Posts tagged brain tumors

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.

The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.

Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.

The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.

“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.

The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.

“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”

The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.

Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.

This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.

Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.

Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.

Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.

“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”

(Source: stjude.org)

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.

The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.

Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.

The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.

“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.

The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.

“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”

The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.

Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.

This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.

Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.

Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.

Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.

“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”

(Source: stjude.org)

Study finds fog-like condition related to chemotherapy’s effect on new brain cells and rhythms.

It’s not unusual for cancer patients being treated with chemotherapy to complain about not being able to think clearly, connect thoughts or concentrate on daily tasks. The complaint – often referred to as chemo-brain – is common. The scientific cause, however, has been difficult to pinpoint.

New research by Rutgers University behavioral neuroscientist Tracey Shors offers new clues for this fog-like condition, medically known as chemotherapy-induced cognitive impairment. In a featured article published in the European Journal of Neuroscience, Shors and her colleagues argue that prolonged chemotherapy decreases the development of new brain cells, a process known as neurogenesis, and disrupts ongoing brain rhythms in the part of the brain responsible for making new memories. Both, she says, are affected by learning and in some cases are necessary for learning to occur.

“One of the things that these brain rhythms do is to connect information across brain regions,” says Shors, Professor II in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “We are starting to have a better understanding of how these natural rhythms are used in the process of communication and how they change with experience.”

Working in the Shors laboratory, postdoctoral fellow Miriam S. Nokia from the Department of Psychology at the University of Jyvaskyla in Finland and Rutgers neuroscience graduate student Megan Anderson treated rats with a chemotherapy drug – temozolomide (TMZ) – used on individuals with either malignant brain tumors or skin cancer to stop rapidly dividing cells that have gone out of control and resulted in cancer.

In this study, scientists found that the production of new healthy brain cells treated with the TMZ was reduced in the hippocampus by 34 percent after being caught in the crossfire of the drug’s potency. The cell loss, coupled with the interference in brain rhythms, resulted in the animal being unable to learn difficult tasks.

Shors says the rats had great difficulty learning to associate stimulus events if there was a time gap between the activities but could learn simple task if the stimuli were not separated in time.  Interestingly, she says, the drug did not disrupt the memories that were already present when the treatment began.

For cancer patients undergoing long-term chemotherapy this could mean that although they are able to do simple everyday tasks, they find it difficult to do more complicated activities like processing long strings of numbers, remembering recent conversations, following instructions and setting priorities. Studies indicate that while most cancer patients experience short-term memory loss and disordered thinking, about 15 percent of cancer patients suffer more long-lasting cognitive problems as a result of the chemotherapy treatment.

“Chemotherapy is an especially difficult time as patients are learning how to manage their treatment options while still engaging in and appreciating life. The disruptions in brain rhythms and neurogenesis during treatment may explain some of the cognitive problems that can occur during this time. The good news is that these effects are probably not long-lasting,” says Shors.

(Source: news.rutgers.edu)

A new type of prophylactic treatment for brain injury following prolonged epileptic seizures has been developed by Emory University School of Medicine investigators.

Status epilepticus, a persistent seizure lasting longer than 30 minutes [check this, some people say FIVE], is potentially life-threatening and leads to around 55,000 deaths each year in the United States. It can be caused by stroke, brain tumor or infection as well as inadequate control of epilepsy. Physicians or paramedics now treat status epilepticus by administering an anticonvulsant or general anesthesia, which stops the seizures.

Researchers at Emory have been looking for something different: anti-inflammatory compounds that can be administered after acute status epilepticus has ended to reduce damage to the brain. They have discovered a potential lead compound that can reduce mortality when given to mice after drug-induced seizures.

The results are scheduled for publication Monday in Proceedings of the National Academy of Sciences Early Edition.

"For adults who experience a period of status epilepticus longer than one hour, more than 30 percent die within four weeks of the event, making this a major medical problem," says Ray Dingledine, PhD, chair of the Department of Pharmacology at Emory University School of Medicine. "Medications that would reduce the severe consequences of refractory status epilepticus have been elusive. We believe we have an effective route to minimizing the brain injury caused by uncontrolled status epilepticus."

Dingledine’s laboratory has identified compounds that block the effects of prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Prostaglandin E2 is also involved in the toxic inflammation in the brain arising after status epilepticus.

