Author: Nancy Fliesler

Pediatric brain tumor responding well to melanoma drug, targeting a shared mutation

low grade glioma dabrafenib

When Danny Powers showed gross motor delays and poor balance as a toddler, early intervention specialists told his mother, Christi, that the problem was likely weak muscle tone. But when Danny developed severe headaches at age 4 during a family vacation, Christi took him to a local emergency room, where a CT scan revealed a mass in his head. His eventual diagnosis back home in Massachusetts was low-grade glioma, the most common pediatric brain tumor.

Fortunately, low-grade gliomas are non-malignant, slow-growing and highly curable, and most children can look forward to decades of survival. Unfortunately, the standard treatment — chemotherapy and, in some cases, radiation, in addition to surgery — is toxic and can damage the developing brain and body. Moreover, the tumors often regrow, requiring retreatment. By the time Danny was 13, he had been treated twice with surgery and once with a year of chemotherapy, which Mark Kieran, MD, PhD, clinical director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, likens to carpet bombing.

Instead of undergoing another course of chemotherapy when his tumor regrew yet again, Danny entered a clinical trial of a new, targeted drug that acts more like a guided missile — aimed directly at his cancer-causing mutation. 

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Real-time contextual information could help doctors interpret children’s brain scans

Radiologists who can tune in to the nuances of brain scans in children are a pretty rarified group. Only about 3 percent of U.S. radiologists, some 800 to 900 physicians, practice in pediatrics. Those specifically trained in pediatric neuroradiology are even scarcer.

To a less trained eye, normal developmental changes in a child’s brain may be misinterpreted as abnormal on MRI. Conversely, a complex brain disorder can sometimes appear normal. That’s especially true when the abnormality affects both sides of the brain equally (see sidebar).

It can be hard to find the cause of a child’s developmental delay without a proper read. “Pediatric brain scans of children under age 4 can be particularly tricky to read because the brain is rapidly developing during this period,” says Sanjay Prabhu, MBBS, a pediatric neuroradiologist at Boston Children’s Hospital. “If you’re looking at adult scans all the time, it’s incredibly difficult to transition to pediatric scans and understand what is considered ‘normal’ and ‘abnormal.’ Clinicians often wonder, ‘Should I repeat the scan? Should I send the patient to a specialist?’”

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Antisense drug for spinal muscular atrophy nears the clinic

spinal muscular atrophy
Max High of South Carolina was diagnosed with SMA before the age of 1. (Ron Brinson/Flickr)

In recent weeks, two Phase III clinical trials have shown a clear benefit of nusinersen in children with spinal muscular atrophy (SMA), a genetic motor neuron disease that robs children of muscle control and is the leading genetic cause of infant mortality. The ENDEAR trial, involving infants with the more severe SMA Type 1, was first to terminate randomization. The CHERISH trial, involving older children with milder Type 2 SMA, was halted on November 8 because it also met its efficacy target.

Both trials are now open-label, and the FDA has granted nusinersen a priority review. The drug, formerly called SMNRx and now brand-named Spinraza, is an antisense oligonucleotide works by altering gene splicing (see sidebar).

Vector asked Basil Darras, MD, director of the Spinal Muscular Atrophy Program at Boston Children’s Hospital, to put these developments in perspective. Darras is site principal investigator at Boston Children’s for both trials. The hospital was the first in the world to enroll a child with SMA Type 1 in the ENDEAR study, in 2014.

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger et al).

A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.

In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically.

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Parents are generally open to placebo use in children – with caveats

placebo use in children

Placebos are a key ingredient of any controlled clinical trial, the yardstick against which experimental drugs are measured. Placebos are also increasingly used as a treatment in their own right, as studies show that they make people feel better through a “mind-body” effect. But do parents find placebos acceptable for their children? A study published today by The Journal of Pediatricsled by Boston Children’s Hospital, found the answer is mostly yes, provided ethical guidelines are followed.

“The question of placebos is more complex when it comes to children, since parents must make medical decisions on their behalf,” says Vanda Faria, PhD, a research fellow at Boston Children’s Hospital’s Center for Pain and the Brain and first author on the study. “Large placebo responses have been seen in a variety of pediatric conditions, and parent’s perceptions can influence how well placebos work. At the same time, little is still known about the potential harms of prolonged drug therapy on children’s development. Sometimes, the best intervention might not involve pharmacotherapy.”

