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Silvia Regina Brandalise

Silvia Regina Brandalise: Nonconformity in the blood

Léo RamosAt an art auction, the physician Silvia Brandalise wanted to purchase a work of art that wasn’t for sale. She insisted, but to no avail. Days later the artist herself offered her the painting—a kneeling angel holding a daisy—today hanging in the chapel with large stained-glass windows depicting trees at the Dr. Domingus A. Boldrini Children’s Center for Hematologic Research in Campinas. The Boldrini Center, as it is better known, is a hospital specializing in treating children with cancer. Brandalise started it in 1970 in the basement of a two-story house in front of the Santa Casa Hospital in Campinas. In 1978, with the support of a Ladies Club, the Boldrini Children’s Center—with labs, a chemotherapy room, and a clinic, with emphasis on providing free services to patients and families—began operating in a rented house in front of the Santa Casa Blood Bank. The hospital was founded with a grant from the Robert Bosch Institute, which financed the construction of 1,500 square meters (m2), and grew with the help of other institutions and businesses to reach the current 40,000 m2 of floor area on a plot of 100,000 m2.

Silvia Brandalise helped establish the foundations of pediatric oncology in Brazil, centralized care, thereby avoiding the pilgrimage of children and parents to several hospitals, and established treatments with greater efficacy and lower toxicity. She coordinated the studies that defined treatment protocols for acute lymphoid leukemia—the most common childhood cancer, affecting white blood cells— indicated by the Brazilian Society of Hematology and Hemotherapy and the Brazilian Society of Pediatric Oncology. As a result, the cure rate of children with acute lymphoid leukemia rose from 5% in the late 1970s to the current 70%. She is not satisfied with these results however. “The incidence of cancer among children and adolescents is rising, and the five year mortality rate in Brazil is 50%, still very high compared with 20% in the United States and other countries,” she said on August 5th, when receiving the award from the São Paulo Institute of Cancer (Icesp) in the category “Outstanding Individual of the Year.” Whenever she can, she warns mothers who attend the Boldrini center about the hazards of pesticides to children: “Dengue fogging kills mosquitoes and affects human health,” she warns. Her current plans include the construction of a hospital for pediatric specialties with 200 beds and 14 operating rooms in a neighboring lot. “I’m checking with God to see if he can give me another 20 years of life, at least. Didn’t Abraham die at 120? He said he’s looking into it,” she says, with her usual good humor.

Married to a surgeon, Brandalise has four children—one is also a surgeon, two are psychologists and the last is a biologist who really wanted to be a gourmet—and seven grandchildren. “When I got married, I said I wanted six children. I thought it would be great to have a big family. My husband didn’t want any more after the fourth, but I went to the courts because I wanted to adopt. The judge said I needed my husband’s approval, and I explained that my husband didn’t want more. ‘Why?’ The judge asked. Because I spent little time at home and he would be left taking care of them. I tried to insist that we be put on the list, because I thought that after the child arrived, he’d like having another. The judge did not agree, but then a nephew came to live with us. He studied medicine and specialized in ophthalmology. ”

The hospital’s colors
Most of this interview was conducted while Silvia Brandalise showed us around the main areas of the Boldrini Center. The hallways have large windows, the walls are colorful and covered by drawings made by artists, medical students, sick children or their mothers, which reduces the usual stress associated with hospitals. “Art and music help to alleviate suffering,” says the physician. 

In front of the hospital, across the street, is Boldrini Station, where children who arrive at 7 am wait until they are seen and then rest, have a snack or take a shower before returning home. “This is a landmark for the ambulances that transport the children. We must also take care of the driver, who brings the child on a Saturday or Sunday, or in the middle of the night if necessary,” she says. “With guaranteed, humanized transportation, treatment avoidance drops significantly.” The station was built in 1996 by an association of parents in the city of Americana, led by Maria Delfina de Oliveira, whose son had leukemia, but was cured. “Someone who has gone through this type of experience sees life differently,” said Brandalise, who in the morning had seen four volunteers there, in blue smocks, making pizzas for the children because the bread had not yet arrived. 

