May 21 2015

Research Needed to Address Unique Health Needs of Adolescents With HIV

HIVEvery day Sarah M. Wood, MD, a Fellow in the Craig-Dalsimer Division of Adolescent Medicine at The Children’s Hospital of Philadelphia, is stunned by the resilience and strength of the young people she works with who are living with human immunodeficiency virus (HIV) and the obstacles that they overcome. Yet, they have fallen into an extremely vulnerable space.

At this point in time, about 2.1 million adolescents worldwide are living with HIV. While recent data has shown that AIDS-related mortality declined from 2005 to 2012 for adults and children, adolescent mortality has increased by 50 percent. What is creating such a huge equity gap in treatment for adolescents?

In an editorial published in JAMA Pediatrics, Dr. Wood and colleagues suggest that adolescents living with HIV are a “generation at stake.” A significant barrier to achieving their optimal care is that youth with HIV who are older than 13 often are treated as adults, which fails to recognize that adolescence is a unique and distinct transition of physical, psychosocial, and neurocognitive development. These years also are a crucial time for youth who are not yet HIV positive but are at high risk for infection.

“They are still developing their brains, and they are subject to intense social pressures,” Dr. Wood said. “Those things can work together for youth who are not yet infected with HIV to increase their risk of becoming HIV positive through risk-taking behaviors. Or, for youth who have been born with HIV, their adherence to antiretroviral therapy is going to face significant challenges during this adolescent period.”

As an adolescent medicine expert, Dr. Wood recognizes that the concept of future orientation — teens’ ability to think about how poor adherence when they are feeling well will eventually impact their future health — is a difficult concept for most teens with chronic conditions to grasp. But that should not relegate the teen years as a tumultuous time of bad choices. Instead, she said, we must begin to prioritize adolescent HIV care as a “dynamic process of overlapping stages” and develop systems tailored to help youth navigate this continuum.

Then researchers can begin to pinpoint and pilot test interventions targeted at different levels of that cascade:

  • finding youth who are HIV positive
  • increasing uptake of testing
  • facilitating linkage to care interventions
  • looking at the barriers to prescribing antiretroviral therapy
  • identifying the challenges and facilitators for adolescents to stay in care and adhere to antiretroviral therapy throughout their life cycle.

Dr. Wood especially is interested in exploring how to use and strengthen adolescents’ social support, which includes family, partners, and other people in their social network, to make improvements in these areas. Part of a program at CHOP called the Adolescent Initiative uses an integrated, medical case management model that emphasizes social support when helping youth to become more knowledgeable and competent in managing their HIV. Oftentimes, this means working with youth who have been left homeless due to stigma and discrimination related to their sexual orientation or gender identity.

“We’re doing work to optimize the social support that adolescents have because we can care for them while they’re in the clinic, but in the month or months in between when we see them, they must rely on the support that they have in their lives to be able to sustain treatment,” Dr. Wood said. “Many of our youth are thinking about where are they going to sleep that night and how are they going to eat. The stress of survival may outweigh their ability to think about taking a medication.”

Hearing firsthand from youth living with HIV about their daily difficulties has prompted Dr. Wood to pursue some important research questions: What factors in adolescents’ lives may challenge their ability to stay adherent to their therapy and stay suppressed from a viral load standpoint? And over time, how does housing, social support, substance abuse, and mental illness play into our ability to provide optimal care for youth living with HIV? Another one of her research priorities is looking at ways to increase uptake of HIV pre-exposure prophylaxis.

“We live in an amazing time,” said Dr. Wood, who has 17 years of experience in the area of HIV and sexual health preventative care. “Keeping people adherent with their antiretroviral therapy can reduce their risk of transmitting to their partners. But we also now know that we can give antiretroviral medicine to our negative youth and keep them from becoming HIV positive.”

Prior to starting Adolescent Medicine fellowship, Dr. Wood was a site investigator at CHOP for Project PrEPare, which aims to examine the acceptability and feasibility of daily medication to prevent HIV for young men who have sex with men. The study began in 2012 and included approximately 100 participants between the ages of 15 and 17 from 12 cities across the U.S. Now in its final stages, the project is a prime example of adolescent-specific research that will be essential to advancing HIV care and prevention for youth in years to come.

“We need to begin to build an adolescent care competent world in HIV,” Dr. Wood said.

Project PrEPare was organized by the Adolescent Trials Network for HIV/AIDS Interventions, a research network fund by the National Institutes of Health that develops and implements intervention trials for HIV positive and at-risk adolescents.

Permanent link to this article:

May 20 2015

Pilot Grant to Support Genetic Eosinophilic Esophagitis Investigation

Eosinophilic EsophagitisThe 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.

Permanent link to this article:

May 19 2015

Children With Nightly Bedtime Routines Have Better Sleep Outcomes

bedtime routineSweet dreams. G’nite. Shubh ratri. No matter how you say it, a consistent bedtime routine makes a difference in children’s sleep outcomes, according to a study that included mothers of 10,000 young children from 14 countries.

Sleep problems in children are a common concern among parents, and increasing evidence suggests that inadequate sleep can lead to behavioral and cognitive consequences. Most parenting books and pediatricians recommend a bedtime routine as an effective way to improve children’s sleep difficulties, but this research is the first to demonstrate its importance in a dose-dependent way.

“With each additional night that a family institutes a bedtime routine, their child’s sleep is better,” said Jodi A. Mindell, PhD, associate director of the Sleep Center at The Children’s Hospital of Philadelphia, who reported the results in the journal Sleep. “It was a universal finding. We found it across a multitude of countries, which is amazing.”

Dr. Mindell and her co-investigators collected the data online from a questionnaire offered on a popular parenting website and through emails. The questions asked mothers of children ages 0 to 5 about their child’s daytime and nighttime sleep patterns and behaviors.

Overall, the results suggest that a regular nightly bedtime routine is associated with earlier bedtimes, shorter time needed to fall asleep, fewer awakenings after sleep onset, more total sleep, decreased parent-perceived sleep problems, and decreased daytime behavior problems. They also found that children who start sleep routines as infants are likely to have better sleep outcomes as they grow into toddlers and preschoolers.

“This is a clear message that for every family a bedtime routine should be recommended,” Dr. Mindell said. “A pediatric practitioner should ask how many nights a week they do it, and then encourage them to try to increase it, even it’s just by one night.”

In future studies, the researchers would like to take a closer look at which activities before lights out are most effective at improving children’s sleep. For example, does a relaxing bath before bed or reading a book result in better outcomes? Or, on the other hand, does an energetic 2-year-old benefit from more lively engagement before being tucked in?

“Sometimes I think it is frustrating for families because they have a hard time making bedtime calm for a child who has a lot of energy and won’t sit still for books,” Dr. Mindell said. “Maybe it’s OK to have a more active aspect of your bedtime routine, as long as it’s done every night and it’s an effective signal to your child. We don’t know yet.”


Permanent link to this article:

May 15 2015

Research at CHOP: It’s Not Just a Job, It’s an Adventure!


External Keynote: Ronald M. Evans, PhD, of the Salk Institute

Bookended by references to the 1980s and 1990s — in the form of an iconic U.S. Navy commercial and a discussion of the 1991 measles outbreak in Philadelphia — the 2015 CHOP Research Institute Scientific Symposium offered a snapshot of the inspirational work going on at CHOP every day. Researchers from a variety of disciplines gave talks on everything from the challenges intrinsic to running a large research enterprise, to the human microbiome, to traumatic brain injury.

The day started off with a presentation from Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research (OCTR). Dr. Durbin, who took OCTR’s reins a little more than a year ago after many at the Center for Injury Research and Prevention, is a recognized leader in pediatric injury prevention research. Discussing his time at the helm of OCTR, Dr. Durbin compared the work of aiding investigations to the aforementioned Navy commercial, the tagline of which is “Navy. It’s not just a job, it’s an adventure”.

The morning’s first session saw two more presentations, including one from gene therapy expert Beverly Davidson, PhD, whose talk was largely focused on the neurodegenerative disorder Huntington’s disease. Characterized by uncontrolled movements and progressively worsening mood issues and cognitive abilities, the condition affects approximately 10 to 17 per 100,000 live births. Dr. Davidson and her team have been investigating using gene therapy to treat Huntington’s disease in animal models.

Dr. Davidson’s presentation set the tone for much of the rest of the day, as many symposium presentations were highly focused, often basic, microbiological, immunological, and genetic investigations. An exception was the presentation by the Center for Injury Research and Prevention’s Yi-Ching Lee, PhD, on her work developing computational techniques to model teen drivers’ behaviors.

Let’s Do Lunch

The timing of the symposium’s external keynote speech — by Ronald M. Evans, PhD, of the Salk Institute — was particularly appropriate this year. As attendees ate lunch, Dr. Evans gave a talk on nuclear receptors, a class of proteins that play a key role in metabolism.

A faculty member at the Salk Institute since 1978, Dr. Evans has also been a Howard Hughes Medical Institute investigator since 1985. His numerous awards and honors include a 2004 Albert Lasker Basic Medical Research Award and the 2012 Wolf Prize in Medicine.

During his speech, Dr. Evans discussed the research that led to the development of fexaramine, and investigational compound developed in his laboratory that, per the Salk Institute, “tricks the body into thinking it has consumed calories, causing it to burn fat.”

In short, fexaramine, “reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production,” write Dr. Evans and colleagues in a February Nature Medicine study. The drug’s “pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome,” the authors write.

After lunch, attendees settled in for a series of talks about vaccinology, genetics, neurology, and oncology. A highlight was the presentation given by former Research Institute Chief Scientific Officer Philip R. Johnson, MD, on his lab’s work developing an HIV vaccine. Dr. Johnson’s efforts have led to a Phase 1 clinical trial sponsored by the International AIDS Vaccine Initiative to study the safety of the vector carrying the broadly neutralizing antibody PG9, which has been shown to protect against HIV.

And last, but most certainly not least, the day’s events were capped off by a presentation by Paul A. Offit, MD. Perhaps CHOP’s best-known vaccine advocate, Dr. Offit is co-creator of the rotavirus vaccine Rotateq, director of CHOP’s Vaccine Education Center, and author of numerous books, the latest of which is Bad Faith: When Religious Belief Undermines Modern Medicine.

Dr. Offit’s talk, “The Philadelphia Measles Epidemic: Lesson from the Past or Prologue to the Future,” discussed the 1991 Philadelphia measles outbreak in depth, with a focus on the role several churches played in the outbreak. Though it was largely dormant in the U.S. for many years, measles seems to be somewhat resurgent, with 166 cases diagnosed between January 1 and April 24, 2015, in the District of Columbia and 17 states across the U.S., according to the CDC. The recent rise in measles cases is largely due to children and adults not being vaccinated.

“The reason that we’re hearing about these epidemics is because parents aren’t vaccinating their children because they’re not scared of the disease,” Dr. Offit said. “But I am.”

To learn more about the day, and to see the entire 2015 CHOP Research Institute Symposium’s lineup of presentations, check out the Symposium web page.



Permanent link to this article:

May 14 2015

The Brain is Important: CHOP Expert Discusses False Brain Tumor Syndrome

brain tumor

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

The work of The Children’s Hospital of Philadelphia’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.

Permanent link to this article:

May 13 2015

Community Scholar Project Addresses Needs of Gender Variant Youth

gender youth variantTransgender, gender non-conforming, and gender variant youth oftentimes are misunderstood or ignored when they try to get the attention of healthcare providers. Pediatrician and adolescent medicine specialist Nadia Dowshen, MD, founder and co-director of The Children’s Hospital of Philadelphia’s Gender and Sexuality Development Clinic, wants to help alleviate the frustration of these marginalized youth by improving their access to health resources and services.

“This care is really a matter of life and death,” said Dr. Dowshen, who also is a faculty member at CHOP’s PolicyLab and serves as director of Adolescent HIV Services in the Craig-Dalsimer Division of Adolescent Medicine at CHOP. “Among people who are transgender, 40 percent have attempted to commit suicide at some point in their life, which are numbers that are staggeringly high. We need to do a better job of identifying who these youth are and offering support.”

In order to accomplish this, Dr. Dowshen has been selected to participate in the 2015-2016 inaugural cohort of the Community Scholars-in-Residence Program, a collaboration that includes CHOP and the University of Pennsylvania’s Community Engagement and Research Core, School of Nursing, Office of Inclusion and Diversity, Center for Public Health Initiatives, and the Implementation Science Working Group. The program is designed to provide exceptional junior faculty with dedicated time, mentoring, and support so that they can pursue research projects that cultivate engagement with community partners.

“The ultimate goals are to demonstrate that these kinds of resources and support can improve the quality and quantity of research funding, scholarship, and translation to improve population health,” said Karen Glanz, PhD, MPH, George A. Weiss University Professor and director of the UPenn Prevention Research Center. “This is a pilot program that we hope to build on for the future. We’re excited that our first cohort of Scholars includes Dr. Dowshen, who has already initiated productive research collaborations in the community.”

Over the next two years, Dr. Dowshen will work with the City of Philadelphia Department of Public Health’s Division of Maternal, Child, and Family Health (MCFH) to gain insights from the thoughts and experiences of transgender and gender non-conforming youth and other key stakeholders. She will use this information to increase healthcare providers’ knowledge and increase access to needed services.

“In order to develop programs and policies that will improve health outcomes among marginalized youth, I believe that our key stakeholders — the youth themselves and those in the community who work closely with them — need to be involved in all aspect of the research process in order for the research to be relevant and implementation of findings to be successful,” Dr. Dowshen said.

For the first part of the project, Dr. Dowshen and her colleagues at the MCFH will interview these adolescents, their parents, and community groups to identify and summarize their healthcare needs. The study team also will compile national policies that affect transgender and non-conforming youth and determine how they apply practically in the Philadelphia area. These steps will lead to the formation a community advisory board.

The second part will be to survey providers both throughout the CHOP Care Network and within the city health department clinics about their knowledge, attitudes, and practices with transgender and gender non-conforming youth. Based on the responses, Dr. Dowshen will identify focus areas for a curriculum to train the providers on ways that they can help to better care for this patient population.

“We know that when they do have the support of a multidisciplinary team of medical and mental health providers and a family and community, that gender non-conforming youth can grow up to be happy and healthy, productive adults,” Dr. Dowshen said.

Permanent link to this article:

May 12 2015

Improving Asthma Care With Shared Decision-Making

shared decision makingA quick search for the term “shared decision-making” on PubMed (the US National Library of Medicine’s study database) shows an interesting progression. The term first appears in the title of a 1968 paper on education, and then in five studies 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 42 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. Much of Dr. Fiks’ research has been focused on using technology — such as electronic health records (EHRs) — to improve outcomes for pediatric patients

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.

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, such as videos on asthma triggers and medications; 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 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.

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.

Permanent link to this article:

May 09 2015

Pathways in Cornelia de Lange Syndrome Open New Possibilities

Cornelia de Lange Syndrome

May 9 is CdLS Awareness Day!

Cornelia de Lange Syndrome (CdLS) is a relatively rare developmental diagnosis that involves a constellation of symptoms affecting almost every body system in children who have the most severe form of the diagnosis. Finding out its causes could be extremely important to understanding human development at all levels, which is why Ian Krantz, MD, medical director of the Center for Cornelia de Lange Syndrome and Related Diagnosis at The Children’s Hospital of Philadelphia, and his colleagues have dedicated the past two decades to research that is piecing together the basic biology of CdLS.

A unique aspect of the studies, which have been funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is that it is a collaboration of scientists from across the country who started out by studying yeast and then small flies called Drosophilia, continued on to analyze zebrafish and mouse models, and then translated their findings to humans.

“This is a model of how you can go from a rare diagnosis, studying it clinically, and providing excellent care to the kids and the families, and then leveraging that population for discovery to find the genes and causes, and then to move on to the next level, which would be therapeutics, and hopefully give that back to the families,” Dr. Krantz said.

In recognition of Cornelia de Lange Syndrome Awareness Day May 9, let us take a look at the projects’ history and recent findings.

Finding the First Genetic Mutation That Causes CdLS

Most children with CdLS do not inherit the disease from their families. It results from a new change in their genetic makeup, which can be tricky to find. Using DNA sequencing technology, Dr. Krantz’s study team made an exciting discovery in 2004 when they identified the first gene, NIPBL, which causes CdLS when altered or mutated.

The gene, and the pathway it controls — called cohesin — had never been known to be mutated in any other human condition, but it is essential to cell division. Humans have 23 pairs of chromosomes that are packages of DNA, a long molecule that contains our unique genetic information. When new cells are forming, two daughter cells separate at a precise moment toward the very end of cell division and are released with duplicate copies of each chromosome.

The process that holds these duplicated chromosomes together until the end of cell division is known as sister chromatid cohesion and is regulated by cohesin, a protein complex. If it is disrupted, the chromosomes cannot go into the new cells in the right number or complement, and that is generally lethal to the cells.

Creating a ‘New Realm of Biology’

Dr. Krantz’s co-investigator, Dale Dorsett, PhD, of the department of Biochemistry and Molecular Biology at St. Louis University School of Medicine, revealed in his studies of Drosophilia that NIPBL and cohesin play another integral role in gene expression, a complicated process that involves elements in DNA called regulators that act as enhancers and repressors for target genes. Basically, these regulators communicate with a region of a gene called a promotor that tells the gene when to turn on or off, what cells to turn on or off in, and how much the gene should be turned on or off.

About 60 percent of the children with CdLS have an NIPBL mutation that the study team suggests interferes with cohesin’s role in the regulation of normal gene expression, resulting in diverse genes being turned on or off at inappropriate levels in different cells during development. For example, a child’s heart cells or brain cells may not form properly because the appropriate genes are not being told to turn on at certain levels at the right time. Since sister chromatid cohesion defects are not seen in CdLS, the investigators suggest that early dysregulation of appropriate gene expression during development is what causes the symptoms seen in children with CdLS, which include limb differences, developmental delays, autistic-like behaviors, small stature, cardiac problems, and gastrointestinal issues.

“So this is a whole new realm of biology that has been created, which is cohesin’s role in gene expression regulation and development,” Dr. Krantz said. “It has many, many roles, and it’s been one of the complexes now that is at the core of all cellular processes. It’s become a very important, very basic, fundamental biologic pathway.”

Advancing Understanding of Isolated Birth Defects

In order to further understand the basic molecular determinants of structural birth defects, the next step was to build a biological model using zebrafish and mice. Developmental biologists at the University of California Irvine, Arthur Lander, MD, PhD, and his wife, Anne Calof, PhD, had a child with CdLS who had died as a newborn. They wanted to help the researchers understand how the NIPBL gene functioned. They joined Dr. Krantz and Dr. Dorsett in successfully submitting the initial grant application to the NICHD in 2006 to leverage this information to find causes for the isolated birth defects that are seen in constellation in CdLS.

Since then, the team as achieved many discoveries, including identifying four more genes that cause CdLS when mutated all involved in the cohesin pathway. The NICHD grant was renewed in 2011, which is allowing the study team to figure out if cohesin is a master switch that regulates many genes’ expression. So far, they have found about 240 genes out of 20,000 in the human genome that are significantly up or down regulated consistently among children with CdLS. The next step is to determine if any fluctuations in those genes could disrupt downstream targets that potentially interfere with normal development.

“We could use our insight into this rare diagnosis to track down causes for much more common birth defects and intellectual disability,” Dr. Krantz said.

Translating Research Into Future Treatments

The study team is not only concentrating on identification of the causes of birth defects, but they also hope to uncover ways to treat them. Since we have two copies of all of our genes — one set inherited from our mother and one set inherited from our father — when one copy of the NIPBL gene is mutated, it results in CdLS, even though there is still another normally functioning copy. Since one mutated copy is sufficient to cause CdLS, the diagnosis follows an autosomal dominant pattern of inheritance.

The study team has shown that the normal copy of NIPBL tries to compensate for the deficient copy by increasing its level to make more normal acting NIPBL protein. If NIPBL expression levels fall below 50 percent, then the cells will likely die due to sister chromatid cohesion problems.

The study team suggests that if they can identify the regulatory mechanisms that allow the normal copy of NIPBL to somehow turn up its expression up from 50 percent to 60 or 70 percent, then perhaps they could test some drugs that could boost the gene’s expression to 80 to 90 percent and potentially help to correct some of the physiological differences seen in CdLS such as intellectual disability and slow growth.

“We’re hoping that the research will result in breakthroughs that we can then give back to the families and improve the outcomes of their children,” Dr. Krantz said.

Many families who have children with CdLS helped to establish an endowment for The Center for Cornelia de Lange Syndrome and Related Diagnoses, a “medical home” that provides multidisciplinary care for children with CdLS. Their goal is to fully fund the center with an endowment of $5 million, which will allow the Center to continue its remarkable progress in advancing novel diagnostic, management, and therapeutic tools through research.

Permanent link to this article:

May 08 2015

Cookies for Kids’ Cancer Funds Support Rapid Discovery of New Therapies

Cookies for Kids' CancerWhat comes from a “Box of Hope?” Inside you will find three kinds of scrumptious cookies, but what you are truly unwrapping is the potential for pediatric cancer researchers to advance novel treatments to clinical trial as quickly as possible.

Cookies for Kids’ Cancer, a nonprofit foundation dedicated to pediatric cancer research, uses the proceeds from its cookie sales and other fundraising events to provide grants to support the work of scientists at five of the nation’s leading pediatric cancer centers. The Children’s Hospital of Philadelphia has received continuous funding since the Cookies for Kids’ Cancer foundation was established in 2008. Most recently, two CHOP teams received a total of $200,000 in grants to focus on pediatric neuroblastoma and acute myeloid leukemia (AML) research.

John Maris, MD, a CHOP pediatric oncologist and the Giulio D’Angio Chair in Neuroblastoma Research, met the Cookies for Kids’ Cancer founders, Gretchen and Larry Witt, when their son, Liam, was at CHOP to receive treatment for neuroblastoma. An aggressive cancer of the peripheral nervous system that usually appears as a solid tumor in the chest or abdomen, neuroblastoma accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.

“The family saw early on that for children who have relapsed or refractory types of cancers there was a huge gap in funding,” Dr. Maris said. “There were not enough effective treatments, and the key to changing that was research.”

In the first Cookies for Kids’ Cancer bake sale, Gretchen baked and sold 96,000 cookies with the help of 250 volunteers, raising more than $400,000 for research. Since 2008, the foundation has supported four dozen childhood cancer research grants that have led to nine new treatments being tested in clinical trials.

“The foundation is unique in that it will only fund research projects where there is a tangible deliverable to the clinic,” said Dr. Maris, who also serves on the foundation’s medical advisory board and gives advice on other institutions’ projects that have the highest potential to make an impact.

That is certainly the case for Dr. Maris’ research program, which is capitalizing on findings supported by a previous Cookies for Kids’ Cancer grant that helped investigators to identify a good therapeutic target called CDK6, which is a protein that is hyperactivated in certain neuroblastoma tumors. The current grant will extend this discovery.

Some cancer cells can figure out how to escape a single drug target. Lori Hart, PhD, a senior research scientist, is leading a program within Dr. Maris’ study team and focusing on a combination approach that aims to promote the killing of neuroblastoma cells with two new drugs in development. One inhibits CDK6, while the second inhibits MEK, a molecule that is part of a signaling pathway essential to regulating many cellular processes. Dr. Hart has shown therapeutic synergy when these two drugs are used together in neuroblastoma models.

“Cells that may be a little bit sensitive to one drug or a little bit sensitive to the other drug appear to be very, very sensitive to both,” Dr. Maris said. “There is exquisite cell death in our laboratory models.”

Based on these results, Dr. Maris has proposed a clinical trial to see if the novel combination therapy shows any benefit for children with neuroblastoma whose tumors have the genetic vulnerabilities that these drugs target. He expects that about 30 percent of children with relapsed neuroblastoma will fit the genetic qualifications required to enter the trial.

Chimeric Antigen Receptor Immunotherapy for Pediatric AML

The Cookies for Kids’ Cancer foundation also is supporting drug discovery research for AML, another pediatric cancer that urgently needs new drug options to prevent relapses and improve long-term cures. AML is the second most common blood cancer in children, affecting about 500 children in the U.S. each year. Despite treatment with the most intensive multi-agent chemotherapies available, approximately 30 to 40 percent of children with AML will relapse.

“We’re just so thankful for the support from Cookies for Kids’ Cancer,” said Richard Aplenc, MD, PhD, a CHOP pediatric oncologist and Hematologic Malignancies section chief. Dr. Aplenc and his co-investigator Sarah Tasian, MD, also a CHOP pediatric oncologist and physician-scientist, are leading the study that aims to increase therapeutic strategies for AML by rigorously testing new chimeric antigen receptor T cell (CART) approaches. “This funding will make a world of difference in our research.”

A team of investigators at CHOP and the University of Pennsylvania leads the CART field in pediatric leukemias and has demonstrated remarkable success using immunotherapy for acute lymphoblastic leukemia (ALL). B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. The study team demonstrated in a groundbreaking trial that they could genetically program immune system T cells taken from patients’ own blood. The bioengineered “hunter” T cells, called CTL019, multiplied when they were returned to the patients’ bodies and eliminated the malignant B cells. One of the first pediatric patients to receive the investigational treatment — formerly known as CART19 — achieved a complete response and remains cancer-free now three years later.

Progress in using CART for AML, however, has proven to be more problematic so far. Many of the protein targets that researchers have identified on AML cells also appear at lower levels in normal cells that are critical to bone marrow formation. In previous studies, Dr. Tasian and colleagues have shown that CART cells can be successfully engineered to attack the protein CD123 on AML cells in mouse models, but this toxicity is long-lasting and has side effects on healthy bystander cells.

In the Cookies for Kids’ Cancer study, Drs. Aplenc and Tasian will investigate various “suicide switch” modifications to CART123 technologies that will allow effective eradication of AML but then turn off the CART cells to minimize collateral damage to healthy tissues.

“We’re looking at ways either to eliminate the T cells after they’ve killed the leukemia, perhaps with a treatment with an antibody, or even incorporation of a gene into the T cell itself that we can then turn off with a chemical or medication,” Dr. Tasian said.

In addition to finding an effective CART123 termination approach, the AML team is studying other proteins expressed by AML cells with the goal of identifying potential candidates for new CAR-based immunotherapies. Their ability to gain a better understanding of leukemia biology and explore more CAR strategies is crucial, as it is unlikely that a single agent will achieve a cure for the broad spectrum of children with AML.

Drs. Aplenc and Tasian, who are also associate and assistant professors of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, respectively, ultimately hope to develop a spectrum of innovative immunotherapies that will translate swiftly to the clinic. Based upon the team’s initial preclinical findings, a phase 1 trial of immunotherapy for pediatric AML is already under development in conjunction with co-investigators at the University of Pennsylvania.

“There is a very big need for new therapies in AML because there is not a pipeline of medications that are coming through and are available for children,” Dr. Aplenc said. “This grant is fantastic for us because its resources helped us to get started rapidly on an exciting new project.”

Sounds like both study teams are going to work up an appetite over the course of the two-year grants. Cookies, anyone?