The first author of the paper is postdoctoral fellow Jianxiong Jiang, PhD, and the medicinal chemist largely responsible for developing the compounds is Thota Ganesh, PhD.

Jiang and colleagues induced status epilepticus in mice with the alkaloid drug pilocarpine, and gave them a compound, TG6-10-1, starting four hours later and again at 21 and 30 hours. TG6-10-1 blocks signals from EP2, one of four receptors for prostaglandin E2.

Among animals that received the EP2 blocker, 90 percent survived after one week, while 60 percent of a control group survived. The scientists also used nest-building behavior and weight loss as gauges of damage to the brain. Four days after status epilepticus, all the animals that received TG6-10-1 displayed normal nest-building, but more than a quarter of living control animals were not able to build nests. In addition, the brains of TG6-10-1-treated mice had reduced levels of inflammatory messenger proteins called cytokines, less brain injury and less breach of the blood-brain-barrier.

Consequences of refractory status epilepticus can include brain damage, difficulty breathing, abnormal heart rhythms and heart failure.

Dingledine says the first clinical test of an EP2 blocking compound would probably be as an add-on treatment for prolonged status epilepticus, several hours after seizures have ended. It could also be tested in similar situations such as subarachnoid hemorrhage, prolonged febrile seizures or medication-resistant epilepsy, he says.

Dingledine and his colleagues have a patent pending for novel technology related to this research. Under Emory policies, they are eligible to receive a portion of any royalties or fees received by Emory from this technology.

(Source: eurekalert.org)

Injury to the subcortical structures of the inner brain is a major contributor to worsening neurological abnormalities after “awake craniotomy” for brain tumors, reports a study in the February issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

During a procedure intended to protect critical functional areas in the outer brain (cortex), damage to subcortical areas—which may be detectable on MRI scans—is a major risk factor for persistent neurological deficits. “Our ability to identify and preserve cortical areas of function can still result in significant neurological decline postoperatively as a result of subcortical injury,” write Dr. Victoria T. Trinh and colleagues of The University of Texas MD Anderson Cancer Center, Houston.

Risk Factors for Neurological Deficits after Awake Craniotomy

The researchers analyzed factors associated with worsening neurological function after awake craniotomy for brain tumor surgery. In awake craniotomy, the patient is sedated but conscious so as to be able to communicate with the surgeon during the operation.

The patient is asked to perform visual and verbal tasks while specific areas of the cortex are stimulated, generating a functional map of the brain surface. This helps the surgeon navigate safely to the tumor without damaging the “eloquent cortex”—critical areas of the brain involved in language or movement.

The study included 241 patients who underwent awake craniotomy with functional brain mapping from 2005 through 2010. Of these, 40 patients developed new neurological abnormalities. Dr. Trinh and colleagues examined potential predictive factors—including changes on a type of MRI scan called diffusion-weighted imaging (DWI).

Of the 40 cases with new neurological deficits, 36 developed while the surgeon was operating in the subcortical areas of the brain. These are the inner structures of the brain, located beneath the outer, folded brain cortex. Just one abnormality developed while the surgeon was operating in the cortex only.

MRI Changes May Reflect Subcortical Damage

Neurological abnormalities developing while the surgeon was operating in the subcortex were likely to remain after surgery, and to persist at three months’ follow-up evaluation. Dr. Trinh and coauthors write, “Patients with intraoperative deficits during subcortical dissection were over six times more likely to have persistently worsened neurological function at three-month follow-up.”

In these patients, MRI scans showing more severe changes in the DWI pattern in the subcortex also predicted lasting neurological abnormalities. Of patients who had neurological deficits immediately after surgery and significant DWI changes, 69 percent had persistent deficits three months after surgery.

Patients who had “positive” cortical mapping—that is, in whom eloquent cortex was located during functional mapping—were somewhat more likely to have neurological abnormalities immediately after surgery. However, the risk of lasting abnormalities was not significantly higher compared to patients with negative cortical mapping.

Awake craniotomy with brain stimulation produces a “real-time functional map” of the brain surface that is invaluable to the neurosurgeon in deciding how best to approach the tumor. The new results suggest that, even when the eloquent cortex is not located on cortical mapping, subcortical areas near the tumor can still be injured during surgery. “Subcortical injury is the primary cause of neurological deficits following awake craniotomy procedures,” Dr. Trinh and colleagues write.

