Aug 04 2015

New Ways Needed to Predict, Treat Relapsed Leukemia

leukemiaBench-to-bedside research at The Children’s Hospital of Philadelphia involves talented scientists who make discoveries in the lab that translate into investigations of clinical applications. CHOP experts studying T-cell acute lymphoblastic leukemia (T-ALL) are taking this model one step further — bench to bedside and back again — by turning around their findings from clinical studies to better inform new series of basic science experiments.

T-ALL is a cancer of a type of white blood cells called T-lymphocytes. Normally, T-lymphocytes help fight infections. When the bone marrow and thymus gland produce too many immature T-lymphocytes, the body’s ability to fight infections becomes compromised.

Despite advances in T-ALL treatment, between 15 and 20 percent of children and young adults who achieve an initial complete remission will have the disease return (relapse). They may need more intensive therapy or alternative approaches, but physicians do not yet have a reliable way of predicting which patients are at high-risk of relapse.

David Teachey, MD, an attending physician and researcher at CHOP with expertise in both oncology and hematology, is leading a study involving researchers from across the country who aim to develop new insights to improve risk stratification of T-ALL by increasing their understanding of its biochemical underpinnings. This work is being funded by the National Cancer Institute through an R01.

“This new grant is trying to tackle two problems,” Dr. Teachey said. “One is we don’t know how to identify the kids who relapse when they walk in the door — you don’t know until it’s too late. And two, we need to develop new therapies for the ones who do relapse.”

The study team will analyze patient samples collected from an international, phase 3 clinical trial called AALL1231 that Dr. Teachey chairs for the Children’s Oncology Group. AALL1231 includes approximately 1200 children and young adults from more than 200 hospitals, and the goal is to determine if standard chemotherapy with or without the drug bortezomib is more effective in treating T-ALL.

In the new study, the investigators will take a protein level approach to help identify subsets of patients with T-ALL who are likely to relapse. They will study participants’ leukemia cells and the proteins that they make, looking for patterns that clinicians could use as a high-risk molecular signature. Next, they will see if there is any correlation between these protein profiles and results from sophisticated next-generation sequencing that allows researchers to detect minute levels of cancer cells that remain after intensive, high-dose, multi-agent chemotherapy.

If the study team can figure out which proteins are abnormal in the patients who do poorly, then they could eventually test drugs that target those altered pathways. They will accomplish this by generating mouse models using the participants’ leukemia cell samples. Since the patients already are involved in the AALL1231 trial, the study team will know who did well and who went on to relapse, so they will be able to see how different therapies affect their prognosis.

For instance, the JAK/STAT signaling pathway is implicated in a high-risk subtype of T-ALL, according to a paper published in the journal Blood earlier this year by Dr. Teachey and colleagues. If drugs are available that can turn off that pathway, then they may be beneficial in combination with existing chemotherapy agents. The study team intends to identify other signaling pathways that are abnormally activated in T-ALL, which may give them clues to better predict chemotherapy response and resistance.

“In the big picture, the hope is the correlative biology performed in the lab will let us learn how to better diagnosis and treat children with T-ALL. Then, we can open a future trial using new drugs to treat children who we think aren’t going to do well and improve their chance of being cured,” Dr. Teachey said.

The project will involve researchers from Seattle Children’s Hospital; UCSF Medical Center, California; The University of Texas MD Anderson Cancer Center, and the University of Texas Southwestern Medical School, in addition to researchers from The Children’s Hospital of Philadelphia.

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Jul 30 2015

Researchers Launch New Investigations With CPCE Pilot Grants

CPCEIf scientific research were like building a house, pilot studies would be the foundation. Their purpose is to establish solid evidence that will attract external support for large-scale studies. The Center for Pediatric Clinical Effectiveness (CPCE) at The Children’s Hospital of Philadelphia is giving three investigators the tools that they need to get to start digging.

Through the CPCE Pilot Grant Program, fellows, junior faculty, and other Children’s Hospital investigators interested in clinical effectiveness research have the opportunity twice a year to receive funding to support their pilot studies designed to produce evidence of what works best for treating, diagnosing, and preventing disease. The three recipients of the 2015 Spring Pilot Grant Award are Sandra Amaral, MD, MHS, Sabrina Gmuca, MD, and Laura Figueroa -Phillips, MD.