We returned to the Boldrini Center and crossed through a garden with large colorful sculptures by the artist Vera Ferro and arrived at the National Healthcare System (SUS) outpatient oncology clinic, which serves an average of 50 patients with solid tumors daily. Another clinic, for hematology, serves about 50 children with leukemia each day. “The volunteers do a craft project with the children and mothers, and they learn the techniques and it become a source of income for them in the cities where they live. When you arrive at 10 am and everyone is working, it is a joy, because the children do not cry while waiting for the doctor. And they are happy because they have a present to take home.” Further on, after corridors decorated with drawings and clay pieces, is the classroom. “It’s a real school, in partnership with the Municipal Department of Education. The hospital class is providing counseling on the education of children who are in treatment.” 

Next to the playroom—large, high-ceilinged, bright and colorful, with a stage and different corners for children and adolescents—is the cytogenetics laboratory. “Here we do a genetic profile of all patients with leukemia. Identification of the degree of response to chemotherapy is essential in deciding whether to intensify or reduce the treatment,” she says, showing a chromosome on a computer screen. “This here is a mutation, translocation (9; 22), which in itself indicates a poor prognosis, it indicates that it is better to use a specific treatment, imatinib, or Gleevec, previously used only for adults,” she says. “The systematic search for genetic mutations has become as important as the stethoscope.”

The oldest wing of the building now houses microbiology and biology laboratories and equipment, which also assess the need to change treatments. Almost all diagnoses, tests and surgeries are done at the center. The ward area is a circular space. The rooms are situated around the observation post of a nurse or doctor. “The mother or father is always with the child and we have this bird’s eye view of the situation. This was done 30 years ago in a bold architectural design.” It was inspired by the St. Mary’s children’s hospital, in Rochester, Minnesota. But it is even better. “We have a room for the mother or the father, attached to the child’s room, with separate bathrooms. I also wanted each patient’s room to have a view of the garden.” Then she complains that, by order of the health surveillance department, she had to cut the trees in the small indoor gardens, and recounts the alternative she is planning: “We are creating metallic trees, with flowers made of a hard material I saw in Lyon. It is going to be wonderful. When the child can see the sky and the plants, he almost feels like he is out of the hospital.”

Up to what age are children accepted at the Boldrini Center?
We apply a modern concept of “child.” Before, we went up to age 18, then 21, due to the demand from the health network itself. Then we increased the limit to 25 and now it has reached age 29, the same as in the United States. Anyone who has kids knows that until about age 20, when a son or daughter is sick, he or she reverts to being a child… This is the group that has the worst treatment results in the United States, because in this age range the cancers are very similar to those of children. Few have the typical adult cancers, like breast, stomach, lung, or prostate. The older ones do not do well with physicians who treat adults. Treatment is better when it is done by physicians who treat children, who take the patient and the family under their wing.

Age: 70
Specialty:
Pediatric oncology
Education:
Medical degree from the Federal University of São Paulo (1967)
PhD from the University of Campinas (1975)
Institution:
Dr. Domingus A. Boldrini Children’s Center for Hematologic Research and the University of Campinas
Scientific production:
79 articles, 1 book, 22 book chapters and 6 childhood cancer treatment protocols

Doesn’t the concept of a child being anyone under 29 result in problems?
There is huge internal pressure for us to send them to the adult hospital because 95% of the doctors here are pediatricians specializing in hematology/oncology, but the neurosurgeon has general training, as does the orthopedist, and we also have a general cardiologist, a general endocrinologist and a general gynecologist. There is also pressure from the patient who wants to stay here. Recently we saw a girl who had Hodgkin’s lymphoma at 4 years of age and relapsed 20 years later. Now she is over 30. They wanted to send her somewhere else and she didn’t want to go. The physicians came to me and I said I thought we should treat her here because we know how to treat these tumors better than many physicians who treat adults exclusively. The girl said that she would not leave and I told her that if she needed an ICU or had an infection, she would be sent to the Hospital das Clínicas. She only calmed down when I assured her that she would only be sent away over my dead body. Now she is staying in a house next door, because she lives far away.

