NEW YORK – "I wish I did not have that hand anymore," my 4-year-old son said as he woke up one winter morning.
"Why, my dear?"
"Because it's no good," he said, tugging on the almost lifeless fingers of his left hand with his stronger partner.
Already tired of fear and worry about Natan's cascade of symptoms, I felt painful as he did He described his body cheating on him
It was March 201
Now, Natan had been away from a delicate operation for a few days for a few days The removal of the tumor, which the doctors had finally found weed-like from his spinal cord. It had penetrated his brainstem and beyond, slowly stifling the nerves that control breathing, swallowing, and movement. Without control it could kill him.
But even if it had succeeded, the operation would be just a stopover, a starting point in a process that would push our family to the limits of medical research. There, the genomics revolution, as it is known, has made it possible to understand and confront what drives some cancers and other diseases. The doctors told us to take tissue from the tumor, they would determine if it was caused by a rare genetic mutation that could radically alter the course of its treatment.
Only a few years earlier, this course would have been relentless: more than a year of chemotherapy that could prevent the growth of the tumor. Patients like Natan have had to repeat this punitive therapy several times in their childhood, and are exposed to increasing impairment as the mass has deprived them of their ability to breathe or walk alone. Well, we were told there was little chance Natan could hit the tumor by swallowing a pill twice a day, with few, if any, side effects.
In the 15 years that scientists have come up with the first map of a human genome – the sequence of DNA molecules that represent the unique genetic blueprint of each individual – the process has become steadily faster and cheaper. With the information provided by such test results on tumor cells, researchers are developing drugs to specifically target certain disease-causing genetic abnormalities that prolong and enhance the lives of tens of thousands of people whose illnesses were once sentenced to death. And they have just started.
"Forty years ago, we did not understand the cancer, and we did not understand the drugs," Dr. Richard Schilsky, chief physician of the American Society of Clinical Oncology. "Now we can actually examine a patient's cancer, gain insight into its influence, and in some cases identify proven, effective therapies that can target these drivers. That's a huge difference.
These advances also create new risks for patients already facing a devastating diagnosis, who may be required to consider costly new treatments without their efficacy or safety being low. It is a topic of debate in the cancer community: how can one lessen the hope for a few against the likelihood that most patients in these therapies will still find no answer.
"The majority of people do not benefit from it, but some benefit from it And that's what drives the field forward," Schilsky said.
In Natan's case, we learned that in a clinical trial, one of the newer targeted Therapies approved to treat aggressive adult cancers had led to similar slow-growing tumors in a small group of children, and when DNA sequencing detected the relevant mutation, the experts said Natan was a candidate for the drug.
Doubtless, I did not want to accept treatment with little evidence and a treatment whose long-term effects were unknown.As the US health editor for Reuters News, I had worked for several years on articles describing the promise and disappointments of so-called precision medicine. I knew claims about new drugs in question put the tumors "melted away".
The expert was now personal, and me and my equally skeptical husband set about learning as much as possible about the options for Natan. We consulted with relatives and friends in the medical field and developed referral networks in our Jewish community. We interviewed experts and read what research we could find. It was exhausting, especially in addition to the emotional and physical efforts to look after a sick child, but we had no choice.
The survival of our little boy was at stake.
Natan was a healthy baby and toddler who played active and mischievous with his older brother. Our only criticism was that he often woke up at night, but in those years there was always a reasonable explanation: Feeding, teething, growth spurts.
Our first real panic hit in the spring of 2016. Natan, then 3rd woke up on a Sunday with a runny nose but otherwise he seemed to be fine. I went to the gym. Within that hour he had a high fever, and when I returned, my husband held him over the sink and splashed cold water on his face.
"He became limp as if he were not breathing," he said. "I called an ambulance."
After a few days in the hospital he was treated for pneumonia, Natan rebounded. The speed of his decay worried us, but it seemed to be similar to other parents' stories about frightening but treatable respiratory illnesses in toddlers and our own pre-school struggles with pneumonia and bronchitis.
Soon we wondered why his sleep was still so interrupted, and why his voice sounded soft and hoarse.
The first doctor's visits were nothing unusual. When someone recommended more detailed tests, such as a sleep study, my husband and I, faced with unnecessary medical procedures, asked about the practical difference the information could make.
Natan cried now many mornings before school. "I'm sick!" He said, even though his vital signs seem normal.
