Childhood brain tumors affect working memory of adult survivors

Adult survivors of childhood brain tumors have lower working memory performance compared to healthy adults, according to researchers at Georgia State University and Emory University.

The findings, published in the Journal of the International Neuropsychological Society, report that adult survivors of pediatric posterior fossa brain tumors performed significantly lower than controls on standardized clinical tests of working memory performance administered in the study.

The researchers studied the working memory of adult survivors of childhood posterior fossa brain tumors versus a healthy control sample using functional magnetic resonance imaging (fMRI) and neuropsychological measures. Each group consisted of 17 participants.

During fMRI, the participants completed a measure called the n-back task. They were asked to monitor a series of letters and respond “yes” or “no” with their index or middle finger on a button box if an item was presented “n” items before, ranging from one to three letters back. Accurately recalling a letter two or three letters back represented higher working memory capabilities. Participants also completed other standardized clinical measures.

Whole-brain fMRI analyses also found survivors had significantly greater blood-oxygen level dependent (BOLD) activation in the left superior/middle frontal gyri and left parietal lobe of their brain during a verbal working memory task, demonstrating higher activation in these structures. Analyses revealed higher levels of activations in prefrontal regions were associated with lower behavioral performance on higher-load working memory tasks.

Our goal was to identify the neural mechanisms underlying working memory difficulty in adult survivors of childhood brain tumors,” said Tricia King, associate professor of psychology and neuroscience at Georgia State. “The results suggest that adult survivors of pediatric posterior fossa brain tumors recruited additional resources to control cognitive ability in the prefrontal lobe during increased demands for working memory. This increased prefrontal activation is associated with lower working memory performance.”

Adult survivors of childhood brain tumors are at risk for neurocognitive deficits, such as working memory impairment, that contribute to poor long-term outcomes. While advances in diagnosis and treatment have led to improved clinical outcomes and increases in the five-year survival rates of pediatric brain tumor patients, research has shown that long-term childhood brain tumor survivors suffer from adverse health, disrupted quality of life, and impaired cognitive and social outcomes.

Working memory deficits are also common in other neurological conditions, such as schizophrenia, multiple sclerosis and traumatic brain injury, because working memory is an essential component for higher-order cognitive processes in humans.

Understanding of the neural mechanism underlying working memory impairments in adult survivors of childhood brain tumors is limited and little fMRI research with these survivors has been reported. This study was designed to address this gap in knowledge and improve treatment for survivors of childhood brain tumors.

King et al. Neural Underpinnings of Working Memory in Adult Survivors of Childhood Brain Tumors. J Int Neuropsychol Soc. 2015;21:494-505 DOI: http://dx.doi.org/10.1017/S135561771500051X [Abstract]

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New smart robot accelerates cancer treatment research

A new smart research robot accelerates research on cancer treatments by finding optimal treatment combinations. 

Complex diseases like cancer are almost exclusively treated by combining several different drugs. These combinations are typically composed from drugs that show an effect on their own, but do not necessarily constitute the best possible combinations. The new robot system finds optimal treatment combinations and was developed by a research group led by Dr Mats Gustafsson, Professor of Medical Bioinformatics at Uppsala University.

We have built a robot system that plans and conducts experiments with many substances, and draws its own conclusions from the results. The idea is to gradually refine combinations of substances so that they kill cancer cells without harming healthy cells‘, says Dr Claes Andersson, also a leading scientist in the project.

Instead of just combining a couple of substances at a time, the new lab robot has the ability to handle on the order of a dozen drugs simultaneously. The aim for the future is to be able to handle many more, preferably hundreds.

We are now one among the few laboratories in the world with this type of lab robot. However, so far researchers have only used the systems to look for combinations that kills the cancer cells, not taking the side effects into account‘, says Mats Gustafsson.

The next step in the development is to make the robot system more automated and smarter. The current version still involves a few manual steps that could be automated. The scientists also want to build more prior knowledge into the guiding algorithm of the robot, for example, prior knowledge about drug targets and disease pathways.

For patients with the same cancer type returning multiple times, sometimes the cancer cells develop resistance against the pharmacotherapy used. The new robot systems may also become important in the efforts to find new drug compounds that make these resistant cells sensitive again.

An article about the robot system was presented today in Scientific Reports, and is part of a doctoral thesis on drug combinations, recently defended by Dr Muhammad Kashif.

Kashif et al. In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index. Sci Rep. 2015;5:14118. doi: 10.1038/srep14118 [Article]

Acupuncture reduces hot flashes in breast cancer survivors

Findings also highlight acupuncture’s ability to induce a stronger placebo effect than oral medications.

Acupuncture may be a viable treatment for women experiencing hot flushes as a result of estrogen-targeting therapies to treat breast cancer, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania. Hot flashes are particularly severe and frequent in breast cancer survivors, but current FDA-approved remedies for these unpleasant episodes, such as hormone replacement therapies are off-limits to breast cancer survivors because they include estrogen. The results of the study are published in the Journal of Clinical Oncology.

Though most people associate hot flashes with menopause, the episodes also affect many breast cancer survivors who have low estrogen levels and often undergo premature menopause, following treatment with chemotherapy or surgery,” said lead author Jun J. Mao, MD, MSCE, associate professor of Family Medicine and Community Health. “These latest results clearly show promise for managing hot flashes experienced by breast cancer survivors through the use of acupuncture, which in previous studies has also been proven to be an effective treatment for joint pain in this patient population.”

