Dr. Ignacio Blanco is not only a highly recognized professional but also a reference for people affected with NF2. His work places patients at the center and he focuses on the progressive complexity the disease carries into their lives. He works as the Coordinator of Consulting and Clinical Genetics at the Hospital Germans Trias i Pujol, Barcelona, and he was one of the organizers of the 16th European Neurofibromatosis Meeting held in the same city, last September.
How did your interest in NF2 arise?
In 1998, I joined the Catalan Institute of Oncology to develop a project in Cancer Genetic Counseling. Our role was to serve, assess and advise patients and families with suspected predisposition to develop tumors. The larger number of queries were related to families with suspected hereditary predisposition to breast or colon cancer Subsequently, Dr. Conxi Lázaro joined our team and directed our molecular diagnostics laboratory. She had a vast experience in NF1 research and she was the one who introduced me to the world of NF. In 2009, we opened an office of Genetic Counseling in Badalona ICO at Hospital German Trias i Pujol. At the hospital, we met Dr. Francisco Roca-Ribas, otolaryngologist, who was very interested in the NF. Back then, we decided to join forces and create a Multidisciplinary Unit to take care of patients with NF2. During all these years, all my colleagues´ wish has always been to improve the quality of life of NF2 patients. Sharing their personal and family experience, every day, made my interest in this disease increase significantly.
Many people affected with NF2 wonders about the chances their children may have to inherit the disease. Can we talk about 1 in 50 in all cases?
NF2 is an inherited disease that follows a pattern called "autosomal dominant". This means that it is a disease that can be transmitted to the offspring and that can be inherited by both men and women (autosomal) and that each child has a 50% chance of inheriting it. Sometimes, when the affected patient has a segmental or mosaic NF2, the chances of transmitting the disease may vary.
How can genetic counseling help families with NF2? How is the process to be followed to get that aid?
It is important that we differentiate between "genetic counseling" and "genetic testing” from the beginning. Genetic counseling is the process of communication through which properly trained professionals may address their patient needs in relation to the possibility of developing or transmitting a specific disease. During this process, each patient at risk is provided with information about the disease and its manifestations, a prognosis and a set of measures that may be undertaken to modify the natural history of the disease. That is to say that prevention and treatment are offered. Both the emotional as well as the social impact (such as the psychosocial needs of the patient and his family) are also taken into account. Sometimes, conducting a genetic study to the patient or family allows doctors to measure the risk level more accurately. In the case of NF2, the genetic study can confirm the disease and it is extensive to the family at risk, (i.e. children) and it also can identify who has inherited the disease and who has not. Consequently, those who do have not inherited the disease should not continue making screening tests.
Up to date, you are part of the first multidisciplinary unit of NF2 in Spain. Can you tell us about this unit?
In 2010, we created the Unit for Comprehensive Care of NF2 in the campus Can Ruti. This Unit was formed by professionals from Hospital Germans Trias i Pujol, the Catalan Institute of Oncology (ICO) and the Institute of Preventive and Predictive Medicine of Cancer (IMPPC). The philosophy of this Unit was to put the patient with NF2 at the center of attention. The Unit staff is composed by a team of professionals (otolaryngologists, neurosurgeons, neurologists, dermatologists, geneticists, etc.) who take management decisions by consensus. In this way, we try to avoid the patients’ pilgrimage to multiple specialists’ consultations and we assure that a comprehensive assessment of each individual case is guaranteed. As this Unit developed so successfully, the Ministry of Health pointed it out as a reference center. Recently, we have been accredited and designated as Reference Centre for the Care of phakomatosis (neurofibromatosis type 1 and 2, family schwannomatosis, Von Hippel-Lindau disease and tuberous sclerosis). It represents a big professional challenge, but we are convinced that this is the best way to care for minority patients who suffer from complex diseases such as NF2.
Those who integrate AMANDOS would love to have one unit in each country. What resources are needed to build them up?
First, you need human resources, professionals interested and involved in caring patients with minority diseases such as NF2. These professionals should be willing to work as a team, by sharing treatment decisions, discussing all cases and providing material resources such as a physical space and equipment. As you can see, the most important thing is to make a clear decision to provide patients with the best possible care. It is also essential that the professionals involved are eager to learn every day and that they have a clear commitment to teamwork by putting the patient and his family as the center of attention. In Europe, a new step is taken forward to set a network of expert centers which share resources and knowledge. The National Focal Points are key elements of these networks of experts. From my point of view, it would be appropriate to develop networks of Latin American experts. Advances in information technology and communication allow us to prevent patients to move from one place to the other. Experts can perform remote visits, review radiology images and share decision-making. We must make a clear commitment to create and sustain these centers.
Your laboratory was able to reverse, in vitro, the functionality of the protein synthesized in the NF2 gene for a specific identified mutation. How has this study evolved? Have you done any clinical trial?
