Bench to Bedside

October 2016

New Collaborative Driven by Power of Genetic Medicine and Philanthropy


The power of highly innovative, cutting-edge research in genetics can transform patients’ futures. A key part of advancing this important work is the creation of the new $50 million Roberts Collaborative for Genetics and Individualized Medicine at Children’s Hospital of Philadelphia.

Chief Scientific Officer and Director of the Research Institute, Bryan Wolf, MD, PhD, hosted a special scientific symposium along with CEO of CHOP Madeline Bell Sept. 23 at the Research Institute to announce how this new approach, made possible by a remarkable $25 million gift by the Roberts family, will broaden the scope of genetic medicine across the institution and position it at the forefront of pediatrics genetics research. The Roberts family is committed to bolstering local non-profits focused on improving the quality of life for all Philadelphians, including social services, education, and the arts community.

Eight CHOP scientists spoke at the symposium about their strategies and commitment to individualized medicine. They are finding the genetic basis of complex childhood diseases, creating tools to diagnose those diseases, testing new therapies, and identifying patients who have diseases with unknown etiology and could possibly benefit from uncovering the secrets of their genetic code.

Another superstar speaker was Lainey Moseley, a mother who shared her gratitude for the time, energy, and resources that CHOP clinicians and researchers have devoted to her family. The Moseley’s spent 16 years searching for a diagnosis for their medically fragile daughter, Leta. CHOP medical geneticist Ian Krantz, MD, and his genetics team “didn’t give up on Leta,” and used a breakthrough in sophisticated gene-sequencing technology to identify the genetic basis for her unique constellation of symptoms. In a Nature Genetics article published in 2015, they named the condition CHOPS Syndrome.

“My family has traveled a medically and emotionally challenging road of raising our daughter all these years without a diagnosis,” Lainey Moseley told the audience. “But today, because of the availability of advanced genetic testing, so many families’ lives will be dramatically different than ours.”

Indeed, the discovery that ended the Moseley’s medical odyssey has begun a new journey. So far, 10 children with CHOPS Syndrome have been identified across the world. Clinicians are able to better navigate the clinical issues related to CHOPS Syndrome. Genetic counselors can more effectively help families understand the recurrence risk for themselves and family members. And it is a starting point to work toward precisely tailored therapeutics.

The Roberts Collaborative for Genetics and Individualized Medicine will allow CHOP researchers to continue their relentless pursuit of genetics medicine for more families with other rare, complex diseases. The multidisciplinary collaborations will focus on these core components:

Already, CHOP researchers are making genetic breakthroughs in the fields of inherited disorders, mitochondrial disease, cancer, and autism. In the future, they will aim to expand genomic sequencing capabilities to all newborns, with the hope of one day preventing the onset of pediatric diseases.

“Genomics is revolutionizing what we do in medicine,” said Dr. Krantz, who also is co-director of the Roberts IMGC. “We’re beginning to understand the significance of changes in the genome and leverage it to drive counseling and management of patients and to develop new and targeted therapeutics. We now have a truly individualized approach to medicine.”

See the CHOP press release.

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Removing Roadblocks to Advance Research in Juvenile Spondyloarthritis


Sometimes in medicine, it’s all about the way you look at things. Not noticing a subtle finding on an X-ray, for instance, can result in a missed or delayed diagnosis. On the other hand, radiology overcalls can lead to unnecessary treatments. Large variations often occur in the interpretation of imaging results for children and adolescents suspected of having juvenile spondyloarthritis (JSpA), even by the most experienced radiologists.

Children with JSpA experience inflammation and stiffness of joints that can result in growth disturbances and loss of range of motion if not controlled properly. They tend to develop arthritis of lower extremities and are as at risk of developing arthritis of the lower back or spine (sacroiliac joint). JSpA is associated with more frequent and higher intensity pain and poorer quality of life than other categories of juvenile arthritis. Biological medications, such as anti-tumor necrosis factor agents, can have a beneficial effect on JSpA’s inflammatory features, but clinical evidence supporting their use mostly comes from studies of adult patients.

“There is a critical need not only to accurately diagnose these children, but also to identify the impact of expensive biologics,” said Pamela Weiss, MD, MSCE, an attending physician in the division of Rheumatology at Children’s Hospital of Philadelphia, a core faculty member of the Center for Pediatric Clinical Effectiveness at CHOP, and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Research in JSpA has encountered several roadblocks that Dr. Weiss is starting to chisel away at with the help of an Innovative Research Grant from the Rheumatology Research Foundation, a charitable organization dedicated to advancing treatment for patients living with rheumatic disease.

First, clinicians and researchers lack age and gender reference data for the appearance of the sacroiliac joints in the growing skeleton. The study team will scan 60 children across a range of ages (8 to 18 years) with magnetic resonance imaging (MRI) to compile a detailed assessment of what these joints look like in healthy children. This project aim is “desperately needed in this field,” Dr. Weiss said.

