A skin cancer drug can improve Alzheimer-like symptoms in mice engineered to mimic the condition, it has been widely reported.
Many national newspapers have covered the news, which is based on aninal tests involving the drug bexarotene (brand name Targretin , which is currently only used to treat a rare form of skin cancer. This drug was given to mice that had been genetically engineered to develop a condition similar to Alzheimer’s, and in a short space of time the mice showed lowered brain levels of a key protein called beta-amyloid. Beta-amyloid is the substance that forms the protein plaques in the brain that are characteristic of Alzheimer’s. The researchers also observed post-treatment improvements in the brain function of the mice – for example, they were better able to build nests and remember the way through a maze.
Although this research is in animals and there is limited direct application to humans at the current time, these early findings do show some potential for further research. Notably, the drug had a rapid effect on amyloid plaques that are characteristic of Alzheimer’s, and the fact that drug is currently licensed means it will have undergone safety regulations for its current use. That said, there are no guarantees it will prove as safe or effective in people with Alzheimer’s.
At the current time no tests have been carried out in humans with Alzheimer’s, only an animal model of the disease. The research will undoubtedly be of interest to researchers, doctors, and patients and their families, but it is far too early to suggest that this could be a cure for Alzheimer’s.
Where did the story come from?
The study was carried out by researchers from Case Western Reserve University School of Medicine, Cleveland, and other institutions in the US. The study was supported by a number of research funding foundations, including the Blanchette Hooker Rockefeller Foundation, Thome Foundation, and the Roby and Taft Funds for Alzheimer’s.
The study was published in the peer-reviewed journal Sciencexpress.
BBC News gives accurate coverage of this study. The Sun, Daily Mail and The Daily Telegraph featured slightly optimistic headlines, but their articles generally do make it clear that this was a study in mice and give good accounts of the research.
What kind of research was this?
This was animal research aiming to investigate the effects of a drug called bexarotene on a mouse model of Alzheimer’s disease.
Bexarotene activates a receptor on the surface of cells that is known to be involved in triggering the production of a protein called ‘apolipoprotein E’ (ApoE . The ApoE protein is involved in the breakdown of soluble beta-amyloid, a protein that builds up to form the characteristic insoluble plaques seen in the brains of people with Alzheimer’s.
All humans carry a gene containing the code for producing the ApoE protein, but some people carry a particular variant of the ApoE gene known as the ApoE e4 allele. People carrying this variant are known to be at increased risk of developing Alzheimer’s disease, and carrying this variant seems to be associated with the build-up of beta-amyloid plaques in the brain. Therefore the researchers were interested whether a drug that increases production of ApoE could potentially have an effect on the build-up of beta-amyloid in the brain. To explore this possibility they decided to test the drug in mice with Alzheimer’s-like symptoms, looking at whether it could reduce their their beta-amyloid levels and improve their cognitive performance.
What did the research involve?
The researchers used various different genetically engineered mouse models of Alzheimer’s in their experiments. The researchers carried out a number of tests to assess the effects of bexarotene on soluble beta-amyloid in the fluid surrounding the brain, insoluble beta-amyloid plaques in the brain, and cognitive performance of these mice.
The mice were administered oral bexarotene for three, seven, nine, 14, 20 or 90 days. These mice were compared with similar mice that did not receive bexarotene. The researchers looked at mice of three different ages: two months, six months and 11 months in order to look at the effects of the drug when given to mice at different stages of their Alzheimer’s-like condition – the older mice having more beta-amyloid protein build-up.
The mice in models of Alzheimer’s display impairments in their performance in several tasks: navigating a water maze (an indicator of cognition ; nest construction (an indicator of social behaviour ; fear response to placement in a shock chamber; and sense of smell. In a sample of mice the researchers tested performance in these four areas after administering the drug.
After the treatment periods the mice’s brains were examined to look for any changes.
What were the basic results?
The researchers found that administering a single dose of bexarotene gave a rapid reduction in levels of soluble beta-amyloid in the fluid surrounding the mice’s brains. There was a 25% reduction within 24 hours and this reduction was retained for over 70 hours. Up to 84 hours after treatment there was a return to pre-treatment levels of soluble beta-amyloid.
In six-month-old mice treated with bexarotene, insoluble beta-amyloid levels in the brain were reduced by 40% after 72 hours. When bexarotene was given to mice for longer periods of time they found a sustained reduction in beta-amyloid throughout the treatment period. They found comparable effects of the drug when testing in older, 11-month-old mice with greater beta-amyloid build-up.
