr. Akers’ clinical trial, funded by a grant from Bayer Healthcare, is an investigation of the new Skyla intrauterine system (IUS), which was approved by the FDA in late 2013. Her second study, meanwhile, is supported by a four-year R01 from the NIH Dr. Akers received to study the role romantic and peer relationships play in the sexual behavior of obese and non-obese adolescent girls.

After spending eight years at the University of Pittsburgh Medical Center’s Magee-Womens Research Institute, Dr. Akers came to Children’s Hospital in August 2014. In addition to being a practicing gynecologist, Dr. Akers — who is also a faculty member at PolicyLab — conducts research focused on adolescent sexual behavior and reproductive health services. Her move to CHOP constitutes a homecoming of sorts, as she attended medical school at Johns Hopkins University, did her undergraduate work at Byrn Mawr College, and grew up in Philadelphia.

“What was really attractive to me about this job is in addition to being trained as an OB/GYN I trained as a health services researcher,” said Dr. Akers. “Therefore the idea of coming to a place where I can interface with multiple different subspecialties and ask, ‘What are the needs of your patients? and ‘How can we optimize care?’ is exactly what I love doing.”

A big part of Dr. Akers’ job is director of the Division of Adolescent Medicine’s new Adolescent Gynecology Consultative Services, which she will be developing in conjunction with Hospital of the University of Pennsylvania (HUP) gynecologists.

The Division of Adolescent Medicine has provided non-surgical gynecologic services to adolescent girls for many years. However, historically the Division has had to partner with the CHOP Pediatric Surgery Department and HUP OB/GYN department to make sure the needs of adolescent patients are met. Dr. Akers was brought on, in part, to centralize and optimize surgical and non-surgical gynecologic services at CHOP.

Her first task has been to build a LARC (long-acting reversible contraceptives) clinic at 3550 Market Street, within the Adolescent Medicine Specialty Clinic. Her next tasks are to develop CHOP’s capacity to provide outpatient surgical services and to establish an inpatient GYN consult service. Going forward, she plans to make meet with other CHOP subspecialties to understand the gynecological needs of the patients they serve, she added.

IUS Trial to Investigate Paracervical Nerve Blocks

Dr. Akers’ IUS trial is rooted in the fact that adolescents experience the highest rates of unintended pregnancy among women of all reproductive age groups, she said. Indeed, according to CDC data, the birth rate for teens aged 15 to 19 years old outpaces that of the general population, at 26.5 live births per 1,000.

LARC devices are considered first-line options for pregnancy prevention in adolescents, and are very effective at treating adolescent menstrual disorders, but their uptake remains low among adolescents, Dr. Akers noted. Many adolescents, she said, cite the fear of pain during insertion of these devices as a major barrier to adoption.

While many studies have examined pain control options among adult women, few have been focused on adolescent women under age 21, who are unlikely to have ever had a pelvic exam or gynecologic procedure. To that end, Dr. Akers has been leading a study of pain associated with the latest IUS to hit the market, the Skyla.

Manufactured by Bayer Healthcare, Skyla is the smallest IUS currently on the market. Skyla’s smaller size could mean its insertion is less painful than other, larger IUS devices. In fact, “in clinical testing it was demonstrated to be slightly less uncomfortable compared to Mirena,” Dr. Akers said.

The next question is whether medication can further mitigate pain during IUS insertion. Although many pain medications have been studied, almost none have been shown to be effective at reducing IUS insertional pain. However, Dr. Akers pointed out, recent literature shows that paracervical nerve blocks — medication injected into sites around the cervix — show promise in adult women.

With this trial Dr. Akers hopes to answer the question of how effective paracervical nerve blocks are at reducing IUS pain in women aged 14 to 22 years. Subjects will be randomized to receive an anesthetic versus those who will receive a “sham” paracervical block, meaning they will be touched with the end of a Q-tip rather than injected.

There are “a lot of potential reasons adolescents may benefit more from pain control during IUS insertion,” Dr. Akers said. Because Skyla doesn’t carry the same minimum uterus size restrictions as other IUS devices, it could be used in adolescents who need menstrual cycle control or help with family planning, Dr. Akers noted.

