The blood-brain barrier prevents most drugs from reaching brain tumors.
A new method using nanoparticles transported drugs across this barrier in mice.
The nanoparticles target a protein on tumor blood vessel cells called P-selectin.
The nanoparticles improved the treatment in a model of aggressive pediatric brain cancer.
Brain tumors are notoriously hard to treat. One reason is the challenge posed by the blood-brain barrier, a network of blood vessels and tissue with closely spaced cells. The barrier forms a tight seal to protect the brain from harmful substances, but it also prevents most drugs from getting to brain tissue. This severely limits therapies that can be used for brain tumors.
Now, a Memorial Sloan Kettering Cancer Center (MSK) team led by Sloan Kettering Institute biomedical engineer Daniel Heller, PhD, in collaboration with Praveen Raju, MD, PhD, a pediatric neurologist at Mount Sinai Medical Center, may have found a way to carry drugs across the blood-brain barrier using nanoparticles — tiny objects with diameters one-thousandth that of a human hair. The researchers showed that this approach could work in mouse models of medulloblastoma, the most common malignant (cancerous) pediatric brain tumor.
Here, Dr. Heller explains how this method, reported March 2 in Nature Materials, could potentially improve treatment for medulloblastoma, other brain tumors, and other brain diseases.
How are nanoparticles used to target tumors across the blood-brain barrier?
In 2016, my laboratory found that a protein called P-selectin is an especially good target on cancer blood vessels for steering nanoparticles, loaded with drugs, to tumors. P-selectin is abundant in blood vessels that feed tumors. We found a substance that has a natural affinity for P-selectin. It’s called fucoidan, a polysaccharide (a chain of sugar molecules) that is widely available and extracted from brown seaweed from the Sea of Japan. Fucoidan binds to P-selectin.
In the 2016 study, we filled fucoidan nanoparticles with different cancer drugs and showed that the nanoparticles selectively attached to cancer sites, including metastatic tumors in the lungs of mice. This showed the promise of targeting P-selectin to treat cancer.
How does targeting P-selectin get drugs across the blood-brain barrier?
The blood vessels in the blood-brain barrier are lined with a layer of cells that are packed very close together. We discovered that when the nanoparticle binds to P-selectin, it triggers a process called transcytosis, a mechanism that shuttles a particle across the cells lining the blood vessel wall. This allows something inside the blood vessel to pass through the vessel wall to reach the surrounding brain tissue. We found we could exploit this natural mechanism to get drug-loaded nanoparticles across the blood-brain barrier, which has been very difficult to achieve.
This could be an important step in improving treatment of brain tumors and other brain diseases. People have tried different ways to disrupt the barrier, like using ultrasound to poke tiny holes. For many reasons that are probably obvious, these methods carry risks. But now we may have a way to get around some of these risks.
How did you end up testing this approach on medulloblastoma?
A pediatric oncology fellow working in our lab, Hiro Kiguchi, MD, was studying the use of these nanoparticles for pediatric cancers. He presented our work to scientists and physicians in MSK’s pediatrics department, and Praveen, who was working here at Memorial Sloan Kettering and Weill Cornell Medicine at the time, asked: “Could you could get these nanoparticles across the blood-brain barrier?” I was skeptical because even though nanoparticles are small, they still are bigger than drugs or proteins, and the barrier is so tight.
But it turned out Praveen had developed a mouse model for medulloblastoma. This was ideal for testing our technology because the blood-brain barrier is intact in this model, unlike many other brain tumor models, which have leaky barriers. We collaborated with Praveen, who is a co-corresponding author on the study, to put this nanoparticle approach to the hardest test.
How did you demonstrate that the nanoparticles can reach the medulloblastoma in mice?
We loaded the nanoparticles with a drug called vismodegib, which targets the Sonic hedgehog signaling pathway. Sonic hedgehog proteins play an important role in promoting cancers. Vismodegib has already been approved for treating basal-cell carcinoma, the most common skin cancer, and the drug had been tested for medulloblastoma and other cancers driven by Sonic hedgehog proteins. However, this drug resulted in significant bone-related side effects when it was tried in pediatric medulloblastoma patients.
We found this side effect does not occur when we put the drug into nanoparticles. We injected vismodegib-loaded nanoparticles into the tail vein of the medulloblastoma mouse models and let it circulate to see if it passed through the barrier. Using special imaging, we could see the particles accumulating at the site of the medulloblastoma tumors, where P-selectin is prominent, and not in normal brain regions or other parts of the body. Daniel Tylawsky, a PhD student in our laboratory, discovered that particles that target P-selectin use the transcytosis transport route to cross the blood vessels to reach the tumors.
One key to making this treatment effective is using radiation, which is a standard therapy for both children and adults with brain tumors. Radiotherapy boosts levels of P-selectin in tumors. This means we can direct radiation to give the nanoparticles more P-selectin to grab onto in the tumor so more nanoparticles, and their drug cargo, will end up there. In the case of medulloblastoma, we could give the radiotherapy to the specific location in the brain before injecting the drug into the vein. There are many cases where we don’t want drugs to go to other parts of the brain even if we get them across the barrier, so using radiation allows us to focus a drug to the target area.
What’s Next for Treating Diseases Beyond the Blood-Brain Barrier?
Test the technology in people.
We know fucoidan is safe. You can buy it at a health food store, and some people claim it boosts immune function and reduces inflammation. Nanoparticle-based fucoidan therapy would not necessarily replace surgery, which is still the standard treatment for medulloblastoma. But it could improve the effectiveness of many classes of cancer drugs to prevent the cancer from returning, allow the use of lower doses of radiation therapy to the brain, and also reduce many drug side effects.
Use therapies in the brain cancers that have never been tried before.
Currently, the few drugs used to treat brain tumors are those that get through the blood-brain barrier. But now, we may have a much wider range of drugs that can reach brain tumors effectively. From our studies so far, it seems that it doesn’t matter what drug you put inside the particle; we can get it across the barrier.