The drug also improved the cognitive, social and sensory deficits of the mice:
- both six-month and 11-month-old mice treated for seven days showed improvements in fear conditioning; the six-month old mice also showed improvements in fear conditioning with 90 days of treatment
- performance in the water maze improved after 20- and 90-day treatment periods
- nest construction behaviour was restored after 72 hours of treatment
- ability to sense odours was restored by three days of treatment
How did the researchers interpret the results?
The researchers conclude that activation of the receptor involved (the retinoid X receptor through use of bexarotene helps to clear beta-amyloid build-up in mouse models of Alzheimer’s and gives a rapid reversal of the associated cognitive and neurological deficits.
Conclusion
This animal research has demonstrated that bexarotene can have a positive effect in clearing the build-up of the characteristic beta-amyloid protein plaques and improving cognitive impairments in mouse models of Alzheimer’s. Bexarotene (brand name Targretin is an anti-cancer drug that is currently licensed specifically for the treatment of a rare type of skin cancer called advanced cutaneous T-cell lymphoma.
Although this research is in animals, and therefore has a limited direct application to humans at present, these early findings do present some genuine potential that needs further research. There is bound to be great interest in the finding that the drug seemed to have an early effect on the amyloid plaques characteristic of Alzheimer’s, particularly as the study involved a drug that is already licensed for use in a specific, rare type of cancer (advanced cutaneous T cell lymphoma . Given its existing use, there may be the possibility of earlier testing in humans than there would be if this were a completely new chemical in development, which would have completely unknown health and safety effects.Nevertheless, this drug has not yet been tested in humans with Alzheimer’s, and results from such studies will be needed before we know for certain whether it is also helpful in humans.
Better treatments for Alzheimer’s in humans are needed, and research such as this is is an important early step towards achieving this goal. While it is far too early to say whether this drug could be a cure for Alzheimer’s, at least in the context of this early research the drug has marked itself out as a clear candidate for further exploration.
Links To The Headlines
Alzheimer's brain plaques 'rapidly cleared' in mice. BBC News, February 10 2012
Skin cancer drug 'reverses Alzheimer's'. The Daily Telegraph, February 10 2012
Skin cancer drug 'clears Alzheimer's protein from the brain'. Daily Mail, February 10 2012
Does skin cancer drug offer Alzheimer's hope? Channel 4 News, February 10 2012
Links To Science
Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-Directed Therapeutics Rapidly Clear ?-Amyloid and Reverse Deficits in AD Mouse Models Science. Published online February 9 2012
“Parents who frequently move house put children’s health at risk,” according to the Daily Mail. The newspaper said that research found moving several times can affect children’s health and psychological state, and also increases the likelihood that a child may use illegal drugs.
This Scottish research, which looked at potential links between moving house in childhood and adult health, produced far more mixed results than the Mail implied. However, the press release accompanying the research did not always clearly reflect the findings of the study, which found very few significant links between moving frequently and poor health.
In fact, once the researchers accounted for factors such as social deprivation and moving schools, moving house was only significantly linked to a higher chance of using drugs in later life. Adults who had moved frequently showed no greater risk of being overweight, having high blood pressure, long-term illness, psychological distress, drinking or smoking later in life.
While researchers say the risk of having certain measures of poor health was “elevated” in people who moved house more frequently as a child, the increase in risk was not statistically significant, which means it could have happened by chance.
Where did the story come from?
The study was carried out by researchers from the Medical Research Council, the University of Stirling, Queen’s University and Scotland’s Chief Scientist Office. It was funded by the Chief Scientist Office of the Scottish Government Health Directorate. The study was published in the peer-reviewed Journal of Epidemiology and Community Health.
The study’s findings were overstated by the Daily Mail. The newspaper reported that there were “negative health effects” from frequent moves, whereas the study found that frequent moving was only significantly linked to an increased chance of drug use. This finding on drug use was independent of other variables.
Moving during childhood was not significantly associated with adult measures of physical health, such as weight and blood pressure. The Mail only touched on these elements towards the end of its report.
It’s worth noting that in the press release that accompanied publication of the study, only the penultimate paragraph stated that only illegal drug use was independently associated with frequent moves.
What kind of research was this?
This research was part of a large cohort study from the west of Scotland, which has taken place over 20 years. It compared the health of people who had been “residentially stable” during childhood with those who had moved house, using a range of health measures.