“Even at CHOP, which is one of the top children’s hospitals in the U.S., we encounter variation in terms of how images of the sacroiliac joints are interpreted,” Dr. Weiss said. “If there is variation here, you can imagine that variation may be even greater at other institutions without as much expertise in musculoskeletal imaging. The impact of our research could be far-reaching.”

Early signs of inflammation due to spondyloarthritis do not usually show up on X-rays, and if mild changes do appear, they are easily overlooked. Most radiologists and rheumatologists agree that MRI imaging is a more sensitive tool for detecting early disease inflammation in JSpA, Dr. Weiss said, yet most insurance companies still insist that X-rays be performed first before they will agree to pay for a MRI. Requiring X-rays that are potentially not useful is a costly practice that also subjects young children to unnecessary radiation exposure, Dr. Weiss added.

The study team will assess the overall utility of X-rays in the initial evaluation and management of sacroiliitis by delving into CHOP’s imaging archives from 2005 to 2016. They will review the imaging results of children who were seen by orthopedics or rheumatology for suspected early arthritis of the sacroiliac joints and had a pelvic X-ray and a pelvic MRI performed within six months of each other. The researchers will track the number of sacroiliitis cases that would have been missed by relying solely on X-rays. They also will look out for patients who were identified as being positive on X-rays, but who actually were negative on MRIs.

“It would be enormously helpful to definitely show that X-rays don’t really play a role in screening and evaluating children for early inflammatory sacroiliac disease,” Dr. Weiss said. “That would be practice-changing.”

Another obstacle is that rheumatologists oftentimes must borrow from adult medicine research findings in order to demonstrate to insurance companies the efficacy of biological agents for use in children with JSpA. The study team will partner with the University of Alabama to assess the impact biologics had on a group of children diagnosed with JSpA who also had an MRI prior to or very early in the course of their treatment.

The researchers will try to establish proof of concept that when children with JSpA start biological medication, the inflammation seen on the MRIs improves or completely resolves. The study’s findings will lay the groundwork for future prospective studies to evaluate these changes more objectively and standardly.

By addressing these gaps in knowledge, Dr. Weiss hopes that she will build enthusiasm among other clinicians and scientists to pursue this unique research niche. The current project involves experts from both rheumatology and radiology, and she is excited to collaborate with Nancy Chauvin, MD, director of Musculoskeletal Imaging with the department of Radiology at CHOP, and David Biko, MD, an attending radiologist in the department of Radiology. Together, they will ensure that development of effective and targeted intervention strategies for JSpA to prevent irreversible damage of children’s axial joints does not remain at a standstill.

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Scientists Seek Mitochondrial Mechanism to Overcome Cancer Treatment Resistance


If a cancer cell were an enemy spaceship in a science fiction movie, defeating it would be pretty easy: Just look for the big red self-destruct button and manipulate someone inside into pressing it.

In a sense, this strategy underlies many existing cancer treatments. Though cancer cells don’t technically have a big red button, all of our cells have a built-in self-destruct mechanism. Many cancer treatments, from chemotherapy to radiation to newer targeted immunotherapies, are simply different ways of making a cancer cell experience enough stress to initiate its own self-destruction via this natural process that exists in all the body’s cells.

“If I were a cancer cell, and I wanted to become resistant to treatment, and I wanted to have a life in a setting of abundant stress, I would look for opportunities in which I could change my threshold for how much stress it takes to kill me,” said Michael Hogarty, MD, a pediatric oncologist at Children’s Hospital of Philadelphia and associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

If cancer cells were to raise their stress threshold, they could become broadly resistant to any treatment through a strategy akin to putting ear plugs on the operator of the big red button: No matter where the order to self-destruct comes from, he can’t hear it. Scientists have indeed found repeatedly in many cancers that, after treatment and relapse, no matter what kind of therapy the cancer was initially exposed to, it becomes resistant to most or all other treatment approaches. But early investigations into this phenomenon of broad cancer resistance fell short and largely fell out of favor.

In a new project, Dr. Hogarty and colleagues are focusing on organelles called mitochondria that are in charge of initiating cellular self-destruction. They are seeking ways to keep the big-red-button strategy working even in cancers that have developed broad resistance to therapy.

“Mitochondria are the hub for integrating all these stress signals and regulating programmed cell death, or apoptosis, apart from their role in producing energy,” said Jorida Coku, a cancer biology doctoral student in Dr. Hogarty’s lab who leads the project. “They integrate all these signals from within the cell, such as stress signals resulting from DNA damage caused by chemotherapy or radiation.”

She is building on preliminary work that pointed to a hypothesis about how mitochondrial signaling may be altered in most or all cancer-resistant cells. Several years ago, Dr. Hogarty began by extracting mitochondrial-associated membranes from numerous cancer cell samples in the lab. After exposing them to varied concentrations of different stress signaling molecules, he measured whether the mitochondria then released the characteristic molecular signals of apoptosis.