The researchers add, “Preserving subcortical areas during tumor resections may reduce the severity of both immediate and late neurological sequelae.” Based on their findings, they believe subcortical mapping techniques may play an important role in avoiding complications after awake craniotomy.

(Source: lww.com)

The causes of learning problems associated with an inherited brain tumor disorder are much more complex than scientists had anticipated, researchers at Washington University School of Medicine in St. Louis report.

The disorder, neurofibromatosis 1 (NF1), is among the most common inherited pediatric brain cancer syndromes. Children born with NF1 can develop low-grade brain tumors, but their most common problems are learning and attention difficulties.

“While one of our top priorities is halting tumor growth, it’s also important to ensure that these children don’t have the added challenges of living with learning and behavioral problems,” says senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology. “Our results suggest that learning problems in these patients can be caused by more than one factor. Successful treatment depends on identifying the biological reasons underlying the problems seen in individual patients with NF1.”

The study appears online in Annals of Neurology.

According to Gutmann, who is director of the Washington University Neurofibromatosis Center, scientists are divided when considering the basis for NF1-associated learning abnormalities and attention deficits.

Mutations in the Nf1 gene can disrupt normal regulation of an important protein called RAS in the hippocampus, a brain region critical for learning. Initial work from other investigators had shown that increased RAS activity due to defective Nf1 gene function impairs memory and attention in some Nf1 mouse models.

However, earlier studies by Gutmann and collaborator David F. Wozniak, PhD, research professor in psychiatry, showed that a mutation in the Nf1 gene lowers levels of dopamine, a neurotransmitter involved in attention. In this Nf1 mouse model, Gutmann and his colleagues found that the branches of dopamine-producing nerve cells were unusually short, limiting their ability to make and distribute dopamine and leading to reduced attention in those mice.

The new research suggests that both sides may be right.

In the latest study, postdoctoral fellow Kelly Diggs-Andrews, PhD, found that the branches of dopamine-producing nerve cells that normally extend into the hippocampus are shorter in Nf1 mice. As a result, dopamine levels are lower in that part of the brain.

Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, showed that the low dopamine levels disrupts the ability of nerve cells in the hippocampus to modulate the way they communicate with each other. These communication adjustments are a primary way the brain creates memories.

Researchers then found that giving Nf1 mice L-DOPA, which increases dopamine levels, restored their nerve cell branch lengths to normal and corrected the hippocampal communication defect. L-DOPA also eliminated the memory and learning deficits in these mice.

“These results and the earlier findings suggest that there are a variety of ways that NF1 may cause cognitive dysfunction in people,” Gutmann says. “Some may have problems caused only by increased RAS function, others may be having problems attributable to reduced dopamine, and a third group may be having difficulties caused by both RAS and dopamine abnormalities.”

To customize patient therapy, Gutmann and his colleagues are now working to develop ways to quantify the contributions of dopamine and RAS to NF1-related learning disorders.

(Source: news.wustl.edu)

In what could be a breakthrough in the treatment of deadly brain tumors, a team of researchers from Barrow Neurological Institute and Arizona State University has discovered that the immune system reacts differently to different types of brain tissue, shedding light on why cancerous brain tumors are so difficult to treat.

The large, two-part study, led by Barrow research fellow Sergiy Kushchayev, MD under the guidance of Dr. Mark Preul, Director of Neurosurgery Research, was published in the Sept. 14 issue of Cancer Management and Research
The study explores the effects of immunotherapy on malignant gliomas, cancerous brain tumors that typically have a poor prognosis.

What the researchers discovered was that immune cells of the brain and of the blood exhibit massive rearrangements when interacting with a malignant glioma under treatment. Essentially, the study demonstrates that the complex immune system reacts differently in different brain tissues and different regions of the brain, including tumors.

"This is the first time that researchers have conducted a regional tissue study of the brain and a malignant glioma to show that these immune cells do not aggregate or behave in the same way in their respective areas of the brain," says Dr. Preul. "This means that effective treatment in one area of the brain may not be effective in another area. In fact, it could even cause other regions of the tumor to become worse."

The results of the study provide important insight into why clinical trials involving immunotherapies on glioma patients may not be working.

(Source: eurekalert.org)