The authors say previous research suggests that frequent childhood moves may be associated with poorer health outcomes and behaviour in adolescence. The researchers say their present study brings together a wider range of health outcomes than has previously been considered, and also looked at the extent to which associations between childhood mobility and health in adolescence last into adulthood.
What did the research involve?
The study was based on a cohort of 1,515 participants who were 15 when it started in 1987 and who were followed up for 20 years. Data from this cohort were collected at five points in time, the final time when the participants were 36. The final sample analysed in the study was 850 participants, so 665 original participants (44% were not included in the final analysis because they had left the study.
Researchers collected their data through face-to-face interviews conducted by nurses. A parental questionnaire was completed at the start of the study.
The researchers got information about moving house from the number of addresses people had lived at between birth and 18 (they excluded recent moves out of the family home . They collected information on a range of health measures including:
- Physical health measures - these were all taken by nurses and included body mass index, waist-to-hip ratio, lung function and blood pressure.
- Overall health - people were asked to report whether they had limiting long-term illness (answering yes or no and to give their own assessment of their general health, as rated on a four-point scale.
- Psychological distress - this was assessed using a standard 12-item questionnaire (with a cut-off score of 3 points taken to indicate psychological distress . Whether people had thought about suicide was also examined, with people asked at certain points whether they had thought about taking a drug overdose or deliberate self-injury. The third measure of psychological distress was anxiety, as measured on a standard scale.
- Health behaviours - the behaviours examined were heavy drinking (defined as exceeding maximum weekly safe limits , illegal drug use and smoking.
Importantly, the researchers also looked at participants’ family and household circumstances based on information provided by the children’s parents at the start. They also looked at other factors such as social deprivation (calculated by postcode and using recognised deprivation categories , housing status (home-owner or not , social class, family structure (intact or not and number of siblings. Also included were data on school mobility, derived from the number of primary and secondary schools attended. The researchers also looked at participants’ social class, education and marital status in adulthood.
The researchers then analysed the relationship between number of house moves in childhood and health at the ages of 18 and 36. They adjusted their findings for possible confounders, such as social class, deprivation and family circumstances.
What were the basic results?
The researchers found that approximately one in five people did not move address throughout childhood. Three in ten moved once or twice, and a further one in five had moved at least three times. They also found that children in single-parent households and those with two or three siblings were significantly more likely to have moved home (while those with at least four siblings were more likely to have stayed put .
After they adjusted their findings for both socioeconomic circumstances and the number of school moves, the researchers found that, when the participants were 18:
- People who had moved at least three times were significantly more likely to have used illegal drugs than those who had never moved ( odds ratio [OR] 2.44, 95% confidence interval [CI] 1.45 to 4.10 .
- Those who moved at least once had a significantly higher chance of scoring 3 or more (indicating distress on the questionnaire for psychological distress than those who had not moved at all (OR 1.62, 95% CI 1.11 to 2.35 .
- The risk of several outcomes (having a long-term illness, having suicidal thoughts for those who had moved at least once, and heavy drinking and smoking for those who had moved at least three times were “elevated” compared to those who had not moved at all, but the increased risks were not significant.
- There was no association between childhood mobility and physical health measures such as blood pressure and weight.
When the participants were aged 36, the researchers found that:
- Frequent moving in childhood was independently associated with illegal drug use (OR 1.92, 95% CI 1.00 to 3.69 .
- The odds of poor health across other measures remained “elevated” but not statistically significant.
- There was no association between moving address during childhood and physical health measures such as blood pressure and weight.
How did the researchers interpret the results?
The researchers concluded that increased residential mobility in childhood is associated with an elevated risk of poor health in adulthood, across a range of measures. This is explained in part, they say, by both social and economic circumstances and the frequency of school moves.
The relationship between childhood residential mobility and poorer health appeared to be stronger in adolescence than adulthood, possibly because people’s own socioeconomic circumstances lessened the effects over time.
Conclusion
This study looked at the effect of multiple address moves during childhood on people’s physical and psychological health at the ages of 18 and 36.
The way the authors interpreted the results of their study is confusing. They say that a higher risk of poor health outcomes is associated with frequent moves of home in childhood. However, the only significantly higher risk, once the results were adjusted for various confounders, was illegal drug use. This is important because it means that the other increases in risk identified are more likely to have occurred by chance.
The study examined an important issue, and one strength is the length of time of it covered. Another is its detailed collection of data, which might help explain why frequent moves of house could have an association with poorer health outcomes. For example, this could be because of frequent school moves, family break-up and deprivation.