Within a few months it became clear that we needed more answers. When Natan returned to preschool in September, his voice was barely audible to his teachers. Sometimes he seemed to choke while eating or drinking. An ear infection gives way to sinusitis, which leads to bronchitis. After his antibiotic course, he was soon back in the office of his pediatrician or in the emergency room and struggled to breathe.
"There's no reason why a neurologically normal kid should sound that way," a pulmonologist said, after hearing only one doctor take a few breaths.
From Thanksgiving, the tests piled up, as did the drugs Natan needed daily. The list of "complaints" in his chart became longer with each visit: louder breathing, sleep disorder, chronic bronchitis, asthma. He was hospitalized again for Christmas because of pneumonia. Nothing we did made him better, and that helplessness nourished our fear.
Natan cried now many mornings before school. "I'm sick!" He would say, even if his signs of life seem normal. At work, I was persecuted by the feeling that his teacher or babysitter called at any moment and said he had stopped breathing. As I picked him up from class, I noticed his heavy gait stumbling forward as he walked and his eyes dull.
Every new specialist brought in Nathan's case, another symptom that suggested a neurological disorder: rapid, involuntary eye movements, weakness on the left side of the body. But we still had no explanation.
"What's the diagnosis?" My husband demanded on each visit to the doctor.
In late February 2017, we two sat in the cafeteria of the hospital and waited for Natan to be awakened from anesthesia for an MRI scan. We have tried to keep our worst fears at bay.
"When that's over, we should take the boys to the beach for a month. It's the best medicine, "said my husband.
I looked at the clock, the call from the nurses' station had not been received even though more than enough time had passed and I was crazy.
" Let's go upstairs Then, my cell phone rang.
It was the neurologist who ordered the MRI, and the scan showed something unusual: a large "infiltrating" lesion centering in the medulla oblongata, the structure at the bottom The end of the brainstem, which controls the breathing and other involuntary functions, the thickest part was firmly wrapped in the cervical spine, and the tentacles snaked into the midbrain and cerebellum, which regulates balance and motor coordination.
"What I asked.
"You need to talk to a neuro-oncologist," she said, adding that she was trying to get us an appointment within days. "There's no ke Some signs of fluid retention in the brain, so you can take your son home. "
" Are you telling me that my son has a massive brain tumor but should go home now? "I asked.  We refused to leave until someone who could interpret the scan spoke to us.
An hour later, an expert in pediatric brain tumors said that Natans lesion was probably a rarer, slow-growing type that occurred in about 100 cases a year in the United States. Natan may even have been born with it, and only now was he tall enough to smash the nerves that run through his four-year-old's brainstem, a structure about the size of an adult thumb connecting the brain and spinal cord ,  These dying nerves lost their ability to control, breathe, swallow, and sleep in Natan's gait and fine motor movements.
"At least now you have a diagnosis that explains everything," said the doctor. "It may take a long time for some families to arrive at this point."
"I WANT THIS TUMOR OUT"
Like many people in crisis, we have every available resource in our midst Claimed. We were lucky enough to have access to great doctors and world-renowned hospitals nearby. My employer's health insurance covered almost all of our expenses.
Two weeks after the diagnosis, Natan was operated on for six hours at New York Presbyterian / Weill Cornell Medical Center. Dr. Mark Souweidane, director of pediatric neurological surgery at Weill Cornell and the Memorial Sloan Kettering Cancer Center, removed about 20 percent of the tumor, mainly in the cervical spine. It would have been too dangerous to go further into the brainstem, where the tumor was more difficult to distinguish from healthy tissue.
Within a few days, pathological tests confirmed the tumor type: a slow-growing ganglioglioma, a mixture of cells that contained components of the central nervous system and supporting tissues.
The good news was that such low-grade gliomas are not malignant, which means that unlike aggressive cancers they do not grow fast and generally do not spread to other organs. In many cases, they stop growing completely when patients are 20 years old. The size and location of the tumor had already significantly affected Natan's ability to swallow and breathe. As a result, there was a risk of inhaling fluids and small food particles into the airways, resulting in fatal pneumonia or asphyxiation.
It would take another two months for the sequencing results to be performed separately by Weill Cornell and Sloan Kettering Second confirmation of the genetic profile of the tumor.
