It was a time before Clarence Berger-Greer had begun to wear the rainbow of awareness wristbands on her left wrist. A feeling of peace washed over her as she watched a crowd of medical staff and families stroll along a serpentine path into Kaiser Oakland’s Serenity Garden. National Childhood Cancer Awareness Month was here again and after two years, her little boy Theodore, or “Teddy”, was finally on his way to recovery. He’d beaten miraculous odds by surviving a rare form of cancer that killed over half the children it affected. As if in the rarest of dreams, Teddy was fully alive on this mid-August day, laughing and running as Clarence looked on - indistinguishable from the other healthy children except for his fragile frame and little, bald head. Her child, at long last, had a glimpse of a “normal” life after spending close to a year living in and out of a hospital.

This was before the some of the bands would slowly switch from yellow and pink to black. This was before the little boy, once indistinguishable from the other healthy children, would lie still in his bedroom for hours at a time, crying at the slightest noise. In less than 6 months, Teddy would take his last breaths, lying in between his mother and father at their house in Berkeley, California. The pain that tormented him would wash from his face like a receding wave, replaced by a subtle smile as his gaze broke away from his parents for the last time.

At Teddy’s memorial service, his father Jim spoke to a standing-room only audience. He looked across the room and took a long breath in. “The more I have thought about him and how to process this stunning loss,” he said, “the more I realized that we all have to make a choice in regards to how we honor this little boy. We have to choose what to make of our time with him.”

In the afternoon glow of May 8, 2003, inside her soon-to-be husband’s tour van, Clarence Berger looked out the window at the cedar trees and yellow pines that dressed the Yosemite landscape and smiled. Her dream of making a life together with Jim Greer was finally about to come true. It had been five long years since she first set eyes on Jim, five years since their first date when he snuck her into Kepner’s bar, took her to the village green in his hometown of Hudson, Ohio, and sang to her for the first time. She knew then she wanted to be with him, and now, driving up to their wedding ceremony, with her family just flown in from France beside her, Clarence felt that happiness once again.

Theirs was a small and simple wedding, with drinks and paper plates bought at Costco. Friends came in from all over to witness the marriage of the young musician and the quiet, reserved girl from France. Clarence’s family flew in from the Loire Valley, and Jim’s family from Ohio and Nashville.

While relatives helped set up tables and chairs, Clarence put on the silk dress she’d made with her mother, and Jim donned a black tuxedo. The remains of an unusual May snowstorm shrouded the day in overcast skies, but as the ceremony commenced and the couple prepared to say their vows, the sun slowly broke through the clouds and blanketed the valley in an amber hue. “I only remember feeling the warmth of the sun on my face when I kissed this beautiful girl,” Jim would later write, “who had left behind her whole life and family in France to go on an adventure with me, a self-employed struggling musician.” The moment was so inspiring that three other couples in attendance proposed to each other.

A year later, Clarence would give birth to their first son Leo, and their second son Teddy in 2009. The two boys were innately intuitive, with a constant interest about the world around them. Leo began walking two weeks before his first birthday and spoke full sentences soon afterwards. At one, he knew every single letter of the alphabet.

Teddy, on the other hand, was a quiet, contemplative child. He had lapis blue eyes and bright blond hair. He was a child who appeared outwardly to be young for his age and didn’t begin speaking until he was well into his first year. Yet he possessed an intense focus, sometimes sitting and painting in his room for two hours.  When he did interact with people, he expressed himself through emotions—cries and laughter, facial expressions and movement. Clarence taught him sign language so he was able to communicate the basics: milk, strawberries, pacifier, sleep.

Garth May, now Teddy’s godfather, remembers visiting Jim and Clarence, and meeting their 6-month-old son for the first time. Teddy wasn’t talking yet, but the little boy had a hearty laugh that reminded Garth of a wise, old soul. May told Jim and Clarence he could picture Teddy giving his older brother Leo love advice, despite the four-year age difference between the two. When he was driving back to his home in Yosemite, east along Route 140, through golden hills spotted with Black Oaks, Garth remembers he had an “inescapable feeling he’d met a lifelong friend.”

Seven years later, it was at May’s cabin, where Jim and Clarence had gotten married, that the young parents first noticed that something wasn’t quite right with Teddy.

It had been a “perfect August Yosemite week,” May remembers. Summer had filled the valley with the aroma of wildflowers and the sweetness of bear clover. The couple had brought the boys and Clarence’s nieces to stay in one of the small cabins on May’s property. Cabin #9 wasn’t much of a cabin—more like camping, really. There was just enough space to fit the six of them—Clarence, Jim, Leo, and Teddy, then 16 months old, crowded in one room, and Clarence’s nieces, Nolwen and Emily, in the other. August temperatures climbed to 100 degrees during the day, so the family took short hikes and then swam in the river to cool off. From the beginning of the trip, Teddy appeared increasingly lethargic, as if he were coming down with the flu. He was sleeping more and taking long naps during the day. He usually loved the water, but he started crying whenever Clarence or Jim tried to put him in an inflatable swimming pool.“He was sick as if he had a cold or an ear infection,” says Clarence. “It was just normal toddler stuff.”

Towards the end of the week, Teddy was able to muster enough energy to go to a barn dance one evening, but otherwise he was listless. May would bring him outside to play, but the boy didn’t seem to have enough energy to smile. “Teddy’s just not himself,” he told Jim. “He’s a little off.”

Then Teddy stopped drinking. “That freaked me out because it was so hot outside,” says Clarence. “There was no way, in that heat, that you couldn’t be thirsty. So we packed up and drove back to Berkeley.”

