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Inside Pediatrics, Nephrology

Improving Renal Transplant Outcomes

Blood pressure is one of the most basic biometrics, taken nearly every time someone visits a health care provider. It’s also one of the most important indicators of kidney problems in both native and transplanted kidneys, with studies suggesting a direct benefit of maintaining normal blood pressures on transplant outcomes.

But taking a child’s blood pressure when they’re seen in clinic provides just a snapshot in time in a non-standard environment that can be associated with high anxiety, said Michael E. Seifert, M.D., a pediatric nephrologist at Children’s of Alabama and the University of Alabama at Birmingham (UAB). That’s why the gold standard for assessing blood pressure control is a 24-hour ambulatory blood pressure monitor, which the Pediatric Kidney Transplant Program strives to perform at least once a year in each eligible patient. The device takes and records blood pressure every 30-60 minutes, providing a slew of important information for clinicians. In fact, studies suggest that ambulatory blood pressures are a better predictor of long-term cardiovascular outcomes than clinic blood pressures.

It can also highlight unique blood pressure patterns in children with transplants that can’t be detected with the occasional clinic visit, such as masked hypertension, when blood pressure is normal in the clinic but high the rest of the day. Or nocturnal hypertension, in which it is only high at night or when the patient is asleep. A normal pattern for blood pressure over a 24-hour period is called nocturnal dipping, where the blood pressure is lower during the nighttime and sleep periods than when patients are awake.

However, when the staff dug into its data, they found that only about 20% to 25% of their eligible patients had had an ambulatory blood pressure monitor in the past year. So they launched a quality improvement project as part of the Improving Renal Outcomes Collaborative (IROC), a learning health system of 32 pediatric kidney transplant centers in the U.S. that share data and best practices in an effort to improve transplant outcomes. The quality improvement project was supported by a Quality Improvement Award from the Kaul Pediatric Research Institute at Children’s of Alabama.

The team already had a weekly pre-visit planning meeting in place that helped prepare for each patient’s needs during the next week of clinics. They used that opportunity to generate lists of patients who had not had the ambulatory blood pressure monitor, and systematically made it a part of the transplant anniversary visits. After just six months, placement rates jumped to over 40%, even throughout the pandemic and telehealth visits.

“We are really proud of our team for being able to improve and sustain that during some pretty challenging conditions,” Seifert said.

Even more important, in about three-fourths of the patients, the ambulatory blood pressures turned up a problem that required intervention.

“We assumed we were doing a great job with this because we’re nephrologists and we have hypertension clinics focused on proper blood pressure measurement and control,” Seifert said. “But until you start looking hard at your data, you can’t presume you’re doing as well as you think you are. We didn’t know we needed to improve until we turned the lens on it.” The project has been so successful other solid organ transplant programs at Children’s are also considering implementing it as part of their cardiovascular risk assessments.

Inside Pediatrics, Neurology & Neurosurgery

Pediatric Neurosurgeon Launches Interactive Website Fostering Global Collaboration

Having partnered over the years with neurosurgeons in Vietnam and Ghana, James Johnston, Jr., M.D., a pediatric neurosurgeon at Children’s of Alabama and the University of Alabama at Birmingham (UAB), knew many in his field who craved this type of global collaboration but didn’t know where to start. That’s why he co-founded an interactive website designed to bring specialists and organizations together to improve the care of surgical patients worldwide.

Known as InterSurgeon (https://intersurgeon.org), the effort is the joint vision of Johnston and British pediatric neurosurgeon William Harkness, M.D., who focused on the stark fact that 80% of the world’s population lacks access to safe, timely and affordable surgical care. The pair, with support from multiple international organizations and Dean Vickers at the University of Alabama at Birmingham (UAB), raised funds to build InterSurgeon to help fill this void. It matches surgeons from disparate locations to not only collaborate, but form a supportive global community of like-minded professionals.

Initially launched with pediatric neurosurgeons in mind, InterSurgeon now also includes members from many other surgical specialties. The free service empowers surgeons, anesthesiologists, allied health professionals and equipment providers to partner on training, education and clinical care as well as share equipment and other resources.

“We’ve tried to create a stand-alone nexus for all players in global surgery to be able to join with others to better collaborate,” said Johnston, also an associate professor of pediatric neurosurgery at UAB.

“The World Health Organization passed a resolution in 2016 that put new emphasis on global surgery training as a major priority for global health,” he said. “We focus so much on infectious diseases, but what’s ended up happening is that the annual morbidity and mortality from surgery worldwide dwarfs all of that. It’s stunning.”