At that time, we focused on Natan's recovery after surgery with weeks in hospital and an acute rehabilitation center.
Removal of part of the tumor helped improve some of the symptoms. The fast eye movements were almost gone. In daily therapy sessions, Natan learned to use his left hand again and walk without tripping. But we noticed or confirmed new problems: hearing loss, severe sleep apnea, long bouts of hiccups, which are hallmarks of brain stem tumors.
I tried to stick to the idea that the operation would be enough for a few months. or years before the tumor progresses. I had even hoped that growth would cease on its own, as some doctors had suggested, and feared that the new surprises that he would encounter in the treatment. Even without major complications after surgery, he was physically and emotionally vulnerable.
My husband was restless, whether he had been waiting for the tumor to continue growing before he started therapy.
"It feels like we're just sitting waiting for a miracle to happen," he said. "I want this tumor to be eliminated."
Sequencing confirmed that a mutation known as BRAF V600E, which is most commonly observed in adults with deadly skin cancer melanoma, drives Natan's tumor.
"I have something for you" Dr. Matthias Karajannis, Sloan Kettering's chief pediatric neurooncologist, told us at a meeting to review the test results. This "something" was a drug called Dabrafenib, which is marketed by Novartis AG under the brand name Tafinlar. It helped to keep a significant percentage of melanoma patients alive after five years when used with a second drug, Mekinist, a great improvement over older therapies.
Karajannis recommended using Tafinlar to treat Natan. While chemotherapy is the first standard treatment for low-grade gliomas that can not be surgically removed, previous evidence has shown that the new therapy could be much more effective.
In some cases, he said, "The tumors are simply melted away." 
Roche's Herceptin or trastuzumab, introduced in 1998, was the first so-called targeted cancer therapy that interfered with a growth-promoting protein that was found in about 20% Percent of breast cancer patients was found. The drug has improved overall survival, especially in women with early cancer.
The next major breakthrough came in 2001 with the approval of Novartis & # 39; Gleevec or Imatinib. Gleevec made deadly blood cancer, known as chronic myeloid leukemia (CML), a lengthy, manageable disease. In almost all CML patients, the diseased blood cells exhibit a fusion of two normally separate genes. Gleevec blocks the activity of the fused genes and leaves healthy cells untouched – a tremendous advance over potentially lethal chemotherapy that is toxic to both sick and healthy cells.
With Gleevec's success, other targeted therapies were on the agenda For any potential new drug, this meant first identifying a aberrant gene that would fuel a cancer and then developing a drug to counteract this divergence.
The reality is much more complex, as the researchers get to know the multiple influences on working in cancer cells. Many Gleevec-approved targeted therapies only help a small percentage of patients with a specific cancer, often only a year or two before their tumor cells make new mutations to overtake the drug.
"The feeling was there. We wanted to defeat cancer with these approaches," Dr. David Hyman, Chief of Early Drug Development at Sloan Kettering, who leads the research of new targeted therapies. Now, the medical community has recognized that cancer is "a number of rare diseases," each with its unique biological mechanisms.
But these new discoveries can change the lives of small groups of patients. The US Food and Drug Administration has approved more than 30 therapies that are prescribed based on the results of genome testing. Most of these treatments have been introduced to the US market since 2012.
"Unfortunately for many patients we do not find a magic bullet, but it is also an area under development," Karajannis said in an interview. "A few years ago, we had no treatment options."
A study published in the JAMA Oncology journal in April estimated that 15 percent of the nearly 610,000 advanced cancer patients in the United States could be candidates for treatment for genomic sequencing and nearly seven Percent would probably show some benefit.
For example, Pfalzers Xalkori and Alecensa from Roche are targeting mutations that occur in about five percent of patients with non-small cell lung cancer. In late November, US newcomer Loxo Oncology received approval for Vitrakvi, a pill proven to shrink a variety of tumors caused by TRK fusion, a genetic abnormality found in less than one percent of cancer patients ,
The side effects of Tafinlar were far milder than Chemos, the specialists said. The long-term safety in children was and still is not known.
Worldwide sales of such targeted treatments reached $ 28 billion last year, according to research firm GlobalData Plc.
In the small community of children with low-grade glioma, the potential for a targeted approach emerged nearly a decade ago when two different BRAF abnormalities were found in these tumors. The BRAF V600E mutation occurs in approximately 10 percent of the 1,000 US children diagnosed with low-grade gliomas each year. The research coincided with the development of Tafinlar, which was approved in 2013 for melanoma patients with the same BRAF mutation.