Back home on Derby Street, Jim laid Teddy’s tiny body on top of him. The boy seemed to drape over him like a rag doll, having completely lost any emotional affect. Jim could feel his son’s heart racing against his chest. “I’ve never felt a heart beat that fast before,” he told his wife.

The two called Teddy’s pediatrician and set up an appointment. “I thought he was dehydrated after Yosemite,” Clarence recalled. “Leo would spike fevers all the time when he was a toddler, so we didn’t worry that much. We tried giving [Teddy] Tylenol, but he wouldn’t take it.” When she mentioned the heart rate to the nurse on the phone, the nurse asked her to count the beats. “I can’t keep up with it,” Clarence told her. “It’s too fast.”

By the time she reached the doctor’s office the next morning, Clarence had a difficult time rousing Teddy. His eyelids barely opened at the mention of his name. The pediatrician immediately sent the two over to the Kaiser Richmond emergency room, sensing a much more serious cause.

At the ER, Clarence waited patiently as the triage nurse assessed her son. The nurse had a calming presence. He pressed the rear of his hand to Teddy’s forehead and gently listened to his lungs. Clarence recognized him from a previous hospital visits. He’d been there when Leo needed stitches and when Clarence came down with appendicitis after giving birth to Teddy. But this time, he seemed nervous.

Alarms immediately began going off. The pulse-oximetry machine read 80 percent, indicating that Teddy’s body was severely deprived of oxygen. His heart was pounding far above the normal range for a child of his age, trying in vain to pump oxygen-deprived blood through his body. Teddy also had an extremely high fever. The thermometer blinked at 104. The little boy sat in his mother’s lap, gasping for air.

As the doctors took Teddy back for blood work and a chest x-ray, they peppered Clarence with questions.

How long had he been like this?

Had he been in pain?

Had he run temperatures this high in the past?

She told them exactly what had happened in Yosemite—that he appeared to have the flu or some sort of infection, that the fever was something that seemed to happen overnight. She also explained that since April, the family had noticed Teddy’s appetite increase, a lot. He seemed ravenous at times, yet he didn’t gain any weight.

The doctor returned with the results of the x-ray, and Teddy was rushed to the resuscitation area of the emergency room.

“They told me to call Jim right away,” said Clarence. “As far as I knew, he just had pneumonia.”

Instead, as Jim arrived, doctors explained that Teddy had a massive pleural effusion – fluid build-up that collapsed one lung and shifted Teddy’s heart to the right side of his chest. A pediatric specialist, Dr. Albert Chan, was on his way from Kaiser Oakland to place a chest tube that would drain the fluid compressing his vital organs.

Hours passed. Jim held Teddy down as he screamed from the pain of the chest tube insertion. But soon, his heart rate slowed and he appeared to be more comfortable and alert. The drainage canister below his bed, responsible for evacuating the fluid in his chest, gently bubbled with each tiny exhalation.

Chan started a round of fluids to treat his dehydration and antibiotics to treat any underlying infection. Still, the doctors were unsure of the cause of Teddy’s symptoms? How could a healthy child suddenly become so sick?

The doctors told the family they’d need to keep Teddy in intensive care to observe him. Kaiser Oakland’s Pediatric Intensive Care Unit was full, so a critical-care ambulance transported Clarence and Teddy to the hospital group’s Santa Clara branch. Jim went home to check on Leo and Clarence’s nieces, grab a few clothes, and then head to Kaiser Santa Clara.

By the time they arrived at Santa Clara, it was late in the evening. Teddy was asleep but stable. Clarence had traveled from Richmond in the ambulance with him, her hand softy caressing his face throughout the trip. She finally felt some peace as she watched her son sleep.

Everything’s fine now, she thought.  We’ll only be in the hospital a few days. He’ll be just fine.

A doctor from the Santa Clara ICU sat down with her to review the day’s events.

“So, how much did they tell you about the tumor?” he asked her.

“Oh no. It’s pneumonia or something,” Clarence responded, exhausted.

“They didn’t tell you about the tumor?” the doctor repeated.

Clarence looked at the doctor with tears in her eyes, bowed her head, and threw up.

At 16 months of age, Teddy Berger-Greer had been rushed to the hospital with a high fever, rapid heart rate and a collapsed lung. His symptoms were so alarming that doctors at Kaiser Permanente Richmond initially wore hazardous material suits, fearing the boy carried a contagious infectious disease. What pediatricians had initially thought was pneumonia was actually a large tumor growing inside of his chest. It had progressed from the rear portion of his chest and mushroomed through the bony crevices of his spinal column.

“What went through my head was, ‘This was literally like being in a war,’ says Jim. “You’re on a 24-hour watch. There are a thousand things to do and they’re all important. The surgeon has just gotten shot and someone’s says, ‘We’ve got to take this bullet out of this guy!’ And he points to you. ‘You need to deal with this!’ You can either say, ‘I can’t!’ and just fall apart or say, ‘Ok. I have the scalpel. Where do I cut?’ That was how I got through it all. I was totally Spock about it. Totally logical.”

As the medical staff worked to diagnose his illness, Teddy screamed in fear every time a doctor or nurse came into the room. A central line catheter, providing direct access for medications, hung from his right chest. He was placed inside the giant ring of a CAT scan, and sandwiched in a SPECT bone scan while two giant cameras rotated around him.

A urine test finally confirmed the diagnosis: Teddy had neuroblastoma.

Neuroblastoma is a cancer of the nerves outside of the brain, specifically part of the nervous system responsible for the “fight-flight-freeze” response.