When receiving the Icesp award, you said that cancer among children and adolescents is increasing a lot. Why?
From ages 0 to 18, the most important factors are contamination by pesticides and heavy metals, and hormone use in food, for cosmetic purposes and in gyms for weight lifting. Something that was unimaginable in the past is hormones in groundwater. This is because anovulatory drugs are not biodegradable in Brazil. A person takes an anovulatory [a drug that inhibits ovulation], drinks water, urinates, and the drug passes to the soil and groundwater. There was an article in the Correio Popular, here in Campinas, about contamination in the Atibaia river, with high hormone levels. It’s very serious. Dengue fogging kills mosquitoes and affects human health. I have always paid attention to pesticides because of bone marrow aplasia, a condition in which the individual can no longer produce blood, and only a transplant can solve the problem. The leukopenias [decrease in the number of leukocytes, a type of white blood cell], which frequently appear here, are highly related to exposure to pesticides. Exposure to monazite sands and natural radiation are other serious dangers when a child lives near that type of soil. Since children walk close to the ground and radiation reaches 30 cm in height, children are the most affected by this natural radiation.

What can be done?
The basic question I ask when I work in the clinic is about housing conditions. I immediately explain to the mother the risks of environmental issues. Not to scare them, but to impress upon them the importance of the matter. You can’t perform pest control at home and at school with children around. At a meeting of the World Health Organization (WHO) in Geneva, I received a 300-page tome on the environment and children’s diseases. My jaw dropped open when I read the statistics on organ failure and congenital malformations resulting from exposure to benzene derivatives and secondary radiation. The WHO had called in some experts to plan a study of more than 1 million children. We, in Campinas, represent Brazil. I came back from this meeting with the task of gathering a group of 100,000 pregnant women and children to follow for 18 years, by using an epidemiological questionnaire, to study maternal exposure to risk factors during pregnancy and during the first year and a half after the birth of the child. I set the number at 100,000 to keep up with the United States. China will follow 300,000 and England will follow 40,000. I think that, this semester, we have already begun to go to health centers to administer the questionnaires and collect blood from mothers and babies. In total, there are four questionnaires: one in the first trimester of pregnancy, one in the last, one in the first six months of the baby’s life and one when the baby turns one and a half. There are more than 200 questions on each. If the individual were to suffer from cancer, we can correlate this with epidemiological data for the entire population of newborns in the city of Campinas who underwent the screening test at Unicamp. But we will only know the results in about 15 years.

You were a pediatrician who was not really interested in cancer. What made you change your mind?
I graduated in 1967 and did my first year of residency in clinical medicine and my second in pediatrics at the São Paulo School of Medicine. I came to Campinas in 1969 with my future husband, in the early years of Unicamp, and thought it was horrible. The campus was scrubland. But we moved here and I started working in the Department of Pediatrics of the School of Medicine. In 1978 I was head of the pediatric ward at Unicamp, which was still operating at the Santa Casa Hospital. There were 50 beds and I did not treat children with cancer. I think I avoided them to protect my heart. I always said that cancer patients should be treated by hematologists or surgeons. I have always been a one-job, one-husband woman. I only know how to work full time, I can’t stand going back and forth from hospital to hospital. In the ward, I knew everyone’s name and forced medical students to memorize the name and history of each patient. One day, a resident physician told me that a boy with leukemia, in intensive care, was very ill. I searched for the hematologist, but couldn’t find him. I sent for another specialist, who also was not there. Aparecida Brenelli, a resident at the ward, who years later became head of the Department of Pediatrics, said she had not been able to find any physician to treat the boy, André. She was so distressed that she began to cry. Since I cannot bear to see anyone crying, I decided to see the child. I immediately identified a number of errors and corrected prescriptions the hematologists had written, errors due to their lack of experience with pediatric cases. The boy improved and his mother asked me to treat him. I stated again that I couldn’t, because I didn’t know how to treat leukemia. She refused to deal with the hematologists at Unicamp and I gave her a list of other names. Her choice was professor João Rhomes Aur of the São Paulo School of Medicine, who was in Memphis, in the United States. Just before the trip, the mother told me that her husband wouldn’t travel with them and asked me to accompany her with André. I refused and she said that if I didn’t go, André wouldn’t either, and he would die here. Everyone cried, the mother, the grandmother… I went to Memphis and, there, Rhomes gave me protocol VIII to read and said that if I followed it, patients would have a 50% cure rate. I thanked him very much and said that I didn’t want to specialize in pediatric hematology, I wanted to be a general pediatrician. Just before we returned to Brazil, the mother told me that she knew that her son had no chance of surviving. For that type of cancer, acute lymphoid leukemia, the chance at the time was less than 5%. I treated the boy until he died.