Obesity, Relationships, and Sexual Behavior

Where her Skyla investigation is clinical and patient-based, Dr. Akers’ second project, funded by an R01 from the NICHD, is data-based and behavioral. Over the course of the investigation, she will be leading a study examining the role social relationships play in the sexual behavior of obese and non-obese girls. By studying large datasets, Dr. Akers and her team hope to determine whether body mass index accounts for differences in how girls develop relationships, and whether that has an impact on their sexual practices.

“There is previous literature that shows that there is a relationship between obesity and reproductive health and relationship formation for women,” noted Dr. Akers.

Adolescent obesity is associated with higher rates of sexual risk-taking and drug use. For example, a 2014 Journal of Obesity study showed obese, sexually active adolescent girls were more likely to have multiple sex partners and engage in unprotected intercourse. And previous work by Dr. Akers, published in Pediatrics in 2009, showed girls who perceive themselves to be overweight may be less likely to negotiate condom use and more likely to initiate sex early. Moreover, the relationship between obesity and sexual behaviors varied significantly by race.

Dr. Akers’ NICHD R01 follows an R21 from the same agency, which was designed to explore the relationship among obesity, obesity and weight perception. This work resulted in three papers currently under review that show among adolescent girls, obesity is linked with greater sexual risk behaviors regardless of age at sexual initiation.

In their current investigation, the researchers will be making use of two datasets: the Pittsburgh Girls Study (PGS) which completed 14 years of data collection in 2013 and the National Longitudinal Study of Adolescent Health (Add Health), which started in 1994 and is currently collecting its fifth wave of data. Both are large datasets, and compliment each other; because Add Health is national and the PGS is local and population-based, data seen in each can be confirmed in the other.

The overall point of the work, Dr. Akers said, is to ask, “if we look at how peer relationships develop for children, and if we look more at how romantic relationships develop … is there a relationship between the two, and can we identify some key factors that begin to help us to think about how we may want to structure prevention efforts, educational efforts for these girls?”

To learn more about Dr. Akers’ work and adolescent medicine at CHOP, see the Craig-Dalsimer Division of Adolescent Medicine.

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New Guideline Curbs Overuse of Antibiotics for Tonsillectomies


Antimicrobial resistance is spreading around the world, hampering physicians’ capacity for treating bacterial infections swiftly and reliably. Partly to blame is clinical overuse of antibiotics, so researchers are examining ways that clinicians can change or improve their antibiotic stewardship practices.

For example, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published a guideline in 2011 recommending that “clinicians should not routinely administer or prescribe perioperative antibiotics to children undergoing tonsillectomy.”

“This is a big deal because tonsillectomy is the second most common surgical procedure in kids — each year, more than 500,000 children undergo the procedure in the U.S.,” said Jeffrey S. Gerber, MD, PhD, MSCE, an attending physician in Infectious Diseases at The Children’s Hospital of Philadelphia. “Just at CHOP and our satellite ambulatory surgical centers, we perform about 3,000 tonsillectomies per year.”

Tonsillectomy is usually an outpatient procedure in which a surgeon removes a child’s tonsils. In many cases, the reason for a child having a tonsillectomy is a history of recurrent throat infections or obstructive sleep apnea.

Prior to implementing the AAO-HNS guideline, patients undergoing tonsillectomy at CHOP received antibiotics in the operating room and then were sent home with a prescription for three to five days of outpatient oral antibiotics. Do some quick math, and that equals about 12,000 additional patient-days of antibiotic use. Reducing children’s exposure to antibiotics not only would help combat antimicrobial resistance, but it also would avoid antibiotics’ adverse side effects and reduce drug costs.

Dr. Gerber and colleagues designed a study to see what happened at CHOP after this guideline was published. If clinicians followed the guideline, did this change in practice have any effect on patients’ health? In order to assess these trends, they conducted a time series analysis, which basically is a before-and-after study that takes into account trends over time. They used data from CHOP’s shared electronic health record and narrowed it down to 5,359 routine tonsillectomy cases performed from January 2009 through August 2012.