It’s the most common form of solid tumor cancer found in children outside of the brain, but its incidence is quite rare. Of the 13,000 children diagnosed each year with cancer in the United States, only 650 cases are neuroblastoma, with 450 cases falling to the intermediate to high-risk category (1). The name doesn’t have universal recognition like leukemia or lymphoma, and for most physicians, neuroblastoma is one of the cancers they read about in medical school and rarely encounter in their practice. It is one of a handful of cancers that can begin in a fetus before a person is even born.

At birth, Teddy’s health had been perfect, his parents recall; he came into this world without any complications. He had a calm demeanor and was always comfortable around people. “Having Leo around him helped him develop faster,” recalls Clarence, referring to Teddy’s brother, who was then age 5. “He was ahead of his time because of his brother."

But later there were subtle signs that something was amiss. When Teddy was 9 months old, both parents noticed his appetite increase dramatically. Everything they put in front of him, from sweet potatoes to yogurt, he’d gobble up as if he hadn’t eaten in days. “It was shocking considering the amount of food he was eating,” says Jim. “We called him ‘the ogre’ because he was stuffing his mouth all day long.” Teddy would also wake up in the middle of the night crying for no reason. “I thought he was just teething,” says Clarence. “He was doing normal baby stuff.”

At diagnosis, more than half of neuroblastoma patients have cancer that has spread to other parts of their body (2).  Many patients, like Teddy, don’t show signs of the disease until it has spread, which makes it very difficult for physicians to detect it early, when there’s a chance of curing it. There are a few warning signs, but these mimic common childhood illnesses.

Written Sep 23, 2010 2:57pm by Clarence Berger-Greer

Adult cancers are often associated with environmental factors and exposure (3) to carcinogens. Tobacco, for example, has been implicated in many forms of cancer. There is now a clear link between viruses (humanpapilloma virus) and cervical cancer. But in children, oncologists believe that cancer is caused by development gone wrong. When a child’s body is growing, rapid cell growth and division increase the probability of a cancer-causing genetic mutation.

Cells divide all the time, and most genetic mistakes will result in the death of the cell. Even if the DNA makes a replication error, it’s extraordinarily rare for most kinds of cells to become cancerous. The human immune system is designed to specifically identify and destroy abnormal cells. But neural cells, present in the brain and spinal cord, are different. They aren’t designed to divide. Humans are born with a set number of them.

Doctors have determined an association between the onset of a certain type of cancer and a developing body system in children. Oncologists often see nervous system cancers, like brain tumors and neuroblastomas, originate around the time an infant’s nervous system is growing, between the ages of 6 months to one year.  Blood and bone marrow cancers often occur between the ages of 5 and 10, when the immune system is maturing. Similarly, bone tumors happen around the age of 13, when the adolescent growth spurt begins.

There is some evidence that suggests a genetic component may be involved.Scientists have found increased copies of a gene that stimulates cell division (MYCN) in approximately 20 percent of neuroblastoma cases (4)“About 2 percent of children diagnosed are born with a hereditary predisposition,” says Dr. Katherine Matthay, head of the Pediatric Malignancies Program at the University of California San Francisco, who served as an advisor for Teddy’s case. “But it’s very rare that we find that. Most of the time, it just comes out of the blue.”

.

The family began desperately reading everything that offered clues to this mysterious disease. Little information appeared to exist outside of trifling descriptions from hospital pamphlets or analytical papers from medical studies. But eventually their search led them to an online support group called the Association of Cancer Online Resources (ACOR).

Founded in 1996 by Gilles Frydman, ACOR was founded on the premise that coping with cancer lay in a combination of community and expert advice. “It’s impossible to get optimal care in the American medical system today if the patients or the caregivers are not completely informed about their condition,” says Frydman. “It became obvious to me to me that in communities with unusual types of cancers, we needed strength in numbers.”

Frydman was intimately aware of the role of community in medicine. His wife Monica had been diagnosed with breast cancer and was informed her only option was the removal of her entire breast. Through ACOR’s listservs, Frydman learned that Monica was a candidate for a lumpectomy, which spared her the traumatic operation, and discovered communities of deeply engaged people able to recommend doctors, treatments, and provide emotional support.

To the Berger-Greers, the website became a lifeline. “I found this forum and typed, ‘Do some of the children survive?’” says Clarence.

Immediately, her email was inundated with responses from parents around the world.

Yes the messages read.

Of course they survive.

“From that point on,' Clarence remembers, 'there was hope for us.”

Because of its relation with the nervous system, neuroblastoma is particularly hard to treat. A neuroblast is the precursor to the neural tissue that develops into the brain and nervous system. These cells are highly protected by the body, which wants to make sure that they are not affected by toxins. The cell itself is armed with protective mechanisms—proteins and enzymes—primed to eliminate infection and destroy pathogens.

The paradox of having such mechanisms is that when the cells become cancerous, they can elude chemo drugs or other therapies. Oncologists continuously find that after they give patients their first chemotherapy regimen, neuroblastoma cells stop responding to it over time.

For oncologists, chemotherapy is the mainstay drug in the ongoing war against cancer. Chemotherapy drugs target rapidly dividing cells, such as cancer cells, damaging them at the point when they divide, or targeting cells before they split. The result is that cancers that occur in cells that divide rapidly, such as skin and stomach cancers, are highly treatable.

But with some cancer cells, the ability to resist chemotherapy is built into their DNA. Through a peculiar process of self-selection, neuroblastoma cells have the potential to genetically change.