At a medical conference in Copenhagen in October 2016, just as we were beginning to study the symptoms of Natan, Dr. Mark Kieran, the then director, presented data from 32 children treated with Tafinlar at the Dana-Farber Cancer Institute's Pediatric Brain Tumor Program and the Boston Children's Hospital.
All of the children's tumors were positive for the BRAF V600E mutation, and nearly three quarters of them saw tumors shrink or grow on the drug. In two cases, the tumors disappeared while the tumors of eleven patients shrank by more than half. The side effects were relatively minor – rash, fatigue, fever.
Less than a year later, we read about these results and asked ourselves: could that be enough proof for our child?
19659082] My husband and I have sought as many authoritative sources as possible. Specifically, we wanted to learn more about treating children whose diagnosis is identical to Natan's: a brain stem ganglioglioma with a BRAF V600E mutation. We looked at several leading pediatric neuro-oncologists. Some had treated or followed a few dozen patients like Natan. Others had direct clinical experience with a handful or none.
They told us that chemotherapy and the new drug are both options, but they differed in what they emphasized. Some seemed to be more supportive of chemo. They cited data collected over decades that indicate that 25 to 40 percent of low-glioma patients have stopped growing after their chemotherapy, usually resulting in one or more weekly infusions of carboplatin and vincristine. Even though the disease returned, a majority of children survived into adulthood, the studies said.
The potential side effects of chemotherapy during the treatment of a patient were severe, including neuropathy – nerve damage that can cause both debilitating pain and deafness – and the risk of bleeding or severe infection. Thereafter, however, there were no cognitive or other long-term damage.
The survival data summarized many types of low-grade gliomas, including tumors that were healed by surgical removal. Brainstem gangliogliomas like Natan's were a very small subgroup. Recent research and clinical experience suggest that chemotherapy was far less effective in children with brain stem tumors, especially those with a BRAF V600E mutation, resulting in repeated treatments and poorer survival rates.
"Do not trust this tumor!" Eric Bouffet, head of neuro-oncology at the SickKids Hospital in Toronto, and co-author of the Tafinlar study. Bouffet knew many of the low-grade glioma patients in Canada. He and his colleagues continue to investigate their findings and track data from other medical centers around the world.
The BRAF mutation appears to make the tumors more aggressive, Bouffet said during a telephone consultation. He told us about children like Natan, whose brain stem tumors caused severe sleep apnea, a sudden respiratory arrest. A little boy died in his sleep before he could get therapy, Bouffet said.
Tafinlar's side effects were much milder, the specialists said, and children taking the drug did not have a school like chemo patients. You could enjoy a family vacation. But his long-term safety in children was – and still is – unknown and will take years to establish.
The medical literature was scarce. One of the earliest published case studies from 2014 featured the heartbreaking story of a 21-year-old man whose ganglioglioma had returned after repeated chemo and radiation and left him in a wheelchair. His tumor shrank dramatically with Tafinlar, and he started walking again and suffered a fatal brain hemorrhage within a few weeks. His doctors asked if the rapid withdrawal of such a large tumor had contributed to the bleeding.
A second report showed a hopeful outcome for a child with massive low-grade glioma who shrank dramatically and saved their lives within two months of treatment
When we consulted with Kieran in Natan's case, he recommended Consider chemotherapy first as it is safe, and if this fails, try Tafinlar. Prior treatment with chemotherapy was also a prerequisite for inclusion of children in the clinical trial of Novartis.
There were good reasons to be careful. Even if drugs are tested on hundreds of patients, identifying security issues can take years. Regulators are now more willing to approve targeted therapies, especially those that treat advanced cancers, based on testing in smaller groups of patients. For someone who has a few months to live and has no choice, the risk can be worth it. But was the compromise with a slow-growing tumor adequate?
We wanted to understand why Kieran, who led the clinical trial with Tafinlar, would not recommend using it from the start. In June, when we thought Natan was ready for the trip, we took him to Boston. After an examination of our son and a nearly two-hour long discussion, Kieran nodded to the new therapy.
In an interview he recently said that when we met, he had just discussed therapies such as Novartis & # 39; Tafinlar as a first choice treatment with other families, depending on the circumstances of the patient.
