Weight and CHD, Tumor Biology, I-ACT Grant, Mitochondrial Disease Guidelines

As the November chill settles in, warm up to new scientific discoveries and novel projects for improving children’s health from our researchers at Children’s Hospital of Philadelphia. In our roundup of research headlines, we share the latest findings on the biology of pediatric low-grade gliomas – the most common childhood brain tumor – congratulate Christopher Forrest, MD, in his role as co-investigator of a new FDA-funded clinical trials network, and give you the highlights on two new papers from researchers in mitochondrial medicine and cardiology.

New Research Associates CHD Patients’ Weight with Post-Surgery Outcomes 

How does weight affect the outcomes for pediatric patients with congenital heart disease (CHD)? According to new research led by Michael L. O'Byrne, MD, MSCE, a cardiologist at CHOP, children, adolescents, and young adults with CHD may have a higher risk for adverse outcomes after cardiac surgery if they fall under extreme ranges of body mass index (BMI), a calculation based on weight and height. In a study published in Circulation, Dr. O’Byrne (who was at Children’s National Medical Center at the time of the study) and his colleagues conducted a retrospective study of over 18,000 cardiac surgery patients between the ages of 10 and 35 years old. The researchers found that compared to patients of normal weight, both obese patients and severely underweight patients were 1.3 times more likely to have an adverse outcome – including death, longer hospital stays, or wound complications like infections. The nationwide study was the first to examine how BMI affects post-surgery outcomes in children and received support from the National Institutes of Health. 

“This is an observational study with some limitations, but it demonstrates an avenue for research that has the potential to benefit our patients,” said Dr. Byrne in a press release. “The next steps are studies that evaluate the biological mechanisms underlying these associations, paired with clinical studies evaluating whether targeted interventions for obese and underweight patients can help improve outcomes.”

Learn more in the press release.

Distinctions in Tumor Biology Provide Insights for Precision Treatments

Pediatric low-grade gliomas (PLGG) are the most common type of brain tumor in children. Gaining a precise understanding of how PLGG develops can lead to more effective anticancer treatments. Two new studies co-led by researchers at CHOP’s Center for Data Driven Discovery in Biomedicine (D3b) have discovered important biological differences in how mutated genes – specifically the BRAF and CRAF genes of the RAF gene family – combine with other genes to drive PLGG. Mutations in both BRAF and CRAF can cause the gene to combine with a partner gene to express an abnormal fusion protein that results in cancer.

In the first paper, published in Oncogene, a research team led by Adam C. Resnick, PhD, director of D3b, Angela Waanders, MD, director of clinical research for D3b, and Jay Storm, MD, co-director of D3b and division chief of Neurosurgery at CHOP, found that one crucial distinction between BRAF and CRAF is that CRAF-fusions may not respond as well as BRAF-fusions to anticancer drugs called RAF inhibitors.

Complementing that study, the second paper, published in Oncotarget and also co-authored by Drs. Waanders and Storm, revealed biological mechanisms by which RAF-fusion tumors develop drug resistance and suggested a solution might be to use a combination of drugs that bypass the difference in how RAF inhibitors succeed against CRAF-fusions compared to BRAF-fusions.

Parsing the molecular details of tumor subtypes and resistance mechanism allows us to better define the therapeutic landscape as we pursue translational research,” said Dr. Resnick in a press release. “Large-scale clinical sequencing and molecular profiling can better inform collaborative programs such as the National Cancer Institute-Children’s Oncology Group Pediatric MATCH clinical trials and the Pacific Neuro-Oncology Consortium. Our findings in these new studies will advance our clinical efforts to develop more effective, personalized treatments for children.” 

Learn more about the two new papers in the press release.

Dr. Christopher Forrest Co-Investigator for New Clinical Trials Network

Christopher B. Forrest, MD, PhD, pediatrician at CHOP and the principal investigator of PEDSnet, will be the co-investigator of a new global clinical trials network that will strengthen the development of medical devices and treatments for children. The network, which received $1 million in funding for the fiscal year 2017 from the U.S. Food and Drug Administration last week, seeks to fill an unmet need in the healthcare industry as the development of pediatric-specific therapies still lags behind that of similar products for treating adults. The network was launched under a new national nonprofit program, the Institute for Advanced Clinical Trials (I-ACT) for Children, whose goal is to improve the completion and management of pediatric clinical trials by identifying key challenges.

The network will leverage the power of collaboration between itself, the James M. Anderson Center for Health Systems Excellence, Critical Path Institute, the National Capital Consortium for Pediatric Device Innovation and, notable to CHOP, PEDSNet – a national clinical research network led by CHOP that involves eight other children’s hospitals. According to Dr. Forrest, the new I-ACT network will support the development of new pediatric medicine and devices by focusing on planning and strategy, best practices and education, and the management of trials infrastructure.

“This award brings together leaders in pediatric trials innovation from across the public and private sectors in an exciting new clinical trials network, and creates an environment of continuous learning and quality improvement to ensure its sustainability,” said Dr. Forrest in a press release.

Learn more about I-ACT and Dr. Forrest’s involvement in the press release.

Dr. Amy Goldstein Helps Establish New Mitochondrial Disease Guidelines

Mitochondrial disease, a group of conditions that result from inherited dysfunction in our body’s tiny energy-generating cells, can affect nearly every system in the body. When our mitochondria fail us, the disorder often results in multiple co-occurring health conditions that can range from vision problems to cardiac concerns, to neurological issues, and beyond. Physicians who see complex mitochondrial patients can benefit from a standard set of guidelines that can optimize outcomes for individual patients.

In a new paper published in Genetics in Medicine, the Mitochondrial Medicine Society (MMS) sought to provide just that, issuing a set of recommendations for managing and treating patients with mitochondrial disease. Amy Goldstein, MD, newly appointed Clinical Director of the Mitochondrial Medicine Frontier Program and president of MMS, co-led the study. The guidelines cover a broad range of medical specialties including audiology, cardiology, ophthalmology, and more, address medications commonly used to treat mitochondrial diseases, and touch on specific issues that patients might encounter during pregnancy or high-altitude travel. For both clinicians and patients, the recommendations are a much-desired tool: In a TK survey, the MMS found that 99 percent of 200 clinicians surveyed worldwide reported wanting additional guidelines to assist in managing care and according to Dr. Goldstein, families have also asked for a document of recommendations to bring to their own physicians.

“Standards of care are not uniform across centers or clinicians,” Dr. Goldstein said. To take just one example, clinicians need to know how often to order laboratory tests to monitor the health of patients with mitochondrial disease. Our guidelines reflect expert consensus based on our current knowledge of mitochondrial medicine.”

Read more in the press release.

ICYMI

Recently on Cornerstone,we shared exciting news about the launch of the new Penn Center for Health, Devices, and Technology that will support CHOP innovators, gave you some key highlights from the 10^th annual Friedreich’s Ataxia Symposium hosted by the Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence, and spent an exciting (and educational!) day in the life of Joshua Zigmont, RN, BSN, a nurse research coordinator at CHOP.

Catch up on our headlines from our Oct. 20 edition of In the News

• Flaura Winston Joins National Academy of Medicine
• Philadelphia Pediatric Medical Device Consortium Funds Two Pediatric Devices
• CHOP Collaborates With Medline to Reduce IV Insertion Pain
• Dr. Kathleen Sullivan Wins Boyle Scientific Achievement Award

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