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Pediatrics, Research, Stanford News, Stem Cells

Near approval: A stem cell gene therapy developed by Stanford researcher

Near approval: A stem cell gene therapy developed by Stanford researcher

It has been a momentous month for Stanford researcher Maria Grazia Roncarolo, MD. Following decades of research in Roncarolo’s lab and the clinic, pharmaceutical company Glaxo SmithKline has applied for final approval by European Medicines Agency (EMA) of a treatment she developed to cure a deadly childhood immune disorder. If approved by the EMA, which is Europe’s equivalent of the U.S. Food and Drug Administration (FDA), the treatment would be the first gene stem cell therapy to be granted approval by a major medical regulatory agency.

The therapy cures a disease called severe combined immune deficiency (SCID), sometimes called the “bubble boy disease,” by inserting a gene into blood stem cells and transplanting the stem cells into the patient’s body. The treatment is still being evaluated by the FDA.

My greatest satisfaction is that kids who were once incurable now have options

If approved, the treatment will no longer be considered an experimental therapy in Europe, and “people will be able to get this treatment as they would any other, and will be able to get their insurance company to pay for it,” Roncarolo told me. The final regulatory review marks the beginning of a new era in which genetically modified stem cells might be used to treat or cure a wide variety of human diseases, she also noted.

Roncarolo developed the treatment while she was scientific director at the San Raffaele Scientific Institute in Milan, Italy. There, she treated kids who were born with an inability to make the enzyme adenosine deaminase (ADA), which leaves them unable to make certain immune cells that protect them from infection. For that reason, children with ADA-SCID are forced to spend their lives in a sterile environment that protects them from infections that most people would easily fight off but are deadly for them.

Roncarolo and her team inserted the gene for ADA into blood stem cells which were transplanted into 18 children with the disease. Once the modified blood stem cells could produce the enzyme, they were able to form the necessary immune cells and the children were able to leave their sterile environment. “Those children have been effectively cured,” Roncarolo said.

Other gene therapies have been developed before, but those therapies modified more mature cells that cannot reproduce themselves. Only stem cells can both make more copies of themselves and also produce more specialized cells. If gene therapy is used to modify cells that are not stem cells, the treatment will only last as long as the cells last. Eventually, mature cells age and die, and the disorder returns.

Last year, Roncarolo was recruited to Stanford to continue her work while serving as co-director of the Institute for Stem Cell Biology and Regenerative Medicine. She is busy researching cures for other congenital immune disorders and developing methods that could lead to stem cell treatments for a wide variety of other diseases.

“My greatest satisfaction is that kids who were once incurable now have options,” Roncarolo said.

Previously: Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

Patient Care, Pediatrics, Research, Stanford News, Technology

A new tool for tracking harm in hospitalized children

A new tool for tracking harm in hospitalized children

Medical-chartsIn the 15 years since the Institute of Medicine issued its groundbreaking report showing frequent harm caused by medical care, researchers have worked to devise efficient, reliable ways to detect harm to patients. Finding out what aspects of care most often hurt patients is a key step in reducing these harms, but voluntary reports, in which caregivers are asked to document harm they cause, only identify a small percentage of total harms.

New research published today in Pediatrics describes a better approach for tracking harm to kids in hospitals. Using the system on 600 medical charts from six U.S. children’s hospitals, the researchers found that almost 25 percent of patients included in the chart review had experienced at least one harm, and that 45 percent of these harms were probably preventable. The approach, called a “trigger tool,” was based on a similar harm-tracking method designed for hospitalized adult patients. Researchers look at each medical chart for “triggers” – events or lab measurements often associated with harm – and when they find a trigger, explore the medical chart in detail around the time of the trigger to see if harm occurred.

“This tool will allow us to better understand the epidemiology of harm in hospitalized children, as well as give us the capacity to track harms over time to determine if our interventions are making an improvement,” said senior study author Paul Sharek, MD, an associate professor of pediatrics and chief clinical patient safety officer at Lucile Packard Children’s Hospital Stanford and Stanford Children’s Health. He collaborated with scientists from several other institutions on the research.

I talked with Sharek last week about the study’s findings and implications. To start, I asked him to give me an example that would help me understand the difference between preventable and non-preventable harm. A child who receives a medication that provokes an allergic reaction has experienced a non-preventable harm if it’s the first time the child ever got the drug, and there were no clues beforehand that she had the allergy, he told me. But if the drug allergy was already known and the patient got the drug anyway and had an allergic reaction, that is a preventable harm.