Find out more about the awardees and highlights of their projects in this Q&A:

Sandra Amaral, MD, MHS

Tell us a little bit about your background:

I am an assistant professor and attending physician in CHOP’s Division of Nephrology and the Kidney Transplant and Dialysis Program. I received my MD from the MCP-Hahnemann University School of Medicine and a Master of Health Science degree in clinical epidemiology from Johns Hopkins University, Rollins School of Public Health.

What is unique about your pilot research study?

My pilot study, “Using a Mobile Game Application to Improve Healthcare Self-management in Adolescents With Solid Organ Transplants” aims to develop a novel educational mobile health (mHealth) game for adolescents with solid organ transplants (SOT) and test its feasibility and acceptability among adolescent SOT recipients and their caregivers. Adolescent SOT recipients have poor long-term graft survival rates, and are at particularly high risk for unnecessary graft loss due to non-adherence in the management of their complex chronic health conditions. This study will employ novel mHealth gaming technology to augment current care practices and to change how adolescents think about healthcare management, with the ultimate goal of reducing graft loss due to non-adherence.

How do you anticipate your study results will lead to future research?

The findings from this study will provide pilot data in support of future research to test the generalizability and efficacy of the mHealth game in a broader adolescent patient population. If successful, this study will transform positive health behavior and medication adherence research, making patient-centered interventions available in an enjoyable and user-friendly platform. This line of research will be broadly relevant to improving outcomes for all pediatric patients managing complex treatment regimens for chronic health conditions.

What was your reaction to receiving the CPCE award?

I was tremendously grateful and excited. The seeds for this project were planted for me about two years ago when I took a class at Penn on Healthcare Innovations. I have been working steadily on refining the project since then but progress has been slow — mostly due to lack of funding. The CPCE pilot funding will provide me with the opportunity to work closely with a game developer and programmer so I can move this idea into a real, testable product for patients and modified by patients and their caregivers.

Sabrina Gmuca, MD

Tell us a little bit about your background:

I am a first-year Rheumatology fellow in CHOP’s Department of Pediatric Rheumatology and the Center for Childhood Arthritis and Rheumatic Diseases. I received my MD from State University of New York Downstate Medical Center College of Medicine and completed my residency in pediatrics at NYU Langone Medical Center. My research interests include the evaluation of treatment and outcomes in autoimmune conditions affecting the central nervous system.

What is unique about your pilot research study?

Pediatric Neuromyelitis Optica (NMO) is a chronic inflammatory disease of the central nervous system that preferentially targets the optic nerves and spinal cord. By analyzing NMO patient outcomes data over a 13-year period, my retrospective cohort pilot study, “Treatment and Outcomes in Neuromyelitis Optica,” will attend to the current lack of standardized care in the therapeutic management of pediatric NMO.

How do you anticipate your study results will lead to future research?

The results of this study will provide an increased understanding of disease outcomes in pediatric and adult NMO, and its findings will be clinically useful for both rheumatologists and neurologists. Further, if successful, the study’s findings will facilitate future comparative effectiveness trials of treatment with biologics, and it will ultimately make possible the establishment of the first standardized therapeutic protocol for pediatric NMO.

What was your reaction to receiving the CPCE award?

Upon receiving word that I had been awarded funding through the CPCE pilot grant, I felt immediately honored and overjoyed. The Center for Pediatric Clinical Effectiveness allows fellow physicians such as myself to jumpstart our research interests and put ideas into action by providing us both valuable mentorship and important financial support. I am excited and eager to start my research and help improve patient outcomes in autoimmune diseases.

Laura Figueroa-Phillips, MD

Tell us a little bit about your background:

I am a first-year Pediatric Hospital Epidemiology and Outcomes Training fellow at CHOP. I received my MD from the University of Maryland School of Medicine and completed my residency in pediatrics at CHOP. My research and clinical interests revolve around improving patient-centered outcomes for children and their families in an inpatient setting, as well as the epidemiology, diagnosis, and treatment of healthcare related infections.

What is unique about your pilot research study?