“When you look at the kids I treat with leukemia, I’ll kill 99 percent of the leukemia cells on the first five days of chemo,” says Dr. Steven Bergstrom, one of Teddy’s oncologists at Kaiser Oakland Medical Center. “Those leukemia cells die with what we give them within the first 24 hours. But that’s never true of neuroblastoma. You hack at it. Burn it out with radiation. Attack it with the immune system. There is no chemotherapeutic agent to get rid of the cells that survive. And if they do survive, they will change and alter and grow.”

The surviving cells repair themselves faster. They can rid themselves of the chemotherapeutic agent. They break it down. They pump it out. Some neuroblastomas have even been shown to thrive on certain chemotherapy drugs.

In his book "The Emperor of All Maladies" (5), oncologist Siddhartha Mukherjee describes this phenomenon:

“Some cells acquire mutations that activate molecular pumps. In normal cells, these pumps extrude natural poisons and waste products from a cell’s interior. In cancer cells, these activated pumps push chemotherapy drugs out of the interior of the cell. Spared by chemotherapy, the drug-resistant cells outgrow other cancer cells. Other cancer cells activate proteins that destroy or neutralize drugs.”

Within a week of his diagnosis, Teddy had a combination of chemotherapeutic agents running through his veins. There was hope that the tumor could be surgically removed, but some disease would have to remain interwoven between his fragile nerves and blood vessels. Teddy’s cells also showed amplification the MYCN regulator gene that causes unchecked cell growth. While a normal cell would have two copies, Teddy’s had eight. Some patients have hundreds.

“The best [doctors] seem to have a sixth sense about disease. They feel its presence, know it to be there, perceive its gravity before any intellectual process can define, catalogue, and put it into words. Patients sense this about a physician as well: that he is attentive, alert, ready; that he cares. No student of medicine should miss observing such an encounter. Of all the moments in medicine, this one is filled with drama, with feeling, with history.”

                   -Michael LaCombe

                   Annals of Internal Medicine, 1993

"L

ong, long ago—long before the baby was born—there was one cell. And that one cell had to grow into many, many cells,” says Dr. Steven Bergstrom. He’s sitting in his office on the 14^th floor of Kaiser Oakland Children’s Hospital, looking out the grassy expanse of Mosswood Park. On a desk behind him sits a framed picture of Dr. Bergstrom and Teddy Berger-Greer. The photo, taken by Clarence on Halloween, shows Teddy dressed as Bergstrom, wearing a long lab coat over a pinstriped shirt; a stethoscope and a photo ID lanyard are draped over his neck. Of all the children he has treated throughout his 25 years as a pediatric oncologist, Teddy’s is the only picture Bergstrom keeps in his office.

“At each point, these cells had to decide what they were going to become,” Bergstrom continues, narrating the maturing process. “I’m going to become a thumb.” He slowly stretches his hand out in front of him. “I’m going to become a nose. I’m going to become a heart.”

Then he leans forwards and touches the back of his neck. “All along here is where a chain of those cells become the sympathetic nerve ganglia,” he says, describing clusters of nerves that dispatch the stress response from the brain to the body. Bergstrom’s voice is calm, almost a whisper. “Some of the cells get there and don’t become what they’re supposed to become. So what can happen to them? They can stay where they are. They can die. They can mature into what they’re supposed to become. But if that doesn’t happen, then something else happens. They can start growing out of control without being what they’re supposed to be. And that’s neuroblastoma.”

When Teddy first met Dr. Bergstrom, he’d been playing with his mother on a large sheet she’d laid across the hospital floor. The family had been moved out of the main Pediatric Intensive Care Unit at Kaiser Oakland—a crowded, incandescent environment filled with the constant din of cardiac monitors and hospital chatter—and into private room with large windows and natural light. Despite the change, Teddy had stopped walking and was screaming in fear of every doctor or nurse who entered the room.

Bergstrom entered the room and leaned against the wall, watching Teddy play. He observed the little boy’s behavior, happy to see Teddy active and interested in life again. He had been so sick when he first came into the intensive care unit, bleary from the pain medication running through his body.

Bergstrom smiled at Clarence, and slowly knelt to the floor and sat next to Teddy. He was particularly cautious around the boy, aware that it often took months for a relationship to develop between a child and a physician. But to his amazement, Teddy crawled over to Bergstrom and without hesitation, gave him a hug.

Bergstrom laughs aloud when he remembers the moment. “Funny,” he says with a deep breath, “You don’t forget that kind of thing. Why he chose me? I don’t know. Teddy was such a natural for those sorts of things, just so gregarious. He had this incredible sense of himself and understood that the world around him was there for him. It was really wonderful. And it was something I needed at that point in my life as well."

Bergstrom has treated thousands of children in his 25 years as an oncologist, but to him, Teddy was exceptional. “You build this structure of trust with sick children,” he says. “And slowly they come out of their cocoon of illness and feeling that they need to be protected. Then you’re a part of their world. But Teddy didn’t wait for me to build that trust. Somehow, and this is very rare, he was already seeking that from me.”

Over the next 2 years, Bergstrom would lead a team of pediatric oncologists at Kaiser Oakland Children’s Hospital responsible for Teddy’s overall care. Dr. Laura Campbell would be the physician guiding Teddy’s treatment, a process that would involve, among others, chemotherapy, radiation, and antibody therapy. Each oncologist would contribute their personal expertise, but it was the relationship of a single doctor that would help the family interface with the labyrinthine hospital world.