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If I have the mutation, will I get the disease? New research looks at genetic ‘penetrance’

genetic penetranceRecently announced preliminary results of the BabySeq study included pathogenic or “likely pathogenic” variants linked to heart conditions in three apparently healthy babies. Two are being followed at Boston Children’s Hospital and have had cardiac testing. But is this testing necessary, and are these infants truly at risk? It’s too soon to tell.

Then, last week, a report from the Mayo Clinic raised an alarm about overzealous use of genetic testing in healthy individuals. After a 13-year-old boy died from a heart syndrome, about two dozen family members had genetic testing. All tested positive for variants in a gene linked to long-QT syndrome and were diagnosed with the disease. Yet none had cardiac symptoms, and only one had a positive EKG at any point — the boy’s brother, who had a defibrillator implanted. When the Mayo team reanalyzed the test results using a more up-to-date genetic database, they concluded the variant is harmless.

And this week, in Science Translational Medicine, researchers at Brigham and Women’s Hospital, Boston Children’s and Massachusetts General Hospital address the question: If people carry a genetic mutation linked to a condition, what are the chances they will develop that condition over time? As part of the genomes2people project, the researchers tested participants in two long-term population studies — the Framingham Heart Study and the Jackson Heart Study — for 56 genes representing 24 hereditary cancer and cardiac syndromes. They did not know the participants’ actual health status. As it turned out, carrying a mutation increased risk for the related disease 4.7-fold in African Americans and 6.4-fold in European Americans, who had longer follow-up. This was true regardless of family history.

Vector sat down with Nina Gold, MD, a senior resident in Pediatrics and Medical Genetics at Boston Children’s, for her perspective. Gold is a first author on this week’s report.

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It’s not just how long teens sleep, but when, that’s important to self-regulation

teen sleep

Chronic insufficient sleep is at epidemic levels in U.S. teens. It’s been associated with depression, substance use, accidents and academic failure. But according to a survey of some 2,000 7th to 12th graders in Fairfax County, VA, the number of hours of sleep isn’t the core problem. It’s being a “night owl” — unable to fall asleep until late at night.

Forced to get up early for school, night owls are in a state of chronic “jet lag” on school days. And that can lead to poor self-regulation, or an inability to alter thinking, emotions and behaviors to meet varying social demands, finds the study, published last week by Pediatrics.

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News Notes: Research and innovation news

A few things that caught Vector’s eye during the week:

FDA drug evaluation staff: An unmet need

overflowing inbox at FDA

New laws or initiatives to expedite drug approvals, especially for orphan drugs, have prompted the Food and Drug Administration to create new positions to review the applications. Unfortunately, these slots are proving hard to fill. Kaiser Health News reports that the FDA has more than 700 job vacancies in its Center for Drug Evaluation and Research (CDER), which approves new drugs. The problem? Pharma pays more — “roughly twice as much as we can,” said CDER director Janet Woodcock at a recent rare-disease summit. The 21st Century Cures Act, still awaiting Senate approval, could help by allowing the FDA to offer higher salaries and relaxing postgraduate degree requirements for some positions.

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Placental MRI to monitor fetal health?

Placental MRI

Prenatal ultrasounds monitor fetal health in part by gauging blood flow from mother to fetus through the placenta. But researchers at MIT, Boston Children’s Hospital and Massachusetts General Hospital are diving deeper with magnetic resonance imaging. They’re taking advantage of MRI’s ability to measure oxygen concentrations in the placenta and fetal organs.

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BabySeq: Early results of newborn genomic sequencing are mixed

BabySeq
While a previous study indicated parents were very interested in newborn sequencing, just 7 percent of those approached have enrolled in BabySeq so far.

It seems like a great idea. We all have our genomes sequenced at birth, and any findings that suggest a future medical problem are addressed with early interventions, optimizing our health and extending our lives. But are parents of newborns ready to embrace the vision? Yes and no, according to interim results of a first-of-its-kind randomized trial of newborn sequencing. Findings from what’s known as the BabySeq Project were presented last week at the American Society of Human Genetics (ASHG) 2016 Annual Meeting.

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