“That’s a very measurable thing in the mitochondria,” Dr. Hogarty said. “They basically open up their pores and dump all of these death proteins. It’s definitely not like an, ‘Oops, I didn’t mean to do that, can I stay alive?’ It’s a point of no return.”

Through that work, he found three distinct fingerprints or profiles of how different cancer cells’ mitochondria responded to stressors. All the mitochondria that ultimately responded to a stressor with that “death protein dump” did so in one of two distinct patterns. The key finding for the current project was that a third profile comprised all the mitochondria that would not respond to any stress signal at any biologically plausible concentration. Although the signals were shouting to the mitochondria at high volume, they did not initiate the self-destruct sequence. And, it turned out, all of the samples in this third group came from tumors in children who had undergone treatment for cancer and then relapsed.

“It was one of those ‘aha’ moments when you say, I think we’re looking at the whole phenotype of resistance right here,” he said. “It’s at the mitochondria.”

Coku picked up the then-dormant project when she joined Dr. Hogarty’s lab in January 2015 and is now testing the specific hypothesis that the mechanism of this broad resistance phenotype involves the loss of physical tethers connecting mitochondria to another organelle, the endoplasmic reticulum (ER). The ER is an important source of calcium signals to mitochondria that are involved in triggering apoptosis, as well as other signals such as lipid signals.

Although traditional textbook diagrams of a cell show mitochondria floating free within the cell, they are actually physically connected via several types of molecular bridges or tethers to the ER that are pathways for delivering those signals. Dr. Hogarty hypothesized that this tethering was a key factor in cancer therapy resistance based on multiple lines of evidence in his preliminary studies of in vitro mitochondrial membranes which were variably connected to ER membranes in his samples.

Coku’s experiments involve cutting the tethers between mitochondria and ER in therapy-sensitive tumor samples, re-attaching tethers in therapy-resistant tumor samples, and measuring the results. She is also working to elucidate more of the mechanism of how a loss of tethering could change calcium signaling to produce the resistant cancer phenotype, which could lead to finding targets for intervention. This could also allow researchers to develop tools to measure the degree of linkage between ER and mitochondria in patients’ tumors as a proxy for their sensitivity to drugs.

“And, moreover, we could investigate drugs or interventions that might not look like cancer drugs by themselves,” Dr. Hogarty said. “They might be completely incapable of killing a tumor, but by doing something to restore this ER-mitochondrial function in a relapsed cancer, they might make a difference between not responding to the drugs a clinician would choose, and responding again, which would be fabulous.”

An added potential implication of this work is for improved design of clinical trials of investigative cancer treatments, which, for ethical reasons, only enroll patients after relapse when no proven treatment remains. If these patients’ tumors show a phenotype of broad therapy resistance, then most investigative new treatments would seem doomed to fail. Future trial designs might take this factor into account and seek additional or different molecular indicators of a new drug’s activity in tumors, even if it cannot shrink tumors that already have broad resistance, Dr. Hogarty suggested.

“We want to show that this is a model that explains broad therapy resistance in various types of cancers, not only in pediatric cancer, but even in adult cancer,” said Coku, whose master’s thesis research project prior to coming to Penn involved investigating the increased crosstalk between mitochondria and the ER in the context of Alzheimer’s disease — the opposite effect of that hypothesized to have a role in cancer treatment resistance. She noted that findings about these mechanisms in cancer might also inform studies of neurodegenerative disorders.

The team recently received grant support from the National Cancer Institute for the project, and they expect to submit their first manuscript soon.

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Finding of Variability in Antibiotic Prescribing Yields Improvements, Accolades


If you could hire sick children as mystery shoppers, you could learn a lot about care quality and variability in the health system. Imagine sending a child with a common ailment, such as an ear infection, to see a series of unwitting pediatricians, then comparing their performance. Which pediatricians prescribed antibiotics, which ones chose the most appropriate type for that child’s infection, and how many of them fell short of meeting recommendations for when and how to prescribe antimicrobial drugs?

Following these guidelines consistently is key, both for avoiding overtreatment and side effects for children and for preventing resistant bacterial strains. But because individual pediatricians generally work alone, they may not recognize if their regular prescribing habits are less than ideal.

“Even though clinicians often work in large practice groups, the day-to-day practice of medicine in primary care is usually solitary, and that lends itself to variability,” said Jeffrey Gerber, MD, PhD, an attending physician, medical director of the antimicrobial stewardship program, and associate director of the Center for Pediatric Clinical Effectiveness at Children’s Hospital of Philadelphia. “Primary care antibiotic prescribing is probably one of the best templates to look at that because it’s a common, bread-and-butter scenario we can capture in large numbers, and there are only a few diagnoses for which antibiotics are prescribed.”