Treat other brain cancers, brain metastases, and brain diseases.
Although this approach first could be used against medulloblastoma, it has broader potential applications. Most brain tumors occur in adults, so if the therapy works against other brain malignancies, including glioblastoma or brain metastases, it could benefit many people. We also could use the approach to deliver drugs to treat noncancerous brain diseases.
Researchers at the University of Waterloo and the University of Toronto have partnered with St. Michael’s Hospital in Toronto to analyze MRI data from multiple glioblastoma multiforme (GBM) sufferers. They’re using machine learning to fully analyze a patient’s tumor, to better predict cancer progression.
GBM is a brain cancer with an average survival rate of only one year. It is difficult to treat due to its extremely dense core, rapid growth, and location in the brain. Estimating these tumors’ diffusivity and proliferation rate is useful for clinicians, but that information is hard to predict for an individual patient quickly and accurately.
The researchers analyzed two sets of MRIs from each of five anonymous patients suffering from GBM. The patients underwent extensive MRIs, waited several months, and then received a second set of MRIs. Because these patients, for undisclosed reasons, chose not to receive any treatment or intervention during this time, their MRIs provided the scientists with a unique opportunity to understand how GBM grows when left unchecked.
The researchers used a deep learning model to turn the MRI data into patient-specific parameter estimates that inform a predictive model for GBM growth. This technique was applied to patients’ and synthetic tumors, for which the true characteristics were known, enabling them to validate the model.
“We would have loved to do this analysis on a huge data set,” said Cameron Meaney, a PhD candidate in Applied Mathematics and the study’s lead researcher. “Based on the nature of the illness, however, that’s very challenging because there isn’t a long life expectancy, and people tend to start treatment. That’s why the opportunity to compare five untreated tumors was so rare – and valuable.”
Now that the scientists have a good model of how GBM grows untreated, their next step is to expand the model to include the effect of treatment on the tumors. Then the data set would increase from a handful of MRIs to thousands.
Meaney emphasizes that access to MRI data – and partnership between mathematicians and clinicians – can have huge impacts on patients going forward.
“The integration of quantitative analysis into healthcare is the future,” Meaney said.
The study, Deep Learning Characterization of Brain Tumours With Diffusion Weighted Imaging, is published in the Journal of Theoretical Biology.
Patients with brain tumors bearing a mutant form of the enzyme IDH1 (isocitrate dehydrogenase 1) generally survive longer than patients without the mutation as such tumors are less aggressive at early stages. However, when they recur, they are more difficult to treat due to their resistance to ionizing radiation and invasive nature.
Of therapeutic significance, when researchers reduced the expression of ZMYND8 in radiation resistant glioma cells bearing mutated IDH1, the cells became susceptible to radiation-induced cell death. Mutant IDH1 changes the epigenetic regulation of chromatin, leading to hypermethylation of adult glioma. This work identifies gene targets epigenetically dysregulated by mutant IDH1 that confer resistance to radiation in glioma cells.
“These tumors almost always recur, and when they do, the tumors are much more aggressive. This finding gives us a new therapeutic avenue to treat these patients. It’s a very promising and novel therapeutic target,” said Maria Castro, PhD, professor of neurosurgery at Michigan Medicine and senior author of the study.
Glioma cell cultures bearing IDH1 mutations that the researchers used in this study were obtained from surgical biopsies of patients. The cells were treated with an inhibitor designed to block a metabolite produced by the mutated IDH1. The researchers then screened cellular mRNA and identified ZMYND8.
“After treating with the mutant IDH1 inhibitor, ZMYND8 was significantly downregulated. It’s overexpressed in mutant IDH1 glioma cells, but when you treat the cells with an inhibitor, ZMYND8 protein expression goes down. When this gene goes down, the cells become radiosensitive,” said Stephen Carney, a graduate student in the laboratory of Castro and Pedro Lowenstein, MD, PhD, also a professor of neurosurgery at Michigan Medicine.
Radiation therapy works by damaging cellular DNA and the biological role of ZMYND8 is to regulate DNA damage response. When ZMYND8 protein expression is high, researchers noted resistance to radiation. When ZMYND8 was low, radiation could successfully damage DNA in the glioma cells resulting in their death.
The results seen in human glioma cells were recapitulated in a new mouse model that the researchers developed. The mice had gliomas with mutated IDH1. The researchers found knocking out ZMYND8 in mice sensitized the tumors to radiation therapy and increased their survival.
“ZMYND8 contributes to the survival of mutant IDH1 glioma in response to radiation,” said Lowenstein. “We now have a new way of treating these tumors by using mRNA-based therapeutics in which we can downregulate the expression of ZMYND8 to render the cells radiosensitive.”
The synergistic actions of ZMYND8 knockdown in combination with other cancer drugs, such as PARP (Poly ADP-ribose polymerase) and HDAC (histone deacetylase) inhibitors further decreased resistance to radiation in the glioma cells, the researchers found. This hints at a potential for combinatorial therapy for patients with mutant IDH1 glioma.
Earlier work by the team developed synthetic protein nanoparticles (SPNPs) that can make it across the blood brain barrier. Castro intends to collaborate with colleagues at the U-M Biointerfaces Institute to design ZMYND8-inhibiting RNA, which could be delivered using these nanoparticles as vehicles.
Summary: A new method that targets the astrocytes surrounding glioblastoma brain cancer eradicates tumor cells and extends lifespan in animal models.
Source: Tel Aviv University
A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer.
The researchers achieved the outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth.
The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the U.S.
The paper was published in the journal Brain and was highlighted with special commentary.
The researchers explain, “Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years.
“Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.”
Dr. Mayo says, “Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells. Specifically, we studied astrocytes—a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape.
“Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth.”
Using an animal model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks.
Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived.
Dr. Mayo says, “In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse—indicating that the astrocytes are essential to tumor progression and survival. Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?”
To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.
Credit: Tel Aviv University
They found two main differences—thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.