Long-term, outpatient central venous access is necessary for the treatment of many pediatric conditions, but can result in serious complications, including central line-associated bloodstream infections (CLABSIs). My nested case-control pilot study, “Development of a Clinical Prediction Model for Pediatric Outpatients at Risk for Central Line-Associated Bloodstream Infections” aims to identify risk factors and derive a preliminary clinical prediction model for CLABSI among ambulatory pediatric patients with central venous lines presenting with bacteremia-associated symptoms. This study will be the first to determine the overall rate of CLABSI among the ambulatory pediatric population with central venous lines, to evaluate the entire population of patients at risk for CLABSI, and to derive a clinical prediction model for CLABSI.

How do you anticipate your study results will lead to future research?

The results of this study will serve as a first step in the development of a clinical prediction tool to guide clinical decision-making when patients present to the Emergency Room, and it could ultimately decrease unnecessary hospital admissions, lower the number of adverse effects associated with exposure to broad spectrum antibiotics, improve patient and family quality of life, and decrease healthcare spending.

What was your reaction to receiving the CPCE award?

I was thrilled and honored to be chosen as a CPCE Pilot Grant awardee. The grant will give me a great launching pad to successfully complete my project and will help me set the groundwork to receive funding for related projects in the future.

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Jul 28 2015

Young Adults Find Selecting Health Insurance Plans Confusing

health insuranceWhile young adults are essential to the implementation of the Affordable Care Act (ACA), the process of applying for health insurance using the federal insurance marketplace can be confusing to them, according to a small, observational study.

Historically, a significant part of the young adult population in the U.S. has been uninsured. Under the ACA’s goal to expand access to health insurance for everyone, they have new choices when shopping for affordable insurance plans. They can compare insurance options on with plans outside the marketplace such as those offered by employers, schools, or their parents’ health insurance.

“Most of the young people in our study were buying health insurance for the first time since many had previously been on their parents’ plans, and they found the process of selecting from 30 plan options in Philadelphia challenging and overwhelming,” said Charlene Wong, MD, principal investigator of the study published in the Journal of Adolescent Health. “The young adults’ thoughts on health insurance and, for example what they are looking for and the challenges they identified, can inform more effective outreach efforts and improvements to the website.”

In the study conducted from January to March 2014, Dr. Wong and colleagues described young adults’ experiences using and their attitudes toward health insurance, health insurance literacy, and benefit and plan preferences. Thirty-three study participants’ ages 19 to 30 who lived in Philadelphia County and were highly educated spent up to 30 minutes exploring During the sessions, the study team recorded study participants’ “think aloud” reactions in real-time.

For example, one participant said, “I just wasn’t able to comprehend all of the things on — I got confused. I’m not a person to give up, not at all — but with the system, I just wanted to quit.”

Study participants struggled with many of the basic insurance terms that appeared on the website. Of the 33 participants, 48 percent incorrectly defined “deductible” and 78 percent incorrectly defined “coinsurance.”

The investigators conducted follow-up interviews with the participants to discuss their perspectives in more detail and also to identify factors important to their enrollment decisions. The results showed that deductible and premium amounts and preventive care coverage were most important to the participants’ plan selection.

“Based on this study, we developed recommendations for improvements to that have been disseminated to the Office of Health Reform. For example, the young adults suggested that pop-up explanations that appear when your cursor is over an important term like ‘deductible’ would have been helpful. We also have ongoing work on the tools available to consumers on and other state-based insurance marketplaces to help simplify or support them in making informed health insurance choices,” said Dr. Wong, who is a fellow with the Craig-Dalsimer Division of Adolescent Medicine program at The Children’s Hospital of Philadelphia.

The next open enrollment period for and other state-run health insurance marketplaces is November 2015.

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Jul 23 2015

Clinical Network Aims to Advance Food Allergy Research

food allergyFood allergy is a potentially life-threatening disease and a growing public health issue. The Centers for Disease Control and Prevention states the number of U.S. children with food allergies has increased by 50 percent from 1997 to 2011. Currently one in 13 American children, roughly two in every classroom, has a food allergy.

Food Allergy Research & Education (FARE), a leading advocacy organization working to benefit 15 million American children and adults with food allergies, launched the FARE Clinical Network on June 29 and named The Children’s Hospital of Philadelphia as one of its 22 centers for excellence.