Since an actual “mystery shopper” study would clearly not be practical or appropriate for the care of real sick children, Dr. Gerber and colleagues used statistical analysis of prescribing data to model that type of scenario instead. Using data from electronic health records across CHOP’s Pediatric Research Consortium (PeRC) primary care practices representing more than 100,000 patient visits for common childhood infections in one year, they adjusted for patient differences so they were statistically the same, with the physician practice as the only variable. This effort was part of a study to identify whether and where there was room for improvement.

The article describing this effort, published in the Journal of the Pediatric Infectious Diseases Society in December 2015, has earned Dr. Gerber the Caroline B. Hall Clinically Innovative Research Award from the Pediatric Infectious Diseases Society (PIDS) Education and Research Foundation, presented during IDWeek 2016, a combined annual scientific meeting of PIDS and several other professional organizations focused on infectious diseases held in October. In recognition of this project and his work more broadly, Dr. Gerber was also selected as Penn Medicine’s 2016 recipient of the Marjorie A. Bowman New Investigator Award for achievements in the health evaluation sciences, which will be presented Nov. 9.

The study’s adjusted analysis showed a threefold variation in whether antibiotics were prescribed, ranging from 18 percent to 36 percent of patient visits among different practices. There was nearly a fourfold variation in prescribing broad-spectrum antibiotics (which are not recommended as a first-line choice for most common infections), ranging from 15 to 58 percent of visits across practices. No matter how they sliced the data — looking only at visits when ear infections were diagnosed, or only sinusitis, for example — the story was the same. Some practices prescribed antibiotics in general, and broad-spectrum antibiotics in particular, far more often than others did. The analyses excluded well visits, patients with chronic conditions, and patients who had been prescribed another antibiotic on a recent prior visit.

For Dr. Gerber, this study was only a first step in more ways than one. The project began while he was wrapping up his fellowship and moving toward his current faculty position, in which he is also an assistant professor of Pediatrics and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania. Working with senior colleagues including Louis Bell, MD, Alex Fiks, MD, MSCERon Keren, MD, MPH, and Theoklis Zaoutis, MD, MSCE, he led the study of prescribing variability which was awarded funding from the U.S. Agency for Healthcare Research and Quality (AHRQ).

“That convinced us that there was an opportunity to try to create an intervention to improve this,” Dr. Gerber said.

In that intervention, participating physicians could see their own and their peers’ rates of antibiotic prescribing based on their electronic health record data. Dr. Gerber and colleagues reasoned that if more physicians could see beyond the walls of their solitary exam room to the prescribing rates of their most adherent colleagues, they would respond to that positive influence. The cluster randomized trial showed that physician practices that received this intervention had substantial improvements in their prescribing compared to other practices. The results were so noteworthy that Dr. Gerber and colleagues published their findings in the Journal of the American Medical Association (JAMA) in 2013, before attempting to publish the initial study of variability.

This next step was also not the end of the story. After physicians in the intervention trial stopped receiving feedback reports, their prescribing practices reverted back to their previous rates — a finding the team reported in a subsequent research letter in JAMA. Recognizing that continuous feedback was key to the intervention’s success, Dr. Gerber partnered with Dr. Keren, who is vice president of quality and chief quality officer at CHOP, and Lisa Biggs, MD, associate chief medical officer of the CHOP Care Network, to translate the intervention into a quality-improvement project.

“It’s an idea that has gone from an exploratory research project to research intervention to something that is now embedded into the culture of CHOP as an ongoing quality initiative thanks to Ron and Lisa’s leadership and the hard work of their group,” Dr. Gerber said. “In every physician practice, we’re now seeing almost 90 percent first-line prescribing of narrow-spectrum antibiotics.”

The project’s influence is extending beyond CHOP as well. The team received additional grant funding from AHRQ to support disseminating the intervention to other hospitals and health systems. Dr. Gerber and colleagues have created a version of the intervention and data collection protocol that can work with any electronic health record. Any practice with a clinician champion or staff who are able to work with data analysis can download the tools for free from the AHRQ website.

“That all started with this first paper,” Dr. Gerber said. “I’m really honored and pleased that PIDS recognized this as important work to help improve outpatient antimicrobial stewardship. We need to do better as researchers to bring the science of stewardship to the implementation stage and disseminate more broadly into primary care, emergency departments, and hospitals across the country.”

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Friedreich’s Ataxia Natural History Study Moves Research Forward


One of the biggest obstacles to advancing the development of therapies for pediatric rare diseases is that oftentimes we do not fully understand how a certain condition progresses in individuals over time. It is like driving someplace with a stalled navigation app and not knowing where to head beyond the next few turns.

Natural history research studies can point researchers in the right direction by providing a roadmap of the course a disease takes through different clinical stages. Knowing what to expect around the corner as a disease manifests allows researchers to establish valid end points for their studies. As they try various routes of investigation and collect data on the way, they can gauge new approaches’ effectiveness and help new drugs reach their final destination — U.S. Food and Drug Administration (FDA) approval.