“Every time we would bring him into the clinic, Teddy would run up, hug him, and kiss him on the cheek,” remembers Clarence. Teddy couldn’t pronounce Dr. Bergstrom’s last name so he called him “Docker The B”.

Bergstrom pushes his glasses forward. “I think Teddy came here because he needed us. He needed to know we were still thinking about him. I often wonder, amidst everything he was dealing with, if he knew how much moments like that meant to us?”

Steven Bergstrom has a way of describing how he became a doctor: “Pediatricians are born. They’re not made.”

Bergstrom’s medical career began when he was age 21. He hadn’t yet graduated from college, but he knew he wanted to go into medicine. He was inspired, in large part, by his childhood physician Dr. Ralph Olsen, a humble man who personally delivered him into this world. Olsen, Bergstrom says, was a principled doctor who took it upon himself to build relationships with the families of the patients he treated. He made house calls. He relied on his intuition, built over decades of clinical practice, and avoided prescribing medication unless it was absolutely necessary.

Bergstrom was working as a medical technician at Utah Valley Hospital in Provo in 1978. Every week at the hospital lab, Bergstrom was tasked with drawing blood samples from patients, some children sick with leukemia or lymphoma. “It was the 1970’s and the kids had no chance. They were all dying…” His voice trails off, recalling the time.

Suddenly, something changed. The children Bergstrom saw every week for their blood draws began to get better. Oncologists had begun to treat their patients with multi-agent chemotherapy. “I got very close to these kids, many of them with Hodgkin’s disease, and watched them come back from the brink of death. I knew from then on I wanted to be a pediatric oncologist,” he says.

Bergstrom studied at the University of Minnesota School of Medicine, completed his residency through Johns Hopkins Hospital in Baltimore, and a fellowship at the Stanford University’s School of Medicine. He enjoyed every aspect of medicine. “I loved doing surgery and enjoyed adult medicine. Obstetrics was fun because you got a baby out of it,” he says with a chuckle. “But I knew my heart was in pediatric oncology. And it’s been the hardest thing I’ve ever done in my life.”

He clasps his hands over his knee. “People ask me, ‘How can you do this work?’ and my answer is always, ‘How can you not do this?’ Your choice is to walk away and let it happen, or go in there and do something for these children. And in the 25 years I’ve been practicing, more and more children have survived cancer.”

Written Dec 14, 2010 5:56pm by Jim Greer

Milestones...

Teddy & I came home from round 6 of his chemotherapy this morning at about 6 a.m. after a lovely night of both of us tossing and turning. He was in great spirits throughout these few days, and it seems that this chemo may not drag him down too much in the next few days although you never can tell. In any case, this means that we have been at this for four months now, and that the first big part of it is over - six chemotherapy treatments. Next up is surgery.  The surgery will be long and precise and a bit scary - and we are in great hands - but we are going to put off thinking about it until it gets a little closer, and in the meantime, Leo and Teddy are going to have a Christmas they will never forget. We decided if there was ever a time to go totally nuts with way too many Christmas presents, these last four months warranted it.

Merry Xmas and cheers,

Jim

By 1986, Steven Bergstrom was working as an attending physician at the University of Connecticut. At the time, oncologists had begun to experiment with a new form of therapy that used the patient’s own bone marrow to fight off cancer cells. The idea was to attack the cancerous cells with extremely high-dose chemotherapy and then transplant previously harvested bone marrow cells back into the patient(6).

Bergstrom personally took care of the first two children involved in the study. They were ages 3 and 4 at the time of transplant, and today, both of them are adults. At the time, survival rates for high-risk patients jumped from 25 to 40 (7) percent with the introduction of the new therapy.

“But the truth was for every kid we saved from neuroblastoma, we lost to the toxic drugs you we were giving them,” Bergstrom says. “There was a schism in the world of pediatric oncology between people who only wanted to do transplant and those who only wanted to do chemotherapy. Veteran oncologists began to conclude that unless there was as specific way target chemotherapy, we’d have to find new ways to treat this cancer.”

The possibility of directing a surgical strike against cancer cells has intrigued oncologists for decades. Chemotherapy is like an atomic bomb for cancer. Once it’s introduced, it causes damage to any actively dividing cell because there is no way to direct it to a particular place in the body. Based on the dose, it can also severely weaken the immune system, necessary in fighting off disease. The result is that foreign pathogens, fought off on a regular basis, can wreak havoc on sick patients.

“Eventually, you reach the maximum dose and currently we’re there with neuroblastoma,” says Dr. Campbell. “Now, we’re trying to attack it in other ways. That’s where immunotherapy comes in.”

Because neuroblastoma originates in cells of the body, the immune system won’t attack it because it sees it as a normal cell. But in the late 90’s, scientists found that is was possible to engineer antibodies outside of the body, designed to attach to a specific receptor called GD2 that sits on neuroblastoma cells. Once the cancer is targeted, the body’s immune system, bolstered by immune stimulants, recognizes it as foreign and kills it. The result was a man-made molecule called a monoclonal antibody (ch18.14). Since 2009 (8), it has been a mainstay in frontline high-risk neuroblastoma therapy.

O

nce high-risk patients reach the end of frontline treatment, oncologists can place them on a treatment derived from an unusual source - a drug originally developed to treat acne. As early as the 1980’s, scientists observed that retinoic acid (Vitamin A) caused some premature neuroblasts to differentiate, or mature, into non-cancerous cells. “In your body, retinoic acid is used as a signal for cells to transform from their immature phase to their mature phase,” explains Bergstrom.