However, the study has a number of limitations. Its high drop-out rate (around 43% raises the question of reliability and it is possible that those who dropped out or were lost to follow-up also had the most mobile childhoods. The study’s reliance on the parents to report outcomes, such as overall health, is another limitation as their reports may be subjective or difficult to appraise.
Families move home for a range of different reasons, including improved schooling and employment opportunities, change in financial circumstances or family break-up, and the study did not assess the reasons for the family moves. It seems obvious that children are more likely to be negatively affected when disruption or financial problems cause a family to move, rather than when the motive is to seek better schools or a better job.
The way children’s wellbeing is affected by frequent moving is an important issue, but it is also a complex one which needs to be examined further.
Links To The Headlines
Parents who frequently move house 'put children's health at risk'. Daily Mail, February 9 2012
Links To Science
Brown D, Benzeval M, Gayle V et al. Childhood residential mobility and health in late adolescence and adulthood: findings from the West of Scotland Twenty-07 Study. Journal of Epidemiology and Community Health, 6 February 2012 (published online first
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“Children born to women undergoing cancer drug treatment show normal results in physical and mental development tests” The Guardian has reported.
The news is based on research that examined the health of 70 children who were exposed to chemotherapy in the womb during the final two-thirds of pregnancy. Between the ages of 18 months and 18 years of age the children were given examinations of their general health, brain and heart function and hearing. Their cognitive function, hearing, heart function, growth and development were all comparable with the general population. However, being born prematurely was associated with lower cognitive scores, leading the researchers to recommend against doctors inducing early delivery in women requiring chemotherapy. The researchers also say their results do not support delaying chemotherapy in pregnant women.
During pregnancy treatment decisions have to be made that are in the best interest of the mother’s health, while trying to avoid the risk of harm to the fetus. Unfortunately though, this relatively small dataset cannot provide conclusive proof that chemotherapy poses no risk at all to the unborn child. The researchers say that their study is currently gathering longer-term data on wider numbers of children to help explore the issue further.
Where did the story come from?
The study was carried out by researchers from Leuven Cancer Institute and Katholieke Universiteit Leuven in Belgium, and other institutions in Czech Republic, the Netherlands and Canada. The study was funded by a number of European medical research and technology funds and the Belgian Ministry of Health. The study was published in the peer-reviewed medical journal The Lancet.
In general the news provided balanced coverage of this study. The Daily Mail’s headline declared that pregnant women with breast cancer can have chemotherapy and surgery and “still give birth safely”. However, this is slightly confusing as the focus of this study was not women with breast cancer, and the study looked at children’s long-term development rather than the safety of their delivery. The researchers’ main finding was actually that premaurity was associated with lower IQ scores, meaning that planned premature delivery may not be the best option.
What kind of research was this?
This was a cohort study looking at how foetal exposure to maternal cancer and treatment, including chemotherapy, affected the physical and cognitive development of child at various points through their childhood.
While it is known that exposure to chemotherapy during the first 12 weeks of pregnancy can increase the risk of congenital defects in the baby, there is uncertainty over whether exposure during later stages of pregnancy can also affect heart and brain development. The researchers say that up until now, limited data has been available on the longer-term outcomes of children exposed to chemotherapy in the uterus. With this in mind they intended to record the general health, cardiac function, and brain development in children who were exposed to chemotherapy in the uterus.
Cohort studies such as this are the best way of assessing harms from chemotherapy in pregnancy, as it is generally believed to be potentially harmful to the baby, but is sometimes unavoidable in clinical practice. Setting up a trial randomising pregnant women with cancer to receive cancer treatment or not in order to assess developmental effects on the offspring would be unethical, both for the mother (who may be denied the treatment she needs and baby (who may put at unnecessary risk of harm . Therefore a cohort study is likely to be the most appropriate way of exploring the issue.
What did the research involve?
From 2005 onwards researchers began gathering study subjects from cancer referral centres in Belgium, the Netherlands and the Czech Republic. This included both pregnant women receiving chemotherapy at the time, and children and mothers who had been exposed to chemotherapy several years prior to the study. Dependent on the age of the child the researchers carried out assessments at ages of 18 months, 5–6 years, 8–9 years, 11–12 years, 14–15 years, or 18 years. The study is ongoing, and in time these children will be given further examinations.
The researchers carried out neurological examinations, tests of cognitive function (using recognised child development tests or IQ tests , heart examinations (electrocardiography and echocardiography , and administered a questionnaire on general health and development. Children who were over five years of age also received hearing tests in addition the Child Behavior Checklist, a questionnaire that screens for behavioural and emotional problems.