David Lynch, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia, director of CHOP’s Friedreich’s Ataxia Program, and co-director of the Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence, is the principal investigator of a natural history study conducted by the Collaborative Clinical Research Network in Friedreich’s Ataxia, which is funded by the Friedreich’s Ataxia Research Alliance (FARA). Dr. Lynch and his network colleagues have spent 15 years characterizing and understanding how individuals with Friedreich’s ataxia (FA) change during their lifetimes. Recent findings from the study provide new insights into comorbid medical conditions in FA.

A progressive neuromuscular disease, FA occurs in approximately one in 50,000 people in the U.S. The disease severely affects the flow of sensory information, leading to loss of reflexes, weakness, and poor balance and coordination. For most people with FA, movement problems (ataxia) first appear during childhood and worsen over time. It is caused by an autosomal recessive inherited genetic change (both parents must be carriers of the mutated gene) that silences the FXN gene, which provides instructions for making a protein called frataxin that is necessary for cells’ energy production. No FDA-approved treatments currently are available for FA.

“When we started the natural history study, we realized that to truly move forward with potential drug therapies for Friedreich’s ataxia, we needed to know more about the patient population,” Dr. Lynch said. “We knew a lot at that time about the molecular basis of the disease, but not enough about how we could introduce molecular interventions to patients and prove that they worked.”

The natural history study began with a group of 150 participants with FA gathered by seven medical centers in the U.S., and it has since grown to include a study population base of 850 patients across three continents and 12 sites. Researchers now have a variety of quantitative measures and data on how fast their disease process progresses and what constitutes reasonable improvement in their condition. This information is attractive to pharmaceutical companies interested in developing new drugs to treat FA, said Dr. Lynch, who also is a professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania.

“As a result, we have roughly 20 companies that are actively working on drug trials for Friedreich’s ataxia,” Dr. Lynch said. “It is because of this natural history data that we were able to get people interested in this research. They can understand the confounders of a clinical trial and what factors would make them more likely to be successful.”

For example, results from the natural history study published this year in the Journal of Child Neurology identified two diagnoses that were not traditionally associated with FA that are found at higher frequency in this disease. The prevalence of growth hormone deficiency was 28 times greater in the FA study cohort than the general population. And inflammatory bowel disease (IBD) was 3.5 times more common. As part of the study, the researchers also examined the medications used by patients to confirm the link with IBD.

This new information allows pharmaceutical companies to be more attuned to certain potential adverse events and possible drug interactions when they bring new therapies to market for FA, Dr. Lynch said. On the patient care side, the study findings allow physicians and patients to have a better idea of which medical problems that they observe are truly associated with FA and which are more likely to be coincidental. Other common features of FA that previously have been described medically include cardiac involvement, scoliosis, diabetes mellitus, urinary dysfunction, optic atrophy, and hearing loss.

Adding growth hormone deficiency and IBD to this list will generate new research opportunities within The Friedreich’s Ataxia Center of Excellence into the pathophysiology of FA and its molecular mechanisms. The Center, launched in 2014 with a $3.25 million gift from FARA in partnership with the Hamilton and Finneran families, focuses on expanding research on the cardiology of FA, pursuing new basic research avenues, facilitating drug discovery, and establishing a biomarker development program with the expertise of Ian Blair, PhD, vice chair of Penn’s department of Pharmacology and director of  Penn’s Center for Cancer Pharmacology.

At the ninth annual Friedreich’s Ataxia Symposium held Oct. 17 in King of Prussia, Pa., Dr. Lynch provided patients and families with an update on the Center’s progress. Center researchers have begun to investigate mouse models to help identify the earliest changes that occur in the nervous system in FA. Also, they are completing final data analysis in a phase 3 clinical trial that is looking at a drug that increases frataxin levels. The FDA fast-tracked development of that drug, Actimmune® (interferon gamma-1b, Horizon Pharma Ireland), last year. A small pilot study completed at CHOP showed interferon gamma-1b may have positive effects in children with FA. And CHOP is the principal site for two other ongoing clinical trials, with several more planned for the coming year.

“We expect to have a new form of treatment for Friedreich’s Ataxia within the next several years,” Dr. Lynch said. “While that treatment may not be truly curative, once you start going down that path, the easier it is to make successes. The more you understand, the faster things can move.”

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Project Aims to Automate Adverse Event Reporting in Cancer Clinical Trials


A lot could go wrong in a clinical trial for cancer, even for a treatment that proves effective. Documenting any adverse events thoroughly and accurately — all the bad along with the hoped-for good outcomes — is critically important to show whether there are indeed benefits from a potential new treatment, and whether those benefits are enough to outweigh any potential harms.

Identifying and reporting adverse events in a cancer clinical trial is a laborious process for clinical research assistants. They must manually review patients’ charts to identify symptoms consistent with more than 700 adverse events that are specified in documentation guidelines from the National Cancer Institute (NCI), then report those events via an electronic case report form. Because this process is complex, there is a chance that clinical trials of new therapies might not accurately measure how often patients experience treatment side effects during the study.