And then what?
I thought I would return to my life in general pediatrics when, less than six months later, another boy appeared with the same name, André. He was the nephew of a pediatric medical resident, who wanted me to examine him. I thought it was leukemia, and I referred him to a professor at the São Paulo School of Medicine, but he didn’t think it was leukemia. The boy was getting worse. I myself collected a bone marrow sample, performed a lymph node biopsy, and sent the material to Memphis. Rhomes confirmed that it was acute lymphocytic leukemia and told me to follow that treatment protocol he had given me. I talked to that professor, showed him the protocol, and he replied that they do a lot of research in the United States. I said that I saw people cured there. He told me not to worry because he knew how to treat the illness. However, the patient’s first four weeks are decisive. They can determine whether the individual recovers or dies. The mother came to me and said that the boy was doing so well that the doctor had suspended chemotherapy. The next week, the boy arrived with his mother, who for the first time said nothing. He, the little 5 year-old, was the one who spoke. He said he really wanted me to treat him. I explained that I did not know how to treat his illness, that I was not a hematologist. The boy started to bawl. I can’t stand crying and said I would treat him. That same day I resigned as head of the ward to care for him. The board of the Department of Pediatrics discussed the case and rejected my request. They claimed that to devote myself to a disease in which all patients die is a waste. There was only one vote in my favor. I stated that I regretted that they had rejected my request, but I still intended to leave. I am the daughter of Portuguese father. It’s your word that counts, not a signed piece of paper.

And the treatment worked?
Yes, Andrew was cured, and grew up to adulthood. I called Rhomes to tell him I had been bowled over by a 5 year-old and asked him to come here and stay a month to teach me the ins and outs of the treatment. And he really came. [She stops in front of some old photos of one of the halls of the third floor, a wing of the hospital, with 77 beds] This was the first coagulation laboratory. Campinas still didn’t have one. I found this basement, in a large house in front of the Santa Casa Hospital, and started to beg people for funds. I had to convince the manager of the Santa Casa Hospital that it would be a great deal for him if he set up a lab for me and paid a technician. In return, I would teach the technician and she could perform exams for obstetrics and for cardiac surgery. Then, by chance, an aide of José Aristodemo Pinotti, who was President of Unicamp, asked me to treat a niece. I said I had no office, but that I could see her at Santa Casa Hospital. It was a relatively easy case to solve, but the mother was very grateful. She was Beth Abrahão, and was president of the Clube da Lady (Ladies Club), a ladies’ service organization in the city, and they put the club at my disposal to help with whatever was needed. I asked for an outpatient clinic. And it was her uncle, Jamil Abrahão, who was a journalist, who suggested the name of Dr. Domingos Adhemar Boldrini, who I did not know, for the center.

And then, where did you go?
This first house [showing another picture] was the one that the Clube da Lady let us use. That’s where I started the outpatient oncology and hematology clinic—everything had been in pediatrics before. The house was literally empty when I got the keys. When a mother said she didn’t know how to thank me, I asked if she might have a table or a chair to donate. To pay the rent, the ladies held parties and sales, and sometimes we had to wash the dishes after dinner because we had no money to pay a waiter. We had already set up a chemotherapy room here, but we hospitalized patients at various hospitals around the city, wherever there was a vacancy. This part here [showing another photo], in an area measuring 1,500 m2, was donated by the Bosch Institute. The institute believed that it was worth investing in childhood cancer because at that time, 36 years ago, it was a death sentence. There was nothing available to treat these patients. They were hospitalized in the pediatric ward and died there. Only when the cancer was surgically removable did patients survive.