Accutane, a drug derived from retinoic acid, was first approved by the FDA in 1982 to treat severe, cystic acne. In lower doses, Accutane was found to mature cells called sebocytes—cells on the skin that produced oil called sebum, which blocks skin pores and causes acne. By forcing the cells to mature, it stops them from producing oil. Because retinoic acid’s wide-ranging effect on rapidly dividing cells, scientists began to consider it in the fight against cancer (9.)If a cell could mature, it wouldn’t divide.

In 1999, a brilliant young doctor at UC San Francisco, Katherine Matthay, carriedout a clinical trial determining that long-term survival patients increased by 5 percent with retinoic acid treatment after remission (10.)Today, patients are given Accutane following all of their front-line treatments - chemotherapy, transplant, antibody therapy, surgery - which causes the immune system to clear any remaining neuroblastoma cells.

Like Dr. Bergstrom, Matthay says she’s seen the survival rate for childhood cancer dramatically improve over the course of her career. “When I told my father, who was himself a doctor, that I planned to go into oncology, he said, ‘All you’ll do is watch people die,’” says Matthay. “When I started in this field in the 1970’s, children with metastatic neuroblastoma had a 10 percent chance of surviving. It was a battle. But with the combination of all these treatments, we’re now seeing about 45 percent of those children survive.”

When Teddy was diagnosed, he was given nearly every therapy developed and refined over the careers of his oncologists. Teddy was administered chemotherapy regimens with names like Cytoxan, Topotecan, and Etoposide. He spiked fevers, lost weight, and blond tufts of his hair fell out.

He had surgery to remove the tumor wrapped around his microscopic nerves. Teddy took Accutane for 6 months. He received 20 cycles of high-dose radiation. He completed five cycles of antibody therapy, and afterwards became so puffy his parents could barely recognize him.

After 10 months of treatment, Teddy was declared in remission. His scans showed no evidence of cancer. “He bounced back!” Bergstrom says. “Teddy would be sick for a few days and then all of a sudden, he’d running around and playing.” He sighs and pauses. “That’s why you stay in it,” he continues with a whisper. “I get to be a part of their lives in the best moments. In the most profound moments. It’s a commitment to being with the patient and their family that is entirely unique in medicine.”

In 2002, Giselle Sholler was in her second year as a pediatric oncology fellow at Brown University, when she received a phone call from the hospital’s pathology department.

“Dr. Sholler, I want to talk to you about your patient with Chagas disease,” said a pathologist from lab.

“I don’t have a patient with Chagas disease,” Sholler responded, confused. Chagas was a parasitic disease endemic to South America with little incidence in the United States.

The pathologist persisted. “Just come and see the blood smear for yourself.”

With the pathologist over her shoulder, Sholler leaned down and focused the eyepieces of the microscope. Traces of the worm-like parasite that caused Chagas slowly became clear on the crimson- stained slide.

The blood sample had come from a five year-old patient Sholler was treating for neuroblastoma. The girl had a poor prognosis. Despite intense frontline therapy – multiple cycles of chemotherapy and surgery to remove her cancer, the disease continued to progress. Sholler had little hope her patient would survive the next few months.

The oncologist now had to figure out how the child had contracted a parasitic disease. Throughout her treatment, Sholler’s patient had received a significant number of blood transfusions to replace blood cells killed off by rounds of chemotherapy. After a few days, the blood bank at Brown was able to identify the donor as a carrier for Chagas disease. The man had come from South America unaware he carried the parasite in his bloodstream.

Hoping to rid the girl of the parasite, Sholler and her colleagues were able to obtain the drug Nifurtimox from the Centers of Disease Control. Nifurtimox had been in use in South America since the 1970’s as treatment for Chagas, but the Food and Drug Administration hadn’t approved the anti-parasitic agent for use in the United States. However, when Sholler’s patient was administered Nifurtimox in combination with low dose chemotherapy, her doctors were surprised to find her cancer began to regress and eventually the girl went into complete remission.

“It was nothing short of amazing,” recalls Sholler, who currently chairs the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC). “Her tumors completely disappeared. We all felt this was something that we definitely needed to explore further.”

The patient survived for 18 months on the Nifurtimox therapy, but then relapsed and died. “At the time we couldn’t put her back on Nifurtimox because we couldn’t get access to it. She didn’t have Chagas anymore,” says Sholler. “But she survived for a long time.”

In December of 2011, Teddy relapsed. It became clear to Bergstrom and Campbell that the therapies they’d tried for the boy had failed. The cancer that had been irradiated, cut out, and poisoned had come back. Something had survived. Teddy’s health was failing—the cancer had spread to several lymph nodes and a new tumor was developing in Teddy’s chest.

Written Dec 19, 2011 8:09pm by Clarence Berger Greer

Relapse...

We've been watching a lymph node in Teddy’s neck grow for a few months, so I pushed to have it biopsied on Thursday. The results came back today and it is positive for neuroblastoma.

There is no protocol from this point on and we have to make all the decisions on what's best for Teddy. There is no cure for this, so for now, we are looking at prolonging his life for as long as possible while giving him as comfortable a life as possible.I'm angry, I’m sad and exhausted, but I'm sure I’ll manage to get through this again.

In the meantime, take good care of your kids, hug them, kiss them, and love them with all you've got.

Clarence

W

hen Clarence and Jim Berger-Greer found Teddy was refractory—one of the high- risk neuroblastoma cases that does not respond to frontline therapy—they were faced with the daunting task all parents of relapsed children face: choosing one of hundreds of treatment options, none of which are proven to work long term.