Key partnerships between InterSurgeon and other organizations over the past several years have driven opportunities for collaboration as well as access to surgical education with specialized technology. In addition to the United Nations Institute for Training and Research (UNITAR), partners include the G4 Alliance, which advocates for increased access to safe surgical care; and Ohana One, which has sent “smart glasses” loaded with augmented reality software from Birmingham-based HelpLightning to various sites around the world. This enabled mentor surgeons in developed healthcare systems to virtually interact in real time with mentees performing surgery for training purposes.

 With procedural competence integral to the specialty, surgery requires “a certain amount of infrastructure, and a lot of that has lagged worldwide,” Johnston noted. “But even in places with equipment, the quality of surgical training is not always as good as it could be.”

 With more than 600 members in 95 countries and growing, InterSurgeon aims to “shore up” that gap.            

“It’s a very difficult problem, and no one thing will solve it,” Johnston said. “But in surgery, it’s very important to connect experts and institutions with learners to bring them up to speed and improve the quality of the surgery they’re doing.”     

Inside Pediatrics, Neurology & Neurosurgery

Probing the Molecular Underpinnings of Undiagnosed Muscle Disorders

The Jerry Lewis fundraising telethons of yore educated many people about myopathies, the most famous of which – muscular dystrophy – highlights the often-progressive and disabling muscle weakness afflicting these children. But up to 10% of myopathy cases seen by Michael Lopez, M.D., Ph.D., a Children’s of Alabama pediatric neuromuscular physician-scientist, are undiagnosable, despite comprehensive evaluation.

This dilemma has driven Lopez, also an assistant professor of pediatric neurology at the University of Alabama at Birmingham (UAB), to collaborate with colleagues to use whole genome and RNA-Seq sequencing to potentially solve such cases. Lopez has enrolled 10 patients and their families into innovative clinical research aiming to reveal the molecular basis of undiagnosed myopathies in hopes of offering affected patients a prognosis and steering them toward effective treatments.

“In a small sliver of patients, I’m convinced they have a myopathy but am unable to refine their diagnosis and give clarity on what type,” Lopez explained. “In that group of kids, in which I’m pretty sure the cause is genetic and everything else is ruled out, we end up in this diagnostic odyssey.”

To tackle this problem, Lopez joined with UAB’s Liz Worthey, Ph.D., director of the Center for Genomic Data Sciences, and Matthew Alexander, Ph.D., an assistant professor of pediatric neurology. Using simple blood draws from parents and children and next-generation gene sequencing techniques, the trio hope to identify new genes responsible for muscle disorders or previously unreported variants of uncertain significance, dubbed VUS, in genes already known to cause myopathies. These mutations can be inserted into animal models to build evidence that a specific VUS triggers the condition.

“This allows us to get a snapshot of all the mutations possible in the genome, not excluding places that turn genes on and off,” Lopez said. “Data can help us support or refute a disease-causing mechanism for the VUS.”

Lopez is well aware the project won’t produce quick answers, and participating families also understand the findings may not benefit them personally.

“But it is possible to come back with a molecular diagnosis,” he said. “If we find something that’s already well-understood, that would offer them some treatment options if they’re already available.”

 Longer-term, Lopez hopes the research will point toward targeted treatments for these muscle disorders, some of which might be derived by repurposing old drugs in “off-the-shelf libraries.”            

“Treatment is just one goal, a second is resolving the diagnosis and solving the case,” he said. “That’s a huge burden relieved for both family and patient. And another piece is the science – to improve our understanding of how these diseases occur and how the muscle functions.”

Inside Pediatrics, Pulmonology

Study Shows Long-Term Effectiveness of Ivacaftor in Children and Adults with Cystic Fibrosis

The world of cystic fibrosis was radically changed in 2012 with the approval of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, which targets certain genetic mutations responsible for the disease. Now, a recently published study by the Cystic Fibrosis Foundation’s multi-center Observational Study in People with CF with the G551D Mutation (GOAL) trial (conducted through the Therapeutics Development Network and funded through the Cystic Fibrosis Foundation) finds that ivacaftor remains effective for at least 5.5 years. Study investigators included Children’s of Alabama pediatric pulmonologist Jennifer S. Guimbellot, M.D., Ph.D, Scott Sagel, M.D., Ph.D., at the University of Colorado, and Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama Birmingham (UAB), as well as other GOAL investigators,

The study followed patients who participated in the drug’s original six-month study. Although a small study with 96 participants, 81% continued as throughout the study duration. “To follow them over five years is a big feat,” said Guimbellot. But it allowed the team to understand whether ivacaftor is helpful with long-term use.