“The tumor mass includes up to 40% immune cells—mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection.
“In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it.
“Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly—thereby protecting the tumor and facilitating its growth,” says Dr. Mayo.
The second change through which astrocytes support glioblastoma is by modulating their access to energy—via the production and transfer of cholesterol to the tumor cells.
Dr. Mayo: “The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself—namely in the astrocytes’ ‘cholesterol factory,’ which usually supplies energy to neurons and other brain cells.
“We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor.”
Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor.
Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially “starved” to death in just a few days.
These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis.
Dr. Mayo notes, “This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment.
Using an animal model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks.
“Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability—the tumor’s dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”
The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above.
The researchers explain, “For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients.”
Dr. Mayo concludes, “Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans. The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study.
“We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors.”
It may be possible to identify the presence of an aggressive brain tumor in children by studying their cerebrospinal fluid, according to new research led by Johns Hopkins Kimmel Cancer Center investigators.
Comparing cerebrospinal fluid samples from 40 patients with medulloblastoma — the most common malignant brain tumor in children, accounting for 10% to 15% of pediatric central nervous system tumors — and from 11 healthy children without the disease, investigators identified 110 genes, 10 types of RNA–the machinery that translates proteins–called circular RNAs, 14 lipids and several metabolites that were expressed differently between the two groups. While these details were not specific enough to distinguish among the four subtypes of medulloblastoma, they could be used to identify the presence of cancer versus normal fluid.
“Our study provides proof of principle that all three molecular approaches — studying RNA, lipids and metabolites — can be successfully applied to cerebrospinal fluid samples, not only to differentiate medulloblastoma patients from those without the disease, but also to provide new insights into the pathobiology of the disease,” Perera adds.
“This study provides data for novel biomarkers to detect and track medulloblastoma, which are very much needed to enable improved patient outcomes,” says Chetan Bettegowda, M.D., Ph.D., Jennison and Novak Families Professor of Neurosurgery at Johns Hopkins. “This work also forms the theoretical basis for examining similar biomarkers for other types of brain cancers and other neurological disorders.”
Current diagnosis is based on clinical assessment, imaging and biopsies from tumor tissue. There is an unmet need for diagnostic tests to detect the disease sensitively during the initial presentation and especially during any recurrences, because recurrences are not always seen on magnetic resonance imaging (MRI), Perera says.
Liquid biopsy — the molecular analysis of biofluids — is a minimally invasive method that shows promise for disease detection and monitoring by measuring circulating tumor cells, DNA, RNA or other substances in the urine, cerebrospinal fluid and blood samples. Because cerebrospinal fluid bathes the brain and spinal cord, it was considered a way to provide a window to tumors arising in the central nervous system and disseminating in the fluid, Perera says.
During the study, Perera and colleagues used gene sequencing, metabolic and lipid profiling laboratory techniques to tease out the differences in RNA, metabolites and lipids in cerebrospinal fluid samples from patients with medulloblastoma and healthy controls. Patients with medulloblastoma were found to have a unique RNA metabolic and lipid landscape in their fluid that might be helpful for diagnosis and monitoring, and that reflects biological changes consistent with the presence of medulloblastoma in the central nervous system, Perera says. The metabolite and lipid profiles both contained indicators of tumor hypoxia — a condition in which tumor cells were deprived of oxygen.
More studies in larger patient populations are necessary to confirm the findings, Perera says. The analysis provides several biomarkers that can be studied further.
The management of brain tumors developed in adolescents and young adults (AYAs) is challenging because of their histological heterogeneity and low incidence. The brain tumor and its treatment interventions can negatively affect neurological, neurocognitive, and endocrinological function, and dramatically affect the circumstances of AYA patients progressing to further education, employment, and marriage. Specific support is thus necessary to maintain the quality of life (QOL) of AYA brain tumor patients. AYA patients and survivors require active intervention and support for returning to school or work, progressing to further education, finding employment, and preserving fertility. Recent cancer genome profiling revealed that AYA gliomas include pediatric- and adult-type genetic alteration. Insights into the biology underlying the distribution of tumors in AYAs may influence the development of prospective trials. A more individualized view of brain tumors may influence stratification of patients’ in future clinical studies as well as selection for molecular targeted therapy. Here I review strategies for achieving a better outcome to decrease late effects and improve QOL.
Introduction
Adolescents and young adults (AYAs) comprise a group aged between 15 and 29–39 years. Here in line with other studies, I define AYAs as aged between 15 and 39 years [1,2,3]. Malignant neoplasms are the leading cause of death among AYAs, excluding suicide and unexpected accidents [4]. Oncological care of AYA patients is typically not uniform as they frequently fall between the pediatric and adult services in many countries—including Japan—leading to a poor entry into clinical trials, a poorer survival, and many psychosocial issues for AYA patients [5]. Despite recent significant advances in neuro-oncology, brain tumors among AYAs remain a major contributor to morbidity and mortality [5]. Although mortality rates among AYAs with cancer as a whole have declined by approximately 0.8% per year, the survival rate of AYAs with CNS tumors has not improved [6]. Tumor biology and clinical outcome for a given tumor differ among age groups, suggesting age-specific approaches. Brain tumors arising in AYAs are classified as pediatric- or adult-type [7]. The period from childhood to adulthood entails great physical, psychological, emotional, social, and sexual change [8, 9]. Many AYAs with cancer have unmet needs during cancer treatment and beyond, which result in worse emotional functioning, work or school functioning, fatigue, health-related quality of life (QOL) [10]. Moreover, AYAs with brain tumors have additional issues including cognitive impairment and deterioration, hormonal deficiency and deterioration, and appearance change. However, there is a paucity of literature about these problems in AYAs with brain tumors. Care is divided into adult and pediatric care. Changes in behavioral and endocrine function in AYAs complicate the differential diagnosis of brain tumors, often delaying the diagnosis [4]. Here I review the current concerns surrounding AYA brain tumors and their survivors.