The high rate of preventable harms shows that there is a lot of room to make all hospitals safer for kids, Sharek said. One surprise in the data was that nine common healthcare-acquired conditions that have been targeted by national safety efforts – including central line-associated bloodstream infections, ventilator-associated pneumonia and surgical site infections – together accounted for only 4 percent of all harms identified in this study. “If we were able to eliminate every one of these, according to these data, we’d still be left with 96 percent of the harms we identified,” Sharek said.

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Cancer, Neuroscience, Pediatrics, Research, Stanford News, Videos

How one family’s generosity helped advance research on the deadliest childhood brain tumor

How one family’s generosity helped advance research on the deadliest childhood brain tumor

Back in February 2014, Libby and Tony Kranz found themselves at the center of every parent’s worst nightmare. Their six-year-old daughter Jennifer died just four months after being diagnosed with diffused intrinsic pontine glioma (DIPG), an incurable and fatal brain tumor. At the time, the Kranzes decided to generously donate their daughter’s brain to research in hopes that scientists could hopefully develop more effective treatments for DIPG, which affects 200-400 school-aged children in the United States annually and has a five-year survival rate of less than 1 percent.

As reported in the above Bay Area Proud segment, Michelle Monje, MD, PhD, an assistant professor of neurology and neurological sciences who sees patients at Lucile Packard Children’s Hospital Stanford, and colleagues harvested Jennifer’s tumor and successfully created a line of DIPG stem cells, one of only 16 in existence in the world. More from the story:

Using Jennifer’s stem cell lines and others, Monje and her team tested dozens of existing chemotherapy drugs to see if any were effective against DIPG. One appears to be working.

The drug was able to slow the growth of a DIPG tumor in a laboratory setting. Monje’s hope is that this treatment one day could extend the life of children diagnosed with DIPG by as many as six months.

That would have more than doubled Jennifer’s life expectancy.

“It’s a step in the right direction if we can effectively prolong life and prolong quality of life,” Monje said.

Libby Kranz says that for their family, donating their daughter’s tumor to researchers “just felt right.” She and Tony hope that by aiding the research efforts, parents and families will have more, and better quality time with their sick children.

“It’s incredible and it’s humbling,” she said, “to know my daughter is part of it, and that we’re part of it too.”

Previously: Existing drug shows early promise against deadly childhood brain tumor, Stanford brain tumor research featured on “Bay Area Proud,Emmy nod for film about Stanford brain tumor research – and the little boy who made it possible and Finding hope for rare pediatric brain tumor

Evolution, Parenting, Pediatrics, Research, Women's Health

Just when did it begin to “take a village to raise a child”?

9640826608_e65589c650_zImagine a prehistoric human mother raising her baby outside of any community or family structure, with no help from others. It sure doesn’t fit with my idea of the “village” that raises a child, a phrase I often associate with romantic notions of pre-modern lifestyles. But according to a study done by University of Utah anthropologist Karen Kramer, PhD, if you go far back enough in human evolution, mothers raised their young alone and didn’t feed or care for them past weaning (which happened around 5 or 6 years of age!).

The study, published in the Journal of Human Evolution and interestingly titled “When mothers need others: The impact of hominin life history evolution on cooperative breeding,” examines how humans transitioned into family and community patterns of child rearing. It suggests that the earliest cooperative groups were formed by a mother and many of her children, with older ones helping rear younger siblings; after this was established, other adults were incorporated, probably when bands of mothers with their offspring teamed up. As women became better at reproducing, they needed the extra help.

As noted in a University of Utah press release, this is different from the predominating theories among anthropologists, which point to cooperation among adults. Kramer also comments:

Human mothers are interesting. They’re unlike mothers of many other species because they feed their children after weaning and others help them raise their children. As an anthropologist, I live and work in traditional societies where, like other researchers, I have observed many times that it takes a village to raise a child. Not only do mothers work hard to care for their young, but so do her older children, grandmothers, fathers and other relatives. But this wasn’t always the case.

The consequences for health likely factored into the “economic decision making” that Kramer modeled in her study – children reared cooperatively were more likely to survive, and I imagine mothers garnered more than a few benefits from extra pairs of eyes, ears, hands, and feet, as well.

And another thing this study shows us: Some of the same decisions that parents weigh today – how many children to have, which kind of help to recruit in raising them, and what kind of balance between kids and other pursuits will optimize health – are really not so novel.