While the study found the drug remained effective overall, with clinically important improvements in lung function, pulmonary exacerbations, quality of life, weight gain, and P. aeruginosa infection, there were some differences based on age and baseline lung function. Adults and those with lower baseline lung function experienced greater improvements in lung function at 5.5 years than children and those with higher baseline lung function. As might be expected, quality-of-life improvement was greater in and more sustained in adults who had lower baseline quality of life scores. Importantly, this was the first study to show quality-of-life improvement beyond 2 years.

Another important finding is that while the overall cohort maintained an average lung function above the pre-ivacaftor level, some continued to experience lung function decline, particularly children. Some also continued to experience infections and remained underweight.

This suggests that “there’s something going on that we need to understand better,” Guimbellot said. “It doesn’t mean that ivacaftor doesn’t work for children; it definitely does work for children. It’s just something we don’t understand and there’s still room for improving care.”

One interesting observation is that while most participants gained weight (in part because they didn’t spend as much metabolic energy fighting the lung disease and attendant infections), some gained an unhealthy amount of weight. “This is something we have to pay attention to,” Guimbellot said. This may include revising the typical high-calorie, high-protein, high-fat diet recommended for certain people with CF to a more balanced diet.

The study is important not only because it shows the long-term effects of ivacaftor, she said, but because it can, hopefully, be extrapolated to the newest approved CTFR, a combination of elexacaftor, ivacaftor, and tezacaftor. Unlike ivacaftor, which is effective for just 4% or 5% of the CF population, this combination, approved in 2019, works in up to 90% of people with the disease.

“As a physician who helps diagnose newborns with cystic fibrosis, I am often asked what parents can expect the child’s lifespan to be,” Guimbellot said. Today the median age of survival is 47, but that doesn’t take into account the effect of the CTFR modulators. “With the new drugs,” she said, “we may see a population of children who don’t have the typical findings of cystic fibrosis as long as they adhere to their therapies.”

Hematology and Oncology, Inside Pediatrics

Membership in Elite Consortium Offers Many Benefits to Researchers, Patients

MEMBERSHIP IN ELITE CONSORTIUM OFFERS MANY BENEFITS TO RESEARCHERS, PATIENTS

            Children’s of Alabama has become the only institution in the state – and among an elite group nationally and internationally – to be accepted into a unique clinical trials consortium focusing on personalized therapy approaches for children with malignant brain tumors.

            Accepted into the Pacific Pediatric Neuro-Oncology Consortium (PNOC) in December 2020, Children’s membership in this distinguished group offers many advantages to researchers, clinicians, and ultimately to young patients, said Girish Dhall, M.D., director of the Division of Pediatric Hematology, Oncology, and Blood & Marrow Transplantation.

            The consortium is comprised of about two dozen sites across the United States, Canada, Europe and Australia. Unlike other consortia, PNOC’s clinical trial portfolio includes neurosurgery trials with techniques such as convection-enhanced delivery, fluorescent agents and advanced imaging compounds.

            “The only way to get access to certain cutting-edge or state-of-the-art clinical trials is to be invited by a drug company working on a multi-institution trial or in trials run by these consortia,” Dhall explained. “This means we have access to a multitude of open trials and our patients don’t have to go out of state to be enrolled in trials testing promising experimental drugs that are not yet FDA-approved.”

            In addition to prestigious trial access, PNOC enables basic and translational scientists at Children’s and University of Alabama at Birmingham (UAB) to propose new trials of candidate drugs or therapies and fosters collaboration among them and researchers at other institutions, said Dhall, who was a founding member of PNOC about eight years ago when based in Los Angeles.

            PNOC is unusual because of its focus on personalized therapies for children with brain tumors that aims to improve survival while reducing toxic, treatment-related side effects, he noted.

            “Traditionally we use chemotherapy or radiation therapy for these cancers, but both just kill rapidly dividing cells and don’t discriminate between cells inside the cancer and cells that might normally be rapidly dividing inside the body,” he said. “The focus has shifted to understanding specifically what makes these cancer cells grow and divide by studying the DNA, RNA and protein inside the cancer cells to develop therapies that improve the efficacy but reduce toxicity to normal cells at the same time.”