Teddy’s doctors and his parents weighed his relapse therapy options. There was a new drug parents were talking about on the ACOR listservs - one that had been developed to treat a South American infectious disease - but was being used off-label for neuroblastoma with a promising level of success.

While frontline therapies for neuroblastoma patients are mainly uniform, refractory therapies are incredibly varied. Presently, there is no standard relapse therapy available for patients. Families can follow protocols established by the Children’s Oncology Group, Memorial Sloan Kettering Hospital, Children’s Hospital Of Philadelphia and place their children on stronger types of chemotherapy, or choose to enter their children in clinical trials organized through research groups like New Approaches to Neuroblastoma Therapy (NANT) or the NMTRC.

“At relapse, it’s a completely different ballgame,” says Sholler. “Presently, parents have a choice of placing children back on chemotherapy or a lot of unproven clinical trials.”

With the guidance of Dr. Campbell, Teddy’s family discussed their options—a different chemo perhaps, surgery to remove the growing tumors, clinical trials, or the unfathomable decision to not do anything at all, and let the disease run its course.

The paradox of it all was that Teddy was feeling fine. The disease was strangely enigmatic—one day Teddy would be bed-ridden, feverish with vomiting and diarrhea, and the next he would be eating well and giggling non-stop. “I know how capricious this cancer is,” wrote Clarence. “How it waits until you least expect it to explode into an uncontrollable wildfire.”  

Despite the ongoing whirlwind of midnight trips to the PICU for sudden fever spikes or bouts of pneumonia, Teddy seemed to find solace in life. He learned to kiss everyone the “French way” as Jim describes it- one on each cheek. He also developed an insatiable love for trains.

Nearly every weekend, Jim and Clarence took him to Tilden Park- a 2000 acre park in the Berkeley Hills, dense with Eucalyptus trees, wild grass, and ochre fields of bush poppies. A miniature steam train called the Redwood Valley Railway would bring the family through the wooded spans of the Berkeley Hills. “He was so filled with joy. He sat with his hands crossed like a perfect little angel, and marveled at everything we saw,” Jim wrote describing one of Teddy’s rides through Tilden. “It somehow made all the hard moments we've endured seem like trifles.”

After much thought, the family opted to try an intense combination of chemotherapy in hopes of destroying the remaining cells. “With this new regimen,” Clarence wrote, “his hair will once again be gone, he’ll need transfusions, and be in isolation. It is really scary to think our son’s fate is literally in our hands.”

Yet after three rounds of the chemotherapy, scans showed that Teddy’s cancer was still growing. The family had had enough. “We thought, ‘We’re’ not letting this progress anymore. We have to switch to something else,”

As Clarence culled the ACOR Neuroblastoma forums for answers, Sholler’s name began to appear.

“The study was very limited,” recalls Dr. Campbell of Sholler’s Nifurtimox trial. “We looked into it because, over the years, we’ve seen some abusive therapies claiming to be a ‘cure’ for cancer. It’s never that simple. But Dr. Sholler had credentials like ours and she had this observation that she’d made. So we applied to Kaiser to get Teddy approved for Nifurtimox treatment and sent him down to San Diego.”

A

fter her patient passed away, Sholler moved her base of operations to the University of Vermont and began experimenting on mice to look at the effect of Nifurtimox on neuroblastoma cells. Their research found that when the drug reacted with stress hormones produced by the cancer cells, it produced something called semiquinone free radicals—unstable molecules that disrupted the cellular structure of neuroblastoma cells, causing them to die. In mice, Nifurtimox was effectively shown to reduce tumor size by 75 percent (11.)

As the story of Sholler’s work began to spread, it eventually peaked the interest of John London, a young Manhattan hedge fund manager, whose daughter had relapsed from neuroblastoma. His daughter was diagnosed at 16 months of age, and like Teddy, she had very few options left. “John called and asked me, ‘How can I get this drug for my daughter?’” Sholler remembers. “I said, ‘Unless she has Chagas disease, the government won’t let me give it to you.’”

With certain life-threatening diseases, the FDA will approve the use of drugs that haven’t yet been proven for that patient population. This is called “compassionate use” or “expanded access”. The idea is that a patient’s prognosis is so poor, they have nothing to lose by taking experimental drugs. The guidelines regarding compassionate use are incredibly strict, often limited to one patient, and can take up to two years for approval.

But terminal patients don’t have time on their side. Through compassionate use Sholler was able to acquire Nifurtimox for London’s daughter, who in turn, had a dramatic short-term response while on the drug.

A Phase 1 clinical trial was needed to prove the Nifurtimox was safe for use in children with neuroblastoma. Armed with the evidence in her lab, Sholler was able to obtain Nifurtimox from Bayer Pharmaceuticals and begin a Phase 1 clinical trial in less than three months. Though his daughter passed away before the initial trial began, London and another parent, Scott Kennedy, were instrumental in founding Solving Kids Cancer, a non-profit organization dedicated to financing clinical trials for pediatric cancer. The organization independently funded Sholler’s Phase 1 and 2 Nifurtimox trials.

“When it comes to pediatric cancer research, there’s very little funding,” says Dr. Sholler. “It accounts to 4% of the National Cancer Institute budget. Pharmaceutical companies, which fund approximately 56% of adult cancer research, fund close to 0% (12)of pediatric cancers because they don’t make money. We’re too small a population. Most of our research is funded by parent advocacy groups. They’re the ones that make what we do possible."

When the Lymphoma and Leukemia Society was formed in 1949, it was comprised of a few volunteers in a small office on Wall Street. The Foundation’s annual report in 1955 stated:  

As of this date, Leukemia is 100% fatal. This is almost a unique situation among the many diseases to which man is susceptible.