The results showed “a dramatic decrease in perioperative antibiotic use in concordance with the guideline’s recommendation,” wrote the study’s lead author, Edmund A. Milder, MD, of the Naval Medical Center in San Diego, in JAMA Otolaryngology-Head & Neck Surgery.

The findings suggest that CHOP’s group of 10 ear, nose, and throat surgeons quickly adapted their practices to meet the new guidelines, essentially stopping cold turkey from prescribing perioperative antibiotics for tonsillectomies. The researchers reported a 91 percent decrease in perioperative antibiotic use.

“That is pretty impressive,” Dr. Gerber said. “They perform operations at three different sites, and they were all doing things in a standardized, guideline-adherent way, which was terrific.”

The potential rub of the study, however, is that the researchers uncovered a small but statistically significant increase in the rate of post-tonsillectomy bleeding in the month following guideline publication. Other clinical complications were uncommon, and there was no increase in the rate of surgery office visits, emergency department visits, or hospital admissions.

The researchers found the increased rate of bleeding surprising, Dr. Gerber said, because there is not a plausible biological mechanism to explain to why antibiotics would prevent bleeding or, on the other hand, why it would be an unintentional consequence of the practice change to decrease antibiotic use. The study team plans to investigate this unexpected outcome further in a larger, multicenter study that is underway.

“We are looking at a database of 48 children’s hospitals across the country,” said Dr. Gerber, who also is associate director for Inpatient Research Activities for CHOP’s Center for Pediatric Clinical Effectiveness and director of CHOP’s Antimicrobial Stewardship Program. “We’ll see if other hospitals, in addition to CHOP, changed their practice according to the guideline, and if so, is there a relationship between antibiotic use and post-tonsillectomy bleeding?”

The study team’s goal is to have some preliminary data ready to present at ID Week, an international infectious disease meeting set to be held in San Diego this October.

Mark Rizzi, MD, a CHOP otorhinolaryngologist and assistant professor of Clinical Otorhinolaryngology in the department of Head and Neck Surgery at the Perelman School of Medicine of the University of Pennsylvania; Knashawn Morales ScD, assistant professor of Biostatistics and Epidemiology at UPenn; Rachael Ross, MPH, of CHOP’s division of Infectious Diseases and the Center for Pediatric Clinical Effectiveness; and Ebbing Lautenbach, MD, MPH, MSCE, chief of the division of Infectious Diseases and associate director of the Clinical Epidemiology Unit at the Center for Clinical Epidemiology and Biostatistics at UPenn, contributed to the JAMA Otolaryngology-Head & Neck Surgery article.

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PolicyLab Study Shows Antipsychotics Can Increase Diabetes Risk


Researchers from The Children’s Hospital of Philadelphia’s PolicyLab recently published the largest study to date documenting the significant risks to children’s health associated with prescription antipsychotics, a powerful a class of medications used to treat mental and behavioral health disorders.

The results, which were published in JAMA Pediatrics, suggest that initiating antipsychotics may elevate a child’s risk not only for significant weight gain, but also for Type II diabetes by nearly 50 percent. Moreover, among children who are also receiving antidepressants, the risk may double. Previous PolicyLab research showed that one in three youth receiving antidepressants in the Medicaid program were receiving an antipsychotic at the same time.

In a blog post about the study, Policylab co-Director David Rubin, MD, MSCE, notes, “These new findings should give us pause. With such vast numbers of children being exposed to these medications, the implications for potential long-lasting harm can be jarring.”

Traditionally, antipsychotics have been narrowly prescribed to children with a diagnosis of schizophrenia or bipolar disorder, or to those with significant developmental delays who were displaying aggressive behaviors that were potentially injurious to themselves or others. However, in recent years, antipsychotics are increasingly being prescribed in the absence of strong supporting safety and efficacy data to treat healthier children and adolescents with disruptive behaviors, such as those who are diagnosed with attention-deficit/hyperactivity disorder.

The JAMA Pediatrics study, which used Medicaid data on more than 1.3 million youth ages 10 to 18 with a mental health diagnosis from the Centers for Medicare and Medicaid Services, must be interpreted in the context of emerging evidence that Medicaid-enrolled children are far more likely than privately insured children to be prescribed antipsychotic medications. Overall, over 25 percent of Medicaid-enrolled children receiving prescription medications for behavioral problems were prescribed antipsychotics by 2008, largely for less severe disorders.