Epidemiology of AYA brain tumors
The spectrum of AYA brain tumors—particularly with respect to location—differs significantly from that of younger children or older adults [5]. Although brain tumors can be observed at any age, brain development and the age of brain tumor incidence appear to be interrelated [11]. Choroid plexus tumor and atypical teratoid/rhabdoid tumor incidence peak at infancy. Ependymoma incidence peaks at age 0–4, and medulloblastoma and pilocytic astrocytoma incidence peak at age 5–9. Craniopharyngioma first peaks at age 0–14. Germ cell tumors peak at age 10–19—the timing of testis and ovary development. Pituitary adenoma starts increasing at age 15–19—at activation of pituitary gland hormone secretion—thereafter gradually increasing. Among pituitary adenoma, null cell adenoma and growth hormone-secreting adenoma peak at age 55–59, while prolactinoma peaks at age 25–29. Major adult tumors of meningioma and schwannoma increase from age 30 to 39, while lymphoma is rare in AYAs. Grade III glioma—including anaplastic oligodendroglioma, anaplastic oligoastrocytoma and anaplastic astrocytoma—peak at age 30–39.
In Fig. 1, I show the registered number of primary brain tumors by age group at the brain tumors registry in Japan. Gliomas—including unclassified, neuronal, and glioneuronal tumors—are the most common tumors in all AYAs, followed by germ cell tumors at age 10–19, and pituitary adenomas at age 20–39. Overall, representative malignant brain tumors in AYAs are diffuse gliomas and germ cell tumors.
Fig. 1
Breaking bad news in AYA malignant brain tumors
One of the most important—and difficult—communication situations for both patients with brain tumor and physicians is receiving and giving bad news [12, 13]. No reports have focused on breaking bad news in AYA malignant brain tumors. AYA patients, especially adolescents, would be disappointed and/or confused about their prospects for further education, employment, independence from parents, and marriage. To communicate bad news sensitively, physicians need to be aware of the possible worst news and the patients’ communication preference [14]. Receiving the initial tumor diagnosis was reportedly considered the worst of all bad news for most patients [15]. Some parents desire to hide the name of disease, and the terms “cancer” and “anticancer agent,” because they anticipate the stress these terms will give patients. AYAs are familiar with the internet and readily seek information about their own disease. Patients generally wanted to know “the truth” about diagnosis and prognosis, but what they meant varied; not all patients appear to wish to know the full facts: some desired full honest information to allow for autonomous choices; others preferred general information without details; and some wanted no bad news at all, only positive information [16]. The field of neurosurgery/neuro-oncology is unique, because patients might experience brain tumor-specific problems (for instance, epilepsy, hemiparesis, and changes in cognition and personality). Cognitive changes may complicate the breaking of bad news. Information given about the prognosis should be tailored to the coping styles of individual patients and their relatives, rather than to the preference of individual clinicians or treatment centers [14]. Therefore, physicians need to collect information on the preferences of patients and their families in advance and then break the bad news gradually by grasping their comprehension.
End-of-life care in AYA malignant brain tumors
Advance care planning is an important element in improving end-of-life care, but malignant brain tumors remain under-researched [17]. Some malignant brain tumors in AYAs are incurable. Therefore, some AYA patients with malignant brain tumor are prematurely faced with mortality, and many do not discuss advance directives and living wills. In the final stage, patients with brain tumor present severe symptoms due to the tumor and/or its treatment, which require adequate palliative management and supportive therapy. Few physicians are equipped to explain the terminal nature of malignant brain tumors to AYAs, who, unconsulted, frequently die in hospitals [18,19,20]. AYAs may be forced by their parents to live with them without their spouse or children but against their will. The family preferences and patient’s personal context should be considered before the patient is unable to express a living will, and appropriate psychological support should be provided. In incurable settings for AYAs, as with all patients, early palliative care and advanced care planning with end-of-life discussions are appropriate. Active intervention with sufficient visualized information benefited advance care planning for palliative care, avoiding cardiopulmonary resuscitation, and being confident in end-of-life decision making [21]. Therefore, the first step of breaking bad news is essential.
Dysphagia is an important symptom of patients with brain tumor, because it may affect nutrition and hydration, potentially inducing aspiration pneumonia [22]. In one study 85% of patients presented dysphagia in the last 4 weeks of life (median onset to death 21 days) [23]. Dysphagia also complicates the oral intake of drugs, including anticonvulsants. Seizures in the last 4 weeks before death occurred in 30% of patients and repeated seizures or status epilepticus, in 6% of patients [23]. In the last weeks of life, patients presenting dysphagia require changes from oral to nasogastric intubation for anticonvulsants or intramuscular barbiturates. Some new antiepileptic drugs such as levetiracetam and lacosamide are administered intravenously.
End stage brain tumors often involve consciousness deterioration. Most patients with brain tumor are bedridden for longer than other patients with cancer because of consciousness deterioration and/or severe neurological deficit. Caregivers of large physique AYA patients encounter other challenges. Patients with brain tumor usually die peacefully, but delirium or behavioral disturbances may cause disruption [23]; agitation and restlessness with moaning and grimacing should be interpreted as physical pain. Bulbar palsy or pseudobulbar palsy might disrupt breathing, which may be eased via the nasopharyngeal airway. No-treatment end-of-life treatment decisions for AYA patients with brain tumor—including withdrawal of supportive treatment (steroid, anticonvulsant), withdrawing–withholding of artificial nutrition–hydration in patients in prolonged vegetative state, and palliative sedation—are the most difficult [17]. Advance directives can help in taking such decisions. AYA patients with brain tumor at the recurrent/progressive stage may not be able to decide if they are willing to live with severe neurological symptoms. Hence, earlier active intervention of advance care planning with sufficient information of patients and their families is essential. Early discussions with families and home care personnel are also important.