“It means that we don’t really have the right information to counsel patients,” said Tamara Miller, MD, MSCE, a pediatric oncologist and instructor in the Division of Oncology at Children’s Hospital of Philadelphia, who led a study published this spring in the Journal of Clinical Oncology evaluating adverse event reporting in two pediatric cancer clinical trials. When expert clinicians reviewed patient charts in detail and compared the adverse events they identified to one of the trials’ published rates, Dr. Miller and colleagues found that the adverse events they studied were underreported.

If such undercounting is common, it has widespread implications for patients. For example, if published studies say that 10 percent of patients who receive a treatment have a certain adverse experience, then underreporting could mean that figure is simply untrue. Providing that potentially inaccurate information to patients and families is harmful because they deserve to know what risks they face to make an informed treatment decision.

“It also makes it hard to compare new drugs,” Dr. Miller added. “If you don’t really know the side effects of an old drug, it’s hard to know if the new drug that comes along is better or worse.”

But Dr. Miller is already at work on a solution, along with her mentor, Richard Aplenc, MD, PhD, MSCE, a pediatric oncologist at CHOP and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. She is leading an innovative effort to make adverse event reporting in cancer clinical trials more accurate and more complete by automating the process with computer algorithms. She recently received the Damon Runyon-Sohn pediatric cancer fellowship award from the Damon Runyon Cancer Research Foundation to support this work.

“It’s a great honor to have been selected,” Dr. Miller said. “It’s going to be a great opportunity to meet all the other fellows and hear what research they are doing.”

The other fellows will also have a chance to learn about what Dr. Miller is doing, which is fairly unusual for pediatric cancer research. Her approach uses primary data collection to electronically capture the adverse events in cancer clinical trials instead of relying on a research staffer’s manual review. The algorithms take the data out of a hospital’s electronic medical record and automatically grade it according to the NCI guidelines.

“By doing this, you take out the human error, you take out the human time that’s required, and you might make a system that’s more universal and more standardized between people, in addition to making it more accurate and more efficient,” Dr. Miller said.

She has already demonstrated the concept with a relatively simple algorithm that identifies and grades adverse events that are measured with lab test results, such as a high potassium reading on a blood test. The new grant extends this work to a whole new level to connect multiple types of data from a patient’s electronic medical record, including laboratory results, radiology data, vital sign data, and even clinician notes. These diverse sources are necessary to piece together relevant information about potential adverse events such as acute respiratory distress syndrome, which can be confirmed only with multiple types of clinical data.

Once these algorithms are developed, Dr. Miller plans to test them both at CHOP and at Texas Children’s Hospital which, as one of the largest children’s hospitals in the country, treats a large population of oncology patients. Testing the algorithms in multiple hospitals will help confirm that the tool is applicable beyond a single site. She and expert colleagues will also perform manual chart reviews to compare the rates at which they identify adverse events to the algorithm-generated rates.

If the algorithms can successfully automate adverse event reporting, this new approach may offer numerous potential benefits, in addition to improving accuracy. Automating the process can reduce the amount of time that clinical research assistants spend on adverse event reporting, allowing them to spend more quality time on other essential aspects of running a clinical trial. The algorithms would also generate robust and granular data sets about clinical trial patients’ adverse events that could be useful for epidemiological studies, similar to population studies that are done on a whole hospital or health network’s electronic medical records — but focused on a cancer clinical trial population. Such studies could address new questions to help improve the design of future clinical trials.

“I think that is one of the things that is unique about this project, that we are really trying to use it as a tool to improve clinical trials, rather than simply gain information,” Dr. Miller said. “We really want to make the trials better, to generate data that is as accurate as possible while also running trials better and more efficiently.”

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In a Teenager’s Brain, HIV Infection Could Cause Unique Damage


From the 1990s to today, a lot has changed. Babies born in that decade are now older adolescents and young adults. “Personal digital assistants” disappeared and were replaced with voice-activated intelligent helpers in our cell phones. Plaid went out of style and then came back again.

The face of the AIDS crisis has dramatically changed in the U.S., too. Then highly stigmatized from its 1980s emergence as a rapidly deadly infection highly transmitted among adult men who have sex with men, today HIV infection is often a manageable chronic disease that affects men and women of all ages. A major frontier now in HIV treatment is the need to handle complications for those already infected, including neurocognitive disorders.

And there is one more significant change: Many of those babies of the 1990s, from teenagers up through age 24, now make up about a quarter of new HIV infections each year, according to Centers for Disease Control and Prevention data. Among high-risk subsets of youth age 13 to 24, the annual incidence of new infections has increased by as much as 87 percent — even though, overall, new HIV infections in the U.S. declined 19 percent over the last decade.