“We are proud to be selected as a member of FARE’s Clinical Network, and look forward to collaborating in this effort to improve diagnosis and advance treatment for patients with food allergies,” said pediatric allergist Jonathan M. Spergel, MD, PhD, chief of CHOP’s Section of Allergy.

The FARE Clinical Network aims to accelerate drug development in the field by conducting clinical trials of new treatments, as well as to establish patient registries. FARE will initially fund the centers of excellence with an investment of more than $2 million per year.

FARE selected the centers for excellence based on their focus on applying new evidence based-knowledge to this important field. Earlier this year, Dr. Spergel and other CHOP researchers identified four new genes associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the findings may point toward potential new treatments for EoE.

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Jul 22 2015

Researchers Identify Predictors of Recurrent UTIs


“We think that about 5 percent of kids in the first five, six years of life are going to have a urinary tract infection,” Dr. Keren said.

Urinary tract infections (UTIs) are common bacterial infections that are not only aggravating for youngsters and their parents, but they also can have serious long-term consequences. That is why it is valuable for clinicians to be able to better predict which children are most susceptible to repeated UTIs.

Instigated by a buildup of bacteria in the urine, UTIs cause uncomfortable burning with urination, abdominal pain, and frequent urination or wetting accidents. If the bacterial infection reaches the kidneys, symptoms also may include a fever, lack of appetite, and irritability. Most UTIs do not lead to complications with proper treatment, but permanent scarring of the kidneys may occur in severe cases. The Children’s Hospital of Philadelphia treats more than 800 patients with UTIs each year.

Ron Keren, MD, MPH, of the Center for Pediatric Clinical Effectiveness and an attending physician at CHOP, and colleagues conducted a research study that aimed to identify the risk factors that may contribute to why some children go on to develop another UTI. The results showed that two of the strongest risk factors are vesicoureteral reflux (VUR) and bowel and bladder dysfunction (BBD). These findings reported in the journal Pediatrics may have important implications for clinical practice.

“We think that about 5 percent of kids in the first five, six years of life are going to have a urinary tract infection,” Dr. Keren said. “The focus of clinicians and researchers for the last few decades regarding children who have had UTIs has been on VUR, but there has been very little attention paid to children who don’t have VUR.”

VUR is a condition during urination when the bladder contracts and some of the urine flows up the ureters back toward the kidneys where the urine came from. VUR allows bacteria that may be in the bladder to travel with the refluxing urine to the kidney.

Bladder dysfunction often occurs when a child gets into a habit of holding in urine for long periods, which stretches the bladder so much that it does not empty completely. Bacteria have the chance to multiply in residual urine left over in the bladder after incomplete voiding.

In a previous study, called the Randomized Intervention for Vesicoureteral Reflux (RIVUR) study, children with VUR who had a UTI were randomized to receive daily prophylaxis with antibiotic or placebo. Dr. Keren and his colleagues also conducted a complementary study, called the Careful Urinary Tract Infection Evaluation (CUTIE), in which they compared 305 children from the RIVUR placebo group to another cohort of 195 children who had UTIs but did not have VUR. They observed the children in the two CUTIE groups for two years.

“For the first time, we could follow the natural history of what happens to kids who have had a first or second UTI and aren’t getting any therapy,” Dr. Keren said. “And we could see how much of a differentiator VUR is in terms of subsequent UTIs.”

The rate of recurrent UTIs in children who did have VUR was 25 percent; however, the highest risk of recurrent UTIs was for children who had a combination of any degree of VUR and BBD: 56 percent. If the child only had BBD, the rate was still high: 35 percent. The association between BBD and an increased risk of recurrent UTIs is noteworthy because BBD was a common problem among children enrolled in CUTIE: 59 percent (with VUR) and 46 percent (no VUR).

These observations support the researchers’ suspicions that BBD can be a key driver of UTIs. If future larger studies validate CUTIE’s findings, it may give clinicians evidence in order to tailor their treatment approaches and help families decide whether the benefits of daily prophylaxis outweigh the risks and inconvenience.