Hot flashes are brief episodes of flushing, sweating, racing heartbeat and sensations of heat. Precisely how hot flushes arise isn’t known, though they are closely associated with decreased estrogen levels.

In the trial, the research team enrolled 120 breast cancer survivors, all of whom reported experiencing multiple hot flashes per day. Participants were randomized into four different interventions that would analyze how effectively an acupuncture technique known as electroacupuncture – in which embedded needles deliver weak electrical currents – reduces incidents of hot flushes as compared to the epilepsy drug gabapentin, which was previously shown to be effective in reducing hot flashes for these patients. For an eight-week period, participants received gabapentin (900 mg) daily, gabapentin placebo daily, electroacupuncture (twice per week for two weeks, then once weekly), or “sham” electroacupuncture, which involves no actual needle penetration or electrical current.

After the eight-week treatment period, the subjects in the electroacupuncture group showed the greatest improvement in a standard measure of hot flush frequency and severity, known as the hot flash composite score (HFCS). They were followed by the group that had received the “sham acupuncture” treatment. The gabapentin pill group reported less improvement than the sham acupuncture group, and the placebo pill group placed last.

In addition to reporting the greatest reductions in hot flash frequency/severity, both acupuncture groups reported fewer side effects than either of the pill groups.

The Penn researchers surveyed the subjects sixteen weeks after treatment ended, and found that the electroacupuncture and sham electroacupuncture groups had enjoyed a sustained, and even slightly increased, abatement of hot flashes. The pill-placebo patients also reported a slight improvement in symptoms, whereas the gabapentin pill group reported a worsening.

Compared to its sham version, electroacupuncture produced a 25 percent greater reduction in HFCS, suggesting that it really could work better – though the modest size of the study precluded a statistically definitive conclusion. However, the study did show with confidence that the sham acupuncture procedure worked better than a placebo pill at relieving hot flushes, presumably by creating a stronger expectation of benefit.

Acupuncture is an exotic therapy, elicits the patient’s active participation, and involves a greater patient-provider interaction, compared with taking a pill,” Mao said. “Importantly, the results of this trial show that even sham acupuncture – which is effectively a placebo – is more effective than medications. The placebo effect is often dismissed as noise, but these results suggest we should be taking a closer look at how we can best harness it.”

The sham acupuncture procedure also seemed to create a strikingly lower experience of adverse side effects, which were virtually absent in this group. Only one woman reported an episode of drowsiness from the sham acupuncture, whereas the placebo pill recipients reported eight adverse events such as headache, fatigue, dizziness and constipation.

Some have questioned whether acupuncture has a biological effect apart from the power of suggestion. There is evidence from prior studies that it can boost bloodstream levels of endorphins and related painkilling, mood-elevating molecules more directly than via suggestion. Studies also have found that traditional acupuncture works differently than sham acupuncture in the brain. But for patients, that issue may be moot if they can enjoy dramatic improvements in their quality of life, especially compared to no improvement if they receive no treatment.

Mao et al. Electroacupuncture Versus Gabapentin for Hot Flashes Among Breast Cancer Survivors: A Randomized Placebo-Controlled Trial. J Clin Oncol. 2015; doi: 10.1200/JCO.2015.60.941 [Abstract]

Aspirin could hold the key to supercharged cancer immunotherapy

Giving cancer patients aspirin at the same time as immunotherapy could dramatically boost the effectiveness of the treatment, according to new research published in the journal Cell.

Francis Crick Institute researchers, funded by Cancer Research UK, have shown that skin, breast and bowel cancer cells often produce large amounts of prostaglandin E2 (PGE2). This molecule dampens down the immune system’s normal response to attack faulty cells, which helps cancer to hide. It is a trick that allows the tumour to thrive and may explain why some immunotherapy treatments have not been as effective as hoped.

Aspirin is part of a group of molecules called COX inhibitors, which stop the production of PGE2 and help reawaken the immune system. Combining immunotherapy with aspirin or other COX inhibitors substantially slowed bowel and melanoma skin cancer growth in mice, compared to immunotherapy alone.

Study author Professor Caetano Reis e Sousa, senior group leader at the Francis Crick Institute, said: “We’ve added to the growing evidence that some cancers produce PGE2 as a way of escaping the immune system. If you can take away cancer cells’ ability to make PGE2 you effectively lift this protective barrier and unleash the full power of the immune system.”

Giving patients COX inhibitors like aspirin at the same time as immunotherapy could potentially make a huge difference to the benefit they get from treatment. It’s still early work but this could help make cancer immunotherapy even more effective, delivering life-changing results for patients.”

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “PGE2 acts on many different cells in our body, and this study suggests that one of these actions is to tell our immune system to ignore cancer cells. Once you stop the cancer cells from producing it, the immune system switches back to ‘kill mode’ and attacks the tumour.”

This research was carried out in mice so there is still some way to go before we will see patients being given COX inhibitors as part of their treatment. But it’s an exciting finding that could offer a simple way to dramatically improve the response to treatment in a range of cancers.”

Zelenay et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell, 2015; DOI: 10.1016/j.cell.2015.08.015 [Open Access]