Despite the number of children being exposed to antipsychotics, the researchers remain cautious about over-reacting to these findings.

“We need to incorporate these new revelations about the risk for diabetes into a more thoughtful consideration of the true risks and benefits of prescribing an antipsychotic to a child,” Dr. Rubin said. “Yes, we should try, by all means possible, to minimize the numbers of children and adolescents exposed to these powerful medications. But for some children in immediate crisis, we must also concede that the benefit of the antipsychotic for acute management may still outweigh the risk.”

The study’s authors recommend that clinicians and families who are making medication decisions periodically revisit the treatment strategy to address challenging behaviors. For example, when planning to prescribe antipsychotics to a child, professional organizations recommend beginning cautiously with the lowest dose possible, while strictly monitoring for early evidence of weight gain or abnormal lab tests that often predict later onset of diabetes.

Ultimately, say Dr. Rubin and his co-authors, the prescription of antipsychotics to children and adolescents is likely to continue, reflecting a growing demand to address very challenging behaviors in children.

“At the end of the day, the approach to the individual child who is in crisis is still a case-by-case decision between a family and the treating provider,” said Dr. Rubin. “We can only hope that those decisions are made in full recognition of our findings, and that for some children, alternatives to these powerful medications—such as counseling or other supportive services, will be considered first.”

For more information about the study, see the full press release. To learn more about PolicyLab’s portfolio of work on antipsychotic medications, visit

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Neuroblastoma Studies Show Promise of Nanoparticles in Fighting Tumors


Delving into the world of the extremely small, researchers from The Children’s Hospital of Philadelphia are exploring how biodegradable nanoparticles can precisely deliver anticancer drugs to attack neuroblastoma, an often-deadly children’s cancer.

By bringing together experts in pediatric oncology with experts in nanotechnology, Children’s Hospital investigators aim to thread the needle of delivering effective doses of cancer-killing agents while avoiding toxicity in healthy tissues. The team’s new research shows that this approach inhibits tumor growth and markedly prolongs survival in animal models.

“These nanoparticles allow us to get more ‘bang for the buck’— greater efficacy at lower total doses,” said Garrett M. Brodeur, MD, a pediatric oncologist and expert in neuroblastoma at The Children’s Hospital of Philadelphia (CHOP). “The nanoparticles are designed to slowly deliver a drug to the tumor, where it kills multiplying cancer cells, with lower toxicity to the systemic circulation.”

Dr. Brodeur’s group collaborated with a group of CHOP nanotechnology researchers led by Michael Chorny, PhD, in a study to be published in print May 1 in Cancer Letters.

Dr. Chorny, in turn, led a study to be published in the May print issue of Biomaterials, in collaboration with Brodeur’s group and with Robert Levy, MD, and Ivan Alferiev, PhD, both members with Dr. Chorny of a cardiology research group at CHOP. That paper described how the team engineered the specially formulated nanoparticles.

Exploiting Neuroblastoma Tumors’ Vulnerability

This approach, explained Dr. Brodeur, exploits one vulnerability of tumors: the EPR, or enhanced permeability and retention, effect. “Tumor blood vessels are more leaky and disorganized than blood vessels in normal tissue. In healthy tissue there are tight junctions in blood vessels,” he said. “But tumors don’t have those tight junctions and have inefficient circulation, so the nanoparticles we deliver bypass healthy tissues, but accumulate in tumors where they release the anticancer agents.”

Neuroblastoma is a solid tumor of the peripheral nervous system, often appearing in a child’s abdomen or chest. The most common cancer in infants, neuroblastoma accounts for a disproportionate share of cancer deaths in children, with cure rates lagging behind those for most other pediatric cancers.

“In pediatric oncology, we have largely relied on drugs developed 30 to 40 years ago,” said Dr. Brodeur. “While these have greatly improved overall cure rates over that period from 20 percent to 80 percent, we still need better drugs and more targeted approaches for the most stubborn childhood cancers, including high-risk forms of neuroblastoma.’