            Of PNOC’s current open clinical trials, Children’s will launch its participation in two: One in children with a uniformly fatal tumor called diffuse intrinsic pontine glioma, or DIPG; and another that combines two drugs for children with refractory or recurrent low-grade gliomas, “a population in which this is like a chronic disease and they progress from one therapy to another, so it’s important for them to have multiple options,” Dhall said.

Cardiology, Inside Pediatrics

Planning Complex Heart Surgeries Made Easier with 3D Models

Viewing the heart up close in all its complexity was once only possible during surgery. But specialists at Children’s of Alabama are increasingly tapping the ability to create 3D heart models that help them to better plan intricate surgeries before they take place.

With 3D printing technology becoming far less expensive since its creation about a decade ago, Children’s has been printing hearts for about two years. The arrival of Christian Tan, M.D., a PGY-5 pediatric cardiology fellow at University of Alabama at Birmingham (UAB), has prompted an uptick in its use as he collaborates with specialists in Radiology and Imaging, which operates Children’s 3D printer.

“This provides an additional way for us as providers to assess and look at the anatomy of the heart,” Tan explained. “It gives you different insight when you’re actually able to hold and look at a model and see it from many different perspectives. We can do some of that with digital 3D constructions from CT scans, but it’s different when you can manipulate the heart with your hands and see it from any vantage point.”

Using various materials, including a harder, plastic resin and a softer, rubber-like substance, Children’s 3D printer produces models that realistically portray the heart itself along with outside structures such as the aortic arch and pulmonary arteries, Tan said.

The printer cost several thousand dollars, but 3D heart models cost around $12 apiece to produce, he noted. For a recent surgery on a newborn, the 3D model helped cardiac surgeons determine which pathway from the left ventricle to the great arteries would work best for the repair needed. Specialists at Children’s perform about 450 such surgeries each year on patients born with congenital heart defects.

“It helps the surgeon with some mental planning for the surgery, and it helps the cardiologist understand the anatomy better so when it’s explained to the surgeon, the findings are clearer,” Tan said.

Parents also appreciate the ability to “see” their children’s hearts, he added.

“This also helps us explain the anatomy to parents, especially those with no medical background,” Tan said. “It can be hard to understand the difficult problems these kids have.”

“I think it’s very meaningful to the parents,” he added. “In addition to being an educational tool, parents find it a way to connect to their children when they can see their kid’s heart.”

Inside Pediatrics, Pulmonology

Using Mobile Health To Improve Cystic Fibrosis Care

Gabriela Oates, Ph.D., assistant professor pulmonary and sleep medicine at UAB and Children’s of Alabama, is working to develop a mobile app to to help young children, adolescents and their families manage cystic fibrosis.

It’s not easy living with cystic fibrosis (CF). The multitude of medications, therapies and nutritional supplements that children and adolescents with the disease require can be exhausting and overwhelming, leading to high rates of nonadherence, particularly in adolescents. That’s why Gabriela Oates, Ph.D., an assistant professor of pulmonary and sleep medicine in the University of Alabama at Birmingham (UAB) Department of Pediatrics at Children’s of Alabama, is working to create a mobile health application designed to bridge the gap between what is and what should be when it comes to managing the disease.

The application builds on one developed in Sweden, which 65 to 87% of CF families in that country now use. Called Genia, the app is used to track symptoms, activities and aspects of daily care and share them with the clinical team.

In modifying Genia for the U.S., Oates and her team didn’t rely on what they thought it should look like. They turned to the experts, holding five focus groups with adolescents with CF, families of younger children with CF and the clinicians who care for them. The approach is called “health care service coproduction” and its central tenet is getting buy-in from both clinicians and patients. It’s part of the movement away from the paternalistic view of health and medicine in which the doctor alone drives the process.

The focus groups showed differences between what the clinicians wanted the app to do and what the families and patients asked for, something Oates said the team expected. “The clinicians don’t have the lived experience of managing the disease on a daily basis; our patients and families provided that. However, the clinicians told us what’s necessary to make it work in the clinic; capturing just the patient perspective would have led to an app that’s not workable in the clinical setting.”

Among the changes the focus group participants requested and the team implemented were adding a mental health tracker, making other trackers (i.e., nutrition, medication, physical activity) more specific, syncing the app with calendars and customizing the app with avatars, images and colors.