Previously: Computing our evolution and Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease
Photo by Jaroslav A. Polak

Ethics, In the News, Patient Care, Pediatrics

Study of outcomes for early preemies highlights complex choices for families and doctors

Study of outcomes for early preemies highlights complex choices for families and doctors

3363144800_8c4c7ee6a5_zA tiny fraction of babies born at 22 weeks of gestation survive to childhood without major impairments or disabilities, according to a study recently published in the New England Journal of Medicine. But, although some of these babies can do well, there is variation between hospitals in the rate at which they are resuscitated after birth.

As was widely reported late last week, the results add to the existing debate about providing the earliest-born preemies with intensive medical care. I talked with Henry Lee, MD, a neonatologist at Lucile Packard Children’s Hospital Stanford, to get his take on the new findings. Doctors who work with tiny preemies and their families aren’t surprised by the study’s results, Lee told me, since the generally poor outcomes for 22-week babies are consistent with other studies. But they are carefully considering what to do next.

“We already knew, to a large extent, that there is variation in how different practitioners and hospitals manage patients in this peri-viable range,” Lee said. “Some hospitals tend to be more aggressive at resuscitating and actively treating these babies, others less so.”

The study’s findings highlight that doctors may have difficulty letting parents make the choice about how to handle the birth of a very early preemie, Lee noted. “We’re supposed to be communicating with parents, and they’re supposed to be making an informed decision,” he said. The variation between hospitals suggests that’s not what is actually happening; if parents were deciding what to do, the rate of resuscitation would be more consistent across hospitals. “This data is telling us that we as medical professionals are making the decision for parents, especially at really young gestational ages,” Lee said. “It’s an area that we need to continue to learn to deal with better.” Hospitals also vary in their capacity to care for such babies, he added.

Physicians from several Bay Area hospitals have already begun meeting to discuss their approaches to the earliest-born preemies, he told me. “We might not practice exactly the same, but we want to understand the rationale for what everyone is doing,” Lee said. “If one group is doing something that makes sense, we could learn from them.”

And the study also brings into focus the difficulty of balancing statistics against an individual family’s situation, Lee added. “These larger population studies help us to counsel families, but one thing I always have to say to them is that there’s uncertainty,” he said. “I tell parents that we don’t know what is going to happen to their baby – ultimately their baby is an individual and we don’t know yet. There is that very huge uncertainty.”

Previously: Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges, Stanford-led study suggests changes to brain scanning guidelines for preemies and Talk to her (or him): Study shows adult talk to preemies aids development
Photo by Sarah Hopkins

Cardiovascular Medicine, Pediatrics, Stanford News, Transplants

Ventricular assist device helps teen graduate from high school

Ventricular assist device helps teen graduate from high school

TJ Balliao verticalWhen 17-year-old TJ Balliao was diagnosed with heart failure earlier this year, his doctors at Lucile Packard Children’s Hospital Stanford told him that he needed to receive a ventricular assist device right away. TJ was experiencing bouts of unstable heart rhythm so serious that medication alone wasn’t enough to keep him alive. The VAD, a pump implanted in his heart to help it move blood through his body, could help him survive long enough to receive a heart transplant.

But something unexpected happened after the surgery to implant TJ’s ventricular assist device. He made a strong recovery – so strong that his cardiologist, David Rosenthal, MD, offered him the opportunity to go home with his VAD, graduate from high school with his class this June, and delay a heart transplant indefinitely.

In a recent story I wrote about TJ’s case, Rosenthal explained how this could benefit TJ not just now, but also in the long run:

“It’s possible that using a VAD to intentionally delay a heart transplant could add to the patient’s total lifespan,” said Rosenthal, who directs the hospital’s pediatric heart failure and transplantation program and is professor of pediatrics at the Stanford University School of Medicine. “Survival after transplant is not as long as the natural lifespan, especially for children.”

The benefits of a VAD are many. It helps patients maintain strength while waiting for a new heart; otherwise, heart failure weakens the body, making recovery from eventual transplant more difficult. When a child is stabilized by use of a VAD, the medical team can be more selective about choosing a donor heart that is an excellent match for the recipient, too. “Plus,” said Rosenthal, “there is some likelihood that a small proportion of patients’ hearts will be able to recover and those children will avoid transplant completely.”

TJ and his medical team aren’t sure if or when he will ultimately move toward getting a heart transplant. But he’s been accepted to San Jose State University to study civil engineering, so he may be in class in the fall with his VAD battery pack at his side.