Our Reference Center has a large team of basic researchers, led by Dr. Eduard Serra and Dr, Conxi Lázaro. The main objectives of our research group are to have a deeper understanding of the molecular basis of NF, to analyze the factors that influence the phenotypic variability (why different patients have different forms and at different times) and to develop new therapeutic approaches. On this last point, we were lucky enough to identify a rare mutation in patients with NF2, which we call a deep intronic mutation, which allowed us to test a gene therapy approach. We demonstrated in laboratory that we can "reverse" the effect of this mutation. These laboratory findings are always very difficult to put into practice. Specifically, these mutations are rare in patients with NF2, so we can not conduct a clinical trial. However, as we announced our results, if a patient with such mutations is identified at any time, we might consider using this therapeutic approach. Just keep in mind that research studies are like little grains of sand, one alone can not change anything, but together they allow us to change everything. It is essential to continue investing in research to understand the disease better and hopefully we may reach a day when we can find a cure or at least substantially change its natural history.
Is there a line research of NF2 in your laboratory nowadays? If so, what is it?
We have several open lines. One aims to improve genetic studies in NF2. Another line is trying to develop experimental models of NF2 in the laboratory. If we have cellular and animal models that reproduce the manifestations of the disease, we will be able to evaluate new treatments. Another line tries to establish genotype-phenotype correlations. That enables us to know better what events each patient held. We could better assess the prognosis of each patient and implement more efficient treatments. We also have an open line of clinical research to assess the emotional impact and quality of life of the NF. In these studies, we included not only patients but also their families, key elements in their lives.
A study has been published recently concludes that artesunate could reduce schwannomas. What is your opinion about it?
There are many groups trying to evaluate new therapeutic approaches in NF2. The absence of effective treatment yet does not mean they are not evaluating many substances. We have an example with artesunate, a drug used to treat malaria. This drug has demonstrated in the laboratory that induces cell apoptosis in schwannomas cells, i.e., suicide of these cells. It is a very significant progress made in the laboratory. Now it is important to run tests in animals either using drug alone or associating it to others who favor the apoptosis of cells. These advances are important, but we have to wait to know that they can be used in the clinic. I know this is easier to say for someone who does not suffer from the disease, but it is very important to avoid creating false expectations. We must insist on investigation. I am sure that we can improve NF2 treatment.
We were surprised about the possible use of artesunate because it is proven to be a safe component; it is used to treat malaria and it is available at a low price and without a prescription. Do you think artesunate can be tested in a clinical trial in people today?
Although the results provided are very attractive, I think that is still premature to propose a clinical trial, even more if it combined with other drugs. The results should be compared with other models so as to prove its effect in vivo. We need to meet the necessary dose, etc. Again, there are very encouraging results, which require us to further deepen its effects, but we also have to be cautious.
The Bio30 Propolis, marketed by Manuka Tree, was used by Professor Maruta in his studies. There is a great controversy among patients about this product and we would like to clarify if it may be used for treatment or not. Can you help us?
It is a very interesting question. It is true that certain propolis has shown effects in vitro, i.e., in the laboratory, in cell assays. However, there are insufficient data to demonstrate their effectiveness and to prove to be safe in animal models and humans. Is essential to demonstrate the effectiveness of any new treatment. That is why, as I said before, it is essential to have experimental models to demonstrate the effectiveness of new treatments before proposing clinical trials.
The traditional approach was conducting Auditory Brainstem Implants after removal of vestibular schwannomas. We read that Cochlear Implants after such surgeries allow better hearing rehabilitation. Can you explain what the choice depends on?
The ideal situation is to place a CI. These implants allow maintaining an acceptable hearing. Hearing results from ABI are scarce and its usefulness is mainly support rehabilitation. To place a CI, it is necessary that the cochlear nerve intact. In surgery of vestibular schwannomas is not always possible to preserve the cochlear nerve, so it is not always possible to place a CI. I do wish to comment that much progress is being made in developing both more efficient, CI and ABI.
Are there any new evidence on the fact that the nerves that have been damaged in surgery for tumor removal can regain their function?
Yes, advances in stem cells are generating great expectations. Nerve regeneration area is evolving rapidly. Again, despite this, we must be cautious, we can regenerate a nerve, but the disease will still be there, will it be enough?
If the effect of bevacizumab in reducing vestibular schwannomas and improving hearing is checked; what determines its prescription to a patient with NF2?
The utility of treatment with bevacizumab is proven but on very specific indications. At present, a patient who meets these criteria should receive treatment. I advise all patients to talk to their doctors and assess whether or not to receive treatment with bevacizumab. We should bear in mind that this treatment does not eliminate schwannomas.
How do you think patients groups can help to find a treatment for NF2?