“Now, I can look at a family and diagnose their child with Leukemia and say, ‘I expect your child to live,’” says Sholler. “Nine out of ten kids survive. It’s the parent advocacy groups that started the LLS that caused that to happen. They raised the money for research and development of new drugs. And it’s very similar to what neuroblastoma parent groups are doing now.”

Currently, Nifurtimox is still in a Phase 2 clinical trial with 83 patients enrolled. The estimated completion date for the trial is January 2015.

Written Aug 17, 2012 1:41pm by Jim Greer

August Update

Today, Teddy and Clarence flew to San Diego again for his one day visit with the doctors there to keep up with this trial that we are on, this pill he is taking three times a day in conjunction with the chemo called Nifurtimox.. Something is working.We are going to make this cancer wish it had never bothered our little boy!

Anyways, that's all for now. Happy August to all!

Jim, Clarence, Leo, Teddy

“It’s hard to know what he got out of the Nifurtimox because neuroblastoma can wax and wane in terms of how it’s growing,” explains Dr. Bergstrom. “But he seemed to get some months of fairly good quality of life. At one point, we thought his disease had gotten to the smallest point that we had seen,” he says.

“And then... it came roaring back.”

The day before Teddy died, hundreds of people came to the Berger-Greer home to participate in a candlelight vigil. Garth drove from Yosemite, Clarence’s family flew from the Loire Valley, Jim’s from Ohio, nurses, doctors, and staff came from Oakland Kaiser Childrens, people drove from the family’s old Derby Street block in Berkeley. A bonfire was lit in the backyard. For ten minutes, Clarence lifted Teddy’s frail body in her arms in their bedroom window so he could witness this outpouring of love. The once winsome and flirtatious child laid still and quietly watched the hundreds of flickering candles in the shapes of stars and hearts.

This was after the family had already stopped chemotherapy one week prior. It was after Clarence had written out her wishes for Teddy to pass peacefully in his sleep. Her instincts were to feed him, give him blood- anything to stave off the inevitable. Now, after fighting so hard for 2 and ½ years, her role as a mother would change. She would be there for her son, always his consummate protector, but now as a guardian from life into death.

Written Dec 13, 2012 8:42pm by Jim Greer

And then you blink...

When the sun sets, from our window, on sunny days, we get the full brunt of our powerful star. It is beautiful and blinding. As the sun came into its latitude to be shining directly on us, Teddy was clearly nearing the end. That same sun that cast its light on our wedding day.

Many people have expressed their faiths to us throughout this process, and many people have let us know that it may be God's will this, or God's will that. And it may well be. But I know one thing. We are born of this organic, living universe. Star matter is within us. And never have I ever felt more like I was in the presence of the supernatural than having this mighty being shining on us, and I could almost see Teddy's last breaths, and the stardust that makes up his soul, being pulled back towards that Sun. it was as if the Sun had decided to choose the moment, and envelop Teddy in its light, and take him back, back to the stars. In a way, it was beautiful.  He gave Clarence a little smile in his last moment as she held him in his arms.

Remember that a little boy who only got a few years of life can inspire you to live more fully, more appreciative, and more happily. Don't think of him as someone who died. Think of him as someone who lived.

With much love and sadness,

Jim, Clarence, Leo, Teddy.

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Credits

Charles Berkowitz

Author/Article Design/Producer

Erik Reyna

Photo Color Correction/Photo Editing

William Ryan Fritch

Atmospheric Music

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Special Thanks To

The Berger-Greer Family  - Clarence, Jim, and Leo

Garth May

Hannah Neff

Dr. Steven Bergstrom

Dr. Laura Campbell

Dr. Jorge Gutierrez Jr.

Dr. Katherine Matthay

Donna Ludwinski

Gilles Frydman

Pat Tallungan

Dr. Giselle Sholler

Erika Puentas

Maya Thompson

Max Sierra

Colleen Plummer

Dr. Aaron Low

Stacey Lynn

Kim Sherman

Gina Macintosh

Dr. Albert Chan

Jesse Mangaliman

ACOR Neuroblastoma Forum

Kaiser Oakland Medical Center

__________________________________________________

Additional Thanks

Cynthia Gorney

Kara Platoni

Rachel Witte

Aaron Mendelson

Richard "Koci" Hernandez

Paul Grabowicz

Jeremy Rue

The Graduate School of Journalism, UC Berkeley

© Charles Berkowitz 2014. All Rights Reserved.

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About

Created in memory of Teddy Berger-Greer to help generate awareness and research funds for neuroblastoma through a partnership with The Pablove Foundation.

Donate: http://pablove.org/teddyfund

Description

The Teddy Berger-Greer Neuroblastoma Research Fund was created to generate awareness and research funds for neuroblastoma. Joining forces with The Pablove Foundation in the fight against pediatric cancers, we have committed to raising funds for a research grant in Teddy's memory. All money raised by this Fund will go directly toward a grant awarded by The Pablove Scientific Advisory Committee to an innovative research program in the area of neuroblastoma.

During his short time on earth, Teddy's radiance and positivity touched everyone around him. His smile was infectious and he never lost his gentle spirit. Teddy's home was always filled with music, which brought him joy even on the toughest days. We intend to keep the music playing as we fight cancer in his name.

The cure rate for high-risk neuroblastoma is dismal 30%. We hope that this grant is will be a giant step toward saving the next child diagnosed with the disease.

For more information on Neuroblastoma, download the CNCF Handbook for Parents of Children With Neuroblastoma here: