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Fri 22 Feb 2008 04:00 AM

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Research matters

News from the Harvard Medical School research community.

News from the Harvard Medical School research community.

Oncology

Drug combination shrinks breast cancer metastases in brain

Cognitive decline in aging may be linked to disruption of communication between different regions of the brain.

A combination of a 'targeted' therapy and chemotherapy shrank metastatic brain tumours by at least 50% in one-fifth of patients with aggressive HER2-positive breast cancer, according to data presented by Dana-Farber Cancer Institute investigators at the San Antonio Breast Cancer Symposium.

Lapatinib (Tykerb) and capecitabine (Xeloda) were paired in an extension of a Phase 2 clinical trial in which lapatinib given alone shrank brain metastases significantly in 6% of 241 patients.

In the extension trial, capecitabine was added to lapatinib in 49 patients whose metastases - cancerous colonies in the brain spread from their primary cancer - had progressed while on treatment.

With the combination therapy, brain metastases shrank by 20% or more in 18 patients (37%) and shrank by at least 50% in 10 patients (20%), reported Nancy Lin, MD, of Dana-Farber's Breast Oncology Center.

"Very few medications have shown activity in the treatment of brain metastases, particularly in HER-2-positive metastatic breast cancer patients," said Lin, who led the study with Eric Winer, MD, director of the Dana-Farber Breast Oncology Center.

"Therefore, these data are quite encouraging, and further studies are warranted."

Lapatinib is an oral small-molecule drug from GlaxoSmithKline that is approved along with capecitabine for treating patients with advanced or metastatic breast cancer whose tumours are driven by the abnormal growth signal, HER-2, and who have already undergone therapy including trastuzumab (Herceptin), a taxane drug, and an anthracycline compound. Lapatinib, like trastuzumab, blocks the HER-2 signal.

Up to one-third of women with advanced, HER-2-positive breast cancer may develop metastases to the brain.

"Although radiation treatment is often effective, as women live longer with metastatic cancer, some develop worsening of brain metastases despite radiation," said Lin.

"Because cancer in the brain can have a major impact on quality of life, it is important to have treatment options to address this problem."

Neurobiology

Neurons in the frontal lobe may be responsible for rational decision-making

Scientists have found that when monkeys choose between different options, the value neurons assign to each option does not depend on the menu of choices.

You study the menu at a restaurant and decide to order the steak rather than the salmon. But when the waiter tells you about the lobster special, you decide lobster trumps steak

Without reconsidering the salmon, you place your order-all because of a trait called 'transitivit'y.

"Transitivity is the hallmark of rational economic choice," says Camillo Padoa-Schioppa, a postdoctoral researcher in HMS Professor of Neurobiology John Assad's lab.

According to transitivity, if you prefer A to B and B to C, then you ought to prefer A to C. Or, if you prefer lobster to steak, and steak to salmon, then you will prefer lobster to salmon.

Padoa-Schioppa is lead author on a paper that suggests this trait might be encoded at the level of individual neurons.

The study, which appeared online Dec. 9 in Nature Neuroscience, shows that some neurons in a part of the brain called the orbitofrontal cortex encode economic value in a "menu invariant" way.

That is, the neurons respond the same to steak regardless if it's offered against salmon or lobster.

"People make choices by assigning values to different options. If the values are menu invariant preferences will be transitive."

"The activity of these neurons does not vary with the menu options, suggesting that these neurons could be responsible for transitivity," Padoa-Schioppa explains.

"This study provides a key insight into the biology of our frontal lobes and the neural circuits that underlie decision-making," Assad adds.

"Despite the maxim, we in fact can compare apples to oranges, and we do it all the time. Camillo's research sheds light on how we make these types of choices."
Frontal lobe damage has been linked to "choice deficits" such as eating disorders, compulsive gambling and abnormal social behaviour.

For example, in the first documented case of brain injury impacting behaviour, the infamous railroad construction foreman Phineas Gage became unsociable after a tamping iron passed through his skull in 1848, damaging his frontal lobes.

This area of the brain has also been implicated in drug abuse.

Dyslexia marked by poor reading fluency may be caused by disorganised, meandering tracts of nerve fibres in the brain.

Labs are just beginning to probe normal decision-making at the level of individual neurons, venturing into a new field called neuroeconomics. Such research might eventually help to explain choice deficits associated with frontal lobe functions.

The new study builds on an April 2006 Nature paper in which Padoa-Schioppa and Assad identified neurons that encode the value macaque monkeys assign to juice they choose independent of its type, providing a common currency of comparison for the brain.

In that study, the scientists found that although monkeys generally prefer grape juice to apple juice, sometimes they choose the latter, if it is offered in large amounts.

When presented with 3 units of apple juice and 1 unit of grape juice, for example, a monkey might take the grape juice only 50% of the time.

This indicates that the value of the grape juice is 3 times that of the apple juice. A particular group of neurons in the orbitofrontal cortex fire at roughly the same rate, regardless of the monkey's decision because the animal values both choices equally.