Drs. Brodeur, Chorny and colleagues used their nanoparticle formulations to deliver a precursor of SN38, the active form of irinotecan, a conventional anticancer drug used for the past 20 years against relapsed neuroblastoma. In laboratory mice, the study team compared results obtained with the nanoparticle-encapsulated SN38 to those using a comparable dose of irinotecan.

The injected nanoparticles delivered SN38 to the tumor in amounts 100-fold higher than irinotecan, with sustained drug presence over at least 72 hours, and no evidence of toxicity in the mice. In addition, most of the mice survived tumor-free for over 6 months after nanoparticle delivery, whereas all the mice treated with irinotecan had tumor recurrence shortly after treatment stopped, and they all died shortly after.

The nanoparticles in the study are ultrasmall, less than 100 nanometers in diameter (a nanometer is one-millionth of a millimeter, much tinier than red blood cells).

“We carefully adjust the size of the nanoparticles to find a ‘sweet spot’: small enough to penetrate a tumor, and large enough to carry a therapeutic payload,” said Dr. Chorny. “We can also adjust their composition to keep the active molecule entrapped in a polymer until nanoparticles reach the targeted tumor, and customize the timing of the polymer’s breakdown to allow controlled release of SN38 over a time scale that provides the best therapeutic effects.”

Dr. Brodeur aims to translate these preclinical results to human trials within the next year. “We envision targeted delivery via nanoparticles as a fourth arm of targeted cancer therapy,” he said.

Dr. Brodeur added that if nanoparticle delivery proves its worth in clinical trials, it may join three other molecularly-targeted innovations in pediatric cancer treatment already available at CHOP: immunotherapy using bioengineered T cells, radioactive isotopes that preferentially bind to cancer cells, and kinase inhibitors that interrupt abnormal signaling triggered by cancer-driving mutations.

Some nanoparticles are already being used to treat adult cancers, but if the current technique achieves clinical success in neuroblastoma, it would markedly strengthen the arsenal of approaches currently available for treating a childhood cancer. It holds the potential for broader applications, as well, to deliver other drugs and to treat other cancers currently treated with irinotecan, and perhaps even those that are currently considered resistant to this drug.

For more information about these groundbreaking studies, see the full press release.

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Restoring Cellular Energy Could Lead to Mitochondrial Disease Treatments


Rooted in malfunctions in the power plants that energize our cells, mitochondrial disorders are notoriously complex, with few effective treatments. Now, novel findings may hold great promise for children and adults with mitochondrial disorders. By using existing human drugs to improve metabolism and restore shortened lifespans in microscopic worms, scientists have set the stage for human clinical trials of possible innovative therapies for mitochondrial disease.

Mitochondria are present in up to several hundred copies in nearly every cell, but when they don’t work properly, they impair many systems in the body by short-circuiting normal energy flow. While primary mitochondrial disorders are individually rare, hundreds of them exist, collectively affecting at least one in 5,000 individuals. Abnormal mitochondrial functions also play important roles in common conditions such as type 2 diabetes, epilepsy, Alzheimer’s disease, and even aging.

“This work carries strong promise for identifying effective therapies for mitochondrial diseases,” said The Children’s Hospital of Philadelphia’s Marni J. Falk, MD, director of CHOP’s Mitochondrial-Genetic Disease Clinic. “The drugs we used in this study improve cellular signaling in ways that could directly benefit patients. As all but one of the drugs are currently prescribed for other diseases, they’re already available to now test in clinical trials in patients with mitochondrial disease.”

Dr. Falk and colleagues published their study online recently in the journal Mitochondrion.

Focus on respiratory chain defects

The current research focuses on the respiratory chain, a set of five enzyme complexes that together are a crucial site of energy production inside mitochondria. In respiratory chain (RC) defects, common culprits in many mitochondrial disorders, cells fail to properly produce energy. The most common site of RC dysfunction is complex I, a group of proteins that normally generates a key metabolic product, nicotinamide adenine dinucleotide (NAD+).

NAD+ normally regulates hundreds of other chemical reactions within the cell. When genetic mutations disrupt complex I proteins and the metabolic conversion of NADH to NAD+, patients may suffer often-severe energy shortages in the heart, brain, eyes, muscles and many other parts of the body.