“The idea is to move toward a more individualized but data-driven approach to decide who should and shouldn’t get prophylaxis,” Dr. Keren said.

For example, urologists who run the DOVE Center for Voiding and Bladder Function at The Children’s Hospital of Philadelphia give prophylactic antibiotics to children who are undergoing bowel and bladder retraining to prevent UTI recurrences. The program uses behavior modification techniques to teach children to regain bowel and bladder control, and UTIs likely would sidetrack their success.

Three of the 19 clinical trial centers that collaborated on RIVUR study also enrolled patients in CUTIE: The Children’s Hospital of Philadelphia, The Children’s Hospital of Pittsburgh of UPMC, and Children’s National Medical Center, Washington, D.C. CUTIE was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences.

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Jul 21 2015

National Network Leverages Electronic Health Records to Improve Care

electronic health recordA research group led by The Children’s Hospital of Philadelphia’s Alexander G. Fiks, MD, MSCE, details the creation of a national “super network” devoted to comparative effectiveness research (CER) based on electronic health record clinical data, in a special article published in Pediatrics.

The network — the Comparative Effectiveness Research Through Collaborative Electronic Reporting Consortium (CER2) — comprises 222 sites across 27 states and 2,119 practitioners. CER2 investigators are currently using electronic health record data from more than 1.2 million pediatric patients to conduct long-term pharmacology-related CER.

CER2 was established in 2012 with funding from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, as well as the Health Resources and Services Administration’s Maternal and Child Health Bureau.

By leveraging electronic health records, the consortium has been working to “broadly improve child healthcare,” the Pediatrics authors note. Because it is comprised of seven networks — from CHOP’s Pediatric Research Consortium, to the American Academy of Pediatrics’ Pediatric Research in Office Settings, to the Ohio-based MetroHealth system, to Indiana’s Eskenazi Health — CER2 reflects a broad range of populations and healthcare settings.

“It has been estimated repeatedly over the past 40 years that 75 to 80 percent of pharmaceuticals possess insufficient labeling information for dosing, safety, or efficacy in children,” the authors note in the Pediatrics article.

“To address these knowledge gaps, large EHR databases” — such as those offered by CER2 — “from diverse practice settings are particularly helpful resources because they can link prescribing data with clinical outcomes, can identify cohorts of children for more detailed study, and can drive decision support to improve care based on medical evidence.”

Building upon this focus, CER2 investigators are examining the treatment of hypertension, which the authors note affects between 2 and 4 percent of children, but “often remains undiagnosed.” Ultimately, the consortium seeks to improve the recognition and treatment of pediatric hypertension by using electronic health record tools to automatically alert physicians.

“The goal of CER2 is to engage scholars from around the country in a diverse range of research projects focused on pediatric medication, safety, and effectiveness, as well as other areas including preventative care, treatment of acute conditions, and chronic disease management,” the authors wrote.

In addition to Dr. Fiks, Children’s Hospital’s Robert Grundmeier, MD, of the Department of Biomedical and Health Informatics; Jennifer Steffes of the American Academy of Pediatrics; David Kaelber, MD, of Case Western Reserve University, Cleveland; Wilson Pace, MD, of the American Academy of Family Physicians National Research Network; William G. Adams, MD, of Boston University; and Richard Wasserman, MD, of the University of Vermont, contributed to the article.

To read more about the CER2 Consortium, see the organization’s web page or read the recent Pediatrics study.

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Jul 16 2015

Office of Postdoctoral Affairs Names Research Administration Fellows

Research Administration FellowsThe Children’s Hospital of Philadelphia Research Institute’s Office of Postdoctoral Affairs announced the selection of two new Research Administration fellows. Katherine Yang-Iott, a researcher and lab manager in the Division of Cancer Pathobiology, and Danika Johnston, PhD, a research associate in the Department of Pathology and Laboratory Medicine, are the new 2015 Research Administration fellows.

The Research Administration Fellowship is a part-time, unpaid, six-month program that fellows complete concurrently with their research duties. The overall goal of the fellowship is to provide fellows with a broad overview of leadership in CHOP Research Administration with administrative directors in the fellows’ areas of interest.

