By day’s end, Callie Weatherford, the Florence, S.C., girl clutching a worn stuffed animal named Lamby, will have become just the second child in the world to receive the full treatment, taking pediatric medicine in a new direction against an old foe.

But before all that, before the procedure begins on this morning in mid-July, Callie draws a picture of a vanilla ice cream bar dipped in chocolate as she waits with her mother in the radiology department at Children’s National Hospital in Washington. Ahead lies her third and final encounter with an emerging medical technology known as low-intensity focused ultrasound.

The technique is being tested for safety and effectiveness in clinical trials at Children’s National and at two medical centers in Toronto. They are among more than two dozen trials across the globe trying various methods to treat diffuse intrinsic pontine glioma, or DIPG, a childhood cancer that strikes 1 to 2 of every 100,000 people. It is almost uniformly fatal.

“There are a lot of unknowns” to be confronted in the clinical trials, according to Hasan Syed, Callie’s neurosurgeon and co-director of the focused ultrasound program at Children’s National. Although focused ultrasound has proved safe in adults with brain tumors since 2015, doctors cannot rule out the possibility that it might cause undesirable side effects in children.

Callie knows only this: Inside her brain lurks something that isn’t supposed to be there.

“This is your last treatment,” Stephanie Weatherford tells her daughter. Callie smiles up at her and asks, “What else we got?”

At 8:15 a.m., as she rests in bed, medical staffers place the mask over her face. The anesthetic begins to flow. Her eyes close — the 44th time this year she has been sedated.

“Night-night, gorgeous,” says Adriana Fonseca, her pediatric neuro-oncologist.

Stephanie and Callie’s father, Joey, watch, their faces betraying a sense of worry that their daughter’s never does. “I don’t think she completely understands what she’s up against,” Stephanie says.

Using bubbles to reach the brain

Doctors rate the DIPG tumor among the very worst.

“It takes no prisoners. It universally kills kids,” said Mark M. Souweidane, director of pediatric neurosurgery at NewYork-Presbyterian and Weill Cornell Medicine.

DIPG became widely known in the 1960s as the tumor that killed Karen “Muffie” Armstrong, the 2-year-old daughter of astronaut Neil Armstrong. She died in 1962, seven years before her father became the first man to walk on the moon. In the past 60 years, medicine has made little progress against the cancer that killed Muffie.

“A kid who walked into the emergency room this morning with DIPG doesn’t have a very different treatment or a very different life expectancy from a kid who walked into the ER in the 1970s” with the same tumor, said Nicholas Vitanza, a pediatric neuro-oncologist at Seattle Children’s Hospital and associate professor at the University of Washington.

DIPG becomes entangled in the brain stem, making it inoperable most of the time. Drugs have difficulty even reaching the tumor. Blocking the way are tightly packed cells inside the brain’s blood vessels that keep out toxins. Doctors call this the blood-brain barrier. While radiation can improve DIPG symptoms briefly, in virtually all cases the tumor starts to grow again within six to 12 months.

Just 10 percent of children live two years after diagnosis with DIPG; 2 percent make it to five years, according to a 2018 study in the Journal of Clinical Oncology.

There is new hope, however, thanks to Callie’s clinical trial and to others testing a variety of treatments.

“I don’t know if I’ve become blinded, but I’m wonderfully optimistic,” Souweidane said, explaining that the most effective response to DIPG may involve a combination of therapies.

About 25 years ago, when he began treating DIPG patients, “nothing was being done in the lab or at conferences,” Souweidane said. He saw the situation change as many parents who’d lost children to the tumor established foundations in their memory. Those foundations raised money for research and trials.

The clinical trial that Callie joined will cost an estimated $1 million overall — roughly $50,000 to $100,000 per treatment, according to Roger Packer, who directs the Brain Tumor Institute at Children’s National. Funders include an anonymous donor to the hospital, along with the Focused Ultrasound Foundation, a tax-exempt organization based in Charlottesville that promotes medical use of the technology.

Insurance has covered all of Callie’s medical expenses. Even so, the Weatherfords spend about $500 for gas, meals and hotels each time they make the trip from South Carolina to D.C. — a not inconsiderable sum for Stephanie, a reading teacher, and Joey, a steelworker.

A first in the nation

The family’s introduction to DIPG was swift and brutal.

On New Year’s weekend, while at home in Florence, Stephanie noticed that her daughter’s right eye kept drifting inward, as if she was trying to look at her nose. An eye doctor ordered a CT scan “to rule out the scary stuff.” The scan was taken on a Wednesday, and on that Friday, Callie and her parents were sent to a hospital in Charleston to get an MRI.