And they understood the importance of the clinic?
A journalist here in Campinas, Romeu Santini, who was later a city councilman, did a story on the clinic, describing how we cared for the children. At that time we visited several hospitals in the city, placing children at various hospitals, like we do today in the city of São Paulo. When we hospitalize a child in a general hospital, where people are not trained, the quality of care decreases. It was clear that we needed a large place that could handle everything. Santini’s report was entitled “Who supports this idea?” Well, someone did. A vascular surgeon, John Cook Lane, at the Campinas Medical Center and Unicamp, read the story and spoke with my husband—they knew each other since they were both surgeons. He said he was thinking of talking to the president of Bosch to see if he was interested. It worked: we built the hospital in 1994 and today we have 40,000 m2 of floor space.

How do you keep the hospital running?
About 80% of the clientele is from the national healthcare system (SUS) and 20% have private health insurance. The 20% with insurance pay 30% of the budget. The 80% without private health insurance account for 30% of revenues. That leaves a 40% hole. We supply it with the fundraising we have learned to do. We rely on human solidarity, seek the resources donors provide,  hold sales… And with that, with grants from the city, we manage to obtain from 30% to 35% of our budget. Yet, at the end of the year, we are still short R$1 million to R$1.5 million. The only way to make up the difference, then, is to hold dinners and raffle a car. Someone donates a car, we hold a raffle, and the money goes to the hospital. With that we can pay the bills and make some investments in expansion, laboratories etc.

What is Brandalise syndrome?
Jon Pritchard [a pioneer in the treatment of childhood cancer in Britain] gave it that name. It was because of a 3 or 4 year old child who came here with hemolytic anemia and blood transfusion dependence. When I examined the boy’s blood, I saw something I had never seen before: a light-blue pearl inside the white blood cell. Blue like this sky, which you do not see in São Paulo. I sent it to Pritchard, who thought it was some other type of disease. I insisted that it wasn’t and I sent it to another center, and they said they didn’t know what to make of it either. In the meantime the head of the St. Jude hospital in Memphis, William Chris Mitchell, visited me. I warned him I would show him a slide of something he had never seen before and he replied that it was unlikely there was something in the area that he was unfamiliar with. Mitchell saw the slide and said he didn’t know what it was. But he obtained funds to pay for the child and his family to travel to a Texan center specializing in white blood cells to obtain a diagnosis. The child went and returned with a diagnosis: it was an inherited disorder affecting the metabolism of arachidonic acid, which crystallizes and forms those little blue pearls in white blood cells. The findings were published in the United States by this center and called inherited arachidonic acid metabolic disorder. Pritchard saw this, thought it was unfair, and asked permission to use my name for the disease. What I really wanted was for my name to be on a perfume or something related to haute couture, but I said OK. Then I received a query from a doctor saying he had encountered a case of Brandalise syndrome, which is much easier than the long name they wanted to give it. The boy who had this problem was cured without treatment and I have not seen another case like it.

You are a researcher who does not much like writing articles…
Indeed. My focus is on what I can do to improve patient care. I prefer to work on leukemia treatment protocols. It takes me an average of two years to prepare and write each one. I chose to follow this path—because it gives me pleasure and makes sense to me and I can see the results—rather than pursue an academic career. A protocol is not a Betty Crocker cake recipe—sometimes it is used as a standard, as a guideline, but that’s not what it really is. A protocol requires a question and then an answer. And a question we asked in protocol 80 was: can we decrease the dose of radiation therapy in the nervous system? Then we did a randomized prospective study, and it was wonderful, because we scientifically demonstrated that the radiation can be decreased. In each protocol we ask a question, with the aim of reducing the toxicity of the treatment. In the fourth study, we asked if we could decrease the treatment from 2.5 years to 2 years. The answer was yes, meaning we could subtract six months of therapy with an equal chance of a cure. We are now on the sixth study. In a 2009 study, I shared the work of protocol coordination with a professor at UFRGS, two at Unifesp, one at Unicamp, and one at the Institute for Child Cancer Treatment, (Itaci) [affiliated with the Children’s Institute at the Hospital das Clínicas of the University of São Paulo School of Medicine]. We worked prospectively on maintenance therapy for acute lymphoid leukemia, compared to an unconventional treatment that had greater efficacy and lower toxicity. The traditional treatment is to take one pill a day and get an injection every week for two years. We proposed to have the patient take the pill every day for 10 days and then have a break on the 11th before starting the cycle again, plus the injection only every 21 days. What is the advantage of this? First, the patient prefers coming just every three weeks instead of every week. Second, liver and bone marrow toxicity and infection are much higher in those who take the drugs continuously. The body needs a rest. The problem is that the number of patients—500—is still small and we have to increase it.