Fertility preservation and malignant brain tumors
Loss of fertility is a pitiful outcome of cancer treatment and has been reported to negatively impact the QOL of cancer survivors [24]. Currently, AYA patients with brain tumor are underserved because of poor prognosis and fear of treatment delay. Patients with primary brain tumors risk infertility via: (1) chemotherapy; (2) hypothalamic–pituitary hormonal malfunction through tumor infiltration, surgery, or radiotherapy; and (3) ovary exposure at cerebrospinal irradiation. Among these risks, chemotherapy could impair sperm production in men or deplete the pool of ovarian oocytes in women, hence becoming a target for fertility preservation [25]. Germinoma at neurohypophysis and craniopharyngioma are leading causes of hypothalamic–pituitary malfunction. Applying proton beam therapy for cerebrospinal irradiation avoids radiation exposure of thoracoabdominal organs including ovaries [26].
Due to the poor prognosis for AYA malignant glioma, fertility preservation is a well-recognized but infrequently addressed clinical issue, and only 30% of patients reported having a discussion about fertility preservation [27]. Temozolomide, a representative alkylating agent commonly used in the treatment of gliomas, impairs fertility [28]. Bevacizumab is also reportedly moderately toxic to ovaries [29]. Despite the poor prognosis, reproductive—particularly childless—AYA patients with malignant glioma have significant interest in fertility preservation [25]. However, female patients with glioma have another issue. Tumor progression during pregnancy has been reported in 33–45% of patients with glioma [30]. Another report showed that the growth rate of tumor during pregnancy increased in 87% of cases, while clinical deterioration was observed in 38% of cases. Clinical deterioration resolved after delivery in 21.4% of cases. Hence, it is important to inform female AYA patient with glioma and her partner about the impact of pregnancy on the growth of the glioma.
On the other hand, AYA medulloblastoma is a good candidate for fertility preservation, and NCCN guidelines advise not only fertility preservation but also contraception [31]. Newly diagnosed germinoma at the pineal lesion, usually developing only in males, is the best candidate for sperm cryopreservation. Germinoma at neurohypophysis—a poor candidate for fertility preservation—with equal incidence in both sexes, often decreases gonadotropin secretion. Although the efficacy of postchemotherapy testicular sperm extraction/intracytoplasmic sperm injection was reported recently, informing reproductive AYA males of the potential risk of treatment-induced infertility is important [32]. First line standard treatment in Japan of the three courses of carboplatin and etoposide is considered a moderate infertility risk. Sperm cryopreservation should be also considered for patients with recurrent germinoma, because second remission is possible via treatment with intensive chemotherapy and radiation; newly diagnosed germinoma involving neurohypophysis usually precludes sperm cryopreservation due to impaired gonadotrophs. Highly malignant germ cell tumors including choriocarcinoma, yolk sac tumor, and embryonal carcinoma challenge fertility preservation because of the rapid progression of these diseases.
Technical advances offer cryopreservation of ovarian tissue for not only reproductive age but also prepubertal girls at risk of sterility, and should be offered before initiation of chemotherapy [33]. The cryopreservation of ovarian tissue could instead be systematically offered even to prepubertal girls at risk of sterility due to gonadotoxic treatment. In 2019, the American Society for Reproductive Medicine reported that ovarian tissue cryopreservation and transplantation is no longer experimental, but a standard of care [34]. However, fertility preservation is more difficult for female patients, because they need to undergo extra surgical procedure. Patients and/or parents may decline such offers because of the poor prognosis for malignant brain tumors. Testicular tissue cryopreservation is still under investigation and future technical advancement is expected.
To address these unmet needs and improve the QOL of AYA brain tumor survivors, it is necessary to establish oncofertility programs, including universal counseling on individualized infertility risk assessment and available preservation options, at each institution. In Fig. 2, I schematically show the representative clinical course of patients with brain tumor at reproductive age. An age-based guideline to the establishment of each disease and timely updates are essential.
Fig. 2
Educational supports
AYAs, especially adolescent patients, require educational support during cancer treatment and for cancer survivors [8]—issues dependent on specific national education systems. The Japanese school system comprises 6-year elementary schools, 3-year junior high schools and 3-year senior high schools, followed by 2-or-3-year junior colleges or 4-year colleges. Compulsory education lasts for 9 years through elementary and junior high school. During compulsory education periods, schools for long-term treatment of in-patient children are usually available in cancer centers and university/medical university hospitals. Educational support for senior high school students with hematopoeic malignancy or solid cancer—including malignant brain tumors—is essential. However, the hospital class for senior high school is unavailable in most hospitals. Since 2017, Hiroshima University Hospital has joined the Board of Education in Hiroshima City/Prefecture to teach senior high school inpatients students [35]. Remote teaching using information and communication technology has been applied to patients since 2018; the use of avatar robot OriHime® has been developed and utilized for students at senior high school (Fig. 3). Remote lessons proved effective for continuing learning and communication with classmates and teacher, providing effective preparation for school life after discharge. The establishment of educational systems requires collaboration among hospitals, regional senior high schools, and the Board of Education in each prefecture. Under coronavirus disease 2019, remote classrooms are utilized for healthy students. Therefore, it is expected that the remote class become generalized for AYA patients during long-term hospitalization in the future.
Fig. 3
Educational support for brain tumor survivors—including school reentry after discharge—presents challenges [12]. Malignant brain tumor survivors sometimes encounter difficulty at school reentry due to cognitive impairment, difficulties in concentration, memory, or problem-solving, as well as physical disabilities. Patients who underwent high-dose cranial irradiation may suffer cognitive deterioration due to late effects of irradiation [36]. Brain tumor survivors also suffer from changes in appearance—including alopecia, sparse hair, short stature, obesity, and so on—which may result in negativity, demotivation, and anxiety. The most common side effect is fatigue [37, 38], from unknown causes, with sequelae including cognitive difficulties, hormonal deficiency, seizure and anticonvulsant use, anxiety and depression, and so on. After school reentry, teachers, while encouraging brain tumor survivors, should understand the problem of fatigue. Lack of understanding about the persistent fatigue of brain tumor survivors may be their biggest problem. Both predischarge coordination conferences and periodic coordination conferences with patients, care givers, social workers, hospital–school liaison, rehabilitation staff, nurses, and attending physicians may further understanding of brain tumor survivors’ distress and alleviate their anxiety. Exact evaluation of their cognitive function, neuropsychological condition, and physical disabilities would provide support during compulsory education—but not during postcompulsory education. For AYA brain tumor survivors, assistance in utilizing social resources and peer support may be more useful. It was reported that a vast majority of AYAs remained engaged in education throughout their cancer trajectory with the support of educational support program [39]. Because AYA patients with brain tumor with cognitive impairment have many unmet needs, establishment of a special educational support program is desired. Further research will be required to evaluate the quality of interventions and incorporate the voice of AYA patients with brain tumors to further inform service delivery.