On the two-hour drive, Callie’s mom explained that when doctors looked at the first pictures they noticed something growing in her brain. It wasn’t supposed to be there, but it happens to other kids, too, sometimes. Callie was not alone.

In Charleston, the MRI came back on Jan. 14. The doctor said that Callie had DIPG. Sitting there in the doctor’s office, Stephanie kept repeating the letters in her head. As soon as they left, she plugged them into an internet search on her phone and read the description on Wikipedia.

“Do not Google that,” she told her husband. “Don’t do it.”

But he couldn’t help himself. The first sentence he read included the word “fatal.”

Four days later, Callie and her parents were on a plane to St. Jude Children’s Research Hospital in Memphis. Her little brother, Joseph, 3, stayed home with his grandparents.

The radiation treatments at St. Jude’s stretched from Feb. 2 to March 15; there were 30 in all. Radiation shrank Callie’s tumor to approximately 30 cubic centimeters, about the size of a large marshmallow or a small plum. But the Weatherfords knew it could start to grow again.

Just two weeks into the treatments, they began working with Lauren Kirages. A “nurse navigator” based in Indianapolis, Kirages helps families of children with DIPG find clinical trials. Many families, she said, have been given little hope, advised by their doctors “to go home and make memories.”

The Weatherfords began with a list of 15 trials. They weighed the potential benefits of each treatment against the harm it might do to Callie’s quality of life. They wanted an approach that would be new and promising, but not make her “super, super sick,” Stephanie said. They resisted anything that would require surgery.

Callie had concerns of her own, some harder to address. One night as she prepared for bed, she asked her mom, “What happens if I die, and this thing is still in my brain?” Not knowing exactly what to say, Stephanie told her: “Everything will still be the same.”

The Weatherfords narrowed their list to four trials. They decided against a popular clinical trial in Seattle. Too far away. They preferred the focused ultrasound study at Children’s National, a seven-hour drive from their home in South Carolina. During a video chat with Fonseca, Stephanie asked, “How many kids have done this?”

“She’ll be the first,” Fonseca said.

The answer both terrified and cheered Stephanie. Doctors were going to try something on her daughter that they’d never done before. But Callie could become the first success, the leap forward that brings hope to other children with DIPG.

As it turned out, a child in Toronto became the first in the world to undergo the new treatment. Callie would become the second.

She was not anxious. She told her parents, “I like it when they put me to sleep because I get to sleep really long. I can taste the medicine and everything gets blurry.”

The ‘next frontier’ for ultrasound

Best known for its swirling black-and-white images of the developing fetus, ultrasound technology has become a booming area of medicine.

The Food and Drug Administration has approved the use of focused ultrasound to treat seven conditions, including cancer that has spread into the bones, Parkinson’s disease and prostate cancer. The technology is in various stages of development and testing for more than 160 other medical conditions, including congestive heart failure, traumatic brain injuries, arthritis, glaucoma and schizophrenia.

“We’re trying to target areas of the brain involved in depression and anxiety” with focused ultrasound, said Noah S. Philip, a professor of psychiatry and human behavior at Brown University. Philip is working on the first human tests to see if focused ultrasound can calm the brain’s fight-or-flight response centered in the amygdala.

“This noninvasively gets us to parts of the brain that are inaccessible,” he said. “It allows us to do something that is really unprecedented.”

While focused ultrasound has been used to treat cancers in the prostate, breast and other organs, none of those are encased in bone, said Nir Lipsman, a neurosurgeon at Toronto’s Sunnybrook Hospital, which is collaborating on a DIPG clinical trial with another medical center in Toronto.

“The brain,” Lipsman said, “is the next frontier.”

Moreover, Callie’s trial marks the first time focused ultrasound has been used on the brain stem, which is responsible for crucial functions such as breathing, heart rate and balance, Lipsman said. “There’s basically no margin for error.”

After Callie’s first treatment on May 18, “we watched her like a hawk,” Stephanie said. The family stayed in Washington for a week just in case. Callie experienced none of the nausea or other side effects that typically follow chemotherapy.

About five days after the treatment, the Weatherfords toured the Lincoln Memorial and Washington Monument. Callie walked for miles, tiring little, Stephanie said.

The second treatment, on June 15, also went smoothly. The family spent July Fourth and the days leading up to the holiday at a house on South Carolina’s Lake Marion owned by Stephanie’s parents. One of Callie’s friends had run a lemonade stand and used the money to buy gifts for her, including heart-shaped BFF necklaces.