Previously: Packard Children’s heart transplant family featured tonight on Dateline, Liberated from LVAD support: One patient’s story and Pediatric social worker discusses the emotional side of heart transplants
Photo courtesy of Lucile Packard Children’s Hospital Stanford

Cancer, Pediatrics, Research, Stanford News

Existing drug shows early promise against deadly childhood brain tumor

Existing drug shows early promise against deadly childhood brain tumor

BrainModelAn existing drug may help treat the deadliest form of childhood brain cancer, according to a Stanford-led study published today in Nature Medicine. The findings are the first to show an effect of any FDA-approved drug on the cancer, which is called diffuse intrinsic pontine glioma (DIPG).

The drug, a blood-cancer medication called panobinostat, reduced tumor cell growth in a lab dish and lengthened survival time for mice with the tumor. Stanford’s Michelle Monje, MD, PhD, who led the research, cautioned that panobinostat has not yet been shown to work in children with DIPG. Her team is planning for a closely monitored clinical trial that will track the drug’s effects in DIPG patients.

From our press release about the new study:

The drug repairs a portion of the cellular machinery now known to be defective in DIPG tumor cells, the new research showed. “A key thing that is wrong with DIPG cancer cells gets corrected by panobinostat,” said Monje, who also treats DIPG patients in her role as a pediatric neuro-oncologist at Lucile Packard Children’s Hospital Stanford. However, the new data also showed that some DIPG cells develop resistance to the drug, which means it will likely need to be combined with other drugs to achieve the best results in humans. “I don’t think this is a cure, but I do think it will help,” she said.

The new panobinostat findings are one piece of a larger story about Monje’s efforts to understand DIPG. As we recently reported on Scope, her team has also found that nerve activity — in her study, the nerve firing needed to initiate walking — drives the growth of high-grade gliomas, including DIPG. In that work, the scientists uncovered a piece of the tumor’s molecular workings, called neuroligin-3, that could serve as a target for new drugs.

Neuroligin-3 is distinct from the cellular machinery affected by panobinostat. Ultimately, that’s a good thing, since doctors want to be able to attack the tumor in several ways, with more than one drug. (As an analogy, think of stopping a runaway train: It’ll be easier if you can apply the brakes and cut off the fuel supply.)

In addition to running clinical trials and continuing to study the basic molecular machinery of the tumor, the team plans to use DIPG cells in the lab to screen other drugs in combination with panobinostat. They are also collaborating with many other teams from around the world to try to make a difference in the outcome of this brain tumor, which currently has a five-year survival rate of only about one percent. The federal government’s clinical trials website lists all the trials underway on this tumor, for those who are interested.

“The goal is multimodal treatment to improve outcomes for children with DIPG,” Monje said.

Previously: Brain tumor growth driven by neuronal activity, Stanford-led study finds, Stanford brain tumor research featured on “Bay Area Proud” and New Stanford trial targets rare brain tumor
Photo by GreenFlames09

Events, Global Health, Health Policy, Pediatrics, Stanford News, Videos

Rajiv Shah discusses efforts to end preventable child deaths worldwide at Childx

Rajiv Shah discusses efforts to end preventable child deaths worldwide at Childx

The inaugural Childx conference was held here this month, and video interviews featuring keynote speakers, panelists and moderators are now on the Stanford YouTube channel. To continue the discussion of driving innovation in maternal and child health, we’ll be featuring a selection of the videos this month on Scope.

More than six million children under the age of five die from preventable diseases each year. During this year’s Childx conference, Rajiv Shah, MD, the former administrator of USAID, told the crowd, “I do think it’s possible to end preventable child death.”

In the video above, he explains how innovations in drug development, diagnostics and vaccines are among the solutions that are effectively reducing child mortality rates around the world. But there is still more that can be done. Using global health data to see in real-time where children are dying because of a lack of vaccines and places children are suffering as a result of poor health care, Shah said, could assist in more efficiently directing resources to these areas and other pockets of need. Watch the full interview with Shah to hear more about why he thinks ending preventable child death is achievable in the next 20 years.

Previously: Childx speaker Matthew Gillman discusses obesity prevention, Pediatric health expert Alan Guttmacher outlines key issues facing children’s health today, “It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy and Global health and precision medicine: Highlights from day two of Stanford’s Childx conference

AHCJ15, Ethics, Events, Patient Care, Pediatrics, Pregnancy

Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges

Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges

preemie toesWhen Juniper French was born in April 2011, her mom had been pregnant for 23 weeks and 6 days – a little more than half of a typical 40-week pregnancy. Shortly before her birth, doctors had to try to explain the possible consequences of her very early arrival to her parents.

