Despite modern chemoradiation therapy it is still very difficult to give reliable prognoses for malignant gliomas. Surgical removal of the glioma is still the preferred method of treatment. Doctors at Universitätsklinikum Erlangen’s Department of Neurosurgery have now developed a new procedure for analysing radiological imaging scans which makes it possible to predict the course of a disease relatively precisely.

The Friedlein Grading A/B (FGA/B) classification system – named after the physician Katharina Friedlein – is a quick and precise way of determining whether surgical removal is the best possible treatment method for a given tumour. Essentially, the Erlangen-based doctors classify tumours according to their position in the brain in the context of a routine magnetic resonance imaging (MRI) scan. Tumours that are not located in functional brain regions or that are located at a certain distance from such regions are classified as FGA, while tumours that are close to or inside a functional brain region are classified as FGB.

With the FGA/B method it possible to plan the consequences of tumour surgery, which is crucial for the success of the treatment, in a precise, low-risk and quantitative manner. This makes the Friedlein Grading system the first classification system which can be easily applied in clinical practice. ‘There have already been several attempts in medicine to develop such a classification system. However, most approaches were too complicated and were based on academic values only, which made it difficult to use them in clinical practice,’ says PD Dr. Nicolai Savaskan from FAU’s Chair of Neurosurgery. ‘The FGA/B method can be applied on the basis of a standard MRI scan which glioma patients have to undergo anyway and is highly reliable despite being so simple. We hope that our colleagues in neurosurgery departments in smaller hospitals will also be able to use it successfully in everyday clinical practice.’ Universitätsklinikum Erlangen

A new method for measuring genetic variability within a tumour might one day help doctors identify patients with aggressive cancers that are more likely to resist therapy, according to a study led by researchers now at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Researchers used a new scoring method they developed called MATH (mutant-allele tumour heterogeneity) to measure the genetic variability among cancer cells within tumours from 305 patients with head and neck cancer. High MATH scores corresponded to tumours with many differences among the gene mutations present in different cancer cells.

Cancers that showed high genetic variability – called ‘intra-tumour heterogeneity’ – correlated with lower patient survival. If prospective studies verify the findings, MATH scores could help identify the most effective treatment for patients and predict a patient’s prognosis.

Researchers have long hypothesized that multiple sub-populations of mutated cells within a single cancer lead to worse clinical outcomes; however, oncologists do not use tumour heterogeneity to guide clinical care decisions or assess disease prognosis because there is no single, easy-to-implement method of doing so in clinical practice.

To address this need, James Rocco, MD, PhD, and his colleagues developed MATH to make it easier for doctors to measure genetic variability in patients’ tumours and to help guide treatment decisions.

The new findings confirm that high genetic variability with a patient’s tumour is related to increased mortality in head and neck squamous cell carcinoma.

‘Genetic variability within tumours is likely why people fail treatment,’ says Rocco, Professor and John and Mary Alford Chair of Head and Neck Surgery and Director of the OSUCCC – James Division of Head and Neck Oncologic Surgery. ‘In patients who have high heterogeneity tumours it is likely that there are several clusters of underlying mutations – in the same tumour – driving the cancer. So their tumours are likely to have some cells that are already resistant to any particular therapy.’

For the current study, Rocco and his team used the MATH tool to analyse retrospective data from 305 head and neck squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA). This National Institutes of Health repository of publicly available data was launched in 2006 as a pilot project and now includes samples from more than 11,000 patients across 33 tumour types. The MATH score was calculated from data obtained by TCGA with a genome sequencing technique called whole-exome sequencing.

Researchers confirmed that high intra-tumour heterogeneity was related to increased mortality in this sub segment of patients. Each 10 percent increase in MATH score corresponded to an 8.8 percent increased likelihood of death.

The relationship between MATH score and mortality was not dependent on HPV (human papilloma virus) status or other molecular characteristics of the tumour.

‘Our retrospective analysis showed that patients with high heterogeneity tumours were more than twice as likely to die compared to patients with low heterogeneity tumors,’ says Rocco. ‘This type of information could refine the dialogue about how we tackle cancer by helping us predict a patient’s treatment success and justify clinical decisions based on the unique makeup of a patient’s tumor.’ EurekAlert

Studies on mice reveal that a special protein in the brain’s tiniest blood vessels may affect the risk of stroke. Peter Carlsson, professor in genetics at the University of Gothenburg, and his research team are publishing new research findings about how the blood-brain barrier develops and what makes the capillaries in the brain different from small blood vessels in other organs.

The brain’s smallest blood vessels differ from those in other organs in that the capillary walls are much more compact. The nerve cells in the brain get the nutrients they need by molecules actively being transported from the blood, instead of passively leaking out from the blood vessels.