Molecular biology and treatment of the AYA population in neuro-oncology
Recent advances in molecular study have enhanced integrated diagnosis of brain tumors. For example, pediatric and adult molecular glioma subtypes differ greatly. In adult grade II and III diffuse gliomas, isocitrate dehydrogenase (IDH)1/2 and 1p/19q codeletion status play an important role. Adults with diffuse gliomas harboring both IDH mutation and chromosome 1p/19q codeletion show more favorable clinical outcomes with significantly longer survival. In contrast, adults with diffuse gliomas harboring IDH wildtype and 1p/19q noncodeletion show poor clinical outcomes, which are consistent with glioblastoma. Adults with diffuse glioma harboring IDH mutation and 1p/19q noncodeletion show intermediate clinical outcomes [40]. IDH mutation and O6-methylguanine–DNA–methyltransferase methylation are highly linked, and confer more favorable responses to alkylator therapy—specifically temozolomide [5]. In pediatric high-grade gliomas, histone 3 (H3) K27-altered—usually observed in pons and thalamic tumors—has a poor prognosis. In infant nonbrainstem glioma, 40% of tumors harbor NTRK-fusion [41]. In older child and adolescent hemispheric high-grade gliomas, H3 G34R/V mutation is common [7].
Low-grade gliomas of childhood may be single pathway diseases. In pilocytic astrocytoma—the most common low-grade glioma—activation of the RAS/MAPK pathway via BRAF/FGFR alteration has been reported [5]. Among BRAF/FGFR alteration, BRAF–KIAA 1549 fusion is most common and is associated with a better prognosis [42]. BRAFV600E mutation, also observed in minor populations of pilocytic astrocytoma, was associated with a poorer prognosis. Mutation of BRAFV600E was also identified, most commonly occurring in pleomorphic xanthoastrocytoma and ganglioglioma, followed by astroblastoma [43]. BRAFV600E mutation may be associated with a better prognosis in some glioblastoma populations, but epithelioid glioblastoma with BRAFV600E mutation showed a poorer prognosis [44]. In epithelioid glioblastoma, TERT promoter mutations and CDKN2A/B homozygous deletions were also reported [45].
The 5th edition of the WHO classification has taken a new approach to classifying gliomas, glioneuronal tumors, and neuronal tumors, dividing them into six different families as follows: (1) adult-type diffuse gliomas; (2) pediatric-type diffuse low-grade gliomas; (3) pediatric-type diffuse high-grade gliomas; (4) circumscribed astrocytic gliomas; (5) glioneuronal and neuronal tumors; and (6) ependymomas [7]. AYA gliomas comprise pediatric-type and adult-type. Molecular studies are essential for exact diagnosis. The 5th edition of the WHO classification will include much molecular information: CDKN2A/B homozygous deletion in diffuse astrocytoma IDH-mutant; MYB- or MYBL1-alteration in pediatric diffuse astrocytoma; ZFTA (the new designation for C11orf95, which is considered more representative of the tumor type than RELA, because it may be fused with more partners than RELA) fusion supratentorial ependymoma; MNl-altered astroblastoma; CNS tumor with BCOR internal tandem duplication; CIC-rearranged sarcoma; and so on.
Importantly, special consideration is necessary for AYA brain tumors, because they occur at a developmentally sensitive period and AYAs are likely to survive long enough to experience their sequelae. Each indication of radiation therapy for brain tumors should take into account the risks of functional impairment caused by tumor progression versus the late effects of radiation, including: neurocognitive impairment, endocrine disorder, vascular events such as moyamoya syndrome, infraction and cavernous angioma, and increased risk of secondary malignancy [46, 47]. For example, physicians will recommend local irradiation for middle-aged adult patients with oligodendroglioma, but may try to avoid or postpone local irradiation for AYA patients with oligodendroglioma, a representative chemo- and radio-sensitive adult-type diffuse glioma. On the other hand, physicians need to realize the difficulty of applying the standard pediatric regimen of vincristine and carboplatin against nonresectable AYA pilocytic astrocytoma due to the risk of gonadal toxicity and higher risk of vincristine neurotoxicity [5]. For some diseases, adults with pediatric tumors (such as medulloblastoma and germ cell tumors) seem to have a worse prognosis than is usually reported for children due to under treatment or erroneous treatment, or poor compliance with the therapeutic guidelines [48]. Adult patients’ tolerance of chemotherapy following radiotherapy is generally lower and these treatments should, therefore, be applied at centers with experience in neuro-oncology. Survivorship of AYA patients with brain tumor is another issue. Future development of AYA glioma-specific treatment strategies is anticipated.
The vast majority of AYA patients with brain tumor appear to be spontaneous and unrelated to either carcinogens in the environment or hereditary predisposition, such as family cancer syndromes [4]. For AYA patients with brain tumor, current cancer multigene panel testing may be less useful for discovering therapeutic targets. However, cancer multigene panel testing would allow adolescent patients with brain tumor to reach an exact diagnosis, especially useful in differentiating between pediatric- and adult-type tumors. Accumulation of knowledge about AYA brain tumors using cancer multigene panel testing would enhance the development of integrated diagnosis and treatment. Future development with AYA brain tumor-specific cancer multigene panels would render development of precision medicine.