In the current study, Dr. Falk and colleagues studied microscopic worms with mutations that disrupt their mitochondria and make them a useful laboratory model for investigating mitochondrial disease. Using these nematodes, called Caenorhabditis elegans, Dr. Falk’s research laboratory has done extensive studies to understand mitochondrial disease and potential therapies.

Testing existing drugs as potential therapies

The researchers tested a series of drugs currently used to treat patients with diabetes or lipid disorders. One drug, nicotinic acid, is a form of niacin (vitamin B3) that has been used for decades to treat patients who have high triglycerides in their blood.

The C. elegans worms had mutations that directly impaired their complex I function and shortened their lifespans. Nicotinic acid restored the worms’ lifespans to that of normal animals. It also restored the levels of NADH, enabling it to play its crucial role of initiating the transport of electrons in the RC that is necessary to produce cellular energy, as well as regulating many other cellular processes.

The team showed that other available human drugs also improved key metabolite levels in C. elegans. “In contrast to research that aims to repair defective mitochondria, we are bypassing the damaged mitochondria and focusing instead on how cells respond to mitochondrial problems,” said Dr. Falk. “We’re restoring the ratio of critical metabolic precursors and products that control signaling pathways, thereby improving overall cellular health in respiratory chain diseases.”

Mitochondrial diseases, she added, are highly complex, but her team’s series of nematode studies have revealed fundamental conserved processes that are disrupted in mitochondrial disease. The study team carefully deciphered many of the biological mechanisms at work, marked by changes in oxidant levels, genome expression patterns and other major physiological effects. “Although some specific mechanistic details may differ, we’re looking at how the effects of different drugs may converge to promote an organism’s health and survival,” she said.

Clinical trial planned

Dr. Falk and colleagues are now planning a pilot clinical trial in children with complex I deficiencies to determine whether the effects seen in the animals will translate to meaningful clinical benefits in patients. Ultimately, she expects the complexity of mitochondrial biology will dictate that effective treatments will require combination therapies specific to restoring signaling pathways that are commonly disrupted in major subtypes of mitochondrial disease. “We’re enthusiastic that we have reached a major threshold on the path toward bringing important new therapies to a very challenging group of diseases,” she added.

To read more about this study, see the full press release.

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Blood Investigation Bolsters Mutant Protein in Hemophilia Therapy


Using gene therapy to produce a mutant human protein with unusually high blood-clotting power, scientists have successfully treated dogs with the bleeding disorder hemophilia, without triggering an unwanted immune response. In addition, the “turbocharged” clotting factor protein eliminated pre-existing antibodies that often weaken conventional treatments for people with hemophilia.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said the study’s leader, Valder R. Arruda, MD, PhD, a hematology researcher at The Children’s Hospital of Philadelphia (CHOP) and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Dr. Arruda and colleagues published their results in the recent print edition of Blood.

Hemophilia is an inherited bleeding disorder that famously affected European royal families descended from Queen Victoria. Most commonly occurring in two types, hemophilia A and hemophilia B, the disease impairs the blood’s ability to clot, sometimes fatally. When not fatal, severe hemophilia causes painful, often disabling internal bleeding and joint damage. Doctors treat hemophilia with frequent intravenous infusions of blood clotting proteins called clotting factors, but these treatments are expensive and time-consuming. Moreover, some patients develop inhibiting antibodies that negate the effectiveness of the infusions.

For more than two decades, research teams have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. However, this approach has been frustrated by the body’s immune response against vectors — the non-disease-causing viruses used to carry the DNA. Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent: higher amounts of vectors caused more powerful immune responses.

Dr. Arruda and colleagues therefore investigated gene therapy that used lower dosages of vector produce a more potent clotting factor — a variant protein called FIX-Padua.

In 2009, Dr. Arruda was part of a team that discovered this variant protein in a young Italian man who had thrombosis, excessive clotting that can dangerously obstruct blood vessels. A mutation produced the mutant clotting factor (named FIX-Padua after the patient’s city of residence), the first mutation in the factor IX gene found to cause thrombosis. All previously discovered FIX mutations lead to hemophilia, the opposite of thrombosis.