Upon receiving the Icesp award, you said that reducing the mortality of children with cancer is still a challenge.
In Brazil, mortality is still 53%. For leukemia, which is the most curable cancer, it is 40%, with little difference between regions. The mortality is high compared, for example, with the 25% mortality rate in the United States, because, despite the policy of having centers of expertise, we are still working with separate units for chemotherapy and radiotherapy, you see the patient in one location, operate in another, resolve a complication in still another… Everything should be within the framework of a single hospital. Isolated units are important, but the Ministry of Health could redefine children’s cancer centers. Today there are nearly 160 registered centers, but more than half treat less than 30 new cases per year. In general, those who treat only a few cases do not have a complete infrastructure. Almost 80% of the units treat less than 100 patients per year. This is what makes the difference in the statistics. The creation of regional centers for diagnosis and the systematic use of protocols at the national level would allow better monitoring of the results. For complex pathologies such as brain tumors, bone tumors, neuroblastoma, and acute myeloid leukemia, we have to focus on centers of expertise. Australia did this and managed to spend less money  because it didn’t have to be distributed to so many different locations, and has better results.

What are the rates in Brazil?
In isolated centers like Boldrini in Campinas and GRAAC [Support Group for Children and Adolescents with Cancer] in São Paulo, the survival rate is 80%, but this is not the national average. What is the expectation for new cases of childhood cancer in Brazil? Around 10,000 to 11,000 a year. How many do we treat in Campinas? About 400 to 450. About 20% die from the disease. It’s heart-wrenching. Especially when it comes to a point where you don’t know what else to do. This happens with some congenital diseases, such as porphyria, an inherited bilirubin metabolism disorder. The person has abdominal pain and may have jaundice and mental repercussions. I even thought of writing to Isabel Allende.

But Isabel Allende is a writer, not a doctor.
Yes, but she wrote the book Paula about her daughter, who died of porphyria. In this book she describes the doctors’ diagnosis, the treatment and hospitalization in the ICU. She mentions how the doctor told them serious news without regard for their suffering and how he avoided talking to the mother of the patient about the seriousness of what was happening. Isabel Allende taught me a lot by showing the arrogance of the doctor who does not want to say that there is no cure and, when he does talk, causes the mother even more problems. Isabel Allende’s daughter had the most common form of porphyria and similar cases are appearing here for treatment, and sometimes even more serious cases. So, with so many problems, can I be happy? Happiness is mindlessness!

Do you intend to begin working in this area?
I am highly motivated to treat rare diseases in the state of São Paulo. The State Secretary of Health came to me two years ago and asked me to study and accommodate people with rare diseases. At first I refused, but I ended up seduced by a child who had an inherited lipid metabolism disorder and had spent nine years in the Children’s Institute in São Paulo without a diagnosis. Recently, Alexandre Nowill at Unicamp’s neonatal screening department called me, saying that they intended to buy 10 mass spectrometers. He wants me to support him by taking children with rare diseases. I will see what we can do. Alexander is the son of Dorina Nowill, of the Nowill Foundation, who established the first systematic Braille service for the visually impaired. The adversities and challenges that life brings us are no doubt the driving force behind the changes necessary for the welfare of humanity.

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