One important issue is the low participation rate of AYAs with cancer in clinical trials. A previous study reported that the participation rate of AYAs was 5–20%, which was much lower than that of children (60–80%) [49]. This low participation rate is associated with poor survival outcomes of AYAs. Improved survival has been documented among young adolescents with several tumor types who are treated according to the pediatric protocol as compared with older AYAs [50, 51]. Pediatric oncologists tend to be more aggressive in chemotherapy, whereas adult oncologists are more likely to choose radiation therapy. It is unclear whether this difference in the treatment approach changes the outcomes of AYA patients with brain tumors. Molecular targeted therapy should be developed via clinical trials, because this approach potentially reduces the late effect of chemotherapy/radiotherapy. Cancer multigene panel testing in the diagnostic work-up of AYA brain tumors is critical for the development of molecular targeted therapy. An AYA neuro-oncology program should be developed in major cancer centers to improve the outcomes of AYA patients with brain tumors.
Conclusions
Here, I explained the current status and issues of AYA brain tumors. Although the incidence of entire AYA brain tumors is not rare, each pathologically based disease is rare and integrated diagnosis of AYA brain tumors is currently in transition. Because AYAs experience physical, psychological, emotional, social, and sexual change with many life events, specific consideration is necessary to prevent deteriorating QOL by brain tumor-specific symptoms. Although the prognosis for some malignant AYA brain tumors is poor, physicians must be cognizant that reproductive—and particularly, childless—AYA patients have significant interest in fertility preservation. All AYA brain tumors should undergo molecular profiling not only for diagnosis but also for investigating tumor biology and developing an appropriate treatment. Development of AYA brain tumor-specific treatment strategies and precision medicine are desirable to avoid sequelae and late effects and to improve outcomes.
Are you still thirsty? Or just addicted to this toxic chemical? Well, here’s another reason why you ought to refuse to pour this poison cocktail down your esophagus.
According to an article in Collective Evolution, researchers at the University of Iowa have been taking another look at aspartame, although I really don’t know why they need any more proof of it’s toxicity. It was kept off the market until 1981, thanks to the consumer advocate and lawyer James Turner.
60,000 women took part in the research and here’s what they found:
“… Women who consumed two or more diet drinks a day are 30 percent more likely to experience a cardiovascular event, and 50 percent more likely to die from a related disease.”
Of course the folks who created this study have merely called for more research:
“‘It’s too soon to tell people to change their behaviour based on this study; however, based on these and other findings we have a responsibility to do more research to see what is going on and further define the relationship, if one truly exists,’ says Dr. Ankur Vyas, because ‘This could have major public health implications.’”
Hmmm. The major health implication of these neurotoxins were pointed out over four decades ago. Since it was ole Donald Rumsfeld who commandeered this poison into the food supply, a quote from the liar himself might be appropriate.
Brain cancer takes a variety of forms – and research to better understand and treat it is progressing on a variety of fronts.
One area of focus is the tumor microenvironment the skein of tissues and blood vessels that feed and support a tumor. Researchers are exploring how newly formed brain tumors interact with surrounding cells to turn those cells into aiders and abetters of tumor growth. They’re particularly interested in how brain tumors tap into the body’s blood supply to draw in nutrients. Understanding these processes is a critical first step to devising therapies that prevent tumors from exploiting nearby tissue for their own purposes.
Work is also underway to get a better understanding of the genomic landscape of brain cancer – the set of mutations and other derangements of the genetic code that set normal brain cells on a course for cancer. Mutations found to be drivers of brain tumor cell growth are often prime targets for new drugs.
At Dana-Farber, for example, researchers recently identified several molecular alterationsthat drive high-grade astrocytomas, rare and fatal childhood brain cancers. At least two of the new mutations might be susceptible to blocking by existing drugs, and the others provide new opportunities for future drug development. (This whitepaper dives deeper into the science behind pediatric brain tumor research.)
Another group of Dana-Farber researchers recently identified a protein vital to both the normal development of the brain and, in many cases, of medulloblastoma, a fast-growing brain tumor that arises most often in children. When researchers cut the level of the protein called Eya1 in half in mice prone to develop a form of medulloblastoma, the animals’ risk of dying from the disease dropped sharply.
Such research into the basic mechanics of cancer often provides clues to new therapies. A discoveryby Dana-Farber scientists, for example, revealed how a protein named netrin-1 helps neurons in the developing brain make connections with one another. The finding may have important applications for treating brain cancer because many cancer cells produce netrin to attract blood vessels as a source of nourishment. Switching off that process could starve a tumor or prevent it from growing.
Treatment Advances
Technical advances are helping surgeons treat the disease more effectively. Technology known as stimulated Raman Scattering microscopy helps surgeons better distinguish cancerous from normal tissue in the brain during operations, potentially improving the safety and accuracy of such procedures.
New surgical procedures enable surgeons to treat some brain tumors near the pituitary gland by using an endoscope, a thin tube with a tiny video camera at the tip. By passing the endoscope through a small hole at the back of the nose, surgeons can operate through the nasal passages, limiting potential damage to the brain.
One of the major challenges of delivering chemotherapy agents to the brain is the blood-brain barrier, a dense web of tissue that prevents many drug molecules from reaching the brain. Investigators are testing convection-enhanced delivery, in which a small tube is placed into a brain tumor through a small hole in the skull. An infusion pump connected to the tube can send drugs directly to the tumor.
Immunotherapies, which rally the body’s immune system to fight disease, are showing promise in brain cancer. Dana-Farber investigators recently tested immunotherapy agents known as checkpoint inhibitors in mice with glioblastoma, an incurable form of brain cancer. The results were so encouraging – many of the mice were considered cured, and many had no evidence of tumor two months after treatment – that investigators have begun clinical trials of the agents in human patients.
Long-term use of both mobile and cordless phones is associated with an increased risk for glioma, the most common type of brain tumor, the latest research on the subject concludes.