Yang-Iott graduated from Virginia Tech in 2003 with a bachelor’s of science in biochemistry and a minor in chemistry. After school, she worked as a research associate at Regeneron Pharmaceuticals until moving to Philadelphia. Yang-Iott first came to Children’s Hospital in 2006.

Currently, she is a researcher and lab manager under Craig H. Bassing, PhD, where over the past year she has been learning and using a genome editing system to generate genetically modified mice for the Bassing lab. The lab’s main focus is to elucidate the molecular mechanisms through which the DNA damage response maintains genomic stability and suppresses transformations in cells during VDJ recombination (also known as antigen receptor gene rearrangement), class switch recombination, and DNA replication, Yang-Iott said.

In addition to working on her own research projects, she helps to maintain lab budgets, order supplies, and train new team members.

“My goal for this fellowship is to learn as much as I can about CHOP’s research administration,” Yang-Iott added. “I want to familiarize myself with how they are organized and how they operate and interact with each other to support the hospital’s research community. My intent is to transition away from working at the bench and into a position within Research Administration.”

The second new Research Administration fellow is Dr. Johnston. She graduated from Rutgers University with a bachelor’s of arts in biological science in 2002, and she received her doctorate in genetics in 2008. Dr. Johnston spent several years at Thomas Jefferson University studying the role of nuclear hormones receptors in transcriptional regulation prior to coming to the Children’s Hospital in 2014. She is studying the functional significance of SNPs in the 3’ UTR of IGF1R, which may allow prospective stratification of patients enrolled in clinical trials of IGF1R inhibitors. The main impact of her work is the improvement of neuroblastoma treatments.

“During this fellowship, I hope to increase my knowledge and understanding of Research Administration, as well as learn more about this complex network of units that aid in research and discovery,” Dr. Johnston said. “I also hope to learn some new skills and determine whether a job in Research Administration will be the next step on my career path. I intend to meet with as many administrative directors as possible during this process and find a project that will not only increase my skill set, but [also] provide valuable assistance to the department.”

Both recipients of the fellowship are extremely honored to have the opportunity to work with administrative directors and learn more about the Research Institute’s administrative support for investigators. To learn more about the CHOP Research Administration Fellowship and how to apply, see the CHOP Research training site.

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Jul 15 2015

Steven Douglas, MD, Honored as Paradigm Builder in HIV Neurovirology

NeuroVirologyThe way viruses can infect the nervous system is at the heart of neurovirology, an important field of study that includes not only neuroscience and virology, but also molecular biology and immunology.

Steven D. Douglas, MD, chief of the Section of Immunology at The Children’s Hospital of Philadelphia, has spent the last 40 years investigating the biology of immune cells, with particular relevance to potential treatment for human immunodeficiency virus (HIV) infection. His research has encompassed basic studies of cell biology, identification of mechanisms of HIV infection, and conducting clinical trials in HIV-infected patients.

As a result of his seminal work, last month Dr. Douglas received the Lectureship Award from the International Society for NeuroVirology (ISNV). The Lectureship Award recognizes a leading investigator for a systematic body of scientific research in neurovirology.

Dr. Douglas delivered the Paradigm Builder Lecture to the ISNV in June at the organization’s 13th annual symposium. The lectureship specifically highlights “the establishment of well-defined scientific frameworks within which theories, laws, generalizations, and supporting experiments are formulated and planned.”

“Dr. Douglas has been in the forefront of research in immunology,” according to a statement on the ISNV website. For the past 35 years, he has been at The Children’s Hospital of Philadelphia and at the University of Pennsylvania, where he is a professor of Pediatrics in the Perelman School of Medicine.

Starting in the late 1970s, Dr. Douglas established laboratory methods for investigating two types of immune cells: monoctyes and macrophages. Those cell culture methods have enabled laboratory research throughout the world. Dr. Douglas was among the first scientists to discover that HIV-1 infects macrophages derived from monocytes. He first showed that an important chemical, substance P, exists on these cells, and that it plays a crucial role in neurological manifestations of AIDS. He then identified a pathway shared by substance P and a particular cell receptor as a potential target for treating HIV infection.

Dr. Douglas has received continuous research funding for the past four decades from various centers within the National Institutes of Health. Currently, he is collaborating with co-investigators from Temple University in a joint $4.3 million NeuroAIDS grant from the National Institute of Mental Health. This grant funds research on new methods to eradicate HIV that lurks in brain cells despite conventional antiviral treatments.

The Paradigm Lectureship Award citation notes that “Dr. Douglas’ research has intersected the disciplines of psychiatry, immunology, neurology and AIDS.” Although Dr. Douglas’ previous honors, research publications, and memberships on scientific committees are too numerous to mention, he currently serves as a member of the Scientific Oversight Leadership Committee for the International Maternal Pediatric Adolescent AIDS Clinical Trials.

Dr. Douglas is the seventh scientist to receive the Paradigm Lectureship Award, established in 2006.

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Jul 14 2015

Trends in Antipsychotic Use Among Youth in Foster Care Raise Concerns

AntipsychoticAntipsychotics are a powerful class of medications that increasingly have been prescribed to children to treat disruptive behaviors, particularly for those in foster care. The trend is a disturbing one that has the attention of Pennsylvania state officials.

Researchers from PolicyLab at The Children’s Hospital of Philadelphia performed an in-depth analysis of data from Pennsylvania’s Medicaid program spanning the years 2007 to 2010 and 2012, with a specific focus on foster children between the ages of 3 to 18, at the request of the Commonwealth of Pennsylvania Department of Human Services (DHS). The research focused on the use of psychotropic medications, polypharmacy, off-label psychotropic medication, and behavioral health services.

Psychotropic medications are a class of drugs that is used to treat or manage mental health symptoms or challenging behaviors. Antipsychotic medications, which are primarily used to manage psychosis in serious mental illnesses such as schizophrenia and bipolar disorder, fall under this category. Since they can have significant side effects, antipsychotics should be prescribed under careful consideration and subject to ongoing monitoring over time.

“While data supports the use of antipsychotic medication for aggressive behaviors associated with several behavioral health diagnoses, there is little efficacy data to support use for more routine behavior problems in the absence of aggression,” the investigators noted in their report, “Psychotropic Medication Use by Pennsylvania Children in Foster Care and Enrolled in Medicaid: An Analysis of Children Ages 3-18 Years.”

The PolicyLab investigators found that between 2002 and 2007, there were 354,000 Medicaid-enrolled children ages 3 to 18 using antipsychotics, which was an increase of 62 percent. Although psychotropic medication use, including antipsychotics, was lower in 2012 compared with the four prior years of observation, the authors noted that the rates are still high.

Here are some of report’s key findings:

  • For youth ages 6 to 18 in 2012, the use of psychotropic medications was nearly three times higher among youth in foster care than youth in Medicaid overall (prescribed at 43 percent versus 16 percent).
  • The use of antipsychotics was four times higher among youth in foster care (22 percent) than youth in Medicaid overall (5 percent).
  • More than half of youth antipsychotic users in Medicaid had a diagnosis of attention deficit hyperactivity disorder. The majority of these youth did not have another diagnosis that clinically indicated the use of antipsychotics.

“We commend the Department for recognizing this critical issue, and for working with PolicyLab and stakeholders throughout the state to develop recommendations to respond to this problem,” stated Kathleen Noonan, one of the study’s authors and founding co-director at CHOP’s PolicyLab. “While we know that many children benefit from medication, we also need to invest in proven alternatives, since too many children continue to be prescribed medications for non-approved indications.”

In light of the concerns identified from PolicyLab’s research and analysis, the investigators made several recommendations in their report. One suggestion is for DHS to expand investments in and reimbursements of non-pharmacological behavioral health interventions. Another is DHS should incorporate more robust psychotropic medication oversight and develop comprehensive guidance on psychotropic medication prescribing for children and youth, especially those in foster care. For more information on DHS’ response to the recommendations, see the press release.

The report, two years in the making, was funded by Casey Family Programs.


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Jul 09 2015

Researchers Aim to Find New Pathway Interactions in Colorectal Cancers

colorectal cancerColorectal cancer mainly exists in people older than 50, but it also can occur in young adults who have a genetic condition called familial adenomatous polyposis (FAP). Polyps can begin to form inside the intestinal tract during their teen years. If FAP is not diagnosed and treated, they have almost a 100 percent chance of developing colorectal cancer.