These neurons also fire at the same rate if the monkey chooses 6 units of apple juice or 2 units of grape juice. Thus, these neurons encode the value the monkey receives in each trial.

Now, by adding a third juice to the mix, the team has tested whether these neurons reflect transitivity. The three juices were offered to a monkey in pairs, dozens of times over the course of a session, the quantity of each juice varying from trial to trial.

In general, monkeys preferred 1 unit of juice A to 1 unit of juice B, 1B to 1C, and 1A to 1C. During each session, Padoa-Schioppa recorded the activity of a handful of neurons in the orbitofrontal cortex, and he discovered their firing rate did not depend on whether B was offered against A or against C, indicating that these neurons respond in a menu invariant way.

"The stability of these neurons could help to explain why we make decisions that are consistent over the short term," Padoa-Schioppa says.

"In our study, the neural circuit was not influenced by the short-term behavioural context."

Padoa-Schioppa is now examining the possibility that value-encoding neurons may adapt to different value scales over longer periods of time.

Neurology

The aging brain: failure to communicate

A team of Howard Hughes Medical Institute researchers has shown that normal aging disrupts communication between different regions of the brain.

The new research, which used advanced medical imaging techniques to look at the brain function of 93 healthy individuals from 18 to 93 years old, shows that this decline happens even in the absence of serious pathologies like Alzheimer's disease.

Researchers have known for quite some time that normal aging slowly degrades bundles of axons in the central nervous system that transmit critical signals.

"Our study now shows that cognitive decline in aging may be linked to disruption of communication between different regions of the brain," said Randy L. Buckner, who is a Howard Hughes Medical Institute investigator at Harvard University.

He is also affiliated with the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital/Harvard Medical School.

"Our study now shows that cognitive decline in aging may be linked to disruption of communication between different regions of the brain."

The new research, published December 6, 2007, in the journal Neuron, begins to reveal how simply growing old can affect the higher-level brain systems that govern cognition. "We may have caught the failure of communication in the act," said Buckner.

The human brain can be divided into major functional regions, each responsible for different kinds of "applications," such as memory, sensory input and processing, executive function or even one's own internal musing.

The functional regions of the brain are linked by a network of white matter conduits.

These communication channels help the brain coordinate and share information from the brain's different regions. White matter is the tissue through which messages pass from different regions of the brain.
Scientists have known that white matter degrades with age, but they did not understand how that decline contributes to the degradation of the large-scale systems that govern cognition.

"The crosstalk between the different parts of the brain is like a conference call," said Jessica Andrews-Hanna, a graduate student in Buckner's lab and the lead author of the study.

"We were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another."

Buckner, Andrews-Hanna, and their colleagues looked at crosstalk in the brains of 93 people aged 18 to 93, divided roughly into a young adult group (18-34 years old) and an old adult group (60-93 years old).

The older participants were given a battery of tests to measure their cognitive abilities - including memory, executive function and processing speed.

Each person was studied using functional magnetic resonance imaging (fMRI) exams to measure activity in different parts of the brain. fMRI can precisely map enhanced blood flow in specific regions of the brain.

Increased blood flow reflects greater activity in regions of the brain that are utilised during mental tasks.

For the task used in the Neuron study, subjects were presented words and were asked to decide whether each word represented a living (e.g., dog) or nonliving (e.g., house) object. "Such a task requires the participants to meaningfully process the words," said Buckner.

Buckner's group explored whether aging in the older group caused a loss of correlation between the regions of the brain that - at least in young adults - engage in robust neural crosstalk.

They focused on the links within two critical networks, one responsible for processing information from the outside world and one, known as the default network, which is more internal and kicks in when we muse to ourselves.

For example, the default network is presumed to depend on two regions of the brain linked by long-range white matter pathways. The new study revealed a dramatic difference in these regions between young and old subjects.

"We found that in young adults, the front of the brain was pretty well in sync with the back of the brain," said Andrews-Hanna.

"In older adults this was not the case. The regions became out of sync and they were less correlated with each other."

Interestingly, the older adults with normal, high correlations performed better on cognitive tests.

According to Buckner, it is inferred that in a young, healthy brain, signals are readily transmitted by white-matter conduits. As we age, those conduits are compromised. "Measures of white matter integrity in the older adults point to decline," he said.

Depending on the networks at play, the result may be impaired memory, reasoning or other important cognitive functions.

Buckner and Andrews-Hanna emphasized that other changes in the aging brain may contribute to cognitive decline. For example, cells' ability to express chemical neurotransmitters may also be compromised.

In general, the new work promises a better physiological understanding of cognitive decline in the elderly and may help explain differences among individuals.

"It may help explain why some people are just as sharp in their 90s as they were in their 40s," noted Andrews-Hanna. "We all age differently and cognitive abilities vary considerably among individuals."

Typically, said Buckner, as individuals get into their 70s and 80s, you see some degree of change.

"We can use this new approach (correlating the activities of different regions of the brain) as a tool to understand variation between individuals. We can also explore risk factors for breakdowns (in these pathways) like cardiovascular health."