"The conversation I had with a family five years ago would have been completely different," he said. There is now enough data to immediately consider BRAF therapy appropriate for patients like Natan, provided that families recognize that the image could change as more data emerges.
Not every patient has the luxury of waiting for it. Information: "You can not always say, let's just wait three years and see how the data works," Kieran said. He recently left Dana-Farber to lead the development of childhood cancer therapy at Bristol-Myers Squibb.
One detail emerged in all of our research and consultations with experts: there was a possibility that Tafinlar would actually shrink Natan's tumor, which is unlikely to be the result of chemo. Otherwise, his symptoms may improve, provided the nerves have not yet been irreparably damaged. We had to give him this chance.
Two weeks later, a pharmacist by Sloan Kettering showed me how to turn Tafinlar into a liquid that Natan can safely swallow. In our kitchen, I poured the capsule's white powder into Kool-Aid's lemonade flavor, which, according to Novartis, is the only beverage that can dissolve this advanced drug. I tried not to spill anything. Our insurance covered almost all of the costs, but I was well aware of the cost of replacing just one $ 100 pill in retail.
In the first weeks we observed unusual reactions. One night Natan would almost faint for no apparent reason. Another night, his temperature rose to 105 degrees. It turned out to be a virus. For a few days, hives broke out all over the body. Again a virus was suspected.
And we noticed something else. After a little more than a week, Natan's voice, which had been almost inaudible for months, boomed loudly. At first we doubted it was real. But Natan was so pleased that he could now hear himself and talk about his brother, that he would spontaneously scream and sing.
During the summer, tests confirmed that his hearing had returned. His gait became steady and stronger. With a wink, Natan took an extra deep breath from the nurse and watched the monitor while his oxygen level rose from 99 percent to 100. He was taken off the respiratory medications and the antibiotics, which had almost played a major role for a year.
Natan's next MRI in October 2017 showed a result that went far beyond what we had hoped for: Almost all of his detectable tumors had disappeared. "It almost looks like a normal brain," Karajannis said.
My husband and I wondered if we could have noticed the symptoms earlier and if treatment at this stage would have rid Natan of the worst illness. Considering how fast the science has developed, we now believe that in our case the opposite is true: if the tumor had been found earlier, Natan would most likely have endured chemotherapy infusions and their harsh effects for over a year each week need, with little real benefit.
Der Erfolg von Natans Behandlung gibt keine Garantien. Niemand kann sagen, wie lange die Arznei wirken wird, ob er die Droge auf unbestimmte Zeit einnehmen oder aufhören soll oder ob die Anwendung eines Arzneimittels ein Risiko darstellt.
Auch die Wissenschaft geht weiter. Novartis testet derzeit Tafinlar plus Mekinist – die Kombination zur Behandlung von Melanompatienten – im Vergleich zu einer Chemotherapie bei Kindern, deren niedriggradige Gliome BRAF V600E-Mutationen aufweisen, um zu sehen, ob die Kombination besser und länger funktioniert. Der Arzneimittelhersteller hat auch die Anforderung aufgegeben, dass die Patienten eine vorherige Chemotherapie erhalten müssen. Eine neue Generation von BRAF-Therapien von Unternehmen wie Array BioPharma und AstraZeneca befindet sich in der klinischen Erprobung. Wir hoffen, dass, wenn Tafinlar irgendwann nicht mehr für Natan arbeitet, eine neue Therapie eingesetzt wird.
Es ist mehr als ein Jahr vergangen, seit Natan mit der Behandlung begonnen hat. Er begann wieder zu rennen und zu springen, zu schwimmen und zu klettern. Er ist jetzt in der ersten Klasse und freut sich, jeden Tag zur Schule zu gehen und seine Freunde zu sehen.
Natan schluckt jetzt seine Kapsel mit einem Schluck Wasser und zeigt jedes Mal einen Daumen hoch. Er ist in den Ferien gereist, sogar in Übersee, ohne Missgeschick. Auf unserer letzten Reise hat er sich ein neues T-Shirt ausgesucht. Auf der Vorderseite steht: "Gib niemals auf."
Von Michele Gershberg
Fotobearbeitung: Steve McKinley
Video: Jillian Kitchener, Craig Hettich, Mike Wood
Design: Pete Hausler
Herausgegeben von John Blanton