While FAP is uncommon, understanding its genetic basis could lead researchers at The Children’s Hospital of Philadelphia to better approaches to several kinds of pediatric cancers. In a new study funded by the National Cancer Institute, Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology, and colleagues aim to identify subsets of patients who potentially would benefit the most from emerging drugs targeting pathways that are important to colorectal cancer development.

“It’s a study that harnesses the power of cancer genomics and links it to cancer biology and cancer therapeutics,” Dr. Thomas-Tikhonenko said.

Previously, scientists had identified mutations occurring in the APC gene that could lead to FAP and other types of colorectal cancer. An important target of the APC pathway is an oncogene called MYC that as a result becomes hyperactive. Oncogenes play major roles in initiating and maintaining tumor growth. In addition to colorectal cancers, MYC has been implicated in cancers of the cervix, breast, lung, stomach, and pediatric neuroblastoma. MYC has a broad reach, and it is especially good at helping tumors to make blood vessels that are needed for oxygen and energy.

Dr. Thomas-Tikhonenko’s laboratory has dedicated many years of research to studying how MYC works in the context of cancer cell biology and how it interacts with the unique combinations of genetic alterations that appear in colorectal tumors. The Cancer Genome Atlas (TCGA) project, a publicly available catalog of genetic mutations and deletions discovered by scientists worldwide, reported in 2012 that no less than two dozen genes were mutated in a significant number of colorectal cases.

The study team is leveraging data from these cancer genome studies to determine whether or not some of these mutations are redundant, or epistatic. Basically, epistasis is the idea that one gene depends on a second gene because the two genes control a common function. The researchers hypothesize that when a cancer mutation occurs, it picks only one of the genes at work in the same pathway.

Think of epistasis as a series of landmarks along several avenues that all point to the same destination. A roadblock appears at one of the landmarks, diverting traffic. It would be redundant to erect more roadblocks at landmarks further down the same route. Instead, by strategically placing roadblocks on other avenues, the cancer can block normal organ development more efficiently and in doing so direct different aspects of tumor formation and growth.

“What we’re saying is cancer is parsimonious by nature: It doesn’t tolerate redundant mutations; they all happen for a reason,” Dr. Thomas-Tikhonenko explained. “There is stringent selection for useful mutations.”

In the case of a colorectal tumor, the researchers propose that late-stage mutations in the gene called transforming growth factor beta (TGFβ) might be influenced by seemingly unrelated earlier mutations in MYC, typically found in early-stage cancers. They have shown that TGFβ loss helps tumors to build blood vessels, just as MYC hyperactivation does. Since both drive the same tumor trait, could they be epistatic? Indeed, extensive TCGA data mining revealed that MYC and TGFβ mutations almost never occur together. Conversely, some mutations always seem to co-exist in colorectal tumors, which suggests that the mutations likely act on different, complementary pathways. This analysis was performed in collaboration with Pichai Raman, a bioinformatics scientist from the new Department of Biomedical and Health Informatics at CHOP, and Adam Bass, MD, from the Dana-Farber Cancer Institute in Boston.

Identifying which mutations occur in the same pathway and which occur in parallel is useful because it could help researchers to preselect patients who are likely to respond to certain drug therapeutics. For example, Dr. Thomas-Tikhonenko and his study team will investigate how to maximize impact of drugs within two subtypes of colorectal cancer, called chromosomal instability (CIN) and microsatellite instability (MSI). FAP falls under the CIN class.

Patients with MSI frequently have TGFβ mutations, but they are rare in patients with CIN; MYC mutations generally follow the opposite pattern. Since TGFβ and MYC mutations do not usually appear in the same tumors, the researchers predict that drugs that effectively target MYC could be helpful for FAP but would not have the same impact on patients with MSI.

“The idea is to develop an algorithm that would allow you to use this information in a way that predicts response to therapy,” said Dr. Thomas-Tikhonenko, who also is a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

By the completion of the five-year grant, he expects that scientists will have a new vantage point for colorectal cancer development and treatment. Dr. Thomas-Tikhonenko is looking forward to collaborating on the project with Struan Grant, PhD, a human genetics researcher at CHOP and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

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