“Prematurity is a very unusual condition because it can affect any corner of the body or the mind to any degree,” Kelley Benham French, Juniper’s mother, told a group of journalists at the Association of Health Care Journalism 2015 conference this past weekend. French and her husband were informed that, even with intense medical intervention at birth, their daughter had an 80 percent chance of death or morbidity. Not only was that staggering, but their doctors couldn’t be very specific about what this number might mean if Juniper did survive: “We asked, ‘Do you mean life on a ventilator or asthma? Do you mean blindness or a wheelchair?'” French recalled. “They said, ‘We don’t know.'”

These same uncertainties are faced by all parents of babies born near the edge of viability, between 22 and 25 weeks of gestation. French, a reporter, eventually wrote an award-winning series about Juniper for the Tampa Bay Times that explains the swirl of emotions and statistics she and her husband, Tom, had to navigate in deciding to ask their doctors to resuscitate Juniper at birth. As French told the conference attendees, the choice was excruciating; they desperately wanted to be parents but didn’t want their baby to suffer. They wondered if “it might be less selfish to just let her die.”

Two Stanford experts joined French in Friday’s presentation to discuss difficult conversations about very early preemies.

Neonatologist Henry Lee, MD, gave a sampling of the information he must present to parents when he has these conversations as part of his work at Lucile Packard Children’s Hospital Stanford: Not only are these babies at risk of dying, they face daunting early-life medical complications. Lee rattled off a list: retinopathy of prematurity; necrotizing enterocolitis; bronchopulmonary dysplasia; intraventricular hemorrhage. Referring to the last item on this list, he said “You can imagine, talking to a parent, telling them that ‘Your baby is at risk for having bleeding into their brain’ can cause a lot of anxiety. And often this is the patient’s first time meeting this doctor or nurse. They don’t have any relationship, but they’re talking about these weighty matters.”

Stanford obstetrician Amen Ness, MD, added that women in preterm labor are often asked to make critical medical decisions quickly. Do they want steroids to mature the baby’s lungs? Are they OK with receiving a classical c-section to deliver the baby, which produces a large vertical scar that increases the risk of placenta accreta in future pregnancies? How much fetal monitoring do they want?

Most of these decisions would feel more comfortable if the patient had a few days to think things over and could return for later conversations with more questions. “You really need that time but you don’t always have it,” Ness said.

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Ophthalmology, Pediatrics, Research, Stanford News

Eye injuries in children from non-powder guns on the rise, new study says

Eye injuries in children from non-powder guns on the rise, new study says

paintball-2Eye injuries from BB guns, pellet guns and other non-powder firearms have become more common in recent years in U.S. kids, according to a paper published this month by the Journal of the American Association for Pediatric Ophthalmology and Strabismus. 

The study, led by Stanford ophthalmologist Douglas Fredrick, MD, looked at eye injuries from recreational activities that were severe enough to send children to emergency departments between 2002 and 2012. (Fredrick has seen his share of pediatric eye injuries in his work treating kids at Lucile Packard Children’s Hospital Stanford.)

Non-powder guns caused more eye injuries than all other causes put together, including fireworks and such sports as baseball, tennis and hockey. Many of the injuries caused permanent damage to children’s eyesight, though the proportion of kids who had their vision damaged depended on the type of gun that injured them.

The paper found that since 2006, eye injuries from paintball guns, a type of non-powder gun, have dropped off. Face masks worn for paintball are very effective at preventing eye injuries, as the photo above illustrates.

But this good news was offset by increased eye injuries from air guns, which include BB guns, pellet guns and “airsoft” guns that fire lightweight plastic bullets. From a press release issued by the journal:

“These results demonstrate that air guns can cause severe, yet preventable, eye injury among the pediatric population,” explained [Fredrick]. “To reduce rates of pediatric eye injury, both practitioners and air gun companies should promote and lobby for eye safety mandates among all air gun users. Furthermore, changes in state policy to regulate possession and usage of air guns among minors may be warranted to reduce rates of accidental injury.”

Previously: Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing, Study: ER statistics could be used to reduce gun violence and New retinal implant could restore sight
Photo by Victoria Padevit Brown

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