Hematology

Data confirm dasatinib's effectiveness in resistant chronic myelogenous leukaemia

Updated clinical trial results show that the drug dasatinib (Sprycel) continues to be highly effective in patients with chronic myelogenous leukaemia who were unable to tolerate Gleevec or who developed resistance to it, reported a team led by researchers at Dana-Farber Cancer Institute.

Richard Stone, MD, of Dana-Farber, presented the results of the START-C trial at the annual meeting of the American Society of Hematology on Tuesday, Dec. 11, in Atlanta, Georgia.

"Previous results showed that about 65% of patients who couldn't tolerate Gleevec or became resistant will benefit from dasatinib," said Stone. "Now, with a longer follow-up of at least two years, these responses are durable. Very few people have relapsed on the drug."

Dasatinib, an oral tyrosine kinase inhibitor made by Bristol-Myers Squibb that blocks the abnormal BCR-ABL growth signals of the Philadelphia chromosome, was approved by the Food and Drug Administration in 2006. It is 325 times more powerful than Gleevec in blocking BCR-ABL, and also inhibits other cancerous growth signals.
The international study team reported that progression-free survival 15 months after beginning treatment was 90%, and overall survival was 96%.

Doses of dasatinib were interrupted at times for 87% of patients and doses were reduced in 73% because of side effects, which included lowered blood cell counts and pleural effusions (excess fluid in the chest cavity). "These are manageable problems," said Stone.

Because of its superior potency to Gleevec, investigators are testing dasatinib as an alternative first-line treatment.

Stone said that a large Phase III trial of the drug used as initial treatment is underway at Dana-Farber and other research centres.

Neurology

Slow reading in dyslexia tied to disorganised brain tracts

Dyslexia marked by poor reading fluency -- slow and choppy reading -- may be caused by disorganized, meandering tracts of nerve fibres in the brain, according to researchers at Children's Hospital Boston, Beth Israel Deaconess Medical Center (BIDMC) and the Harvard Graduate School of Education (HGSE).

The study was led by Christopher Walsh, MD, PhD, chief of the Division of Genetics at Children's Hospital Boston, Bernard Chang, MD, a neurologist at BIDMC, and Tami Katzir, PhD, an assistant professor at HGSE (now at the University of Haifa in Israel). Findings appeared in the journal Neurology on December 4.

"We looked at dyslexia caused by a particular genetic disorder, but what we found could have implications for understanding the causes of dyslexia in other populations as well," says Walsh, who is also a Howard Hughes Medical Institute investigator at BIDMC.

Dyslexia, which affects 5 to 15% of all children, has different forms. Subjects in the study had reading problems caused by a rare genetic disorder known as periventricular nodular heterotopia, or PNH.

Although their intelligence is normal, people with PNH have trouble reading fluently, or smoothly, lacking the rapid processing necessary for this aspect of reading.

The genetic mutation that causes PNH disrupts brain structure. In a normal brain, much of the grey matter (consisting mostly of nerve cells) appears on the brain's surface, while white matter (consisting mostly of nerve fibres or "wiring" connecting areas of grey matter) runs deeper in the brain.

In PNH, nodules of grey matter sit deep in the brain's core, in the white matter, having failed to migrate out to the surface as the brain was developing.

To learn more about how these developmental changes in the brain might lead to reading problems, the researchers tested cognitive skills needed for reading in 10 patients with PNH, 10 individuals with dyslexia without neurological problems, and 10 normal readers.

They used a specialized form of MRI called diffusion tensor imaging to look at the structure of the white matter in the brain.

In PNH patients, unlike in normal readers, white matter fibres took circuitous routes around the misplaced grey matter, and in some cases, didn't organize into uniform bundles, which could leave regions of grey matter poorly connected. Importantly, the more disorganized the PNH patients' white matter, the less fluent their reading.

While other studies have found disorganised white matter in the general population of people with dyslexia, these individuals often struggle with several aspects of reading, making it "hard to know exactly what the role of white-matter integrity is in isolation," says Chang.

By demonstrating white-matter problems in PNH patients, who have an isolated reading fluency problem, and correlating that with reading fluency scores, the researchers were able to conclude that white-matter integrity and organisation may be the structural basis in the brain for reading fluency.

"This makes sense," says Chang. "When we read, we need to take in information visually, hook it up with our inner dictionary of what letters and words mean, and when we're reading aloud, connect that with the region that gives us our ability to speak."

For smooth, automatic reading, "the white matter is there to connect different regions of grey matter and allow them to function seamlessly."

When reading fluency is the primary problem, "it may be that the areas of the brain that are important for reading are not connected efficiently," says Chang.

Most people with dyslexia who have trouble reading fluently don't have misplaced grey matter or PNH. But Walsh and Chang believe that disorganised white matter could similarly alter brain function in both groups.

Their next study will examine how faulty white-matter connections alter brain patterns, comparing brain activation while reading in PNH patients and in dyslexic readers with poor fluency, which do not have PNH.

Pinpointing the brain structures responsible for fluent reading may eventually help researchers and educational specialists develop and use remediation techniques that help improve the automatic nature of reading in children and adults with these kinds of difficulties, the researchers note.

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