By continuing with the actions carried out. By encouraging research, raising awareness on the disease, helping patients and families to adapt, meeting the needs that the health system does not cover, etc. Patients groups are essential. The only thing that I would recommend is to act together, to join efforts.
What results can we expect from treatment research under way in the short term?
I am very optimistic about the results of the efforts of all current and future researchers. You wonder about "short term". This is more difficult to answer, because time for researchers and patients is very different. They are making great advances in knowledge about NF2 patient treatment. However, for patients this will always be insufficient, since we are unable, for the moment, to cure the disease or eliminate the consequences it has already caused. I am convinced that with everyone's efforts, researchers, patients and families, we will advance and improve the quality of life of patients.
Questions from NF2 affected:
What do you think about radiosurgery treatments, including gamma knife? What is the percentage of those irradiated that has become malignant? Is it possible to avoid the tumors to become malignant somehow after treatments? (Montse, Spain)
Radiosurgery has its indications. It is important to assess each individual case, assessing the benefits and risks of each treatment strategies that may apply. The malignancy of a vestibular schwannoma is something extremely rare. In the few cases that have been described, there was a history of irradiation, but it is important to remember that the vast majority of irradiated schwannomas has not become malignant. At present, we have no methods to predict which tumors can become malignant, but it is essential to recall that this is something very rare, therefore it is recommended to perform scans, just in case.
After removing the tumor, can it appear again at the same place? (Grace, Chile)
Recurrence, that is, to go back out on the spot, is possible. There is much debate over whether this is because it has not completely removed or that the disease is present in all cells. What we know is that when tumor resection is complete, the risk of recurrence is lower. One problem is that sometimes the complete excision of the tumor can not be done, because this will cause many injuries or side effects.
What are the circumstances that cause mortality in NF2? (Ana, Argentina)
NF2 is a systemic disease in which schwannomas or other tumors, usually nervous strain, can occur in different parts of the body. Sometimes, these tumors arise in vital areas and the inability to remove can lead to death of the patient.
I have several partners in matching the NF1 or NF2 with different types of cancer. Is there any kind of relationship between these two diseases or this is simply an unfortunate coincidence? (María Jesús, Spain)
Yes, that is possible. It is shown that patients with NF have a superior cancer risk to the rest of the general population. That is why sometimes a specific track is indicated
Can NF1 and NF2 occur at the same time? (María, Argentina)
The coincidence of the NF1 and NF2 in the same patient is highly unlikely. We can not say no, but it is very unlikely.
Do the hormone-based contraceptive methods influence in the development of NF2? (Ana, Argentina)
There are no studies that demonstrate a contraindication to the use of contraceptives in the NF2. Sometimes, prudence, it has been recommended that patients with NF2 do not take drugs, or limit their use, also including contraceptives. Is important to note also that the dose of contraceptive hormones in current is very low.
Are the tumors removed when they start bothering? Is it the idea to remove them as soon as you can? When is it the right time to operate a tumor? (Pamela, Chile)
Since treatment of schwannomas is not without complications, for example, hearing loss or facial paralysis, is important to assess the most appropriate time for treatment. There is no fixed rule applicable to all patients. Each patient is different and will need to assess the risks and benefits for each patient at all times.
Is there any possibility of a transplant of the nerve after removing the auditory neurinoma or after radiate to restore hearing, or nothing at all? (Montse, Spain)
The transplantation of nerves right now has not shown a profit. We are very hopeful about the possibility of nerve regeneration from stem cells.
Is it possible to link the NF and increased complications with the consumption of GM? (Rodrigo, Colombia)
No, the NF are diseases that have always existed. Perhaps, we would not have named them, but there is evidence of patients with neurofibromas for thousands of years.
Do you think that the tumors produced by the NF2 should be operated by a surgeon experienced in them? (Lluis, Spain)
Undoubtedly. The skill of the surgeon is a key factor in the results. Health professionals know that a learning curve is necessary. Reference Centres, where teamwork is encouraged, will improve the experience of surgeons, preventing individuals.
Why occurs or what causes spontaneous mutation of NF2? (Ana, Argentina)
During the formation of gametes, sperm or eggs, called meiosis, should be carried out a complex process of gene rearrangement to give these cells particular genetic information to create a new being. This process is so complex that it is not uncommon errors may occur. When one of these errors lies with the NF2 gene, the new being will NF2, although their parents they had none. It is a product of chance.
Could you tell us about the use of octreotide for the treatment of tumors of NF2? (Florencia, Argentina)
Octreotide is a somatostatin analogue, widely used in the management of endocrine tumors. It has been used in this type of tumors arising in the context of NF1, e.g. pancreatic tumors. It has not been used for the treatment of common tumors arising in the NF2 as far as I know.
Interview by Lluis Martinez for AMANDOS
English version by Florencia Sarratea and Carolina Delsoglio