“I would argue that this is really the face of the new epidemic in the United States,” said Jennifer McGuire, MD, a pediatric neurologist specializing in neurologic infections at Children’s Hospital of Philadelphia and assistant professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. McGuire is working to learn more about where two of those national HIV trends intersect with the study of how infection processes might cause age-specific brain changes and cognitive difficulties for young people through mechanisms involving inflammation in the brain. This area is understudied and ripe for new discoveries. No published studies to date focus specifically on neuroimaging data in adolescents with HIV, and published data about cognitive function in this population is also scarce.

“This is a really important question because when teenagers acquire HIV in their mid to late teens, it happens during a very active time of brain development,” Dr. McGuire said. “A lot of people may think that by the time you’re a teenager your brain is fully developed. But, in fact, brain maturation actively continues into the late third decade, particularly in refining areas of logic, abstract thought, planning, and risk assessment.”

Dr. McGuire recently completed a pilot study with 14 young adults with HIV at CHOP. These 18- to 22-year-old participants had measurable cognitive impairments at a rate about as high as that commonly seen in adult HIV populations more broadly, despite having been infected for relatively short periods of time and having healthier immune systems — both indicators that usually predict better cognitive performance among infected adults. MRI brain images from a subset of these youth also showed profoundly lower volumes in specific deep gray matter structures in the brain, compared to age- and sex-matched historical controls without HIV. Studies in adults with HIV had shown volume losses in these brain regions before, but not at such a high magnitude.

“This really prompts us to ask the question, is there some sort of age-specific HIV-mediated neuropathogenesis that’s happening here? And, if so, why?” Dr. McGuire said.

She is continuing to try to answer the first question with a new, five-year prospective study funded by the National Institute of Neurological Disorders and Stroke. The new brain-imaging study will enroll 40 youth from CHOP’s Adolescent HIV Initiative, from Penn, and from Philadelphia FIGHT, who have HIV and no history of cognitive impairment prior to their infection. A novel aspect of the study is its recruitment of a control population of 30 uninfected youth from Philadelphia FIGHT’s community center geared toward HIV prevention and support services for at-risk youth. Youth at the highest risk for acquiring HIV are more likely to be members of disadvantaged and stigmatized groups, including LGBT youth and youth of color, and they are more likely to be exposed to difficulties including poverty, trauma, and illicit drug use. By enrolling youth who share such risk factors and demographics, the researchers can control for the potential influences of these factors on cognitive function to identify whether there are indeed brain changes induced by HIV infection itself that are specific to youth.

While she continues to pursue this question, Dr. McGuire is also performing lab research in an effort to answer her second question: If so, why?

She and colleagues recently published a paper examining one of these possible mechanisms, a part of the innate immune system called the complement system that becomes activated in the body’s periphery when a person becomes infected with HIV. In the healthy brain, the complement system helps prune unneeded neural connections during normal brain maturation in adolescence and early adulthood, so Dr. McGuire and colleagues hypothesized that HIV infection could cause unique neurological damage in youth if it is ramped up in the brain at the time of HIV infection. Their small study, published in the Journal of Neurovirology, offered some preliminary evidence of associations between complement proteins and a biological marker of neurodegeneration in cerebrospinal fluid samples from youth. She is proceeding with a larger study examining expanded immune profiles in an effort to better identify and describe a potential mechanism.

Answering these questions is important to support youth because with antiretroviral medicines, people can live with HIV for decades. If the infection interferes with young people’s brain development, though, it could impede their success with finishing school, getting good jobs, and being functional members of society throughout their lives. In addition, there is a chance that HIV transmission itself might be affected by these neurological impacts if they involve parts of the brain involved in risk assessment and decision making, which are still developing during the teens and early-mid 20s. Knowing the mechanisms and clinical patterns of age-specific neurological damage could lead to new youth-targeted pharmaceutical treatments as well as approaches focused on cognitive rehabilitation.

While she pursues these research questions, Dr. McGuire also continues to help patients in the clinic. Working with infectious disease specialist Sanjeev Swami, MD, she co-leads a new clinical program in neurological infections at CHOP, which may be the first of its kind in the country. The clinic will care for youth with HIV and a variety of other infections affecting the brain and will ultimately integrate clinical care and research.

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Research in Motion to Curb Cell Phone Use While Driving


As you’re driving down the expressway, your cell phone pings, and you glance down at an incoming text message from your best friend. Next thing you know, your car slams the guardrail. The crash leaves you with a severe concussion and a serious lesson learned about distracted driving.

Even though most of us know that using a handheld cell phone while driving is dangerous, we still keep doing it. The availability of more and more of our favorite cell phone functions — texting, checking email, playing music, looking up directions, and posting on social media — poses an ever-present temptation. This is especially true for young drivers, whose adolescent minds are cognitively wired towards instant gratification. A 2015 national survey of 1,243 high school students funded by the National Institutes of Health found that 83 percent reported engaging in electronic device use while driving at least once in the last 30 days.