FIX-Padua is hyperfunctional — it clots blood 8 to 12 times more strongly than normal, wild-type factor IX. Therefore in the current study, the researchers needed to strike a balance: to relieve severe hemophilia in dogs, by using a dose strong enough to allow clotting, but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans,” said Dr. Arruda, “by adapting this variant protein found in one patient to benefit other patients with the opposite disease.”

The recent Blood investigation tested the safety of FIX-Padua in three dogs, all with naturally occurring types of hemophilia B very similar to that found in people. Two of the dogs had never been exposed to clotting factor, and had never developed antibodies. The gene therapy injections changed their hemophilia from severe to mild, with no bleeding episodes for up to two years. They did not develop inhibitory antibodies, nor was there evidence of thrombosis.

The third dog, named Wiley, already had inhibitory antibodies before receiving the gene therapy. Wiley also experienced safe and effective treatment of hemophilia, persisting over a sustained period — three years. The treatment also eradicated the inhibitory antibodies, the first time this occurred in an animal model with pre-existing antibodies.

Another set of preclinical safety studies in mice supported the safety and efficacy of gene therapy using FIX-Padua. Dr. Arruda added that additional studies are needed to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B — at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

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The Brain is Important: CHOP Expert Talks Pseudotumor Cerebri Syndrome


The work of Children’s Hospital’s Shana E. McCormack, MD, was recently featured on Pediatric Research’s “Pediapod” podcast. Dr. McCormack spoke to host Charlotte Stoddart about her review of pseudotumor cerebri syndrome, also known as false brain tumor, in which patients experience the symptoms of a brain tumor despite not having one.

The condition, said Dr. McCormack, is “caused by an increase of the pressure in the fluid surrounding the brain, the cerebrospinal fluid, and it occurs in the setting of that increased pressure but without an actual tumor or other apparent cause of pressure around the brain.”

If left untreated, pseudotumor cerebri syndrome (PTCS) can lead to permanent vision loss, she noted. Precisely what causes the increase in pressure remains an area of investigation, and can develop as consequence of obesity or other conditions, hormonal associations, anemia, and vitamin toxicities, Dr. McCormack said.

“The brain is a really important organ. It’s sensitive to high pressure, but it finds itself in a closed box, a closed space, it finds itself in a skull,” she noted. “So if the pressure goes up by a little, that’s a big risk to the brain, so the brain has several really important conserved mechanisms for maintaining normal pressure in the brain, but we don’t really understand what they are.”

PTCS is most often seen in obese women of childbearing age; this predilection is also seen in late adolescents, Dr. McCormack pointed out. However, the situation in children is different.

“What’s really interesting is that before puberty, instead of being a predominantly female condition there’s an equal mix of affected girls and boys. And before puberty children tend not to be obese, children tend to be normal weight. So it adds to the complexity of understanding this condition, that it changes so significantly over the lifespan.”

The podcast follows Dr. McCormack’s publication of a review of PTCS, in which she and Children’s Hospital’s Grant T. Liu, MD, among others, examined the mechanisms of how the condition arises, hypothesizing that mitochondrial metabolites — which have been shown to regulate fluid in the kidneys — could play a key role in pseudotumor cerebri syndrome.

Though she cautioned treatments are not immediately forthcoming, Dr. McCormack did say work like the Pediatric Research review could be a “springboard” to future work.

“I think we are closer to designing the kind of studies that will produce helpful biomarkers,” Dr. McCormack said. “As a pediatric clinician if I could come up with a blood test to measure cerebrospinal fluid pressure … I think that would really be amazing and would really be a benefit to our patients.”

For more, listen to the whole podcast with Dr. McCormack here.

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Pilot Grant to Support Eosinophilic Esophagitis Investigation


The Children’s Hospital of Philadelphia’s Antonella Cianferoni, MD, PhD, recently received a two-year, $140,000 grant from the American Partnership for Eosinophilic Disorders (APFED) and the Allergy, Asthma & Immunology Education and Research Organization (ARTrust) to study the genetic underpinnings of the severe food allergy eosinophilic esophagitis (EoE).