One thing parents wanted that the adolescents didn’t: the ability to see their child’s entries. On this point, the team decided that the account holder gets to determine the privacy setting and each family decides who the account holder is. “This is normal,” said Oates. “Our children are supposed to become independent and take over the management of their own health condition.”

She and her team are currently conducting a pilot study about the impact of the app’s use on clinical outcomes, with results expected later this year. So far, they are getting high praise from physicians, families and patients. For instance, the patients/families love that they can use the app to submit pre-visit reports instead of completing long paper forms in the waiting room. The clinical team, on the other hand, appreciates having a detailed view of patients’ symptoms or struggles before seeing them in clinic; it helps them understand what’s going on in their patients’ lives and better tailor treatment plans. The app also flags potential problems and shares them with the CF care team on a weekly basis, which allows for earlier intervention.

With the help of the Children’s CF care team, Oates hopes to transition Genia from research settings to a standard of care. Recently, the app was translated to Spanish and made available for both Android and Apple devices. This will allow it to reach a larger segment of CF families to help them manage daily care and better integrate their experiences in treatment plans.

Inside Pediatrics, Pulmonology

When It Takes A Village: A Unique Multidisciplinary Team For Aerodigestive Disease And Complex Conditions

Children’s of Alabama pediatric pulmonologist Tom Harris, M.D., left, and Reed Dimmitt, M.D., MSPH, right, director of the UAB Division of Pediatric Gastroenterology, are among the multidisciplinary team members who make up Children’s Aerodigestive Clinic.

Break down the word “aerodigestive” and you can understand why the condition is so complex and intertwined. Children with aerodigestive conditions often have overlapping disorders involving the upper airway, larynx, trachea, esophagus and lungs, all of which originally developed embryonically from a common source.

One patient may have symptoms affecting multiple systems. At most pediatric hospitals, each condition is treated separately; subspecialists typically focus on the organ of their expertise and not the child holistically.

At Children’s of Alabama’s Aerodigestive Clinic, families don’t need to make multiple appointments and repeated trips to the hospital to see a slew of medical professionals. Instead, they can see a multidisciplinary team of pediatric subspecialists during a single clinic visit and receive coordinated care. Children’s Aerodigestive Program is the only one in Alabama and one of just a few around the country.

“We felt there was a big gap in care, and that led to frustrations that maybe we weren’t meeting their needs,” explained clinic coordinator Ashley Chapman of why Children’s started the program. Chapman focuses on improving communication and facilitating access.

The result of better care has improved both patient and provider satisfaction. “Families appreciate that they don’t feel ‘bounced’ around the medical system,” said pediatric gastroenterologist Reed Dimmitt, M.D.

“Our team is a fun, collaborative group,” added pediatric pulmonologist Tom Harris, M.D. “Previously, we each treated the patients in a general clinic but were limited by our individual skill set. This approach allows us to lean on one another’s expertise, asking, ‘How can we improve care by working together?’”

Consider the triple endoscopy (direct laryngoscopy bronchoscopy, flexible bronchoscopy and esophagogastroduodenoscopy) with the ENT surgeon, pulmonologist and gastroenterologist all in the procedure room. Before, patients would need three separate procedures, requiring three times under general anesthesia with separate interpretations. Now, the three physicians meet together with the family post-procedure to discuss findings and deliver the management plan.

“It’s an additive model, but there’s also a synergy that occurs with everyone meeting together, which contributes to better outcomes,” said Dimmitt. “Collaborating with the multidisciplinary team,” he said, “pushes me to think outside the GI box.” The aerodigestive coordinator, speech pathologist and dietician are central to management plans, providing additional non-M.D. layers of coordination, expertise and pragmatic considerations.

The clinic offers in-person as well as telemedicine visits, and is growing fast, with referrals doubling in the past two years. “That’s also led to more complex patients,” added Dimmitt. “To meet these many needs, we spend a lot of time with the parents.”

The team receives referrals from a variety of sources, including inpatient subspecialists, community pediatricians and speech pathologists, among others. “My favorite referrals,” Harris said, “are families telling friends. That’s when we know we have succeeded.”

“What we hear from parents is that they are so thankful for the collaborative care, the time everyone spends and that their concerns are heard,” said Chapman.

Inside Pediatrics, Pulmonology

New Faculty Expands Pulmonary and Sleep Medicine Division

The UAB Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama welcomed two new faculty in July 2020.

The University of Alabama at Birmingham (UAB) School of Medicine Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama continues to expand, with two new faculty joining in July.