The researchers compared their findings with available norms such as national data for height, weight, head circumference, as well as national and international reference data for neurodevelopmental tests, and heart examination tests.
What were the basic results?
The current analysis of this ongoing study looked at the participating children’s development until March 2011. The researchers assessed 70 children (27 born between 1991 and 2004, and 43 born after 2004 from 68 pregnancies (two of the women had given birth to twins . All women had received chemotherapy; some were also given radiotherapy, surgery or both. Across the group, 19 different chemotherapy regimens had been given, in which 236 cycles of chemotherapy were administered.
On average the babies were born at a pregnancy duration of 35.7 weeks (i.e. most were premature ; only 23 babies (33% of the cohort were born at full term (37 weeks or over . The average period of follow-up for each child was 22.3 months.
The children’s behavior, general health, hearing, growth, and heart function were comparable to the general population. Most children were recorded as having normal cognitive development, with most children with scores below the normal range having been born prematurely. After the researchers adjusted for age, sex, and country, they found an 11.6 point increase in IQ score for each additional month of pregnancy that the baby was carried for. The researchers found that both members of one of the twin pregnancies had severe neurodevelopmental delay, and could not be assessed with the complete set of cognitive tests.
How did the researchers interpret the results?
The researchers conclude that children exposed to chemotherapy in the uterus do not have increased likelihood of neurological, cardiac, hearing or general health and growth impairments compared with the general population.
However, prematurity was common and was associated with impaired cognitive development; therefore, planned premature delivery should be avoided where possible.
Conclusion
During pregnancy difficult treatment decisions have to be made bearing in mind the best interests of both a mother and her unborn child. This valuable cohort study provides follow-up data on children who were exposed to chemotherapy while in the uterus, from young childhood through to adolescence and beyond.
Its findings are reassuring and suggest that a child’s exposure to chemotherapy during later stage pregnancy (beyond the first 12 weeks is not associated with brain, heart or other developmental complications in the child. As the researchers note, their findings do not support the practice of delaying chemotherapy or performing planned premature delivery in order to administer chemotherapy to the mother after birth (the study suggests that premature birth may carry greater risk of adverse cognitive outcome than chemotherapy exposure itself .
However, though it does provide some reassurance, unfortunately this relatively small dataset cannot provide conclusive proof that chemotherapy poses no risk at all to the unborn child:
- As the researchers acknowledge, two children born to a twin pregnancy had important neurodevelopmental delay and they cannot exclude the possibility that exposure to chemotherapy during a critical time of brain development was the cause. However, the researchers considered that the broad nature of the problems in one of the twins suggested that chemotherapy was less likely to be the cause.
- Also, though the general neurodevelopmental assessments for the cohort were within the normal range expected among the general population, the researchers noted that a sample of children had some discrepancy between verbal performance and IQ values on intelligence tests, while a sample of others had raised problem scores on a child behavior checklist. The researchers say that these findings show that it is possible that chemotherapy has more subtle effects on neurodevelopment.
- Additionally, other longer-term effects that this study has not looked at need to be assessed, including risks of cancer in the offspring themselves or fertility effects.
- It is important to note that all chemotherapy in this study was given after the first 12 weeks of pregnancy: chemotherapy in the first trimester is associated with increased risk of congenital malformations, and this study does not assess or refute this.
- The study lacked a direct comparison group of children not exposed to chemotherapy in the uterus. Though the researchers did compare to national averages, the ideal comparison method would have been performing the same range of tests in children who were born at the same pregnancy gestation but who had not been exposed to chemotherapy.
- The researchers say that their Cancer in Pregnancy initiative will need to continue to gather longer-term follow-up on much wider numbers of children exposed to chemotherapy in pregnancy.
Links To The Headlines
Chemo in pregnancy does not necessarily harm baby, says study. The Guardian, February 10 2012
Pregnant women with breast cancer can have chemotherapy and surgery and still give birth safely. Daily Mail, February 10 2012
Chemotherapy is 'safe during pregnancy'. The Independent, February 10 2012
Pregnant women can be treated for cancer 'without harming baby'. Daily Telegraph, February 10 2012
I wanted to live but I also wanted to keep my baby: mother Caroline Swain. The Daily Telegraph, February 10 2012
Links To Science
Amant F, Van Calsteren F, Halaska MJ et al. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. The Lancet Oncology, Published Online February 10 2012
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