Given annually since 2013, the Hope APFED/ARTrust Pilot Grant awards help “initiate projects relevant to eosinophil-associated diseases, with a focus on the development of new and inventive ideas that are likely to lead to future external funding and better patient outcomes,” according to APFED’s site. Past winners of the award include Boston Children’s Hospital’s Michiko Oyoshi, PhD, and Seema Aceves, MD, PhD, of the University of California, San Diego.

Only recognized in the last twenty to thirty years, EoE is marked by inflammation and painful swelling in the esophagus, along with high levels of immune cells called eosinophils. It can affect people of any age, but is more common among young men who have a history of other allergic diseases such as asthma and eczema. Children with EoE experience varying symptoms including belly pain, trouble swallowing, uncontrollable reflux, and failure to thrive.

After receiving her MD and then PhD from the University of Florence, Dr. Cianferoni completed fellowships at Johns Hopkins University and Boston Children’s before coming to Children’s Hospital and the University of Pennsylvania’s Perelman School of Medicine. Much of her work has been centered on food allergy pathogenesis.

Last year Dr. Cianferoni published a pair of papers with Jonathan Spergel, MD, PhD, co-director of CHOP’s Center for Pediatric Eosinophilic Disorders. One, published in Immunotherapy, reviewed immunotherapeutic approaches to treating EoE, while a second paper published in Expert Review of Clinical Immunology examined the role the protein thymic stromal lymphopoietin plays in allergic disease. She also contributed to a Nature Communications study led by the Center for Applied Genomics’ Hakon Hakonarson, MD, PhD, that identified four new genes associated with EoE.

“This award will allow me to focus my research on understanding which role genetic variations play in each individual patient, potentially making it easier in the future to predict the best therapy to use in a single patient based on his/her own genetic makeup,” said Dr. Cianferoni when the award was announced.

To read more about Dr. Cianferoni’s award, see APFED’s press release page. For more information about eosinophilic esophagitis and related disorders, visit the Center for Pediatric Eosinophilic Disorders.

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CHOP, Drexel, Hebrew University Partnership Honored


The Philadelphia-Israel Chamber of Commerce (PICC) recently honored the joint research collaboration among Drexel University, The Children’s Hospital of Philadelphia (CHOP), and the Hebrew University of Jerusalem with the 2015 Yitzhak Rabin Public Service Award. The Rabin Award honors regional businesses, academic institutions, and their leaders who exemplify the organization’s goals of broadening business and academic ties between the United States and Israel.

The agreement among the three institutions was signed in a ceremony at Jerusalem City Hall in the presence of Jerusalem Mayor Nir Barkat and Philadelphia Mayor Michael Nutter on November 11, 2013. The agreement served as a new standard for potential partnerships between US cities and foreign nations to further academic and research projects.

The research partnership — which led to a conference at CHOP in January 2014 — is designed to focus on pediatric translational research and to develop a collaborative platform for advancing pediatric medicine from the lab to the bedside. The conference provided an opportunity for investigators from the three institutions to find collaborators with whom to develop joint projects and proposals in pediatric translational research and for interested funders to learn more about the potential for discovery that this collaborative consortium holds.

Two dedicated “dream teams” of investigators were selected, each receiving $250,000 over two years in institutional funding, as administrators seek external investors interested in advancing exciting pediatric translational research with commercial viability.

One dream team is based at Drexel with Amy Throckmorton, PhD, as the principal investigator of the “Giving Kids a Chance” project that is investigating a new intravascular blood pump for pediatric patients with congenital heart disease. A second dream team is located at CHOP with Robert J. Levy, MD, leading the project “Pediatric Transcatheter Valve Replacements: Preventing Device Failure due to Structural Degeneration.”

“Drexel, CHOP and the Hebrew University’s collaborative research on pediatric care is very important to strengthening and broadening the entire region’s academic, commercial, and friendship ties with Israel,” said Richard Bendit, president of the PICC. “Moreover, such joint research elevates the Greater Philadelphia’s rank as a premier center for medical research while opening myriad of new opportunities for future collaborations and further economic impact.”

To read more about the award, see the full press release.

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