This blood-brain barrier is vital, because it enables strict control over the substances with which the brain’s nerve cells come into contact. It has a protective function that if it fails, increases the risk of stroke and other complications.

The smallest blood vessels, the capillaries, have a type of cell called pericytes. These are essential to the development of the blood-brain barrier. Pericytes are also found in other organs, and researchers have previously been unable to find out what gives the brain’s pericytes this unique ability.

The Gothenburg research team has found that the brain’s pericytes contain a protein, FoxF2, which is not present in the pericytes of other organs, and which coordinates the changes that make the blood vessels compact. FoxF2 is needed in order for the blood-brain barrier to form during foetal development.

“Mice that have too little or too much FoxF2 develop various types of defects in the brain’s blood vessels,” explains Peter Carlsson, professor at the University of Gothenburg’s Department of Chemistry and Molecular Biology.

In humans, researchers have noted that major changes in a region of chromosome 6 have been associated with an increased risk of stroke, but it has not been known which of the genes in the area are responsible for this risk.

“The FoxF2 gene is an extremely interesting candidate, as it is located right in the middle of this region, and research is under way now in collaboration with clinical geneticists to investigate the extent to which variations in the FoxF2 gene affect people’s risk of suffering a stroke,” says Peter Carlsson. University of Gothenburg

Researchers have identified a new host of gene variants that could make people vulnerable to sporadic motor neurone disease.

Until recently, it was thought that genetics made little contribution to the disease – also termed amyotrophic lateral sclerosis (ALS) – and that the environment was mostly to blame.

Motor neurone disease (MND) is a group of diseases in which the nerve cells in the brain and spinal cord controlling the muscles that enable us to move, speak, breathe and swallow to slowly degenerate and die.

Death is caused by respiratory failure, which typically occurs within 2 to 5 years of developing this debilitating condition.

‘This is an advance in knowledge about the role genetics is likely to play in sporadic forms of motor neurone disease,’ says the University of Sydney’s Associate Professor Roger Pamphlett, a co-author of the new study.

‘The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources,’ Associate Professor Pamphlett says.

‘Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly-arising changes in genes that were not present in their parents.’

In an effort to identify genetic variants that may play a role in the disease, the researchers sequenced the protein-coding genes of 44 MND-affected individuals and their parents.

They found that two in five MND-affected individuals had inherited rare, recessive gene variants from their parents, and a quarter had developed novel gene variants that were not present in their parents. The researchers believe these gene variants are ‘promising candidates’ for playing a role in the development of motor neurone disease.

Many of these ‘genetic suspects’ have been identified in other brain-related disease, including Alzheimer’s disease, Parkinson’s disease and autism. Also, many are involved in biological processes or metabolic pathways implicated in the development of motor neurone disease.

While the researchers cannot yet point to a potential therapeutic application of their findings, identifying genetic changes that underlie MND is the first step in finding ways to manipulate these changes using gene therapy. University of Sydney

Huntington’s disease attacks the part of the brain that controls movement, destroying nerves with a barrage of toxicity, yet leaves other parts relatively unscathed.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have established conclusively that an activating protein, called “Rhes,” plays a pivotal role in focusing the toxicity of Huntington’s in the striatum, a smallish section of the forebrain that controls body movement and is potentially involved in other cognitive functions such as working memory.

“Our study definitively confirms the role of Rhes in Huntington’s disease,” said TSRI Assistant Professor Srinivasa Subramaniam, who led the study. “Our next step should be to develop drugs that inhibit its action.”

In an earlier study, Subramaniam and his colleagues showed that Rhes binds to a series of repeats in the huntingtin protein (named for its association with Huntington’s disease), increasing the death of neurons. The new study shows deleting Rhes significantly reduces behavioural problems in animal models of the disease.

In addition, the study took the research further and revealed the effects of adding Rhes to the cerebellum, a brain region normally not affected in Huntington’s.

Remarkably, Huntington disease animals injected with Rhes experienced an exacerbation of motor issues, including loss of balance and co-ordination. Subramaniam and his colleagues also found lesions and damaged neurons in the cerebellum, confirming Rhes is sufficient to promote toxicity and showing that even those regions of the brain normally impervious to damage can become vulnerable if Rhes is overexpressed.

“Perhaps the biggest question to emerge from this study is whether Rhes is a good drug target for Huntington’s disease,” Subramaniam said. “The short answer is ‘yes.’ Drugs that disrupt Rhes could alleviate Huntington’s pathology and motor symptoms.”

“Many Huntington’s disease patients experience psychiatric-related problems, such as depression and anxiety,” added Supriya Swarnkar, the first author of the study and a member of Subramaniam’s lab. “But it’s unclear whether they are the cause or consequences of the disease. We think, by targeting Rhes, we might block the initiation of Huntington’s, which we predict would afford protection against psychiatric-related problems as well.” The Scripps Research Institute