For more information on Cookies for Kids Cancer, visit

Permanent link to this article:

May 07 2015

Study Team Uses Virtual Visits to Help Families Transition to Home

virtual visitsClinicians at The Children’s Hospital of Philadelphia care for patients with complex medical and surgical conditions, and many rely on sophisticated technology long after they return home. The initial transition from hospital to home can be a daunting time for parents, as they take charge of operating this equipment, such as responding to ventilator alarms or keeping gastrostomy tubes in place.

A pilot quality improvement project underway at CHOP aims to reduce the emotional and operational stress on these families by conducting virtual visits via video chat on mobile devices a few days after children are discharged. Lead investigator John Chuo, MD, MS, hopes that by describing and characterizing the kind of issues that parents are facing, the implementation team will be able to better understand how telemedicine could be of value to augment the standard of care and perhaps avoid urgent care or emergency room visits and readmissions.

“The providing staff at CHOP are excellent at educating parents before discharge, but it can be overwhelming for parents who overnight become the sole caretakers for their child,” said Dr. Chuo, who is an attending neonatologist and medical director of telemedicine at CHOP. “It is a vulnerable time, for the patient and their quality of care, so we want to use telemedicine to help them make the transition.”

The research project methodology centers on a quality improvement framework, which gives investigators the flexibility to problem-solve using “plan-do-study act” cycles based on the data learned during the remote check-ins. They already have engaged several CHOP teams such as the Chronic Lung Disease Program in the Division of Neonatology, the Division of Plastic and Reconstructive Surgery, General Surgery, Home Care, and Compass Care, which seeks to improve the health of the most medically complex patients.

Those teams each have dedicated clinicians to participate in the project. Together with the telemedicine team, they will follow specific “swimlane” workflows that include identifying families willing to take part in the study, setting up parents’ mobile phones or tablets, and making appointments for the video chats before discharge. When it is time for the appointment, the clinicians will use a hosted service to connect with the families by video call and interview the parents based on a checklist of questions that are pertinent to their child’s care.

These are typical questions that would be asked via a telephone call with one addition – now, the clinicians can ask “show me” questions that may uncover issues not discoverable before with voice only calls. The items will help to reinforce education and resolve parents’ questions, focusing specifically on use of equipment and supplies, certain medical and surgical screening, compliance with medications and appointments, and unanticipated events and complications.

For example, the clinician will ask, “Are you having any problems administering the medication?” and then follow up with, “Please show me how to draw up one of your medications.” Having parents demonstrate their technique using the syringe could help to avoid medication errors. Another example is asking parents to show the clinician the child’s feeding tube site. Most mobile devices’ cameras have high enough resolution, Dr. Chuo pointed out, that the clinician potentially could see the condition of the insertion site.

Afterward, the clinician will document the virtual patient encounter in a database and communicate information to other providers, as they normally would do. Over a 12-month period, the researchers will track call rates, home visit rate, emergency room referrals, readmission rates, patient and provider satisfaction, and the number of equipment and patient issues that were identified and resolved.

In the end, Dr. Chuo expects to identify clinical scenarios where the use of video calls would have greatest value and learn how to better implement telemedicine in those situations as a way to optimize care coordination and overcome geographic barriers to access. Some families do not have an easy means of seeing a specialist should something unexpected arise, and most go to the emergency room when problems escalate.

“We are dedicated to providing children access to the right care at the right time,” Dr. Chuo said. “From a healthcare community standpoint, better and quicker access can reduce healthcare costs. The use of telemedicine has avoided patient transports by ambulance, thereby from a quality improvement perspective, it reduces travel time, which is non-value added work.”

Dr. Chuo, who also is an assistant professor of Clinical Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, is appreciative that CHOP already has in place the clinical infrastructure and support for patient care to make this project possible. He gave kudos to CHOP’s Information Technology and Telemedicine groups for facilitating the study team’s easy access to a simple-to-use, reliable communications platform. Dr. Chuo also expressed special thanks to Verizon for their ongoing financial support of telemedicine research initiatives at CHOP.

Permanent link to this article:

Older posts «