Callie swam and tested how long she could hold her breath underwater.

Still, Stephanie noticed changes. Callie fell asleep around lunchtime one day, early for a nap. She’d been napping more often since doctors began treating her tumor.

In summers past, she’d loved to ride an inner tube as a motorboat pulled it, splashing over the waves. This summer she was too frightened to try.

One day, as Stephanie watched Callie singing and dancing at one end of a pontoon boat, she could not stop herself from wondering: Will this be her last summer?

Clearing the way for the Red Devil

On July 13, with Callie anesthetized, hospital staffers place a metal frame over her to keep her head in place, then a rubber membrane containing water through which the sound waves will travel on their way into her brain.

At 8:41 a.m., they wheel her into the MRI room and position her head inside the helmet and the scanner. The MRI beams images of her brain back to a room filled with monitors. There, doctors map the precise locations and intensity levels of the sound waves to be aimed at Callie’s brain. Twice, they return to the MRI room to make small adjustments to the helmet.

“Because of the sensitive nature of the brain stem, we have to have millimeter precision,” explained Syed, her neurosurgeon at Children’s National. A minor inaccuracy, and Callie could suffer double vision or difficulty speaking.

Nurses carry blankets fresh from the warmer and lay them over Callie. The MRI room must be kept cold for the machine’s magnets to function properly, and nurses monitor patients for hypothermia, a potentially dangerous drop in body temperature.

One final step must be taken before doctors can trigger the sound waves and attempt to open the blood-brain barrier. Fonseca prepares a vial containing tiny microbubbles, each less than one-hundredth of a millimeter in diameter, thinner than a human hair.

At 10:19 a.m., Fonseca starts the flow of microbubbles through an intravenous line in Callie’s arm, and they circulate through her body. Five minutes later, doctors begin directing the sound waves into the tumor, stimulating the bubbles so that they ricochet around inside the blood vessels of the brain. The pinballing bubbles cause the vessels to widen, creating temporary gaps in the blood-brain barrier.

Around noon, the focused ultrasound procedure finishes and doctors examine new MRI images, checking to make sure the blood-brain barrier inside the tumor has opened.

Finally, at 2 p.m., doctors administer a bright red liquid, the chemotherapy drug doxorubicin, known as the Red Devil both for its color and harsh side effects, such as severe nausea, vomiting and even possible heart muscle damage.

Later, Callie wakes up feeling groggy and sees her parents at her bedside. She looks at her mom and makes a kissy noise.

That night she is sick from the chemo. She cannot take anti-nausea medicine because it can worsen the doxorubicin side effects that involve the heart rate. Within a day, however, Callie feels better. Her energy and appetite return.

A few weeks later she loses her first tooth, just like any child her age.

Subtle but promising signs

“You’re getting taller,” Stephanie says.

On Aug. 8, about 3½ weeks after Callie’s last treatment with focused ultrasound, a nurse at Children’s National weighs and measures her following her latest MRI.

Callie is 4-foot-1 and 56 pounds. She has just started first grade.

That weekend, Callie went to two birthday parties, one at a gym, where Stephanie watched her daughter fall twice on the padded floor. She has been struggling with her balance.

Now, the Weatherfords wait nervously to learn what the new MRI has revealed.

The only patient to complete the clinical trial before Callie, a 7-year-old girl treated at Sunnybrook Hospital in Toronto, has gained strength in the six months since her last treatment, said James T. Rutka, her neurosurgeon. Her tumor has remained the same size.

Fonseca reviews the new MRI scans, then meets the Weatherfords in an exam room. The tumor, the doctor says, “looks maybe a little bit smaller. But I’m an optimist.” She compares the latest scan with others taken weeks and months earlier. In one area, she says, the new scan “looks a little bit less bumpy.” Other regions contain subtle signs that the tumor might have shrunk.

“We don’t expect it to be totally gone,” Fonseca says. “I do think there are very subtle changes that are positive.”

“What do we do now?” Stephanie asks.

Seven months into her fight against DIPG, Callie has finished the focused ultrasound trial. If the tumor starts to grow again, she can join a different clinical trial. The main option is the one in Seattle, 2,500 miles away. Already this year, the family has put 11,000 miles on Stephanie’s car.

Fonseca says no decision has to be made at that moment. The family can decide in the coming weeks, or wait for the results from Callie’s next MRI in two months.

The doctor asks if they have any more questions.

“I think I’ve asked all of my big questions,” Stephanie says.

Callie, who has been playing silently with her mom’s cellphone, mutters to herself: “Really big ones.”