Researchers at the University of Pennsylvania and the Center for Injury Research and Prevention (CIRP) at Children’s Hospital of Philadelphia have teamed up to study this pervasive problem from multiple vantage points. By advancing distracted driving research, they aim to lower the number of crashes resulting from cell phone use and to encourage teen drivers to focus their attention on the roadway. Their efforts align with the U.S. federal government’s “Healthy People 2020” objectives, which highlight motor vehicle crashes due to distracted driving as the top emerging issue in injury prevention that needs further research, analysis, and monitoring.

Kit Delgado, MD, MS, an emergency physician at the Perelman School of Medicine at Penn, too often has the unfortunate job of telling parents when their teen has been seriously injured or has died from a car crash.

“It’s frustrating when there is not a whole lot you can do as a physician, but it also motivates me to think of ways to prevent these injuries in the first place,” said Dr. Delgado, who also is an investigator with the Center for Health Incentives and Behavioral Economics at the Leonard Davis Institute at Penn. “Teens are inexperienced when they get behind the wheel, and they have this ubiquitous distraction of cell phones, which are the reason why teens are more likely than any other cohort to be killed in distracted driver crashes.”

Dr. Delgado became interested in new smartphone apps that interact with windshield-mounted devices to directly measure cell phone use when vehicles are in motion. These tools can be configured to restrict certain types of cell phone functions, such as texting, while driving. He saw a research opportunity to better understand how implementation of this technology could be used to reduce distracted driving crashes and engage teens and their families in ways that promote better driving behavior. Dr. Delgado has two studies underway called Way to Safety 2.0 and 3.0.

The first feasibility study, which CIRP helped to coordinate, is nearly complete. About 34 novice teen drivers enrolled, and they were assigned to a control group or one of three different cell-phone blocking strategies. An “opt-in” approach required teens to turn on the app when they got in the car, comparable to turning on airplane mode when flying. The app locked the phone screen once the car’s speed reached more than 10 miles per hour. Study participants had the option of overriding the blocking with the touch of a button. The second approach, called “opt out,” also allowed participants to override the blocking, but the difference is that the app activated automatically. A third approach was “opt-out” blocking combined with a disincentive: The parents received an email alert telling them whenever the driver overrode the blocking function.

The second study which has just launched is similar in design but with a slight twist. It involves teen-parent dyads who will enroll in the study together. Based on a previous teen survey, the researchers found that about 75 percent of teens who admitted to texting while driving reported that they have observed their parents doing the same thing.

“We wanted to get around the ‘do as I say not as I do’ phenomenon,” Dr. Delgado said. “We will see if teens’ ability to hold their parents accountable both reduces their cell phone use and the parents’ cell phone use while driving.”

The Way to Safety 3.0 study team will install the tracking and blocking app on both the parent’s cell phone and the teen’s cell phone. They will use the “opt-out” configuration so that the blocking automatically activates at 10 miles per hour. In the first study arm, the parents will receive an email alert when teens override the blocking function. In the second study arm, the teens also will receive an email alert when their parents override the cell-phone block feature.

In future research, Dr. Delgado is interested in seeing if frequently delivered behavioral incentives, or perhaps through the repurposing of discounts on insurance premiums, could facilitate adoption of these technological interventions and motivate drivers to stay engaged in using them as a way for the entire family to reduce cell phone distractions while driving.

Catherine McDonald, PhD, RN, an assistant professor of Nursing in the Family and Community Health Department at Penn’s School of Nursing and a senior fellow with CIRP, also is building a program of research aimed at understanding how and why teen drivers crash. Currently, Dr. McDonald is analyzing data from a randomized control trial in which she tested the feasibility of a web-based intervention that she developed addressing teens’ attitudes, subjective norm beliefs, and perceived behavior control related to driver inattention.

The study involved teens who completed self-report surveys and went through CIRP’s simulated driving assessment. Half of the study participants received the online distracted driving intervention, and both groups returned after three months for a second simulated driving assessment to see if their distracted driving behaviors had changed over time.

During the course of her research in the development of the intervention, Dr. McDonald has realized that it is important for researchers to consider the language that teens use about their cell phone habits. It might seem straightforward to ask, “Do you text and drive?” Yet, a teen who answers, “No,” could assume that the question refers to highway driving and may not consider his frequent texting while waiting at stoplights as dangerous. Dr. McDonald also pointed out that context plays a large role in whether or not teens engage in cell phone use while driving. For example, if an incoming message is from a close social contact, such as a boyfriend or girlfriend, they often feel a greater need to respond. Previous CIRP research has shown that parents are among the biggest offenders in terms of calling teens while they are driving.

By combining what they learn from research on both the technological and educational sides of the problem, the researchers will continue to collaborate on figuring out the best ways to reduce the risky behavior of cell phone use while driving. They hope their findings will gain momentum and lead the way to more funding that will allow them to scale up their distracted driving research on a national level and make bigger inroads to prevent deadly teen crashes.

For more information about these research projects and to learn about the teen/parent Way to Safety 3.0 study, visit here or email

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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