The new study shows that the risk for glioma was tripled among those using a wireless phone for more than 25 years and that the risk was also greater for those who had started using mobile or cordless phones before age 20 years.
“Doctors should be very concerned by this and discuss precautions with their patients,” study author Lennart Hardell, MD, PhD, professor, Department of Oncology, University Hospital, Örebro, Sweden, told Medscape Medical News.
Such precautions, he said, include using hands-free phones with the “loud speaker” feature and text messaging instead of phoning.
The recent worldwide increase in use of wireless communications has resulted in greater exposure to radiofrequency electromagnetic fields (RF-EMF). The brain is the main target of RF-EMF when these phones are used, with the highest exposure being on the same side of the brain where the phone is placed.
The new study pooled data from two case-control studies on histopathologically confirmed malignant brain tumours. The first included patients aged 20 to 80 years diagnosed from 1997 to 2003, and the second included those aged 18 to 75 years diagnosed between 2007 and 2009. Cases came from six oncology centers in Sweden.
Cases were matched with controls of the same sex and approximate age who were randomly drawn from the Swedish Population Registry.
All participants filled out a questionnaire detailing exposure to mobile phones and cordless desktop phones.
The analysis included 1498 cases of malignant brain tumors; the mean age was 52 years. Most patients (92%) had a diagnosis of glioma, and just over half of the gliomas (50.3%) were the most malignant variety — astrocytoma grade IV (glioblastoma multiforme). Also included were 3530 controls, with a mean age of 54 years.
The analysis showed an increased risk for glioma associated with use for more than 1 year of both mobile and cordless phones after adjustment for age at diagnosis, sex, socioeconomic index, and year of diagnosis. The highest risk was for those with the longest latency for mobile phone use over 25 years.
The risk was increased the more that wireless phones were used. The odds ratios steadily rose with increasing hours of use.
The risk for glioma was greatest in the most exposed part of the brain. The odds ratios were higher for ipsilateral exposure and for glioma in the temporal and overlapping lobes.
Further, the risk was highest among participants who first used a mobile phone (odds ratio, 1.8) or cordless phone (odds ratio, 2.3) before age 20 years, although the number of cases and controls was relatively small.
Developing Brain
As Dr Hardell explained, children and adolescents are more exposed to RF-EMF than adults because of their thinner skull bone and smaller head and the higher conductivity in their brain tissue. The brain is still developing up to about the age of 20 and until that time it is relatively vulnerable, he said.
There was a higher risk for third-generation (3G) mobile phone use compared with other types, but this was based on short latency and rather low numbers of exposed participants, said the authors. 3G universal global telecommunications system mobile phones emit wide band microwave signals, which “hypothetically” may result in higher biological effects compared to other signals, they write.
Such biological effects, said Dr Hardell, could include an increase in reactive oxygen species, which several articles have linked to cancer. The p53 gene has also been implicated, he said.
The study’s very high participation rate (86% for cases and 87% for controls) makes it unlikely that selection bias influenced the results, said the authors.
Dr Hardell believes the new findings reinforce the message that EF-EMF emissions from wireless phones should be regarded as carcinogenic under International Agency on Research on Cancer (IARC) classifications and that current guidelines for exposure “should be urgently revised” to reflect that.
According to the IARC’s 2013 report, there is a “causal” relationship between use of both mobile and cordless phones and that the risk of glioma is “possible.”
Numerous studies have looked at the link between use of wireless phones and brain tumors. Studies by Dr Hardell and his colleagues dating back to the late 1990s have found a connection with mobile and cordless phones.
But the INTERPHONE study (Int J Epidemiol2011;39:675-694; Cancer Epidemiol2011;32:453-464) failed to find strong evidence that mobile phones increase the risk for brain tumors.
In addition, a large prospective study (Int J Epidemiol2013;42:792-802) found that mobile phone use was not associated with increased incidence of glioma or of meningioma or non–central nervous system cancers in middle-aged British women.
According to Dr Hardell, this last study was limited because it used information at one point in time. “It is not a case-control study and has serious problems with the methods used,” he told Medscape Medical News.
Evidence “Unconvincing”
Reached for a comment, L. Dade Lunsford, MD, Lars Leksell Professor of Neurosurgery, and director, Center for Image Guided Neurosurgery, University of Pittsburgh, Pennsylvania, said the new study provides additional “but as yet unconvincing” evidence of a potential role of cell or cordless phone technologies in the pathogenesis of gliomas.
He noted that some features were not controlled, including ionizing radiation exposure and family history.
As well, he said, the study suffers from recall bias, with results possibly being affected by patients being anxious to solve the question of “why me?”
“It is of interest that the only study that used actual industry data of cell phone use (the Danish study [Lancet Oncol2011;12:624-626; Rev Environment Health 2012;27:51-58]) was dismissed by the authors as ‘uninformative’,” he said. “Perhaps it was not supportive of the author’s premise.”
Although the study didn’t specify the side of the tumor, Dr Lunsford pointed out that about 90% of the world’s population is right-handed and that most hold their mobile phone to their left ear in order to write with their dominant hand. “One could theorize then that left-sided tumors would predominate with the temporal lobe being most adjacent to the cell phone output.”
Dr Lunsford also commented that both glial and Schwann cells are late-responding tissues and that the oncogenesis of such cells by mobile phone technologies remains unexplained. “If cell phones cause such tumors, why do patients not develop higher rates of ipsilateral basal or squamous cell cancers, or melanomas — these are frequently dividing cell lines that theoretically ought to be even more susceptible.”
While the potential role of cell phones as an additional factor in oncogenesis “can’t be dismissed out of hand,” the use of this technology does save lives, stressed Dr Lunsford.
“Cell phone has provided an amazing safety net for citizens of almost all cultures across the world. The lives saved by the proliferation of cell phone communication is phenomenal — emergency calls, quick first responders, warnings of severe weather are only a few examples.”
ARYAN'S BLOG 