Pedro Anis Nourani, M.D., anassistant professor in the division, earned his medical degree at the University of São Paulo and completed his pediatric residency at Texas A&M’s Driscoll Children’s Hospital. He finished his sleep medicine and pulmonary fellowships at UAB and decided to stay.

“It’s definitely the people that work here,” he said of his decision to remain in Birmingham. “The collaboration between everyone, the excellent support from not just the physicians, but everyone in the department. This group has extensive expertise on subspecialities within pulmonary medicine, which provides good support for someone just starting their career.”

He was drawn to pulmonology medicine, he said, because it’s the “best that pediatrics has to offer.” That includes long-lasting relationships with patients; continuity of care; a strong inpatient presence and the ability to perform procedures. And he was drawn to UAB for his fellowship because of its large pediatric sleep lab. He interviewed at other institutions upon finishing his fellowships, “but there just wasn’t the support and excellence.”

He and his wife have three children, the youngest of whom was born at UAB.

Guillermo Beltran Ale, M.D., an assistant professor in pulmonology, was born and raised in Peru, where attended Universidad Peruana Cayetano Heredia medical school. He completed his pediatric residency at Cincinnati Children’s Hospital Medical Center, then stayed for his pediatric pulmonary fellowship. “I’ve been interested in pulmonology forever,” he said. First because of asthma and cystic fibrosis, with its complex management system and physiology. Then because of the strong bronchoscopy program at Cincinnati and its relationship with chronic ventilator management.

He chose Children’s because it offered a place to grow his skills and continue his research on the pathology of long-term ventilation. He moved to Birmingham with his wife and dog in the summer and started his new career at Children’s July 1.

COVID-19 has, of course, changed the experience of moving to a new city. “We meet a lot of people but we can only see their eyes,” he said. Nonetheless, “we enjoy Birmingham so far.”

Hematology and Oncology, Inside Pediatrics, Neurology & Neurosurgery

Children’s of Alabama Launches Second Groundbreaking Trial of Viral Treatment for Brain Tumors

Children’s of Alabama and the University of Alabama at Birmingham are leading studies using a genetically re-engineered herpes virus to treat pediatric high-grade gliomas.

“A uniformly dismal prognosis.” That’s how Children’s of Alabama neurosurgeon James M. Johnston, Jr., M.D., describes what children with recurrent malignant brain tumors face, with an average lifespan of six months given a lack of effective treatments.

Now Johnston, in collaboration with Greg Friedman, M.D., associate professor of pediatric oncology and director of Developmental Therapeutics at Children’s, is leading groundbreaking studies designed to shift that trajectory. The team recently completed a Phase 1 immunotherapy clinical trial of genetically re-engineered herpes virus G207 to treat pediatric high-grade gliomas. Their work builds on adult research on the viral treatment pioneered by James Markert, M.D., MPH, who chairs the Department of Neurosurgery at the University of Alabama at Birmingham (UAB), as well as Friedman’s laboratory work, which showed the virus was more effective against pediatric brain tumors than adult tumors.

In the past three years, 11 patients with high-grade gliomas have traveled to Children’s from throughout the country, Mexico and Canada to participate in the study. They receive special screening to pinpoint the tumor location, which is then biopsied. Johnston then places three to four catheters in the tumor. The next day, Friedman and his team infuse the genetically-modified virus into the brain through the catheters.

“We think the virus works by directly killing the tumor cells,” Johnston said, as well as activating the immune system to destroy any remaining cells. “Brain tumors have a way to hide from the immune system by making themselves immunologically ‘cold,’” he explained. The herpes virus turns a “cold” tumor into a “hot” tumor and generates the immune response. Indeed, months after the surgery tests show that immune cells have infiltrated the tumor and continue killing tumor cells.

The initial phase 1 trial in patients with high-grade gliomas was designed to demonstrate safety and wasn’t powered to show efficacy. Nonetheless, Johnston said, “our median survival was significantly longer than the historical six months,” with several children now long-term responders.

In late December 2019, the team received a three-year, $750,000 R01 grant from the U.S. Food and Drug Administration for a Phase 1 trial in malignant cerebellar brain tumors, which may be even more sensitive to the virotherapy than the gliomas. At the same time, they are submitting grants for a Phase 2 multicenter trial of the virus therapy for recurrent malignant supratentorial tumors.

Johnston stresses that the research is a team effort, involving basic scientists, oncologists, surgeons, nurses and intensivists. “It’s an ‘all-hands-on-deck’ kind of thing,” he said.